ASCO Guidelines - SoundSage

View Details

Dr. Sonam Puri joins the podcast to share the update to the living guideline on stage IV NSCLC with driver alterations. Dr. Puri discusses the practice-changing evidence reviewed for both NTRK rearrangements, including the TRIDENT-1 trial, and HER2 activating mutations, including the Beamion LUNG-1 study. She shares how these results impacted the clinical practice guideline with the addition of repotrectinib and zongertinib, what these new TKIs mean for patients, and where the panel is waiting for additional randomized data to clarify the role of therapeutic options. Dr. Puri encourages listeners to stay tuned for future updates to the living guideline as new evidence is published. Read the full living guideline "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2026.3.2" at www.ascopubs.org/guidelines/therapy-stage-iv-non-small-cell-lung-cancer-driver-alterations"

LINK TO FULL TRANSCRIPT

View Details

Dr. Rahul Banerjee joins the podcast to discuss the latest update to the living guideline on the treatment of multiple myeloma. He explains how sensational results from the MajesTEC-3 trial, which evaluated teclistamab plus daratumumab, prompted a major shift in the recommendations for patients with relapsed or refractory disease. Dr. Banerjee details why immunotherapies, specifically CAR T-cell therapy and bispecific antibodies, are now the preferred treatment options at first relapse over traditional triplets. He also provides context on evidence that did not lead to recommendation changes, the importance of individualized decision-making when choosing between immunotherapy options, and what future updates may be on the horizon, including data on CELMoDs.

Read the full living guideline, "Treatment of Multiple Myeloma: ASCO Living Guideline, Version 2026.1.1," at www.ascopubs.org/guidelines/treatment-multiple-myeloma-asco-living-guideline

View Details

Drs. Tina Lockwood and Stacy Gray share the newly released evidence-based guideline on circulating tumor DNA (ctDNA) testing from ASCO. They highlight recommendations on when ctDNA testing should be offered—including scenarios where tissue biopsies are challenging, unsafe, or unavailable in time to guide management—and explicitly outline situations where testing should not be utilized. They dive into the evidence evaluating ctDNA for treatment selection, molecular residual disease (MRD), and response monitoring across solid tumors and lymphoma. Drs. Lockwood and Gray explain the importance of balancing ctDNA's high specificity with its moderate sensitivity. They also touch on outstanding questions, including standardizing definitions for MRD, disease-specific applications, and the use of multi-cancer early detection (MCED) screening.

Read the full guideline, "Circulating Tumor DNA Testing in Solid Tumors and Lymphoma: ASCO Guideline" at www.asco.org/molecular-testing-and-biomarkers-guidelines"

LINK TO FULL TRANSCRIPT

View Details

Dr. Joshua Reuss returns to the podcast to discuss the update to the living guideline on stage IV NSCLC with driver alterations. The conversation focuses on new cancer treatment strategies for patients with advanced NSCLC and EGFR mutations, including classical EGFR alterations (exon 19 deletions, exon 21 L858R substitution) and rarer alterations (exon 20 insertion mutations). Dr. Reuss discusses results from clinical trials, including MARIPOSA and CHRYSALIS-2 and how these impacted first-line and subsequent line treatment recommendations. He looks to the future on what new evidence and potential updates are in the pipeline for this living guideline.

Read the full living guideline "Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations, ASCO Living Guideline Version 2026.3.1"

LINK TO FULL TRANSCRIPT

View Details

Dr. Lyudmila Bazhenova joins the podcast to share the update to the living guideline on stage IV NSCLC without driver alterations. Dr. Bazhenova discusses the evidence reviewed for both non-squamous NSCLC, including the POD1IM-304 and BAP BRAIN trials, and squamous cell NSCLC, including the HARMONi-6 trial. She shares how these results impacted the clinical practice guideline, what they mean for patients receiving immunotherapy and chemotherapy, and where the panel is waiting for additional evidence to clarify the role of therapeutic options. Dr. Bazhenova encourages listeners to stay tuned for future updates to the living guideline after publication of data from the 2026 ASCO Annual Meeting. Read the full living guideline "Therapy for Stage IV Non-Small Cell Lung Cancer without Driver Alterations, ASCO Living Guideline Version 2026.3.1"

LINK TO FULL TRANSCRIPT

View Details

Dr. Nabil Saba shares the first evidence-based guideline on thyroid cancer from ASCO. He highlights recommendations on first- and subsequent-line systemic treatment – including multikinase inhibitors (MKIs), genomically targeted therapies, immunotherapy, and cytotoxic chemotherapy across four subtypes of thyroid cancer: well-differentiated, differentiated high-grade or poorly differentiated, anaplastic, and medullary thyroid cancer. He dives into the evidence supporting each recommendation and explains the importance of shared decision-making on the risks and benefits of each treatment option. Dr. Saba also touches on outstanding questions including sequencing of agents, addressing resistance, emerging biomarker targets, and management of toxicities. Read the full guideline, "Systemic Treatment of Thyroid Cancer: ASCO Guideline."

TRANSCRIPT

This guideline, clinical tools and resources are available at https://ascopubs.org/topics/asco-guidelines/head-neck-cancer. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology.

My name is Brittany Harvey, and today I'm interviewing Dr. Nabil Saba from Emory University, lead author on "Systemic Treatment of Thyroid Cancer: ASCO Guideline." Thank you for being here today, Dr. Saba.

Dr. Nabil Saba: Pleasure to be here.

Brittany Harvey: And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Saba, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then to dive into what we're here today to talk about, Dr. Saba, could you start us off by providing a general overview of the scope and purpose of this first ASCO guideline for thyroid cancer?

Dr. Nabil Saba: So thyroid cancer is a complex disease, and the complexity has been added with the advent of multiple systemic therapeutic agents that have recently come on as part of the standard of care for treating this disease. The guidelines have lagged behind, I believe, in terms of being able to clearly delineate how to use these agents and what clinical settings to use them. And so this guideline, I think, is a much-needed and much-awaited guideline for clinicians to allow them to understand better the use of systemic agents in the treatment of thyroid cancer.

And when we talk about systemic agents, what we want to specify is this applies mostly for patients with recurrent metastatic disease, patients who have failed the standard initial treatment, which continues to be surgical resection for these patients if surgery is possible, in addition to radioiodine therapy for the right clinical setting.

Brittany Harvey: Absolutely. It's a good point that this patient population for this guideline focuses mainly on recurrent disease and patients who have already received surgery and radioactive iodine therapy.

So then this guideline covers four subtypes of thyroid cancer, including well-differentiated, differentiated high-grade or poorly differentiated, anaplastic, and medullary thyroid cancer. As you mentioned, you address clinical questions on systemic therapies, including multikinase inhibitors, genomically targeted therapies, immunotherapy, and cytotoxic chemotherapy in both the first-line and subsequent lines for each of these subtypes. So I'd like to review the key recommendations by subtype.

So first, what are the key points for systemic therapy for well-differentiated thyroid cancer?

Dr. Nabil Saba: It's important to also stress the point that we have these different subtypes of thyroid cancer. So when we talk about radioiodine refractory, those are for patients who are candidates for radioiodine therapy, of course. This usually encompasses the well-differentiated thyroid cancer. So for this group of patients, the guideline focuses on whether the use of multikinase inhibitors compared to placebo or observation impacts the survival in the first-line setting, whether the use of targeted therapies compared to placebo impacts also the survival in the first-line setting, all in the radioiodine refractory setting, of course.

And then we tackle the issue of immunotherapy because this also is a topic that has entered the realm, if you like, of thyroid cancer and is being used in some subtypes of thyroid cancer. So we thought it would be important to raise the question of the role of immunotherapy compared to targeted agents or multikinase inhibitors, in addition to the role of cytotoxic therapy or chemotherapy, as we say, in this patient population. So the guideline goes through all of these questions and then makes specific recommendations as to the use of some of the agents in the first-line setting and second-line setting in case these patients progress after first-line setting.

So, for example, it's clear that for patients who are radioiodine refractory and who have well-differentiated thyroid cancer, multikinase inhibitors are centerpiece of the first-line treatment option. And for this patient population, the recommendation essentially is to use lenvatinib or sorafenib, even though lenvatinib is considered to be the first choice in this patient population in the first-line setting. For the subsequent line settings, patients should be offered cabozantinib, which has been also proven in randomized trials.

As far as genomically targeted therapy, there is always the contention of whether these agents should be initiated first in case the patient has a genomically altered disease. And so, for example, if the patient has a RET alteration or NTRK alteration, the recommendation here is in favor of using RET-targeted therapies such as selpercatinib or NTRK-targeted therapies such as larotrectinib or entrectinib for these patients as a first-line setting. If they do have the BRAF alteration, which is a commonly seen alteration in these settings, the guideline essentially indicates that this may be offered initially prior to treatment with multikinase inhibitors as well, even though the quality of the evidence here is rather lower, and the strength of the recommendation is conditional. And so it's clear that multikinase inhibitors, in the absence of any of these genomic alterations, is really the first line, and then the question becomes when do we use these genomically targeted approaches in patients who have genomically altered disease?

Which basically introduces also the complexity of the question here because we have multiple agents depending on these genomic findings. And then it is sometimes confusing for practitioners which one to use or what do we use first? And so I think the guideline provides clarity in terms of what is acceptable, what is rather not acceptable, what is based on a strong recommendation, what is based on a rather weaker recommendation. I think that's part of the value of such a guideline.

And then finally we have the question of radioiodine well-differentiated and the question of immunotherapy as a first line. And here we do not recommend using immunotherapy for this patient population. For patients with subsequent line settings, potentially adding pembrolizumab to a multikinase inhibitor is mentioned, however the evidence is low, and the strength of the recommendation is also conditional here. As far as chemotherapy, this is not recommended in this day and age for this patient population, however it may be considered also in patients who fail or progress on genomically targeted therapy and/or multikinase inhibitors.

So this is the summary of the recommendations for well-differentiated thyroid cancer, but certainly, for details, I would refer you to the actual guideline since there are many nuances that cannot be covered during just this discussion.

Brittany Harvey: Certainly. The full guideline will be available for listeners in our show notes, and there are many recommendation tables and figures that can help folks as they think through these recommendations. A lot of those key points are really important as clinicians think through which systemic therapies to offer and sequencing of these agents, as you mentioned.

Following those recommendations for well-differentiated thyroid cancer, what are the recommendation highlights for systemic therapy for differentiated high-grade or poorly differentiated thyroid carcinoma?

Dr. Nabil Saba: This entity is rather a rare entity. It's important to stress the fact that this entity has not really been very well represented in clinical trials, and so when we talk about differentiated high-grade or poorly differentiated, the information here is limited. However, the guideline infers on the recommendations to this subtype of thyroid cancer based on what we know for other subtypes. And I think because of the strength of evidence we have in the well-differentiated and the anaplastic thyroid cancer, this guideline for this subgroup of patients draws from these two guidelines and sort of makes recommendations based on this.

So in the first-line setting, of course, if patients don't have a genomically altered disease, we certainly would recommend lenvatinib or sorafenib like we do in the well-differentiated disease. For patients with genomically altered diseases, we follow sort of the same guideline as we have followed for the well-differentiated setting, with the caveat that the quality is rather lower here and the strength of the recommendation is rather conditional for this subtype of patients. And so I think the take-home message is we do have these recommendations similar to the well-differentiated, but the strength of these recommendations for this particular subgroup of thyroid cancer patients is not as strong, given the under-representation in clinical trials. And that's basically the summary of this disease. Same applies to immunotherapy as well as chemotherapy here.

Brittany Harvey: Absolutely. I think it's important to recognize where the evidence is not as strong, it's really important that the guideline panel has still offered up some recommendations to help clinicians in their daily practice as well.

The next subtype the guideline panel addressed, what does the expert panel recommend regarding systemic therapy for anaplastic thyroid cancer?

Dr. Nabil Saba: So it's important to remind the audience that this is a disease with dismal outcome, and this is rather a very, very rare type of thyroid cancer. So the challenge with anaplastic is we've had very little traditionally in terms of options for patients. However, this guideline highlights the advances that have happened in this disease over a relatively short period of time and stresses the important role of systemic agents. And so, for example, for non-genomically mutant anaplastic thyroid cancer in the first-line setting, the guideline does recommend lenvatinib with or without pembrolizumab. Even though the evidence of the quality is low and the strength of the recommendation is conditional, there is enough data that this recommendation could be made. The added complexity for anaplastic thyroid cancer is that this is a disease where multimodal approaches initially are really encouraged as well, including surgical resection primarily, but also potentially thinking about other modalities such as radiation therapy, as these patients have usually very aggressive disease.

And so as far as genomically targeted approaches, the story of targeting BRAF I believe has been a successful story in this disease. And again, for patients with BRAF V600E mutated anaplastic thyroid cancer in the first-line setting, the guideline is clear in saying that we should offer BRAF/MEK inhibitor targeted therapy, namely dabrafenib and trametinib based on published data; the quality is moderate, though the strength of the recommendation is strong, essentially because of the compelling data in these rather small studies. In the first-line setting, again, we may offer also BRAF/MEK inhibition with or without pembrolizumab as well, and the strength here is low, with the recommendation being conditional as well. So you can see here that unlike the other types, immunotherapy may play a bigger role here in this type of cancer compared to the well-differentiated carcinoma because of the nature of the disease, and this has been also stressed in other guidelines.

For patients who progress on genomically targeted therapy, there are not too many options, even though people can revert back to lenvatinib or lenvatinib and pembro. We do recommend participation in clinical trials for these patients because we really don't have any clear-cut options since the strength of these recommendations is conditional for these patients.

As far as the question of immunotherapy per se, we talked about lenvatinib with pembrolizumab. There is also data on ipilimumab and nivolumab. So we include that also as an option for the first-line setting, and we also include, obviously, the dabrafenib and trametinib in combination with pembrolizumab. And even though all these recommendations are conditional, the size of these clinical trials are single-arm phase II studies. In terms of chemotherapy, again, no recommendation in the first-line setting. However, for patients who fail MKI or fail immunotherapy, clinicians may offer cytotoxic chemotherapy. So you can see that in this rare disease, the recommendations already in 2026 indicate a complex tree of decision-making for a number of these cases. And I think this is where these guidelines offer value to many of the practitioners out there.

Certainly, they don't claim to answer any or every possible clinical scenario for these patients because anaplastic thyroid cancer, like any thyroid cancer or any malignancy, usually has to rely on careful evaluation on a case-by-case basis, and for this disease in particular, on a multidisciplinary evaluation based on evaluation by surgical team, by medical oncology, by radiation oncology. But hopefully, these guidelines help at least put in the systemic therapy within that context.

Brittany Harvey: Absolutely. I think this is also where, in the guideline, the clinical interpretation can really be helpful for readers. And as you mentioned, that multidisciplinary collaboration along with shared decision-making with patients on the risks and benefits of each treatment option is really critical here.

So the final subtype that the guideline expert panel addressed, what systemic therapies are recommended for medullary thyroid cancer?

Dr. Nabil Saba: Yes, so medullary thyroid cancer is a separate disease in its own merit, and biologically it's different from the other diseases. And even though it's a relatively rare thyroid cancer, there has been quite substantial advances in systemic therapy, and I think the guideline importantly highlights these advances for this type of thyroid cancer, and this subtype adds to the value of the guideline as well.

For these cancers, targeted therapy for patients who have RET alteration is really recommended as a first line. So for patients who have RET mutant disease, selpercatinib certainly is the treatment of choice, and this is based on high evidence and the recommendation being very strong here because it's based on randomized phase III data. In the subsequent line settings, however, patients with RET-altered disease who have progressed on selpercatinib, unfortunately, we don't have clear-cut recommendations, however, participation in clinical trials is recommended. If a trial is not available, we recommend that patients be offered vandetanib or cabozantinib in this situation.

For patients without the RET alteration, in other words, for patient populations with wild-type disease, the first-line setting should include cabozantinib or vandetanib based also on improved progression-free survival in randomized clinical trial, and here the recommendation is quite strong.

In terms of the role of immunotherapy here, there is very, very little role, and so we don't recommend using immunotherapy in the first-line setting or subsequent line setting. Similarly, for chemotherapy or cytotoxic chemotherapy, it's not recommended that patients be exposed to cytotoxic chemotherapy outside of a clinical trial, whether this be in the first-line setting or second-line setting. We say that in the second-line setting, if patients have failed genomically targeted therapy, clinicians may offer cytotoxic therapy, however, here the evidence is low, and the strength of the recommendation is conditional. And so clearly that tells you that advances have been substantial in this disease, specifically in the realm of targeted therapies, which is importantly highlighted in this guideline as well.

Brittany Harvey: Yes, it's great to see the advances across these different subtypes. So thank you for reviewing all of these recommendations. It's clear you and the panel spent a lot of time reviewing the evidence to craft these recommendations.

So you've already touched on this throughout our conversation already, but I'd like to ask, in your view, Dr. Saba, what is the importance of this guideline, and how will it impact both clinicians and patients with thyroid cancer?

Dr. Nabil Saba: This is a guideline that's important because of the complexity of management of thyroid cancer, in addition to the fact that there has been quite a few systemic therapeutic agents that have come to the scene in the disease, and those are used in specific situations. We talked about medullary thyroid cancer and the story of RET inhibition, for example, the question of sequencing of these agents is important - what do you choose first in terms of your choice depending on the clinical scenario, I think, is highlighted in this guideline. I think this is going to be extremely helpful to practitioners inside and outside the United States because it is going to offer a guide for them to essentially decide on what would be the standard therapeutic option that should be offered to these patients.

I know that many of these agents are not perhaps available in other countries, and I hope this guideline will also raise awareness, since it is coming from ASCO, that these agents need to be explored and considered for a large group of the population that may not have access to them, especially outside the United States and in third-world countries. And so I think from that angle, I think also the guideline is important in that it sets what is the accepted standard in terms of systemic therapy for these patients with these different diseases.

Brittany Harvey: Yes, these evidence-based guidelines certainly set a standard and it will be really important to have these in the hands of many different people to inform best practices for care.

Additionally, you've also mentioned earlier that several of the recommendations referred patients to clinical trials where there wasn't evidence. So I'd like to ask, what are the outstanding questions and ongoing research you are watching in the thyroid cancer space?

Dr. Nabil Saba: This guideline I would like to look at it as a start. This is a much-needed start, however, it also exposes us to the fact that there are so many unanswered questions yet. We still don't know the exact way or best way to sequence these agents. The story of, for example, multikinase inhibitors in well-differentiated thyroid cancers that have BRAF alteration, what is to be started first? Do you start with a multikinase inhibitor, or do you start with a BRAF inhibition? This is a topic of a cooperative group trial currently answering these questions in terms of what is the best sequencing because, you know, you do have the approved cabozantinib in the second line, for example, but you also have the approved BRAF inhibition, which could be done in the first or second line. And so sometimes that is confusing to clinicians for a good reason because no studies have really examined the question of the appropriate sequencing of these agents. And so I think the more we get these agents as available options for treating patients, the more pressing the question would be of what would be the best sequencing. So I think that's a major question to tackle, and hopefully clinical trials will tackle that.

I think the question of resistance to some of these agents, we don't talk too much about that in the guideline, but certainly these agents have limitations. Not every patient who gets a genomically targeted approach is to benefit from that. We've seen many patients who progress on these, and so the question is, how to overcome resistance? Even for the strong data that we have, for example, on RET alteration or NTRK, resistance mechanisms do happen, and we've seen patients who fail larotrectinib and then they need to go on other therapeutic options. And so I think clinical trials are crucial in answering all these questions, in addition to targeting other subtypes of thyroid cancers that have not really been very common. We know that RAS is also seen in some thyroid cancers, HRAS. There have been some studies along that line. ROS is another potential target. And so the question of resistance, I think the question of sequencing, in addition to the question of toxicity. Because, you know, how best to dose these agents? We talked about this a little in the guideline, but again, the focus on this guideline was not too much the toxicity management. So I think management of toxicities should also be a topic of interest that needs to probably accompany any systemic therapy guideline since we're using agents that people may not be too familiar with when they use it for the first time.

Brittany Harvey: Definitely. We'll look forward to the results of these trials that you mentioned to inform sequencing, resistance, new targets, and addressing toxicity and potentially inform updates to this guideline.

So I want to thank you so much for your work to develop this first ASCO guideline for thyroid cancer and for your time today, Dr. Saba.

Dr. Nabil Saba: It's been my pleasure and it's been a pleasure to actually accomplish this and publish this guideline because I do believe it will be of great benefit to the oncologic community.

Brittany Harvey: Absolutely. And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Timothy Gilligan and Dr. Calvin Chou discuss the updated guideline on patient-clinician communication in oncology. They highlight clinical recommendations and strategies on topics such as communication skills and practices that apply at every visit, principles for telehealth interactions, cross-disciplinary communication, facilitating involvement of the patient's support network, discussing prognosis, goals of care, treatment selection – including clinical trials, end-of-life discussions, overcoming barriers to communication, facilitating discussions of cost of care and financial toxicity, mitigating stigma, and setting boundaries with patients. Dr. Gilligan and Dr. Chou also share how clinicians can enhance their communication skills through skills practice opportunities and experiential learning. They discuss how fundamental communication is to optimal patient care and look to the future on how generative AI may impact healthcare communication. Read the full guideline, "Patient-Clinician Communication: ASCO Guideline Update"

TRANSCRIPT

This guideline, clinical tools and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-26-00118

My name is Brittany Harvey, and today I am interviewing Dr. Timothy Gilligan from Taussig Cancer Institute and the Center for Excellence in Healthcare Communication at Cleveland Clinic, and Dr. Calvin Chou from the University of California and Veterans Affairs Health Care System in San Francisco, co-chairs on "Patient-Clinician Communication: ASCO Guideline Update."

Thank you for being here today, Dr. Gilligan and Dr. Chou.

Dr. Timothy Gilligan: Thank you for having us.

Dr. Calvin Chou: Delighted to be here.

Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Gilligan and Dr. Chou who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then I would like to dive into what we are here really today to talk about. So Dr. Gilligan, this guideline updates the patient-clinician communication guideline that was first published in 2017. What prompted this update and what is the scope of this updated guideline?

Dr. Timothy Gilligan: So I think with the first guideline, that was the first draft of it that we published five or six, seven years ago, really we were focused on getting the content right, what was the state of the knowledge at that time, and I was very happy with what came out of that. But when I looked back on it, I thought there were ways we could make it more accessible and more practical. Because what we really would like would be for people to apply what we know and then communicate more effectively with patients and colleagues. And one of the reasons I was really excited on the membership of the panel we had this time was I thought they were very well selected to help us do that, is to really think about what are practical guidelines, practical steps we can tell people to take that will improve their own experience and the experience of patients and the quality of care.

Brittany Harvey: Absolutely, thinking about operationalizing that guideline really improves the dissemination and the uptake of these recommendations.

So then, Dr. Chou, I would like to review the key recommendations and strategies across the clinical questions that the guideline addressed. I realize today with our limited time we may not be able to go through every recommendation and strategy, so we will start with some of the highlights. First, let's address the highlights of the process of communication with patients and their support networks. This includes the questions that address what communication skills and practices apply at every visit across the continuum of care, principles for telehealth interactions, cross-disciplinary communication, and facilitating involvement of the patient's support network. In your view, what are the most important recommendations across these clinical questions?

Dr. Calvin Chou: I think the thing that all clinicians know in their bones that they want to be able to do effectively with patients is to communicate information clearly, as well as to communicate in a way that really deepens the relationship, demonstrates empathy, and also demonstrates understanding bilaterally between the various parties. So the communication guidelines that we established in this group, they are fundamental to communication in all conversations throughout healthcare. And the first guideline talks about how clinicians and their team can communicate effectively with the patient and the patient's support network. And those include things like preparing ahead of time; getting a list of the topics that are important to the patient support network so that we can consider them in the visit; making certain that we are hearing what the patients' and the patients' support networks are saying very, very closely; responding to those empathically; and being able to have conversations about care throughout the visit that demonstrate respect and deepen the trust; and then finally, to have some kind of bidirectional understanding, usually through teach-back, that allow both sides to know that communication has occurred as opposed to just been downloaded.

The guidelines also talk about applying these same communication skills throughout telehealth communication - that is both in terms of synchronous communication, audio or video, as well as asynchronous communication, i.e., through secure messaging. We also talk about how we can use these same communication skills to communicate effectively with members of our own team. Interprofessional communication is an important part of all the work that we do, and how we can use these very, very same skills in communication with colleagues, with nursing staff, with social workers, and other allied health professionals. These are all very, very important, crucial members of our healthcare team in the delivery of care to our patients. And that is something that we really need to emphasize throughout to try to bring the best of communication in every conversation that we have.

Dr. Timothy Gilligan: I totally agree with that. Those are really important points. When I was looking over it in preparation for this podcast, it struck me that we have a lot of recommendations and a lot of small things that we can do either well or not well. And it reminded me of a quotation from a famous chef, Marco Pierre White, who said that perfection is a lot of little things done well. This guideline has a lot of little things that if you do them well, you get better outcomes. And I think the chef's point was that if you want a really delicious dish, you have to pay attention to all those little details. And I think if people go through the guidelines carefully and apply the skills that are along the lines of what Dr. Chou was talking about, we get better results. And those results are really important results. It is not only patient satisfaction, which is really important, but it is also quality of care and outcomes for patients. It is better medical care. It is a better day for us, we have a better day if we have better conversations. Poor communication creates endless headaches for everybody.

What I see in the guidelines is it is a lot of little best practices and it requires discipline to learn those. The good news is none of them I don't think are all that hard. The bad news is doing it consistently well every day requires discipline and practice. And what I would hope for these guidelines is that people will read them carefully and think about what they can do to apply what we know more consistently.

And I think the interprofessional communication piece, that was something we added this year, is really critical. Medicine has a bad history of really disrespectful behavior. It was almost normalized that different specialties would make fun of each other, that different professions would talk disrespectfully of each other. And we know now that uncivil behavior results in more healthcare errors. And it is not only bad for our teams and our culture, but it is bad for our patients if we are not communicating well with each other. So I thought it was really critical that we added that piece to the update.

Brittany Harvey: Absolutely. Those fundamental principles that Dr. Chou outlined are really key across every healthcare interaction, including those interdisciplinary interactions. And as you alluded to, Dr. Gilligan, I think it will really serve clinicians well to review the details and go through every table to read the recommendations and each individual strategy to help them improve their communication in day-to-day interactions.

Moving to some of those day-to-day clinical communication scenarios, Dr. Gilligan, I'd like to think through some of those key points. So what is recommended for discussion of prognosis, goals of care, treatment selection, including discussion of clinical trials, and end-of-life discussions?

Dr. Timothy Gilligan: So my perspective is that there is a broad theme of flattening the hierarchy that runs through these recommendations and this part of the guideline - that the sections that Dr. Chou just talked about really have a lot to do with the details. What does good communication look like? What are best practices that we can adopt? And I think these other sections are a little bit more, they also have a lot of specific guidelines, but there is a philosophical point that we do better when we talk to the patient at their own level. And we sometimes fail to do that. I remember from about 10 years ago I was in a room with a patient and one of the other doctors said to the patient, "We're going to bronch you tomorrow." And I was trying to think, like, what do they think the patient hears when we use language like that? Like they don't understand what the word means. We are just expecting them to step up to our level. We are not accommodating them, and I think that really interferes with our ability to form effective relationships with patients and communicate clearly.

So if we are going to talk about prognosis, goals of care, treatment selection, clinical trials, end of life, the first step for me is that we have to get down to the patient's level, which means listening. We have to ask them what they know, we have to get their perspective. We have to understand what their health literacy level is so that we can have a conversation that takes into account the patient's perspective. And we need to be humble and remember that the patient often has information that we do not have yet unless we ask them and listen to what they say. That is going to change what we think is the best plan of care. And so shared decision-making is really a critical piece of that.

One of my favorite trainers who I follow online says, "I make suggestions, you make decisions." And I like to bring that attitude into the room when I talk to patients. It is their life, it is their body, it is their health, it is their decision. It is not my decision. I don't get to tell them what to do. I want to make sure that they make a decision that is based on the best available evidence, but also a decision that is based on who they are and what their values are. And we try to give pointers to how we can have these conversations in a way that is really fully respectful of the patient's autonomy and the importance of the patient's expertise in their own body, their own lived experience. Because there is a risk that we come in with our white coat and we overpower them with our authority, our medical authority, our medical knowledge, and no one likes to be overpowered. And I think we all have a better day if we go in and have a conversation as human beings with each other.

Dr. Calvin Chou: I want to underscore this point of having the patient and their support network make the ultimate decisions. Reviewing the evidence from more general literature, it is clear that across demographics that only 10% of patients want us to make decisions for them. 90% of patients want to have at least some say, if not full say, in the decisions that they make, and this is true across age, across gender, educational status, socioeconomic status, veteran status. This is a very, very important point. I think oftentimes we go in thinking we know what's going to happen and we need to make them do that. Thinking about this as a conversation as opposed to a download is an important point.

Dr. Timothy Gilligan: And one thing that I think that the guidelines are relevant for here, which is I think one way to achieve honoring the patient autonomy, is to really make a commitment to having a good process, to not be committed to an outcome. So that when we start the conversation, we're not going to say it's a good conversation based on whether it ends up where I wanted it to end up. It's a good conversation based on whether we have a good process, a fair process. And the steps of good communication that are outlined in this guideline help us to establish a good process. And I think if we have a good process, we can trust it will take us to the appropriate outcome, which may be different than the outcome we thought was going to be the appropriate outcome when we started the conversation.

Brittany Harvey: Definitely. I think, as you mentioned, tailoring discussions to each individual patient and situation is really critical. And I think in every other podcast episode across guidelines we've really emphasized the importance of shared decision-making. And so talking through the process of it in this guideline will really have impacts across all of ASCO's guidelines.

Moving on to the next section of the guideline, this guideline also addresses barriers in the communication process. So Dr. Gilligan, what highlights are there for overcoming barriers to communication, facilitating discussions of cost of care and financial toxicity, mitigating stigma, and setting boundaries with patients?

Dr. Timothy Gilligan: Yeah, it's interesting. I want to hear Dr. Chou's perspective on this too. I thought that the communication skills are really important for these conversations, but less powerful or less effective, potentially. For instance, barriers to communication, the big one that comes to mind is language differences. If the patient and the clinician do not share the same language, that results in less good care unfortunately. It results in less good communication. Having skilled translators or interpreters there is essential, and using them with skill is essential, but it does not get us to equality. I mean the best thing for a patient is to have a clinician who speaks their language. Unfortunately, that's not possible. So the second best thing we can do is to have good interpreters or translators to help us work. And then for us to use those people effectively, because oftentimes we cut corners when working with interpreters and shortchange the patient. So it is important to do the best we can. I think it is also important to acknowledge that it's a challenge and no matter how good your communication skills are, it's not going to be the same conversation if you're talking through another person versus directly to the patient.

Similarly, with financial toxicity, it is important to talk about it. We need to be open about it. We need to talk to patients about it, but financial stress from healthcare is a real problem, and however well you communicate it, it doesn't make that problem go away. You know, in oncology, our drugs are obscenely expensive, and I can't communicate my way to lower prices. So I can talk about it and legitimize it and empathize, but I feel like I have more power in the other sections to really change the outcome by communicating well than I do with these. But it is important to talk about it. Patients are hugely affected by the cost of care and we need to talk about it with them.

I do think for mitigating stigma and setting boundaries, then our communication skills become more powerful. We see everyone in the healthcare system, and when working with individuals who have been subject to stigma because of aspects of their identity, we can help lessen their vulnerability and fear by proactively letting them know that we will strive to avoid perpetuating that stigma, that we will treat them with respect and address them as they wish to be addressed, that we will care for them as dignified and valued human beings. That is not always their experience in the system, but we can choose to be different. We can choose to do better. And our communication skills are important because listening and curiosity are super important in that space. Because if we are talking to people who may be different from us, we need to learn about them by listening and being open and being curious, and replacing, if we have any tendency towards judgment, to replace judgment with curiosity.

With setting boundaries, I think it is also really important. I don't think you can show up and be fully present with patients the way I want to, the way we want other people to, if we don't know that there are boundaries. And we know this in other aspects of our care, right? I go into the room and I do intimate physical exams and I ask about intimate aspects of the patient's life. And I'm allowed to do that because there is a non-negotiable barrier to any kind of sexual or romantic contact between me and my patients. We know there's a hard wall there that we don't cross that line, so that when I am doing an intimate exam, we know where that stops and that we're not going to cross boundaries there. But the same thing applies verbally, and I think doctors sometimes and other healthcare professionals sometimes feel like they need to accommodate the patient no matter what. I was hoping the guidelines would send a strong message that, you know, we don't need to put up with disrespectful behavior. That when you go into the room, as a clinician or as a patient, you should be treated with respect. You should feel safe, you should feel like you belong, and if patients are behaving in a way that violates that, then clinicians have a right to speak up and to set limits and to set boundaries. And if we know those boundaries are there, then I think we can lean in closer. If we don't know those boundaries are there, then we kind of have to hold back to protect ourselves.

And just to give one of like a million examples you can give, I don't know a woman in healthcare who hasn't had a patient say something sexually inappropriate to them at some point. And that's not okay. I want my colleagues to know that's not okay, and it's okay to set boundaries and they don't have to put up with that. And my hope is that if we know where the boundaries are, then we can step in closer. That's my perspective on these, but Calvin, please, I'd love to hear your thoughts.

Dr. Calvin Chou: I want to double-click on everything that you said, Tim. It is so important that we recognize what we have control over and what we don't have control over. And what we don't have control over, for example, language discordance or financial woes of a patient, I have no possible way of controlling that. And so the best I can do in those situations is to sit with them, empathize, and do what I can, whatever power I might have in advocacy or I often refer folks to a social worker that I work very, very closely with, because I have no agency over any of that.

At the same time, when we talk about mitigating stigma in healthcare encounters, we have full control over the biases that we have. We may not be aware of them, but we do have control over them ultimately. And so it is up to us really to examine our practices, to see where we have maybe been steered in the wrong direction, where we double down on internal implicit biases that we have carried for our entire lives. And that requires that we approach all of our encounters with everybody in healthcare, with humility, and with an extra eye toward understanding how we are coming across to them, and whether or not at least some of those interactions are infused with bias that we can decrease.

And then finally, with the idea of boundaries, there are boundaries in two directions, as Tim was saying a moment ago, that there are boundaries that we must place in between ourselves and patients during examinations and also during interactions. And there's also boundaries that we have to set up that require that we uphold the standards ethically of clinical medicine. And that is, there are certain things- I would never ask a patient out, for example, on a date. And that's an important proscription; that's an important boundary that we must set up between ourselves and patients. Those are clear barriers that we must not breach. There are some barriers that are a little bit less clear. For example, there are some instances where physicians are asking patients who have means to perhaps contribute to a foundation or contribute to the university or to make a large donation to an institution. In some instances, that's a much less clear boundary. For myself, I feel uncomfortable making those kinds of requests, and there are other instances where those requests are actually not just okay to do, but the patient is willing to do those kinds of things. So I think we need to consider that these boundaries are not always set in stone. Sometimes the boundaries move, sometimes the boundaries are different.

Brittany Harvey: Absolutely. I think this latest question covered a lot of ground, and I think some key points here are that treating everyone with dignity is really paramount to this guideline. Recognizing the challenges even when they're not solvable is really important, such as thinking about financial issues or perhaps not speaking the same language as a patient. And then building trust and mutual respect between patients and clinicians to establish clear boundaries is really important as well.

So, I want to thank you both for reviewing at a high level the recommendations and the strategies from this guideline, and I encourage listeners to review the full guideline and tables for all of the recommendations and strategies to implement these clinical recommendations.

So, Dr. Chou, this guideline panel also addressed one education question. So, what are the recommendations for effective ways for clinicians to enhance their communication skills?

Dr. Calvin Chou: Thanks for asking, Brittany. When we talk about all of these communication skills, Dr. Gilligan and I have talked for a long time about all these individual communication skills. These are not skills that are necessarily naturally formed within us and that we just roll out without any practice. And that's why we both feel, if I can speak for you, Tim, that we both feel that communication skills training, and high-quality communication skills training, is deeply important. This is training that is less about I'm listening to this podcast and therefore I can communicate better, it's more about skills practice opportunities, experiential learning, oftentimes using that horrifying word 'roleplay' that people don't like to think about roleplay before they're in it, but then once they've done those skills exercises they realize how important it is to actually have practiced some of these skills so that when you get into the real situation, you have an approach to it as opposed to trying to just improvise or make it up on the fly.

The other aspect of communication skills training that is deeply important is not just forming the words and speaking to somebody else, it also needs to incorporate practitioner self-awareness and situational awareness that allows us to understand what's going on within us emotionally and attitudinally so that we are interacting moment by moment with patients and their support networks in a way that's authentic, that brings the appropriate amount of vulnerability and expertise to deepen trust between all of those relationships.

And finally, when we talk about communication skills training, there are ways to do this kind of training that, I've used ChatGPT, for example, when I'm having some difficulty wondering how to navigate a particular situation, sometimes you can use ChatGPT to give you some suggestions on how to approach that interaction. But at the same time, the most important thing is to be able to have really meaningful practice with other people, with other human beings. Because as much as I might interact with a computer, that computer is not a human being. And what we are talking about is interpersonal communication with emphasis on 'person'. And us as human beings, we understand, in a way that ChatGPT probably will never fully understand, the nuances of the emotional reactions and the importance of human connection between people when we talk to each other. And so therefore, if we can't depend on computers to do this communication skills training, we need institutions to emphasize and invest in all of our continuing ability to communicate effectively with everybody in healthcare. This is probably one of the most important outcomes of this guideline, is not just that communication skills are important, and not just that communication skills training is important, it's that we need everybody to invest in everybody's ability to communicate with each other on the highest possible level that we can bring.

Brittany Harvey: Yes, I think it's really important that the panel addressed this question, to emphasize that it's not just individual clinicians, but institutions that really need to value communication and this training to make sure that clinicians are being the most effective communicators that they can be.

So, I'd like to move on to the next question, and Dr. Gilligan, ask, in your view, what is the importance of this guideline and how will it impact both clinicians and people with cancer?

Dr. Timothy Gilligan: So I would build off of what Dr. Chou was just talking about, which is what we're hoping is that it will serve as a resource that will give people interested in communicating better guidance on where to go, what to do, what are the best practices, what do we know at this time. if you want to get better, what are the methods that are going to help you get better. And ideally I hope it will inspire people to want to get better. Communicating is such a fundamental part of our day-to-day work in healthcare that it needs to be something that we're very, very good at. And as professionals we should aspire to be as good as possible.

A lot of this stuff is pretty basic, but we forget to do it. When I had young kids and was teaching them to ski, one of the ski instructors said to me once that there were Olympic skiers who trained at the same mountain where my kids were learning. And he said they would go down easy slopes and just practice basic techniques still. They were good enough to ski in the Olympics going at crazy speeds, but they kept going back to their fundamentals. And my son is a serious soccer player and they do role plays in soccer. They practice drills. They have scenarios they know are going to come up and they artificially recreate that scenario and they practice it over and over again. There's a famous line from a college football coach that you don't practice it until you get it right, you practice it until you can't get it wrong. And I think if people would bring that sense of professionalism to communication, it's a lifelong journey. I'm still trying to get better. It requires practice, it requires discipline. There's a lot that we know, but it doesn't happen without practice.

And as Dr. Chou was saying, it's a motor skill. You don't learn it by reading about it. You don't learn it by listening to us talk about it. You learn it by practicing it. And I practice with patients. Not in the sense that I'm doing an experiment, but I work on my skills with patients. And I see how it goes. And when things don't go well, I think of what I could have done differently. And when things do go well, I think of what did I do that helped it go well that I need to make sure I do again next time. And I think I'd love to see people adopt an attitude that they want to be fantastic communicators and they want to get better. And I think the guidelines provide a lot of clues and steps to take for all of us to get better.

Dr. Calvin Chou: I heard Tim, you talk about communication being a procedure and that we would never think about going into a room and sticking a central line into a patient without having practiced that over and over and over again to get it right. Not to get it right, to never get it wrong, like you were just saying. And so if we think about communication as the most common procedure in healthcare, then it behooves us all to do the best we can with it. It is a frame shift because we are communicating with each other all the time, oftentimes without thinking. And what we're advocating right now is for everyone to really bring it in terms of communication skills in all settings, because the effect of ineffective communication is not necessarily just making people feel bad. As Tim said at the top of the program, it also impinges on quality of care. It's not just the right thing to do, it's the safe thing to do.

Brittany Harvey: Absolutely. And highlighting the fundamentals here and practicing them as clinicians will improve each healthcare interaction.

So then, finally, to wrap us up, Dr. Chou, earlier you mentioned ChatGPT and thinking about maybe some technological advances and how those will impact in the future. What are the outstanding questions and priorities for future research for optimal patient-clinician communication?

Dr. Calvin Chou: I think there's a lot we still need to learn about in this very, very nascent time of interacting with generative artificial intelligence. We won't know what things are going to be like probably even tomorrow given the vast advances that AI is allowing us to do. And also, as I was mentioning earlier, what AI can never do is to bring the human element into these interactions. And I think that's part of what, maybe that's a lot of what brings people to healthcare, is if they're in need and they have some physical issue that we need to help them solve, it's not just a physical issue, it also is a deep emotional experience.

And we have heard many times now cautionary tales of when AI has led people astray to then, for example, allow them to die by suicide. And that is the last thing that we can allow to happen in healthcare. That is the ultimate low-quality item. We need to make certain that everybody is cared for with high quality and high safety. And we're definitely not there yet with AI. We hope that at some point we'll be able to work with AI in order to bring even better healthcare than we have right now, and I think that has been demonstrated to be possible. That is one major outstanding question that we're all going to have to wrestle with.

Brittany Harvey: I think that's absolutely a key point. With generative AI quickly evolving, there need to be guardrails in place. And like any intervention, thinking about how to maximize the benefits of it and reduce the harms to make sure that you're preserving that human interaction and communicating effectively, and that patients can receive their health information in an appropriate way.

So I want to thank you both so much for your work to update this guideline, to draft all of these recommendations and the strategies, and work with the entire panel to create this excellent product. So thank you for all that work and thank you for your time today, Dr. Chou and Dr. Gilligan.

Dr. Timothy Gilligan: Thank you.

Dr. Calvin Chou: Thank you, Brittany, so much.

Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Lakshmi Rajdev and Dr. Manish Shah join the podcast to discuss the updated guideline on immunotherapy and targeted therapy in unresectable locally advanced, advanced, or metastatic gastroesophageal cancer. They share first-line and subsequent-line recommendations for both gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma based on actionable biomarkers including PD-L1 expression, MMR and/or MSI, CLDN18.2 expression, and HER2 status. They note the importance of the algorithms and tables in the guidelines that provide visual illustrations and quick reference guides of the evidence-based recommendations. They also comment on ongoing and recently presented trials that may impact future guidelines in this space.

Read the full guideline, "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update" at www.asco.org/gastrointestinal-cancer-guidelines"

TRANSCRIPT

This guideline, clinical tools and resources are available at www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02958

Timestamps

· 00:00 – 02:15 Introduction and Overview

· 02:16 - 08:20 First-line treatment for patients with pMMR/MSS, HER2-negative gastroesophageal adenocarcinoma

· 08:21 –10:29 First-line treatment for patients with pMMR/MSS, HER2-positive gastroesophageal adenocarcinoma

· 10:30 – 14:39 First-line treatment for patients with dMMR/MSI-H, gastroesophageal adenocarcinoma

· 14:40 – 18:03 First-line treatment for ESCC

· 18:04 – 22:04 Second- and third-line therapy for gastroesophageal adenocarcinoma and ESCC

· 22:05 – 24:38 Importance of guideline

· 24:39 – 27:45 Outstanding questions and future research

My name is Brittany Harvey, and today I am interviewing Dr. Lakshmi Rajdev from the Icahn School of Medicine at Mount Sinai and Dr. Manish Shah from Weill Cornell Medicine, co-chairs on "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update."

Thank you for being here today, Dr. Rajdev and Dr. Shah.

Dr. Lakshmi Rajdev: Thank you.

Dr. Manish Shah: Thank you for having us. It is wonderful.

Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Rajdev and Dr. Shah, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then to dive into what we are here today to talk about, Dr. Shah, I would like to start first with what prompted the update to this guideline, which was previously published in 2023, and what is the scope of this updated guideline?

Dr. Manish Shah: Yes, terrific. So even in the last few years, the pace of drug development in gastroesophageal cancers has just been astounding. So, what prompted this guideline is actually the practice-changing results for a new biomarker, CLDN18.2 hat was based on the GLOW and SPOTLIGHT studies, as well as a practice-changing study in HER2-positive disease where we added pembrolizumab to trastuzumab and chemotherapy for tumors that are HER2-positive and PD-L1 CPS 1 or greater. And then there were also new studies and new approvals in esophageal squamous cell cancer that you will hear about as well.

So there were several studies, overall more than 5,000 patients were reported on, and that led to several new therapies, new indications, and it really necessitated this guideline.

Brittany Harvey: Excellent. It is great to hear about all of these exciting updates in this space.

So then to next review the key recommendations of this guideline by clinical question that the expert panel addressed. So, Dr. Rajdev, what is the recommended first-line treatment for patients with proficient mismatch repair, microsatellite stable, HER2-negative gastroesophageal adenocarcinoma?

Dr. Lakshmi Rajdev: Thank you for that question. So historically, we have sort of used fluoropyrimidine and platinum doublets, which yielded a survival of about one year. More recently, immunotherapy and targeted therapy options have improved outcomes in patients with advanced esophageal and gastric adenocarcinoma, as well as squamous cell carcinoma. Patients with gastric and GE junction adenocarcinoma have a high rate of actionable alterations, so it is imperative that physicians test the following biomarkers upfront so that it can help guide therapy.

The markers recommended by the ASCO panel are HER2, MMR or MSI, CLDN18.2, and PD-L1. And also, it was recommended to use NGS if feasible in this patient population. HER2, as we know, is expressed in about 15% to 25% of patients; PD-L1 expression occurs in about 80% of patients; MSI-high, deficient MMR is present in about 5% to 8% of patients; and CLDN18.2 expression is present in about 40% of patients. There is, of course, biomarker overlap. About 13% to 22% of CLDN18.2 patients are also PD-L1 positive.

For patients with pMMR or microsatellite stable HER2-negative disease with PD-L1 expression greater than 1 and absence of CLDN18.2, the panel recommended a first-line therapy with fluoropyrimidine and platinum-based therapy in combination with immunotherapy. These recommendations stem from large phase 3 trials, and the agents approved in the United States are pembrolizumab, nivolumab, and tislelizumab. It has been shown that immunotherapy benefit is greater in patients with higher PD-L1 expression, and it is not possible to comment on the individual PD-L1 cutoff scores and sort of identify the optimal PD-L1 cutoff score that sort of balances benefits and harms.

But what is recommended is that immunotherapy-based treatments can be offered in patients with a CPS score of greater than 1. With regard to the choice of immunotherapy agents, that is pembrolizumab, nivolumab, or tislelizumab, these agents are considered to have similar efficacy, and the selection of an agent could be based on dosing schedule, cost considerations, toxicity, and the method of administration. Typically, clinicians should avoid withholding the start of chemotherapy while awaiting biomarker testing, depending on the clinical scenario.

Now, for patients with pMMR microsatellite stable disease that is HER2-negative with PD-L1 expression less than 1 and positive CLDN18.2 expression, zolbetuximab-based treatments or in combination with chemotherapy is recommended, and this is based on two global phase III randomized controlled trials, the GLOW and the SPOTLIGHT. And across both studies, the hazard ratio for the overall survival was 0.78, and similarly, there was also an improvement in progression-free survival favoring the zolbetuximab group compared to the chemotherapy group alone.

An important note is that nausea, vomiting is commonly associated with zolbetuximab-based treatments, and the panel recommended prophylactic antiemetics, adjusting zolbetuximab infusion rates, pausing infusion temporarily, using non-prophylactic antiemetics, and hydration intravenously prior to discontinuation of zolbetuximab-based chemotherapy. So effective handling of the GI-related symptoms with zolbetuximab is recommended prior to discontinuation of therapy.

Now, for patients with pMMR microsatellite stable HER2-negative gastric, GE junction adenocarcinoma with PD-L1 expression greater than 1 and CLDN18.2 positivity, the ones with the dual expression with CLDN18.2 as well as PD-L1 chemotherapy, the choice of therapy can be based on the degree of PD-L1 expression, the toxicity profile, the burden of symptoms, and the anticipated improvement in symptoms associated with response to treatment, the patient comorbidities, the prior medical and treatment history. So this decision needs to be made on a case-by-case basis, and these are some of the factors that we suggested that could potentially influence the choice of therapy. For patients with pMMR microsatellite stable disease that is HER2-negative and a PD-L1 expression less than 1 and an absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine and platinum-based chemotherapy is recommended. So you can see we have segmented out patients based on PD-L1 expression, pMMR and microsatellite stable disease expression, and also based on CLDN expression.

Brittany Harvey: Absolutely. And that first point you noted, I think is really important, that biomarker testing is really critical for treatment decision-making in this space.

So then the next subgroup of patients that the panel looked at, Dr. Shah, what first-line therapy is recommended for patients with proficient mismatch repair, microsatellite stable, HER2-positive gastroesophageal adenocarcinoma?

Dr. Manish Shah: So this was an update from a few years ago. So we have known for 15 years now that if you are HER2-positive, you should get trastuzumab plus chemotherapy. That was based on the ToGA trial. And the update now is based on a trial called KEYNOTE-811, where it examined the addition of pembrolizumab to trastuzumab and chemotherapy versus trastuzumab and chemotherapy, and there was a progression-free and overall survival benefit.

And again, here, the biomarkers are important. If your CPS PD-L1 is less than 1, we would not recommend Pembrolizumab in that setting, so you would still get trastuzumab and chemotherapy. But if it is 1 or greater, the PD-L1 CPS score, then we do recommend pembrolizumab unless there is a contraindication to immunotherapy. The take-home message really is from the onset of diagnosis, please check your biomarkers. And I will just, it is worth repeating, it is important to check your PD-L1 status, HER2 status, mismatch repair status, and CLDN18.2 status. And then the optimal therapy, and it is outlined in the publication, is really biomarker-driven. We know that if we are able to hit the target that is overexpressed, we are going to have a better outcome.

And Dr. Rajdev did mention where there is overlap, there can be a lack of data, and that is where we are with both PD-L1 positive and CLDN positive. Here we do have data in HER2-positive cases where if you are both HER2-positive and PD-L1 positive, you would combine trastuzumab and pembrolizumab for the best outcomes.

Brittany Harvey: Understood. I really appreciate you detailing what is most important for each individual biomarker combination that patients may have.

So then following that, Dr. Rajdev, what does the expert panel recommend for first-line treatment for patients with esophageal squamous cell carcinoma that is not amenable to definitive chemoradiation?

Dr. Lakshmi Rajdev: There are three phase III randomized clinical trials that have influenced practice in patients with esophageal squamous cell carcinoma examining the benefit of immunotherapy in this patient population. The RATIONALE-306 was a randomized trial of tislelizumab plus chemotherapy with platinum and fluoropyrimidine or paclitaxel versus placebo with chemotherapy. And then you have the KEYNOTE-590, which compared pembrolizumab plus chemotherapy versus chemotherapy alone. And then you have CheckMate-648, which included comparisons of nivolumab plus chemotherapy versus nivolumab plus ipilimumab or chemotherapy.

And the primary endpoints for these studies were overall survival, and they did look at subgroups with PD-L1 expression. They used TPS score greater than 1% in CheckMate-648 and PD-L1 CPS greater than 10 in KEYNOTE-590. The bottom line is that the overall hazard ratio for overall survival across this patient population was 0.72. So clearly, there is benefit in patients that express PD-L1 CPS greater than 1 for benefit for the addition of immunotherapy.

Now, the benefit again in patients with a PD-L1 expression less than 1 remains limited, and so the panel has made a recommendation for using immunotherapy in combination with platinum-based chemotherapy in patients with a PD-L1 greater than 1. Again, we know that it is hard to make recommendations on what PD-L1 cutoffs are recommended in this patient population, meaning that should it be limited to patients with a PD-L1 of 1 to 4 or greater than 10? I think that the general consensus that has been gleaned from the data is that the higher the PD-L1 expression, the greater the benefit.

I do want to comment on another option that is available in patients with squamous cell carcinoma compared to adenocarcinoma, and that is the combination of nivolumab and ipilimumab. Now, in CheckMate-648, nivolumab with ipilimumab was also recommended as a treatment option in patients that have a PD-L1 score of greater than 1. There was a survival benefit demonstrated with this combination compared to chemotherapy alone.

And an important observation in this study is that, although there was a slightly increased rate in early death, but there was really no significant difference in PFS and OS compared to chemotherapy alone. Importantly, the treatment appeared to be pretty well tolerated by the study population. There was a notable difference in the objective response rate, which was 35% in the nivolumab plus ipilimumab group compared to patients receiving nivolumab and chemotherapy, where it was 53%. So superiority is, so the importance of chemotherapy in patients with esophageal squamous cell carcinoma is to be noted. However, there is no difference in overall survival and progression-free survival when using the combination of nivolumab and ipilimumab, and thus it affords a chemotherapy-free option for this patient population with esophageal squamous cell carcinoma and a CPS with a score of greater than 1.

Brittany Harvey: Understood. I appreciate you reviewing the evidence underpinning those recommendations as well.

So then the next patient population that the guideline panel addressed, what first-line therapy is recommended for patients with deficient mismatch repair, microsatellite instability-high, gastroesophageal adenocarcinoma or esophageal squamous cell carcinoma?

Dr. Lakshmi Rajdev: The rate of MSI-high expression is about 3% to 7% across different studies. Now, the KEYNOTE-158 was a tumor-agnostic study in patients with non-colorectal cancers, and again, the problem with the MSI-high population, given that it is so rare, the numbers in the individual studies are fairly small. But consistent outcomes do emerge, indicating high response to immunotherapy. So in KEYNOTE-158, a response rate of about 46% was noted. The number of patients was small, it was about 24.

In CheckMate-649, which is a study of chemotherapy plus or minus nivolumab in patients with advanced gastric adenocarcinoma, there was again a very small number of patients, and patients that were MSI-high or deficient MMR did experience substantial benefits with the addition of immunotherapy, with hazard ratios in the order of about 0.38. In KEYNOTE-062, again, it was a very small number of patients, again about 6% or so, and similar to CheckMate-649, a substantial benefit was noted in combination with chemotherapy, but also there were benefits noted with pembrolizumab alone.

The RATIONALE-305 again was a study of tislelizumab in combination with chemotherapy and similarly showed benefits to the combination of chemotherapy plus immunotherapy in this patient population. I think that we are all aware of the dramatic benefits of immunotherapy in this particular subset of patients, deficient MMR MSI-high, and also we have seen in CheckMate-649 they did have a subset of patients that received nivolumab and ipilimumab. And in this patient population, they noted unstratified hazard ratio of 0.28.

So I think that the overall consensus is that immunotherapy is a very important treatment modality in patients with deficient MMR MSI-high disease, given that a lot of the trials in gastroesophageal adenocarcinoma have utilized chemotherapy-based options, that is certainly a recommendation of the panel to use chemotherapy in combination with immunotherapy. However, on a case-by-case basis, the panel recommended immunotherapy alone as well, and given the high response rates noted in trials across different diseases as well as noted in this disease as well.

Brittany Harvey: Certainly. And I appreciate you both for reviewing these first-line recommendations.

So moving to later lines of therapy, Dr. Rajdev, what recommendations did the expert panel make for second or third-line therapy for gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma?

Dr. Lakshmi Rajdev: So, I think that the RAINBOW trial that investigated the utility of the addition of ramucirumab as second-line therapy has been around since 2014, and those results have led to the addition of ramucirumab to taxane-based therapy in the second-line setting. Based on the utilization of oxaliplatin and platinum-based therapy in the front-line setting, there may be patients that have an underlying neuropathy, and so we wanted to really include treatment options for this patient population so that an agent that is less neurotoxic could also be recommended in combination with ramucirumab.

The RAMIRIS trial is one such trial where ramucirumab was combined with FOLFIRI, and it demonstrated benefit in combination with ramucirumab. So we have listed that as a potential treatment option for patients in the second-line setting who may have an underlying neuropathy or even for whatever reason that based on the toxicity profile, that needs to be the preferred option by a physician, that recommendation is new from the older guidelines that we have.

With regard to the utility of PD-1 inhibitors, there really has been no benefit noted in the second-line setting with regard to overall survival or progression-free survival, so no recommendation is made for that option. I think an important study that has been recently presented is the DESTINY-Gastric04 trial, which really has been practice-changing and has led to the recommendation for trastuzumab deruxtecan in patients that have HER2-positive metastatic gastric or GE junction adenocarcinoma. Now, this is a phase III trial in patients who retained HER2-positive disease after progressing on front-line trastuzumab-based treatments, and the comparator for this trial was trastuzumab deruxtecan versus ramucirumab plus paclitaxel.

There was significant improvement and progression-free survival in patients that received trastuzumab deruxtecan. The patients that were excluded from the trial are patients that have pulmonary problems, interstitial lung disease; that is one of the toxicities of this particular agent, and close monitoring and prompt initiation of therapy such as glucocorticoid treatment in patients who develop this toxicity was also highlighted by the panel. So to summarize, the new guidelines highlight the possibility of FOLFIRI plus ramucirumab as a second-line option and then trastuzumab deruxtecan as a later-line option in patients that still retain HER2 expression. And that is very important because the trial did retest patients whether they expressed HER2. As we know, in a substantial number of patients, there is downregulation of HER2, and there is emerging data that the benefit for subsequent HER2-directed therapies is best noted in patients that still retain HER2 expression.

Brittany Harvey: Great. So as our listeners have heard, there are many recommendations and new treatment options for advanced gastroesophageal cancer.

Dr. Shah, earlier you highlighted the importance of biomarker testing, but I would like to hear in your view, what is the importance of this guideline and how will it impact both clinicians and patients with gastroesophageal carcinoma?

Dr. Manish Shah: So as we have discussed throughout this podcast, the treatment for gastroesophageal cancer, both adenocarcinoma and squamous cell cancer, is increasingly complex, increasingly biomarker-driven. And I think the value of the guideline is to place all of that into context. So it provides the data for why certain biomarkers are important, what therapies should be indicated. Not only that, but if you are able to review the guideline, it provides the details of each of these studies and summarizes them in a meta-analysis fashion to sort of give you the context, because sometimes the individual studies can be maybe a little bit discordant or confusing and the guideline attempts to harmonize all that.

And then also, I think the tables are very, very interesting because they give you actual numbers in terms of how many patients over a thousand would this benefit or how many patients over a thousand would this cause harm in terms of nausea, vomiting, or other things like that. So it gives you context for helping clinicians and patients weigh the potential benefits of the novel treatment strategies against the potential adverse events. And then finally, the guideline does also provide an algorithm that you are able to follow based on the biomarkers, and those are in figures 4 and 5.

So I think overall, it is a very comprehensive guideline. It intends to make more manageable a very complex subject, and you know, I really encourage our listeners to review it after listening to the podcast.

Dr. Lakshmi Rajdev: If I can add to that, I think that what is also really good about the guidelines is there are quick summaries. So if someone is busy in the clinic, of course, there is the opportunity to review the data supporting the guidelines in great depth in the manuscript, but what is also really good is that there are good summaries. In the event that you are very busy, you can easily identify what the recommendations should be for that particular patient based on these summaries.

Brittany Harvey: Absolutely. Listeners are encouraged to review the full guideline, including those tables and figures that may be more helpful when they are looking for something quick to look at in the clinic as well.

So, as you both mentioned, there have been a number of recent practice-changing trials in this area. So I imagine there is still a lot of ongoing research as well. So Dr. Shah, what are the outstanding questions regarding treatment options for patients with locally advanced unresectable, advanced, or metastatic gastroesophageal carcinoma?

Dr. Manish Shah: I think we touched upon it a little bit. The guidelines are based on the data available, and they are primarily examining one novel therapy with chemotherapy in a specific biomarker population. But as you know, the biomarkers are not either/or; you are not either CLDN18.2 positive or PD-L1 positive. A portion of patients could have dual biomarkers, and you know, I think that we are generating data on how to manage those patients.

At the recent GI Symposium in January this year, the ILUSTRO trial was presented by Dr. Shitara, which looked at combining zolbetuximab and chemotherapy with immunotherapy for dual-positive biomarkers, and that is leading to a phase III study that has begun to enroll. So unanswered questions are: how do we manage dual-positive biomarkers? The other thing that was mentioned is that the current data for mismatch repair deficiency involve chemotherapy plus immunotherapy. Only squamous cell cancer is there a study with a positive non-chemotherapy kind of backbone, that is CheckMate-648 that Dr. Rajdev mentioned. As we move forward, it will be good to get data on non-chemotherapy options in certain biomarker-positive populations.

And then finally, another update, which is likely to be practice-changing, is the HERIZON-GEA-01 study that looked at zanidatamab, which is another biparatopic antibody that targets HER2, and that is likely to change practice. And as that data gets published, we may look to even do a rapid update for the current immunotherapy and targeted therapy guideline that is just being published.

Dr. Lakshmi Rajdev: So, if I can add to that, there are numerous ADCs that look very interesting. There are bispecific antibodies; in fact, the zanidatamab is a bispecific antibody showing improved activity in patients with HER2-positive disease. So I think there are studies from Asia looking at CLDN CAR T-based therapies. So, I think that there are a lot of novel agents and a lot of excitement in the field.

We know that the bemarituzumab study, unfortunately, the FGFR2 inhibitor failed to demonstrate any benefit, but I think that there are other agents that are being explored, so there are newer targets, newer agents, ADCs, bispecifics that could potentially change the field in the future.

Brittany Harvey: Yes, we will look forward to the data to address these unanswered questions and new agents and inform future guideline updates.

So, I would like to thank you both for all of your work to review the evidence here and update this important guideline, and for your time today, Dr. Rajdev and Dr. Shah.

Dr. Lakshmi Rajdev: Thank you.

Dr. Manish Shah: Thank you.

Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast.

To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Bishal Gyawali and Dr. Tessa Cigler share the new, comprehensive, evidence-based update of the ASCO guideline on the use of hematopoietic colony-stimulating factors in patients with cancer. They discuss recommendations on primary prophylaxis, secondary prophylaxis, and treatment of febrile neutropenia along with stem cell mobilization, efficacy, safety, duration, dosing, and administration of CSFs – including biosimilars. They highlight where it is appropriate to use a CSF, and importantly, when not to use a CSF. They touch on the significance of individual patient considerations and cost implications, and future work to refine the risk factors for the development of complications of febrile neutropenia. Read the full guideline, "White Blood Cell Growth Factors: ASCO Guideline Update" at www.asco.org/supportive-care-guidelines

TRANSCRIPT

My name is Brittany Harvey, and today I'm interviewing Dr. Bishal Gyawali from Queen's University in Kingston, Ontario, Canada, and Dr. Tessa Cigler from Weill Cornell Medicine in New York, New York, co-chairs on "White Blood Cell Growth Factors: ASCO Guideline Update." Thank you for being here today, Dr. Gyawali and Dr. Cigler.

Dr. Bishal Gyawali: Thank you very much for having me. It's a pleasure.

Dr. Tessa Cigler: Hi there. Nice to be here as well.

Brittany Harvey: Great. And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Cigler and Dr. Gyawali, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then I'd like to dive into the guideline that we're here today to talk about. So first, what prompted an update to this guideline on the use of hematopoietic colony-stimulating factors in patients with cancer, and what is the scope of this updated guideline?

Dr. Bishal Gyawali: The last version of the guidelines from ASCO on this topic was back in 2015, so it has been more than a decade since ASCO had a guideline on the use of G-CSF in patients with cancer receiving treatment. So it was due for an update because there has been a lot more evidence based on not necessarily new drugs, but evidence for proper timing of these agents and the duration of these agents, as well as there have been a lot of new biosimilars, and there are questions about are these biosimilars equivalent or how do we choose among these different options. One is that content of the evidence that has evolved over time in the last decade, but also I think the last time we had these guidelines, the ASCO guidelines were not incorporated to have those evidence GRADE tables. So the quality of the ASCO guidelines itself has evolved over the years, so we wanted to have a new version of the guideline that includes not only the new evidence, but also contains those evidence GRADE tables that will help to quantify the benefits. And so I think it was high time, and even more than that, the newer ASCO guidelines for any guideline, they also include considerations of cost, access, equity, and all these factors that were not included in the previous version of the guideline. So I think it's only natural that with time the guideline should also evolve.

Dr. Tessa Cigler: I agree completely, and just as a framework, as we all know, neutropenia and its complications, including febrile neutropenia and infections, are still an important toxicity of many myelosuppressive chemotherapies. And these neutropenic complications do require prompt evaluation and treatment and often hospitalization, and we know that hematopoietic colony-stimulating factors, which I'm going to refer to as growth factors, can reduce the duration and severity of neutropenia and the risk of febrile neutropenia, so it remains an important topic in the practice of clinical oncology.

Brittany Harvey: Absolutely. It's an important topic for both clinicians and for patients who are receiving treatment for their cancer. And as you said, there was a substantial amount of literature to review here and updating everything to be in line with the GRADE evidence rating system, so there was a lot of work that you both put into this.

So then next, I'd like to review the key recommendations of this guideline by clinical question. So first, what factors did the expert panel identify that should influence the decision to administer primary prophylaxis of febrile neutropenia with a CSF?

Dr. Bishal Gyawali: Yeah, so I think that constitutes one of the most important recommendations in our guidelines about primary prophylaxis with G-CSF. And this is important because not only it's about when to use it, it's also about when not to use it, as in the ASCO "Choosing Wisely" campaign has also made some recommendations about this. So our guideline recommendations are also aligned with that.

So first of all, we recommend that primary prophylaxis with G-CSF is recommended when the risk of febrile neutropenia because of the chemotherapy regimen is equal to or more than 20% unless an alternative chemotherapy regimen with comparable efficacy and safety that does not need G-CSF is available. And the quality of evidence to make this recommendation is high, so we give a strong strength of recommendation for this. Having said that, even for patients where the risk of febrile neutropenia is not necessarily 20%, it's a little lower, but because of other patient-related factors, the patient is at a higher risk of complications from febrile neutropenia, such as age, comorbidities, and other factors, in such case primary prophylaxis with G-CSF should be offered. And we also make a recommendation that if G-CSF is not affordable or available, then antibiotic prophylaxis can also be offered, but the evidence quality for this is low, and the strength of recommendation is very conditional.

A couple of things to highlight here would be that, I think Dr. Cigler can attest to that, we ran into lots of problems about finding the data for the evidence base to say what are the patient-related factors that actually make them at a higher risk of febrile neutropenia, you know, like how did that 20% benchmark come about? Why 20%? Or when we say even if it's less than 20%, if based on other comorbidities, if the risk is higher, we tried to dig into that evidence. For example, we're talking about our "Box 1" in the guideline, what is the evidence for each item we have included under that "Box 1"? And we tried to do a lot of search to find the evidence for that, and some of them do have strong evidence, and that will tie into our future research ideas as well. And some of them actually don't have such solid evidence too, so that was one of the reasons why we ran into lots of problems about how do we quantify whether someone is at a high risk of febrile neutropenia and where that 20% benchmark comes from.

Dr. Tessa Cigler: And definitely, because there's not very clear data, our guidelines definitely leave room for physician discretion in all these situations.

Brittany Harvey: Absolutely. I find that in a lot of these guidelines the key point is that there's a lot of shared decision-making with patients after talking through what risk factors they may have and what is best for them in their individual clinical scenario.

So then moving on to secondary prophylaxis, what factors did the expert panel identify that should influence the decision to administer secondary prophylaxis of febrile neutropenia with a CSF?

Dr. Tessa Cigler: So for patients who've already experienced a neutropenic complication from a previous cycle of chemotherapy, the question is which patients should then receive prophylactic G-CSF for subsequent cycles of chemotherapy. And without a lot of evidence again to guide us, the panel really felt strongly that secondary prophylaxis should be used when a treatment delay or when a reduced dose of chemotherapy would be thought to compromise cure rates or survival outcomes. We do note that in many situations, certainly a dose reduction or a delay would be a very reasonable alternative or an additional strategy to G-CSF administration.

Dr. Bishal Gyawali: Yeah, I think it's more like if there is going to be compromise in outcomes without using G-CSF, as in if we can't maintain the dose intensity and that's going to lead to inferior outcomes, then we should. But if we can reduce the dose intensity and treatment frequency and still have the same outcomes, then I guess in simple words, we're just trying to say use it when it's absolutely needed, or you can also look into other alternatives that might not need G-CSF but you could maintain the same outcomes.

Brittany Harvey: Understood. It's helpful to review those options for clinicians and showing that there's not just one way to address potential neutropenic complications for later cycles of chemotherapy.

So then following those recommendations for prophylaxis, what does the expert panel recommend regarding CSFs for the treatment of febrile neutropenia?

Dr. Bishal Gyawali: This is an important question because this ties strongly with the "Choosing Wisely" campaign. In other words, primary and secondary prophylaxis we talked about when CSF should be used; here we make a sort of negative recommendation in that we say when CSF should not be used, because this is where we see most overuse or overtreatment with G-CSF. So first, we say that we should not be using a CSF routinely simply because a patient has neutropenia. If they are afebrile but they only have neutropenia, we recommend against using CSF just to boost neutrophil counts; that's not a meaningful metric. Then the second recommendation we make is CSF should not be routinely used as an adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. So the first one was neutropenia, no fever, don't use it. The second one is okay, there is neutropenia and fever, but the treatment for that is use of antibiotic therapy, and so in such situations routinely we should not be using G-CSF just to boost the neutrophil count. And that is tied on to the third recommendation where if the patient has fever and neutropenia but is also at a very high risk for infection-related complications or who have other prognostic factors that we think will lead to poor outcomes for the patient, then in such situations, a CSF can be used as an adjunctive treatment. But we talk about the data in the manuscript, but the data show that the most that this will do is reduce the days of hospitalization by a couple of days. It actually does not have any data that it's going to improve the mortality rates.

So as of now, we use the word "may be offered," it's not "should be offered," it's "may be offered" if there are other factors that we think will make the patient at the very poor risk of mortality outcomes, and the evidence quality here therefore is low and our strength of recommendation is conditional. And we also have a box that lists those items that we think might be associated with poor prognosis for the patients, but again the data for those, are they really hard evidence? No. And that is also tied with our future research recommendation that we should study more about these factors that might lead to these poor outcomes.

Dr. Tessa Cigler: And again, allowing for discretion of the treating physician.

Brittany Harvey: Absolutely. It's just as important to know when not to use CSFs routinely, and those risk factor boxes that you mentioned are available in the full manuscript along with the full list of recommendations, and our listeners can refer to that; a link will be in the show notes of the episode .

Dr. Tessa Cigler: Just so you know, the panel, we really discussed those criteria a lot and agonized over them and gave you our best recommendations.

Brittany Harvey: Definitely, and it sounds like there was varying degrees of evidence to support a lot of those risk factors, and so it's really important that the evidence supports those, but also there was expert consensus of the panel in reviewing each of those factors individually to come up with recommendations that can be applicable for all clinicians.

Dr. Bishal Gyawali: If I may add, we're proud of our panel because I think our panel is quite inclusive of people representing different specialties within cancer care, as in we had radiation oncologist, we had infectious disease expert, pharmacists, and most importantly, we also had patient partners.

Brittany Harvey: Absolutely. Having a multidisciplinary panel is really important for each and every guideline.

So then, this is probably relevant now, but addressing a few more specific sections addressed in the guideline, what is the role of CSFs as adjuncts to progenitor cell transplantation?

Dr. Tessa Sigler: Great question, and so, as solid tumor oncologists, Dr. Gyawali and I really leaned heavily on our hematology experts within the panel. The panel decided that a CSF should be used alone after chemotherapy or in combination with a CXCR4 inhibitor to mobilize peripheral blood progenitor cells. Clearly the choice of mobilization strategy depends on the type of cancer and the type of transplantation. The panel noted that a CSF should be routinely administered after autologous stem cell transplantation to reduce the risk of severe neutropenia, and that a CSF may be administered after allogeneic stem cell transplant to reduce the duration of severe neutropenia. Again, this last recommendation has not a lot of evidence to support it, and so we kind of tempered our language that it may be administered or can be considered based on clinical judgment of the physician and the clinical status of the patient.

Brittany Harvey: And that really highlights the need for a multidisciplinary panel, because as you are solid tumor oncologists, you need the hematologists to make recommendations for all sorts of patients and make sure that these guidelines are comprehensive.

So then moving on to another smaller subset population, for patients receiving concomitant chemotherapy and radiation therapy, are CSFs recommended?

Dr. Bishal Gyawali: I think there is very little evidence for patients who are receiving radiation therapy alone, so there is no evidence to suggest the use of CSF in patients with radiation therapy alone. The bigger question is in patients who are receiving both chemo and radiation together, chemoradiotherapy. In those patients, up until now, the classical recommendation has been to avoid G-CSF use. I think in our updated guidelines we discuss a couple newer trials that are trying to address this issue, but in the totality of evidence, we still stick with the same recommendation as before, which is CSFs are not recommended in patients receiving concomitant chemotherapy and radiation therapy, especially those involving the mediastinum because the biggest evidence of harm is for these patients.

Dr. Tessa Cigler: I agree completely.

Brittany Harvey: Definitely. It's important to recognize when that balance of benefits and harms leans more towards harms, and so that this should not be recommended for those patients.

So there are several different CSFs that are recommended in the guideline, including biosimilars. So do the recommended CSFs differ in efficacy or safety?

Dr. Tessa Cigler: So as supported by evidence, and the panel all agreed, that the various forms of CSFs, including the biosimilars, really have the same evidence for efficacy and for safety, and that the choice of agent really should depend on cost, availability, accessibility, patient convenience, and sometimes disease subtypes and treatment regimens. But, in essence, these can be used interchangeably without concern for efficacy or toxicity differences.

Dr. Bishal Gyawali: I completely agree. I think in terms of efficacy outcomes, I don't think there is anything to choose between these agents. The choice between these agents would largely depend on different patient and treatment-related factors: cost, availability, affordability, feasibility. We even discuss things like where does the patient live, as in how frequently the patient can commit to the cancer center, and we also discussed things like even for the daily shots of filgrastim, patients can be taught and they can get it by themselves at home. So we discussed all these factors, but in a nutshell, the choice within these agents primarily depends not on efficacy factors, but simply based on all these other factors that are equally important but which can lead to informed decision-making about what is best for a given patient. But we mention it explicitly that the biosimilars, there is nothing to choose between them, especially the biosimilars; it's about price competition and what you can get at an affordable rate.

Brittany Harvey: Understood. It's great to have many different options for patients so that there's something that can work for them based off access, cost, and all these factors that you listed. As you mentioned, it may be easier for some patients to get their treatment at home rather than in clinic, and so having different options and reviewing those with patients is very important.

Dr. Bishal Gyawali: As we are having this conversation, I'm thinking that we might be a very unique guideline in that I don't think in many other settings you have this many options that you are asking about, you know, choices between equally good options and making decisions based on cost. I don't think there are any other areas in oncology where we have the privilege of making these decisions based on cost and convenience and all these factors, as well as we might be one of those guidelines where we have, as discussed before, so many recommendations about when not to do things and trying to promote judicial use of treatments.

Dr. Tessa Cigler: As you might imagine, our panel discussions were very lively.

Dr. Bishal Gyawali: Yes. But Dr. Cigler, do you recall any other guideline where there is so much discussion about when not to use things and how we have so many biosimilar options and we can choose the one that's most appropriate? I don't recall any other.

Dr. Tessa Cigler: I agree with you.

Brittany Harvey: It's certainly a unique guideline in that regard.

So we'll move into the last clinical question that the expert panel addressed. But what does the expert panel recommend for the initiation, duration, dosing, and administration of CSFs?

Dr. Bishal Gyawali: Yeah, I think there has been some new data in this regard that were not available in the previous guideline. For example, we have new trials testing a shorter duration of filgrastim injections compared to the standard of care. So we have some data, we call this 'de-escalation of treatment'. So we have more data supporting de-escalation of treatment. We have some data for lower dose of pegfilgrastim, we have data for lower duration of filgrastim, we have also some new data about timing of treatment, as in there has been some newer data presented about the relationship of timing of the drug and the frequency of adverse events from G-CSF such as bone pain. There is also the question about, for patients who don't live near the cancer center, can they get their pegfilgrastim shot on the day of chemo while they are in the cancer center? So all these questions that are very pragmatic and important questions, but were not answered before, we're glad that we had more evidence to talk about all these factors and give a more solid recommendation to our users of the guideline.

Brittany Harvey: Definitely. And listeners can review the full list of dosing and administration recommendations in Table 2 in the guideline, and that will be linked in the show notes of the episode.

So then I really want to thank you both for reviewing all of these recommendations. There's certainly a large amount of clinical questions and recommendations that you went through.

I'd like to next ask, in your view, what is the importance of this updated guideline and how will it impact both clinicians and patients?

Dr. Bishal Gyawali: I think the importance of this updated guideline is that, as mentioned before, we talk about newer data that have come up with regards to not just the most important two questions as in when to use it as primary prophylaxis and when to use it as secondary prophylaxis and when to use it as treatment, but also with regards to the duration and timing and dosing and multiple options and how these all factors as well as patient-related factors should be combined to make an informed decision, the most appropriate decision for the patient. And as mentioned before, we have the GRADE tables that were not in the previous version of this guideline. So I think even those users that are familiar with the 2015 guideline, I think they will find very novel content in this new updated guideline, and they will find it useful for their practice.

I would encourage the readers to not only read the headlines of the box recommendations, but also read the full text of these guidelines because we have worked really hard to incorporate the latest evidence and also interpret them contextually. The discussion regarding de-escalation, patient considerations, cost implications; usually, people just skip these portions when they read a guideline. But I think these are also one of the most important paragraphs in our guideline, so they have been written with very careful thought, and I think reading the whole guideline is very much worth your time.

Dr. Tessa Cigler: As you can imagine, I agree completely, having just spent several months thinking about these guidelines and all their nuances.

Brittany Harvey: Certainly, this guideline is definitely a very comprehensive update, and that nuance in the manuscript is really important for clinicians to understand and read through and understand when it's appropriate to make certain decisions.

So then to wrap us up, I'd like to ask, what are the outstanding questions and active research areas regarding the use of white blood cell growth factors in patients with cancer?

Dr. Tessa Cigler: As you all know from clinical practice and that we've said several times already in this podcast is that the risk factors for the development of complications of febrile neutropenia are still not clearly worked out. And one of the things that is, I think, really needed in clinical practice is the development of predictive algorithms or biomarkers to really allow us to understand who might be more at risk and to allow for the clinician to be able to tailor the use of G-CSF as needed.

Brittany Harvey: Yes, and so we'll look forward to future updates in this space to inform new recommendations and an updated guideline in the future.

So I want to thank you both so much for your work to develop this comprehensive guideline. It was certainly a lot of effort, and thank you for your time today, Dr. Gyawali and Dr. Cigler.

Dr. Tessa Cigler: Oh, my pleasure. It's nice to be here and to speak with you all.

Dr. Bishal Gyawali: Yeah, it was great to speak with both of you but also through you to the audience, and we had a great time. Thank you.

Brittany Harvey: And then finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Sonam Puri discusses the full update to the living guideline on stage IV NSCLC with driver alterations. She shares a new overarching recommendation on biomarking testing and explains the new recommendations and the supporting evidence for first-line and subsequent therapies for patients with stage IV NSCLC and driver alterations including EGFR, MET, ROS1, and HER2. Dr. Puri talks about the importance of this guideline and rapidly evolving areas of research that will impact future updates.

Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2026.3.0" at www.asco.org/thoracic-cancer-guidelines

TRANSCRIPT

This guideline, clinical tools and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02822

My name is Brittany Harvey, and today I'm interviewing Dr. Sonam Puri from Moffitt Cancer Center, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2026.3.0." It's great to have you here today, Dr. Puri.

Dr. Sonam Puri: Thanks, Brittany.

Brittany Harvey: And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Puri, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content that we're here today to talk about, Dr. Puri, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is updated on an ongoing basis. So, what data prompted this latest update to the recommendations?

Dr. Sonam Puri: So Brittany, non-small cell lung cancer is one of the fastest-moving areas in oncology right now, particularly when it comes to targeted therapy for driver alterations. New data are emerging continuously from clinical trials, regulatory approvals, real-world experience, which is exactly why these are living guidelines. The goal is to rapidly integrate important advances as they happen, rather than waiting for years for a traditional update.

Since the last full update of the ASCO Stage IV Non-small Cell Lung Cancer Guideline with Driver Alterations published in 2024, there have been seven new regulatory approvals and changes in first-line therapy for some driver alterations. [This version] of the "Stage IV Non-small Cell Lung Cancer Guidelines with Driver Alterations" represents a full update, which means that the panel reviewed and refreshed every applicable section of the guideline to reflect the most current evidence across therapies including sequencing and clinical decision-making. This is to ensure that clinicians have up-to-date practical guidelines that keep pace with how quickly the field is evolving.

Brittany Harvey: Absolutely. As you mentioned, this is a very fast-moving space and this full update helps condense all of those versions that the panel reviewed before into one document, along with additional approvals and new trials that you reviewed during this time period.

So then, the first aspect of the guideline is there's a new overarching recommendation on biomarker testing. Could you speak a little bit to that updated recommendation?

Dr. Sonam Puri: Yeah, definitely. So the panel has discussed and provided recommendations on comprehensive biomarker testing and its importance in all patients diagnosed with non-small cell lung cancer. Ideally, biomarker testing should include a broad-based next-generation sequencing panel, rather than single-gene tests, along with immunohistochemistry for important markers such as PD-L1, HER2, and MET.

These results really drive treatment decisions, both in frontline settings for all patients diagnosed with non-small cell lung cancer and in subsequent line settings for patients with non-small cell lung cancer harboring certain targetable alterations. Specifically in the frontline setting, it helps determine whether a patient should receive upfront targeted therapy or immunotherapy-based approach. We now have strong data that shows that complete molecular profiling results before starting first-line therapy is associated with better overall survival and actually more cost-effective care.

Using both tissue and blood-based testing can improve likelihood of getting actionable results in a timely way, and we've also provided guidance on platforms that include RNA sequencing, which are specifically helpful for identifying gene fusions that might be otherwise missed with other platforms. On the flip side, outside of a truly resource-limited setting, single-gene PCR testing really should not be routine anymore. This is what the panel recommends. It's less sensitive and inefficient and increases the risk of missing important actionable alterations.

Brittany Harvey: Understood. I appreciate you reviewing that recommendation. It really helps identify critical individual factors to match the best treatment option to each individual patient.

So then, following that recommendation, what are the updated recommendations on first-line therapy for patients with stage IV non-small cell lung cancer with a driver alteration?

Dr. Sonam Puri: Since the last full update in 2024, there have been four additional interim updates which were published across 2024 and 2025. Compared to the last version, there have been several updates which have been included in this full update. One of the most important shifts has been in first-line treatment of patients with non-small cell lung cancer harboring the classical, or what we call as typical, EGFR mutation.

The current version of the recommendation is based on the updated survival data from the phase III FLAURA2 and MARIPOSA studies, based on which the panel recommended to offer either osimertinib combined with platinum-pemetrexed chemotherapy or the combination of amivantamab plus lazertinib in the first-line treatment of classical EGFR mutations. And these recommendations, as I mentioned, are grounded in the results of the FLAURA2 and MARIPOSA trials, both of which demonstrated improvement in progression-free survival and overall survival compared to osimertinib alone in patients with common EGFR mutations.

That being said, the panel actually spent significant time discussing the toxicities associated with these treatments as well. These combination approaches come with higher toxicity, longer infusion time, increased treatment frequency. So while combination therapy is now recommended as preferred, the panel has recommended that osimertinib monotherapy remains a reasonable option, particularly for patients with poor performance status and for those who are not interested in treatment intensification after knowing the risks and benefits.

Brittany Harvey: Absolutely. It's important to consider both those benefits and risks of those adverse events that you mentioned to match appropriately individualized patient care.

So then, beyond those recommendations for first-line therapy, what is new for second-line and subsequent therapies?

Dr. Sonam Puri: So this is a section that saw several major updates, particularly again in the EGFR space. The first was an update on treatment after progression on osimertinib for patients with classical EGFR mutation. Here the panel recommends the combination of amivantamab plus chemotherapy, and this recommendation was based on the phase III MARIPOSA-2 trial, which compared amivantamab plus chemotherapy with chemotherapy alone with progression-free survival as the primary endpoint.

The study met its primary endpoint, showing an improvement in median PFS with the combination of amivantamab plus chemotherapy compared to chemotherapy alone. And as expected, the combination was associated with higher toxicity. So, although the panel recommends this regimen, the panel emphasizes that patients should be counseled on the side effects which may be moderate to severe with the combination therapy approach.

In addition, a new recommendation was added for patients who are not candidates for amivantamab plus chemotherapy. In those cases, platinum-based chemotherapy with or without continuation of osimertinib may be offered, and the option of continuing osimertinib with chemotherapy was recommended and supported by data from a recently presented phase III COMPEL study, which randomized 98 patients with EGFR exon 19 deletion or L858R-mutated advanced non-small cell lung cancer who had experienced no CNS progression on first-line osimertinib, and these patients were randomized to receive platinum-pemetrexed chemotherapy with osimertinib or placebo. Although this study was small, it demonstrated a PFS benefit with continuation of osimertinib with chemotherapy, and this approach may be appropriate for patients without CNS progression who prefer or require alternatives to more intensive treatment strategies.

Next was an update on options for patients with EGFR-mutated lung cancer after progression on osimertinib and platinum-based chemotherapy. Here the panel recommended that for patients whose disease has progressed after both osimertinib and platinum-based chemotherapy, a new drug known as datopotamab deruxtecan can be offered as a treatment option. And this treatment recommendation was based on evaluation of pooled data from the TROPION-Lung01 and TROPION-Lung05 study, in which in the pooled analysis about 114 patients with EGFR-mutant non-small cell lung cancer were treated with Dato-DXd, 57% of whom had received three or more prior lines of treatment, and what was observed was an overall response rate of 45% with a median duration of response of 6.5 months. So definitely promising results.

Next, we focused on updates to subsequent therapy options for patients with another type of EGFR mutation known as EGFR exon 20 insertion mutations. In this section, the panel added sunvozertinib as a subsequent line option after progression on platinum-based chemotherapy with or without amivantamab. Sunvozertinib is an oral, irreversible, and selective EGFR tyrosine kinase inhibitor with efficacy demonstrated in the phase II WU-KONG6 study conducted in Chinese patient population. In this study, amongst 104 patients with platinum-pretreated EGFR exon 20 mutated non-small cell lung cancer, the observed response rate was 61%.

Staying in the EGFR space, the panel added a recommendation for patients with acquired MET amplification following progression on EGFR TKI therapy. In these situations, the panel recommended that treatment may be offered with osimertinib in combination with either tepotinib or savolitinib. As our listeners may know, MET amplification occurs in approximately 10% to 15% of patients with EGFR-mutated non-small cell lung cancer when they progress on third-generation EGFR TKIs, and detection of MET amplification is done with various methods, such as tissue-based methods like FISH, NGS, and IHC, as well as ctDNA-based NGS with variable cut-offs.

Over the last few years, several studies have informed this recommendation. I'm going to be discussing some of them. In the phase II ORCHARD trial, 32 patients with MET-amplified non-small cell lung cancer after progression on first-line osimertinib were evaluated, where the combination of osimertinib plus savolitinib achieved an overall response rate of 47% with a duration of response of 14.5 months.

More recently, the phase II SAVANNAH trial reported outcomes in 80 patients with MET-amplified tumors after progression on osimertinib, and in this patient population, the combination of savolitinib and osimertinib achieved an overall response rate of 56% with a median PFS of 7.4 months.

And lastly, the phase II single-arm INSIGHT 2 trial assessed the efficacy of osimertinib plus tepotinib in patients with advanced EGFR-mutant non-small cell lung cancer who had disease progression following first-line osimertinib therapy. And in this study, in a cohort of 98 patients with MET-amplified tumors confirmed by central testing, the overall response rate with the combination was 50% with a duration of response of 8.5 months. So definitely informing this guideline recommendation.

Next, we had an update on recommendation in patients with ROS1-rearranged non-small cell lung cancer. For patients with ROS1-rearranged non-small cell lung cancer, the panel recommended specifically for patients who progressed after first-line ROS1 TKIs, the addition of taletrectinib as a new option alongside repotrectinib. And this recommendation was based on analysis of the results of the TRUST-I and TRUST-II studies, which showed that amongst 113 tyrosine kinase inhibitor-pretreated patients, taletrectinib achieved a confirmed overall response rate of 55.8% with a median duration of response of 16.6 months and a median PFS of 9.7 months, a very promising agent.

Finally, for patients with HER2 exon 20 mutated non-small cell lung cancer, the panel added two new oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib, as options in addition to T-DXd and after exposure to T-DXd. These recommendations are based on early phase data from two trials: the phase I Beamion LUNG-01 study, which evaluated zongertinib, and the phase I/II SOHO-01 study that evaluated sevabertinib. In this study, zongertinib demonstrated an overall response rate of 71% in previously treated patients, with an overall response rate of 48% amongst patients who had received prior HER2-directed ADCs including T-DXd. Sevabertinib in its early phase study showed an overall response rate of 64% in previously treated but HER2 therapy-naive patients, and an overall response rate of 38% in patients previously exposed to HER2-directed therapy. The panel believes that both agents had manageable toxicity profile and represent meaningful new options for this patient population.

Brittany Harvey: Certainly, it's an active space of research, and I appreciate you reviewing the evidence underpinning all of these recommendations for our listeners.

So, it's great to have these new options for patients in the later-line settings. And given all of these updates in both the first and the later-line settings, what should clinicians know as they implement this latest living guideline update, and how do these changes impact patients with non-small cell lung cancer?

Dr. Sonam Puri: Some great questions, Brittany. I think for clinicians when implementing this update, I think about two practical steps. First is reiterating the importance of comprehensive biomarker testing. That is the only way to identify key drivers and resistance mechanisms that we are now targeting. And second, picking a first-line strategy that balances efficacy and toxicity and patient preference for your specific patient. I think informed decision-making, shared decision-making is more important than any time right now. It has always been important, but definitely very important now.

For patients, this guideline brings recommendations on more personalized treatment options for both first-line and post-progression settings, which potentially means better outcomes. But it is also very important for our patients to continue to have informed conversations about side effects, time commitment, and what matters most to them with their providers. The panel in this version of the guideline specifically acknowledges the real-world barriers that prevent patients from receiving guideline-concordant therapy, including challenges with access to comprehensive molecular testing and treatment availability, and the panel emphasizes on the importance of shared decision-making, and we provide practical discussion points to help clinicians navigate these conversations with the patient.

In addition, the panel has also addressed common real-world clinical complexities, such as treating elderly or frail patients, managing multiple chronic conditions, considerations around pregnancy and fertility, and certain disease scenarios such as oligoprogression or oligometastatic disease. And where available, the guideline summarizes this existing data to support informed individual decision-making in these complex situations.

Brittany Harvey: Shared decision-making is really paramount, especially with all of the options and weighing the risks and benefits and considering the individual circumstances of each patient that comes before a clinician.

We've talked a lot about all of the new studies that the panel has reviewed, but what other studies or areas of research is the panel examining for future updates to this living guideline as it continues to be updated on an ongoing basis?

Dr. Sonam Puri: Yes, definitely, so much to look forward to, right? Looking ahead, the panel is closely monitoring several rapidly evolving areas that are likely to shape future updates of the guideline. This includes emerging data from ongoing later-phase studies, particularly the studies that are evaluating these new targeted agents moving to earlier lines of therapy, alongside studies evaluating additional combination strategies or more refined approaches to treatment sequencing.

We're also closely watching advances in biomarker testing, the evolving understanding of resistance mechanisms, development of new targets, and promising therapeutic agents. I think ultimately the living guideline exists to help clinicians and patients navigate this rapidly evolving field, and we would like to ensure that scientific advances are rapidly translated into better, more personalized patient care.

Brittany Harvey: Definitely. We'll look forward to those updates from those ongoing trials and future areas of research that you mentioned to provide better options for patients with non-small cell lung cancer and a driver alteration.

So I want to thank you so much for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Puri.

Dr. Sonam Puri: Thanks so much. Thanks so much for the opportunity.

Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. There's also a companion episode with Dr. Reuss on the related living guideline on stage IV non-small cell lung cancer without driver alterations that listeners can find in their feeds as well. And if you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Joshua Reuss is back on the podcast to discuss the full update to the living guideline on stage IV NSCLC without driver alterations. He discusses the new evidence and how this impacts the latest recommendations on first-line and subsequent therapeutic options. Dr. Reuss emphasizes the need for shared decision-making between clinicians and patients. He shares ongoing research that the panel will review in the future for further updates to this living guideline, and puts the updated recommendations into context for clinicians treating patients with stage IV NSCLC. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2026.3.0" at www.asco.org/thoracic-cancer-guidelines"

TRANSCRIPT

My name is Brittany Harvey, and today I am interviewing Dr. Joshua Reuss from Georgetown University, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2026.3.0."

It is great to have you back on the show today, Dr. Reuss.

Dr. Joshua Reuss: Happy to be here, Brittany.

Brittany Harvey: Just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Reuss who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

Dr. Reuss, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is updated on an ongoing basis. So, what prompted this latest update to the recommendations?

Dr. Joshua Reuss: Our committee is tasked with making routine updates to the living guidelines and really keeping them living, right? So, evaluating new data as it is coming in to see, is this practice changing? Is this data that should inform and potentially alter our guideline recommendations so that practitioners and other care providers could really make the best treatment decisions for their patients?

So that is something that happens on a more routine basis, but periodically, we are tasked with performing a more comprehensive update of our guideline where we really evaluate every one of our point recommendations, the data associated with these recommendations, to be sure that these are up to date, these are comprehensive, and to see if we need to alter anything in the language of these updates.

Brittany Harvey: Excellent. Thank you for providing that background. And yes, this is truly a comprehensive update that goes through all the latest literature. Given that, I would like to review what has changed and what is new in the recommendations. So, what are the updated recommendations on first-line therapy for patients with stage IV non-small cell lung cancer without driver alterations?

Dr. Joshua Reuss: So there are two main guidelines that we recommend from this panel. One is a driver mutation-positive guideline and the other is a driver mutation-negative guideline. And I think on first blush, one might look at kind of the recent flurry of approvals and new data and say, well, all the excitement, you know, is in the driver mutation-positive guideline.

But I would say that the driver mutation-negative guideline is equally as important and really has several unique challenges associated with it. You know, first and foremost is that there are really a multitude of regimens that can be considered for any one patient. And how to choose between one can be quite difficult and a stressful challenge that clinicians can have, particularly since there are really no randomized studies comparing these regimens in a head-to-head fashion.

In addition, you know, these guidelines are really broken down by two key factors. One is disease histology, so namely squamous versus non-squamous histology. And the other is PD-L1 status, broken down into one of three tertiles: PD-L1 high, which is greater than or equal to 50% expression; PD-L1 low, which is 1% to 49% expression; and then PD-L1 negative or unknown.

So what you are really looking at, if you do that math, is really six unique patient subpopulations where we need to make a recommendation on one of the multitude of treatment regimens that is approved. And what that means is you are oftentimes really looking at subset and sub-subset level data to help inform clinicians in their treatment decision making, which can be quite challenging because as those small subsets of data is more and more parsed, there are many confounders that can be interjected there. And so I think the committee is tasked with really quite a challenge in terms of how to really communicate and broadcast that data in a way that informs clinicians in making a decision on what is the right treatment for their patient.

Brittany Harvey: Absolutely. It can be challenging to interpret that subgroup data across several different studies that are reporting on different regimens and different outcomes. And I appreciate you mentioning the driver mutation-positive guideline as well. Listeners can check out the companion episode with Dr. Puri for more information on what is changed in the driver mutation-positive guideline.

Based on that primer, what is new for first-line therapy for patients with stage IV non-small cell lung cancer without driver alterations?

Dr. Joshua Reuss: Even though I will say there is not a lot of new trial data that was incorporated into this guideline, there were some updates and just some meaningful long-term data that we incorporated. I think first and foremost, there is a new top-level recommendation in this guideline pertaining to molecular testing, which is absolutely critical in both the driver mutation-positive and driver mutation-negative space. I think we tend to think that, oh, well, molecular testing really only pertains to then finding a driver mutation. But the lack of a mutation is absolutely critical as well, right? Because that is what leads us down the mutation-negative pathway.

We also need this molecular testing to assess PD-L1 status. We are seeing emerging data on molecular mutations that might confer resistance to certain immunotherapy-based strategies. So the committee felt strongly that a recommendation on molecular testing is critical to include in both the driver mutation-positive guideline and the driver mutation-negative guideline.

I will also say that we are now seeing five and six-year updates from some of the landmark trials of immunotherapy in driver mutation-negative non-small cell lung cancer. It is really incredible to see that in some of these trials, we are seeing very impressive durability of the treatment in the patient subsets that we are commenting on. In others, perhaps that durability is less clear, and I think that leads to challenges in making a recommendation on any one particular regimen. And I think that is nowhere more clear than in the squamous subset. I think that was one perhaps subtle change that is in this guideline where, particularly in the PD-L1 negative squamous population, the committee felt that no one regimen really was worthy of standing above the others.

Sometimes I think it is important to really champion one unique regimen if we feel that the data is there to support it. But I think it is equally important to list multiple regimens where the data is less clear. I think another point is that while perhaps there were no new regimens that we have added or that led to other clear changes in the prioritization of one regimen over another, there are other unique data subsets that I think come into play in making a decision and that really are important when looking at the discussion on any one recommendation from this guideline.

For example, we know there is emerging data on perhaps the significance of molecular alterations in KEAP1 or STK11 and how that might influence frontline decision-making. You know, there is not a prospective phase III trial in this population, but I think we still need to use that data in certain scenarios to make recommendations for a particular patient.

Another example of a trial that, again, did not change our recommendations, but I think one can incorporate in their decision making is the KEYNOTE-598 trial. Now, this is not a new study, but what it studied was pembrolizumab versus pembrolizumab plus ipilimumab in a PD-L1 high subset, and found that the addition of ipilimumab to pembrolizumab in the PD-L1 high population did not significantly improve clinical efficacy.

And so while pembrolizumab plus ipilimumab is not an approved regimen, it is hard to extrapolate that to our combination treatments that are approved. I think some clinicians might find that data valuable when making a frontline treatment decision on a patient who has PD-L1 high status. So a bit of a whirlwind tour, but I think there are still multiple factors that went into this guideline that are important to review when making treatment decisions for any one patient.

Brittany Harvey: Absolutely. I think what you just mentioned in having that upfront molecular testing is really key for individualized patient care. And the evidence summaries that you provide in addition to the recommendations are really important for clinicians to be able to refer to as they are making decisions in their clinic.

So then beyond those changes for first-line therapy, what is updated for second-line and subsequent therapies?

Dr. Joshua Reuss: For second-line and subsequent therapies, we did see one new treatment recommendation join these ranks, and that was telisotuzumab vedotin. Telisotuzumab vedotin, quite a mouthful. That is an antibody-drug conjugate. I like to think of that as smart chemotherapy, targeted chemotherapy, where you are trying to utilize some aspect of a marker that is selectively expressed or overexpressed on the cancer surface to then shepherd in the anticancer molecule, a highly potent chemotherapeutic in the case of currently approved antibody-drug conjugates, to exert antitumor killing effect.

So in this case, the antibody-drug conjugate telisotuzumab vedotin targets MET overexpression. So telisotuzumab is an antibody targeting MET, and that is conjugated to an MMAE highly potent chemotherapeutic payload called vedotin. So we know MET can be selectively expressed and overexpressed in non-small cell lung cancer in both driver mutation-positive and mutation-negative subsets.

The data that led to this approval was from the phase II LUMINOSITY trial which evaluated telisotuzumab vedotin, or Teliso-V, in many subsets. But the subset that really showed promise and was expanded was the EGFR wild-type, non-squamous, non-small cell lung cancer population with MET overexpression. And so in 78 patients with high levels of expression, the response rate here was 34.6%, median progression-free survival of 5.5 months, and a median overall survival of 14.6 months. With an overall acceptable safety profile; grade 3 or higher adverse events, neuropathy was perhaps the most common at 7%, also increased ALT at 3.5%, and pneumonitis at 2.9%.

Now this was phase II data that led to an accelerated approval. There is an ongoing phase III study randomizing patients with high expression to Teliso-V versus docetaxel. That is the phase III TeliMET study. But it is nice that we now have another option for patients, perhaps a more biomarker-directed option with, again, this MET overexpression. And again, it further reinforces the importance of molecular testing in patients with traditionally driver mutation-negative non-small cell lung cancer, whether that is upfront or at progression, and in particular utilizing immunohistochemistry to assess MET expression in these patients.

And this does join another ADC that we had previously made an update in our recommendation, which is trastuzumab deruxtecan, which is approved for those patients with HER2-overexpressing non-small cell lung cancer. So just again to reiterate the importance of molecular testing in patients both at the outset of their treatment and upon progression on frontline therapy.

Brittany Harvey: Definitely. It is great to have this new antibody-drug conjugate join the treatment options, and as you mentioned, very important in this case to have that molecular testing done at the outset and at progression.

So then in your view, what should clinicians know as they implement this living guideline, and how do these changes impact patients with non-small cell lung cancer?

Dr. Joshua Reuss: Because there are so many different regimens that one can consider for any one patient, I think it is easy to become overwhelmed and stress on, "Am I making the right choice for my patient?" And I think one of the key take home points is that in many cases, there is no one right regimen. And I think one has to weigh several factors. It is the treatment schedule. It is the toxicity profile. It is the molecular profile of the patient. It is the patient preference. You know, there are so many factors here.

And I would like to draw the reader and viewer's attention to an important section of these guidelines, particularly the Patient and Clinician Communication section, where we have a box focused on discussion points between patients and clinicians, which I think focuses on several of the high-level points that one can emphasize in making these decisions, ranging on things from: what are the goals of the treatment? What are the risks and benefits to any one approach? What are comorbidities that should be factored in? Common concerns, toxicity management, clinical trial consideration. All of these factors that I think are incredibly important in making that frontline treatment decision and implementing a regimen that both the clinician and, more importantly, the patient feels comfortable with.

Brittany Harvey: It is really important that there is shared decision-making in these scenarios. And I think that patient-clinician communication section can tease out some of those preferences from the patient end and talk through the risks and benefits of different regimens as well.

As we mentioned at the top of this episode, this guideline is a living guideline and updated on an ongoing basis. So what is the panel examining and keeping an eye on for future updates to this guideline?

Dr. Joshua Reuss: So I think there are a lot of exciting new therapies and more up-to-date trials that we are anxiously awaiting the results of on our committee, and I think the oncology community in general is awaiting the results of. When we will have these results, I think, is a bit of an open-ended question, but I can give some insight on several of the trials that our committee is really keeping a close eye on.

One that we have mentioned for several guideline iterations is the ECOG-ACRIN INSIGNA trial. This is a phase III clinical trial comparing pembrolizumab versus pembrolizumab plus carboplatin and pemetrexed chemotherapy in PD-L1 positive, non-squamous, non-small cell lung cancer. We talk about there being different regimens that can be considered in PD-L1 positive and PD-L1 high subsets, namely immunotherapy alone or immunotherapy plus chemotherapy, but there is no direct head-to-head comparison here. So this trial hopefully will answer that question. It has now finished accrual.

There are other very interesting molecules and trials. I think another interesting compound is ivonescimab. This is a PD-1/VEGF bispecific antibody that is currently approved in China as monotherapy in patients with PD-L1 positive non-small cell lung cancer based off of the HARMONi-2 trial, where the progression-free survival of this bispecific antibody, ivonescimab, appeared superior to pembrolizumab. And we are looking closely at ongoing trials to see if these results will be replicated in an ex-China population. And if so, I think it could have a real impact and change on our guidelines.

Still other very interesting things. There are obviously confirmatory studies for antibody-drug conjugates, such as the TeliMET study that I alluded to earlier, and many promising antibody-drug conjugates, both bispecific and trispecific antibody-drug conjugates, that hopefully can inform practice.

And then there are several unique subsets of populations that I think we now are utilizing data on to make decisions, but a lot of that is retrospective in small subsets where we do not have that prospective data. And there are several trials ongoing in some of these subsets to try to gain clarity on what regimen may be the best for patients.

One example is the phase III TRITON trial, which is looking at comparing CTLA-4 containing regimen, particularly the POSEIDON regimen of durvalumab plus tremelimumab and chemotherapy, versus the KEYNOTE-189 regimen, which is pembrolizumab plus carboplatin and pemetrexed, in patients with non-squamous, non-small cell lung cancer that have alterations in either KRAS, KEAP1, and/or STK11. There is a lot of both preclinical and clinical data to suggest that patients with these alterations in STK11 and KEAP1 may be more resistant to a PD-1 based treatment approach, and perhaps the incorporation of CTLA-4 can lead to a more meaningful response in this unique subset. Obviously, that data, it is retrospective, it is in small subsets. And when you add in a CTLA-4 molecule, you are also introducing greater risk for toxicity. So this trial is going to be very important in elucidating: is there a benefit in that unique subset? Does that data that we see retrospectively in this small subset hold true when evaluated in a prospective fashion?

So while our guideline, our most recent comprehensive panel update, may not have had a lot of new data in it that has influenced frontline treatment decision-making, I think the future is bright and there are a lot of novel studies and novel treatments on the horizon that will hopefully improve the outcomes for our patients.

Brittany Harvey: Absolutely. We will look forward to the results of those ongoing trials to provide more options and particularly clarity for patients with non-small cell lung cancer and to inform this guideline and its many updates to come.

So I want to thank you so much for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Reuss.

Dr. Joshua Reuss: Thank you so much.

Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Mary-Ellen Taplin joins the podcast to discuss the latest changes to the living guideline on metastatic castration-resistant prostate cancer (mCRPC). She reviews new treatment options for patients treated with ADT alone, ADT and an ARPI, ADT and docetaxel, and ADT, an ARPI, and docetaxel whose disease has progressed to mCRPC and the evidence that underpins these changes. Dr. Taplin highlights the updated algorithms within the guideline and the living format which will provide rapid, up-to-date, evidence-based information for clinicians and patients. Read the full living guideline update, "Systemic Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer: ASCO Living Guideline, Version 2026.1." at www.asco.org/genitourinary-cancer-guidelines

TRANSCRIPT

This guideline, clinical tools and resources are available at www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02693

My name is Brittany Harvey, and today I am interviewing Dr. Mary-Ellen Taplin from Dana-Farber Cancer Institute, lead author on "Systemic Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer: ASCO Living Guideline, Version 2026.1."

Thank you for being here today, Dr. Taplin.

Dr. Mary-Ellen Taplin: Thank you, Brittany. It is a pleasure.

Brittany Harvey: Before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Taplin who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

To dive into the content here and what we are here today to talk about, this living clinical practice guideline for systemic therapy for patients with metastatic castration-resistant prostate cancer is updated on an ongoing basis. Dr. Taplin, what prompted this latest update to the recommendations?

Dr. Mary-Ellen Taplin: Thank you, Brittany. Several things prompted the latest update. There have been several phase III trials that have been practice-changing that have resulted in the last several years that needed to be added to the guidelines to inform clinicians of comprehensive treatment options.

Brittany Harvey: Great, and it is great to have this updated guideline for readers. I would like to review the changes to the recommendations in this latest iteration across the patient populations that are outlined in the guideline.

So, starting with: What are the updated recommendations for patients previously treated with androgen deprivation therapy alone whose disease has progressed to metastatic castration-resistant prostate cancer?

Dr. Mary-Ellen Taplin: A nice feature of this guideline is that in addition to the tables, which provide detailed options, is at the end of the guidelines, our readers will find very clear algorithms that describe past treatment scenarios that patients could have had and then outline their treatment options. So it is very clear. Our clinicians will love these algorithms.

And one of the changes for the disease state that you mentioned, which is the least treated castration-resistant state of prostate cancer which is previously treated with ADT alone, is that we recommend testing for mutations in the HRR, homologous recombination repair, genes. And the ones that are specifically known and applicable to prostate cancer are the BRCA genes. So there is clear recommendation of testing to remind us, as treating physicians, that now is the time, if it hasn't been done before, to institute both germline and somatic testing. And somatic testing, if it can be done on tissue, is preferable, but if not, the liquid biopsy approaches, the ctDNA approaches, have now advanced to the point that most patients with metastatic prostate cancer will be able to successfully have testing on the liquid biopsies.

So that is number one, testing. And then the new treatment options include, if a patient does have an HRR gene alteration, and maybe about 20-25 percent of patients will be in that category, the combinations of an androgen pathway inhibitor and a PARP inhibitor are now treatment options. So for instance, talazoparib and enzalutamide; olaparib and abiraterone; or niraparib and abiraterone are some of the newer treatment options if the patient is HRR-positive.

So, Brittany, in regard to patients treated with ADT alone, another new treatment option is the combination of radium-223 with enzalutamide. This is data based on the PEACE-3 trial which did show both an rPFS and OS benefit. For the patient who is HRR-negative and has previously not had an ARPI, just ADT alone, the combination of radium and enzalutamide is a new recommendation added to the algorithm.

Brittany Harvey: Great. Thank you for reviewing those options for that patient population. And as you mentioned, I think those algorithms are very helpful as figures in the document. They are clear and can be used as at-a-glance tools for clinicians in their busy clinics.

So then the next patient population that the guideline addresses: What is new for patients previously treated with androgen deprivation therapy and an androgen receptor pathway inhibitor whose disease has now progressed to metastatic castration-resistant prostate cancer?

Dr. Mary-Ellen Taplin: Right, so there are several new treatment options. So one is lutetium-PSMA-617, the trade name of which is Pluvicto. So that has now been FDA approved to use after progression on an AR pathway inhibitor and prior to the use of docetaxel chemotherapy.

Brittany Harvey: Thank you for reviewing that new option for patients treated with androgen deprivation therapy and an ARPI whose disease has progressed.

So then moving into the next set of recommendations, what does the panel now recommend for patients previously treated with androgen deprivation therapy and docetaxel whose disease has progressed to metastatic castration-resistant prostate cancer?

Dr. Mary-Ellen Taplin: The next group of patients is those treated with ADT and docetaxel but haven't had an AR pathway inhibitor. Treatment options, again the HRR testing is important. So all patients with metastatic castration-resistant prostate cancer should be considered for both germline and somatic testing. I will repeat that. And if they are BRCA mutation positive, then the option of talazoparib and enzalutamide; olaparib and abiraterone; and niraparib and abiraterone. So the AR pathway inhibitors plus the PARPs. There are three choices, so that can be somewhat complicated to think through, but most practitioners will get familiar with one of those combinations and be their go-to.

So those are for BRCA-positive or HRR-positive. The talazoparib/enzalutamide trial also included non-BRCA HRR-positive gene mutations. And if they are HRR-negative, the option that we discussed above of radium and enzalutamide is new to the guideline.

Brittany Harvey: Great. And then the last category of patients that is addressed in this update: What has changed for patients previously treated with androgen deprivation therapy, an androgen receptor pathway inhibitor, and docetaxel whose disease has now progressed to metastatic castration-resistant prostate cancer?

Dr. Mary-Ellen Taplin: Well, in this space, patients who are heavily pretreated with ADT and ARPI, one or even two, and chemotherapy, generally with docetaxel, the recommendations are not new within the last year or two. And they include Pluvicto; a PARP inhibitor if HRR-positive and they have not had one; second-line chemotherapy such as cabazitaxel. And if they are a very rare group and they have been sequenced and they are MSI-high, then considering a PD-1 inhibitor such as pembrolizumab can be considered. I will note that this is a very small percentage of mCRPC patients, probably in the order of 5 percent or less.

Brittany Harvey: Understood. And I appreciate you reviewing the recommendations across all of these patient populations. It sounds like some of the key points is that HRR testing is very important for this patient population, and that the algorithms and the tables in the manuscript provide the full list of options that clinicians and patients can refer to.

Dr. Mary-Ellen Taplin: Those are the highlights. And I will note in the tables, all the sections have "Special Considerations" sections because patients never fall into the black and white of one category. And those practical information or special situations sections of each of the recommendations can also help clinicians think about the individual patient in front of them and how they might choose one therapy over another since there are generally choices in all of these treatment situations.

Brittany Harvey: Absolutely. That information for the individualized patient-clinician decision-making is really key when, as you said, there is a list of options to choose from.

So in your view, what should clinicians know as they implement this living guideline update, and how do these changes impact patients?

Dr. Mary-Ellen Taplin: I am so excited about this living document. ASCO has invested to developing the software to, in real time and iteratively, assess the new data that is published in prostate cancer and other diseases. So now we don't have to wait many years for the next guideline to come out. The guidelines will be updated every six months in prostate cancer based on this automatic search of the literature and a standing panel of both academic and community experts in prostate cancer treatment. So we no longer have to wait.

That is what makes this guideline stand out to other guidelines. And in the digestible format that we have made, a clinician can seek out the table and read some details, seek out practical information for the recommendations, or they can just go right to the clear figure algorithm and take a quick snapshot. "Yep, I need to do HR testing. Done. Oh, okay. HR-positive or negative, these are my options," and then think about the individual patient in front of them when there is more than one option. For instance, a patient with cardiovascular history, abiraterone might not be a good choice for them. Or a patient with neuropathy, docetaxel might not be a good choice for them. But, within this guideline, it really will be up to date and focused on the busy clinician and knowing what the options are for their patient.

Brittany Harvey: Definitely. This new era of living guidelines is very exciting and can provide even more up-to-date, evidence-based recommendations to really support clinicians and patients with metastatic castration-resistant prostate cancer.

So in that vein, finally, what is the panel examining, and what are you excited for for new data coming out for future updates to this living guideline?

Dr. Mary-Ellen Taplin: The future updates will depend on the results of phase III clinical trials. You know, there are many phase III trials ongoing in advanced prostate cancer, some of which include targeted therapy, which has been long awaited in prostate cancer. So such compounds as antibody-drug conjugates that are targeting certain proteins in prostate cancer cells, such as STEAP1, KLK2, B7-H3.

So I think we are entering a new era in prostate cancer where we will be targeting cells and delivering drugs and applying them to prostate cancer if the trials are positive. So I think with AI and a large investment in prostate cancer clinical drug development, I think the treatment options for our patients will be rapidly evolving in a manner not previously seen. So the guidelines need to follow along with these developments.

Brittany Harvey: Definitely. It sounds like an exciting time for research in metastatic castration-resistant prostate cancer. And we will await the result of those phase III trials to inform this guideline and lead to future updates.

So I want to thank you so much for your work to rapidly and continuously update these guidelines and for your time today, Dr. Taplin.

Dr. Mary-Ellen Taplin: Oh, it was my pleasure. ASCO has been a leader in this area, and as a practicing clinician, we are thankful for the investment and guidance that ASCO gives us.

Brittany Harvey: Absolutely.

And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App, available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Lisa Hicks and Dr. Joseph Mikhael discuss the updated guideline from ASCO and Ontario Health (Cancer Care Ontario) on the treatment of multiple myeloma. They cover recommendations for therapeutic options across smoldering multiple myeloma, transplant eligible multiple myeloma, transplant ineligible multiple myeloma, and relapsed or refractory multiple myeloma. They highlight the importance of shared decision making and patient-centric care. They comment on the explosion of new treatment options in this space and the impetus for this guideline becoming a living guideline, which will be updated on an ongoing, regular basis.

Read the full guideline, "Treatment of Multiple Myeloma: ASCO-Ontario Health (Cancer Care Ontario) Living Guideline" at www.asco.org/hematologic-malignancies-guidelines.

TRANSCRIPT

This guideline, clinical tools and resources are available at www.asco.org/hematologic-malignancies-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02587

My name is Brittany Harvey, and today I am interviewing Dr. Lisa Hicks from St. Michael's Hospital and University of Toronto, and Dr. Joseph Mikhael from the Translational Genomics Research Institute, an affiliate of City of Hope Cancer Center, co-chairs on "Treatment of Multiple Myeloma: American Society of Clinical Oncology-Ontario Health (Cancer Care Ontario) Living Guideline."

Thank you for being here today, Dr. Hicks and Dr. Mikhael.

Dr. Lisa Hicks: Thanks so much.

Dr. Joseph Mikhael: It is a pleasure to be with you, Brittany. Thank you.

Brittany Harvey: Before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Hicks and Dr. Mikhael who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then to dive into what we are here today to talk about, Dr. Mikhael, I would like to start by recognizing that this guideline updates the 2019 ASCO-CCO Guideline on the Treatment of Multiple Myeloma. So what prompted this update and what is the scope of this updated guideline?

Dr. Joseph Mikhael: It is amazing when we think back in myeloma years, 2019 actually seems a very, very long time ago because really so much has changed in myeloma over these last six to seven years. Indeed, there have been over 150 randomized controlled trials that we didn't have at the prior guideline that we reviewed for this. Myeloma is a disease that has really changed so dramatically over these last several years. Multiple new agents have been introduced. We now have CAR-T cell therapy, bispecific antibodies, and multiple other agents that were not available at the time.

Furthermore, with this growing complexity, it is becoming more important than ever to be able to provide practical advice and guidelines to the oncology community. For most oncologists, they have less than 5% of their time dedicated to multiple myeloma. It is important to bring a clarity to them that allows them to care for their patients. And the scope of these guidelines, furthermore, really cover the whole spectrum of myeloma. They go further than our prior guideline where now we have included smoldering multiple myeloma along with frontline therapy and relapsed multiple myeloma. So, we have really tried to provide the full spectrum to our colleagues in oncology to ensure that they have the tools they need to provide the best care possible for their patients.

Dr. Lisa Hicks: That is a really terrific summary. And maybe one thing I will just add is it is really unique to have this much literature. I can't think of another guideline that I have ever been involved with that has seen a field move so quickly and develop so many advancements in a period of just over four or five years.

Brittany Harvey: Certainly, there is a large volume of evidence that you all had to review for this guideline update. I think to your point probably one of the greater volumes of literature for a guideline update that you both mentioned.

Based on that, I would like to review the key recommendations that are updated in this guideline. So Dr. Hicks, that new patient population that Dr. Mikhael mentioned earlier, what are the key recommendations for patients with smoldering multiple myeloma?

Dr. Lisa Hicks: So this is the first time that an ASCO guideline is addressing this branch of multiple myeloma care. It is an area where I think some guidance is needed, and smoldering myeloma is not an active cancer. And so one thing that I really want to highlight is that the panel felt very strongly that to recommend any therapy in this space we needed a higher level of evidentiary certainty, of evidentiary confidence, to make recommendations for active therapy.

The panel really made two very important recommendations. First of all, the panel did not recommend treatment for low or intermediate risk smoldering myeloma. That is important. And then the area where I think for the first time we have recommended consideration of treatment is patients with high risk smoldering myeloma. And for patients with high risk smoldering myeloma, the panel recommended that it was appropriate to consider either treatment with daratumumab or careful observation.

Dr. Joseph Mikhael: And I think that move forward as you have mentioned, Dr. Hicks, is particularly important because it is an area to some degree still of equipoise and many trials are going on in the area. But we do now have a strong phase III trial that supports the use of daratumumab monotherapy for three years when compared to close observation. But of course, that is not for everyone. And one of the key themes of all of our recommendations are going to be now that more and more choices are available, that we have discussions with our patients to ensure that we match the right treatment with the preference of the patient. And I think that is particularly important here in smoldering myeloma.

Dr. Lisa Hicks: Multiple myeloma care and the multiple myeloma evidence is really so nuanced, and one of the nuances that readers will appreciate if they read the guideline is that how smoldering myeloma is risk stratified has been different across different trials. And that really adds to the complexity of this recommendation and is one of the reasons that the panel felt that it was appropriate to recommend either observation or treatment.

Brittany Harvey: It is great to have these new recommendations for this unique patient population. And as you both mentioned, that individualized patient care is really important across this entire guideline.

So then following those recommendations, Dr. Mikhael, what is recommended for initial therapy, autologous stem cell transplantation, post transplant therapy, and measurement of response for patients with transplant eligible multiple myeloma?

Dr. Joseph Mikhael: Well, that is an area that has really considerably also grown since the last guideline. Obviously one would have to consult the guidelines to get every last detail, but in essence, we want to assess whether or not patients are transplant eligible or ineligible. And that assessment is not based on age or renal function alone, but indeed on a careful assessment of that patient.

When that assessment is made and deemed that a patient is transplant eligible, our recommendation is that a patient typically would receive a quadruplet. That is to say, a monoclonal antibody directed against CD38, a proteasome inhibitor, an immunomodulatory drug, and dexamethasone to be given for approximately four to six cycles followed by the stem cell transplant, followed by potentially another two cycles of consolidation, and then maintenance therapy.

A couple of important caveats. One, we do have two different CD38 antibodies that can be used, either daratumumab or isatuximab. Although typically bortezomib is the preferred proteasome inhibitor, consideration can be given to carfilzomib by virtue of the potential toxicity from bortezomib. And then lastly in the maintenance setting, we are typically recommending at least lenalidomide alone, but consideration can be given to dual maintenance therapy as the data is emerging to either add to that daratumumab or carfilzomib. All the while using the IMWG criteria for response. The goal of course is to achieve the deepest response possible and to maintain that response until such time as patients would relapse.

Finally, the length of maintenance therapy continues to be an area of equipoise and study in multiple myeloma. And so at minimum, patients would receive two to three years of maintenance therapy, and based on risk status and depth of response it can be considered that patients would potentially come off maintenance therapy, of course always with the caveat that toxicity would influence length of therapy as well.

Brittany Harvey: Yes, as you mentioned, evaluating which patients are eligible is extremely important for considering what is recommended in the guideline for both transplant eligible and transplant ineligible patients.

So then Dr. Hicks, following those recommendations for transplant eligible multiple myeloma, what are the recommended treatments, goals of therapy, and measurement of response for patients with transplant ineligible multiple myeloma?

Dr. Lisa Hicks: You know, I really can't emphasize enough how important an individualized patient assessment is. When we are thinking about the range of patients that are included in this category of transplant ineligible patients, it is a huge range. You may have fairly fit patients in their late 70s all the way to patients in their 90s. And we really want to see that treatments are tailored both to the fitness of the patient, their individual circumstances, and their preferences. And it is a wonderful thing to have lots of options for patients in this circumstance.

What the guidelines have recommended for most patients who are transplant ineligible but fit enough for a stronger therapy is quadruplet therapy. So actually therapy that is very similar to what is being recommended in the transplant eligible population but for a longer period of time. And then for those patients who for whatever reason, be it their fitness or their preference, are not appropriate for that quadruplet therapy, the recommendation is for triplet therapy with a combination of lenalidomide, bortezomib, dexamethasone, or very often, more often in most cases, an antibody based approach with an anti-CD38 plus lenalidomide plus dexamethasone.

Dr. Joseph Mikhael: The only thing I would add to that, I think we have to also, as we do mention in our recommendations, be particularly cautious with the dosing of these medications. Because even though we think of them as a single agent or a particular class, there can be quite a variation within the dosing regimen that can affect a patient's side effects and their quality of life. And so being very careful with dose modifications, and particularly in the transplant ineligible patient, is an important part of the recommendation as well.

Dr. Lisa Hicks: Yeah, this is a podcast so no one can see me nodding vigorously that dose modification is so important particularly with those older and frailer patients, and with particular attention to trying to reduce dexamethasone doses and favoring weekly administration of bortezomib when that drug is used.

Brittany Harvey: Absolutely. Considering the risks and benefits and patient preferences is really key to selecting therapy for these patients.

So then Dr. Mikhael, for the final overarching patient population addressed in this guideline, for patients with relapsed or refractory multiple myeloma, what treatment options are recommended?

Dr. Joseph Mikhael: This of course is, if you will, the biggest part of the guideline because there has been so much done in the relapse setting. And I think we start the guideline by saying a decision has to be made as to when to institute therapy. That there may be some patients with slow biochemical relapse that may be monitored for a period of time. But when the decision is made to initiate treatment, instead of a simple algorithm, the guideline emphasizes the fact that there are multiple choices that can be given to a patient that are going to match what comorbidities the patient has, what they have been treated with before, and of course what their preferences are.

I think we highlight two particular areas. That now that CAR-T cell therapy is available as early as first relapse, it should be a consideration by virtue of the fact that it has resulted in such deep and durable responses. But that triplets should also be considered in that earlier relapse setting because we do have multiple classes of agents that can be used. We know that in later relapse options exist including bispecific antibodies for which we have four different choices. And that in general, patients will ultimately receive either a triplet or CAR-T cell therapy in earlier relapse, but there are some patients who may be eligible only for a doublet by virtue of their comorbidities and of their prior therapies.

Lastly, it really does emphasize the point as we have mentioned a few times in this podcast, and I am so glad it keeps coming up, is that as I often say we don't treat myeloma, we treat people. And engaging the patient in that conversation to ensure that the right treatment gets matched to the right patients is particularly important because with all the new classes that we have with antibody drug conjugates, with XPO1 inhibitors, the traditional three classes of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, along with as we have already mentioned CAR-T and bispecific antibodies, it really is an incredible laundry list of choice. And making that choice specific to the patient becomes absolutely critical.

I should also lastly note that there are patients who may defer their initial transplant. There may be patients who may be eligible for a second transplant. So autologous stem cell transplant, although primarily used in the frontline setting, may still be a consideration for a smaller subset of patients in the relapse setting.

Dr. Lisa Hicks: I think maybe one thing that I would add is an overarching principle which is actually similar to a principle in the first guideline, and that is that in the relapsed or refractory setting, there are many different treatment options. And in fact, the number of treatment options feels like it is evolving every day. But an overarching principle for clinicians to consider is to try and choose combinations of drugs that the patient has either not been exposed to in the past or certainly that they are not refractory to. We really want to be pulling new options out of the toolbox as much as we can.

Dr. Joseph Mikhael: Very often we do see where someone may be on a triplet and they are progressing on it and someone just changes out one drug. We have suggested not to take that approach but to take the approach of completely introducing a new therapy when someone is progressing on their current therapy. I think that point is particularly important and the consensus panel was very clear.

Brittany Harvey: Understood. That is very helpful when thinking about what options to offer to patients in the relapsed and refractory setting. And as you mentioned earlier, the figures in this guideline provide an outline of options and then the tables really go into some of the details and outcomes of the trials, and those are very helpful for clinicians to refer to.

So then Dr. Hicks, we have talked a little bit about some of the nuances of the guideline, but what should clinicians know as they implement these new and updated recommendations?

Dr. Lisa Hicks: I think they should feel comfortable that these are trustworthy guidelines. So these are evidence-based guidelines that have been rigorously developed after a very thorough evidence review and put together by a panel of experts who were extremely thoughtful in their review of the evidence. And so all of this contributes to the trustworthiness of the guidance.

And then I would also encourage people to take a deep look at the guidelines because of the importance of nuance that is addressed in them, and then to also explore some of the tools that ASCO is developing that helps with implementation including the flow charts that are contained within the guidelines and some additional tools that are available online.

Brittany Harvey: Absolutely. The tools and resources for this guideline are available online with the publication and we will provide links to that in the show notes of the episode.

So then following that, Dr. Mikhael, how does this guideline update affect patients with multiple myeloma?

Dr. Joseph Mikhael: As we sort of intimated earlier, I like to say I don't treat myeloma, I treat people. I think we should always be patient-centric and patient-focused. And I think in the discussion we always were. We always wanted to ensure that multiple factors go into a decision-making process. We are not just looking at the biology of the disease, we are looking at patient factors. Those patient factors include their frailty as we commented in a frailty assessment, their preferences, their comorbidities.

And I think, in a day where we have so many choices, we emphasize in the guideline the importance of that conversation with the patient. That, if you will, shared decision-making model where options are laid out and based on the patient factors and the treatment factors they can then be meshed together in the best way so that patients can make the right choice.

And of course in conjunction with the guidelines, we have patient friendly summaries of them. And we involved, of course, patients in the development of these guidelines. And I think that is one of the greatest strengths of the ASCO guidelines is that there is a patient with us at the table who is giving their perspective on the guideline as we go forward. So I am very thankful that we have created a product that is, if you will, not only for the providers, the practitioners that are prescribing these agents and that are directly giving the care, but indeed for the very patients who of course have the most at stake here.

Dr. Lisa Hicks: Yeah Joe, I am so glad you called out the participation of patient partners in the guideline. It is such an important part and they were really- the patient partner was such an important part of this panel in helping us understand the patient perspective as we developed this guidance.

Brittany Harvey: Definitely. It is a hugely important role for the panel and for all of the panel including the patient partners and the experts in the disease to review the evidence and come up with comprehensive recommendations. And yes, as you mentioned, the individualized treatment and the shared decision-making is really paramount to this guideline.

Finally, Dr. Hicks, you alluded to earlier the vast number of treatment options that is really exploding in multiple myeloma. And so this guideline is becoming a living guideline continuously updated by ASCO. So what are the outstanding questions regarding this topic and what evidence is the panel looking forward to for future updates?

Dr. Lisa Hicks: I am really excited about this. This is one of the first guidelines that will be a living guideline for ASCO and it is such a good fit. You have heard Joe and I say a few times how quickly this field is moving, how complex the field is. I think everyone on the panel knew that no matter how quickly we did it and how deeply we reviewed the evidence, it was inevitable that more evidence would be generated as we were putting out the guideline.

In a field like that, it is really important that we find a way to provide evidence-based guidelines quickly to the community. You know, waiting another five years, letting another 150 trials accrue before we do another guideline is not what the community needs. And so ASCO has really risen to this challenge and is committed to living guidelines.

And so a living guideline is a guideline that commits to reviewing the evolving evidence on an ongoing basis, watching for practice changing trials, and having a standing panel that will review evidence and update recommendations on a regularly scheduled basis. So that is what a living guideline is, and that is what this guideline is becoming. That is just the first thing in terms of what a living guideline is.

And then what are we watching? Well, honestly what aren't we watching? There is so much happening in multiple myeloma. We knew as we put the guideline out that there were trials in process, some trials that had been released at conferences but not yet published. We will be waiting for those and if they are practice changing they will be addressed in upcoming updates. There is new evidence just recently presented around combined anti-CD38 and bispecific antibodies. I don't know yet whether that will be addressed but I wouldn't be surprised if it was. There are so many things coming down the pipeline and it is just wonderful that there is going to be a way to try and address them in a robust fashion.

Dr. Joseph Mikhael: Yeah I agree with you, Lisa. I can't think of another disease that would be more relevant for a living guideline. I mean we had difficulty because new data kept coming in as we were making recommendations. And so at some point we had to draw a line and say this is where we will stop and produce this guideline and have it ongoing. And I really look forward to seeing the updates because we know as you mentioned that there are so many things that are on the verge of approval and on the verge of changing the way we manage this terrible disease.

And before I close, I would love to remind all of our listeners that as we commented from the start, patient engagement is critical at ASCO and in our guidelines process. Unfortunately we lost a very dear patient during the guidelines process, and that is Jack Aiello. Jack Aiello had been a patient and a patient advocate for many, many years in the myeloma community. And indeed we have actually dedicated these guidelines to his honor. And so I thought it would be valuable for us to mention that today. And we miss you Jack, but we are very grateful that we have been able to dedicate this excellent body of work to your memory.

Brittany Harvey: Absolutely. This guideline and your dedication to him is an honor to his memory and we really recognize him in thinking about this guideline.

We will look forward to those future trial results that you mentioned, Dr. Hicks, to update this guideline and continue to provide options for patients with multiple myeloma and improve upon those options and shared decision-making with patients.

So I want to thank you both for all of your work to develop this guideline and for your time today, Dr. Hicks and Dr. Mikhael.

Dr. Lisa Hicks: You are so welcome. Thanks for featuring this guideline.

Dr. Joseph Mikhael: Thank you so much, Brittany. It has been a privilege.

Brittany Harvey: Finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/hematologic-malignancies-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Alison Loren and Dr. Ann Partridge share the latest guideline from ASCO on the management of cancer during pregnancy. They highlight the importance of this multidisciplinary, evidence-based guideline and overarching principles for the management of cancer during pregnancy. Drs. Loren and Partridge discuss key recommendations from each section of the guideline, including diagnostic evaluation, oncologic management, obstetrical management, and psychological and social support. They also touch on the importance of this guideline and accompanying tools for clinicians and how this serves as a framework for pregnant patients with cancer. The conversation wraps up with a discussion on the unanswered questions and how future evidence will inform guideline updates. Read the full guideline, "Management of Cancer During Pregnancy: ASCO Guideline" at www.asco.org/survivorship-guidelines

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02115

My name is Brittany Harvey, and today I am interviewing Dr. Alison Loren from the Perelman School of Medicine of the University of Pennsylvania and Dr. Ann Partridge from Dana-Farber Cancer Institute, co-chairs on "Management of Cancer During Pregnancy: ASCO Guideline." Thank you for being here today, Dr. Loren and Dr. Partridge.

Dr. Alison Loren: Thanks for having us.

Dr. Ann Partridge: It's a pleasure.

Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Partridge and Dr. Loren who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then to dive into the meat of this guideline, to start us off, Dr. Loren, could you provide an overview of the scope and purpose of this new guideline on the optimal management of cancer during pregnancy?

Dr. Alison Loren: Sure, thanks, Brittany. So this was really born out of I think a lot of passion and concern for this really vulnerable patient population. We have observed, and I am sure it is not any surprise to your audience, that the incidence of cancer in young people is increasing. And simultaneously, people are choosing to become pregnant at older ages, and so we are seeing more and more people with a cancer diagnosis during their pregnancy. And for probably obvious reasons, there is really no way to do randomized clinical trials in this population. And so really trying to assemble and articulate the best evidence for safely managing the diagnosis of cancer, the management of cancer once it is confirmed, being thoughtful about obviously the health of the mom, but also attending to potential risks to the developing fetus, and really just trying to be really comprehensive and balanced about all the choices for these patients when they are facing some really challenging decisions in a very emotionally fraught environment. And I think it is really emotionally fraught for the providers, too. You know, this is obviously an extremely intense, very emotional set of decisions, and so trying to provide a rudder essentially to sort of help people frame the questions and trying to make as evidence-based a set of recommendations as possible.

Dr. Ann Partridge: And I would just add that "evidence-based" is a strong word here because typically our, as you just heard, our gold standard evidence is a randomized trial, but you can't do that in this setting, in general. And so, what we were able to do with the support of the phenomenal ASCO staff was to pull together kind of the world's literature on the safety and outcomes of treatments during pregnancy, as well as consensus opinion. And I think that is a really, really critical difference about this particular guideline compared to many of the other ones that ASCO does, where consensus and good judgment needed to kind of rule the day when evidence is not available. So, there is a lot of that in our recommendations.

Dr. Alison Loren: That is such a good point. And I just, before we move forward, I just want to reflect that the composition of the panel was really broad and wide-ranging. We had maternal medicine specialists, we had legal and ethical experts, we had representatives who understand pharmaceutical industries' perspectives, and then medical oncologists representing the full spectrum of oncology diagnoses. And so it was a really diverse, in terms of expertise, panel, internationally composed to try to really get the best consensus that we could in the absence of gold standard evidence.

Brittany Harvey: Absolutely. That multidisciplinary panel is really key to developing this guideline and, as you said, looking at the evidence and even though it does not reach the level of randomized trials, still critically evaluating it and reviewing that along with consensus to come up with optimal management for diagnosis and management of cancer during pregnancy.

So then to follow that up, I would like to next review the key recommendations of the guideline across the main sections that the expert panel provided. First, I will throw this out to either of you, but what are the important general principles for the management of cancer during pregnancy?

Dr. Ann Partridge: I think there were three major principles that we hammer home in the guidelines. One is that this is a team sport. It is multidisciplinary care that is necessary in order to optimize outcomes for the patient and potentially for the fetus. And that you really need to, from the beginning, bring in a coordinated team, including not just oncologists but obstetricians, maternal-fetal medicine specialists, neonatologists, ethics consultants, and obviously the patient and potentially her family. So that, I think, is one of the most important things.

Second would be that obviously in a pregnancy, there are two potential patients and that the nuances of safety and risk from treatment is really wrapped up in where in the trimester of the pregnancy the patient is diagnosed, along with the kind of cancer that it is, both the urgency of treatment and the risk of the cancer, as well as the potential risks of any given intervention across the cancer continuum. It is a broad guideline in that regard.

And then finally, and this is particularly timely given what is going on from a sociopolitical standpoint in the U.S., really thinking about informed consent and potential ethical as well as legal implications of some of the choices that patients might have when they are thinking about, in particular, continuing a pregnancy or potential termination.

Dr. Alison Loren: And I will just add that I think that the key to all of this guidance is nuance and individualization and also making sure that patients and their care providers understand all the choices that are available to them and also the consequences of those choices. You know, nobody would choose to receive chemotherapy during pregnancy if that wasn't necessary. So there are risks to treatment, but there are also risks to not treatment. And making sure that in a suboptimal situation where you do not have a lot of evidence, trying to weigh, the best you can, the risks and benefits of all of the choices so that the patient can come to a decision about the treatment plan that is right for her.

Brittany Harvey: Definitely. And those core concepts really set the stage for individualized care on what is necessary for appropriate multidisciplinary care, prioritizing both patient autonomy and informed decision making.

With those core concepts and key principles in mind, I would like to move into the recommendations section of the guideline. So what are the key recommendations regarding diagnostic evaluation for pregnant patients with signs or symptoms of cancer?

Dr. Alison Loren: I think the most important thing is to not delay, that there are very careful and well-thought-out recommendations for how to evaluate a potential cancer. And while there are certain things that we know can be harmful, particularly when certain dose thresholds are exceeded - for instance, abdominal imaging, there are certain radiographic thresholds that you don't want to exceed because of risk of harm to the embryo or fetus - there are still lots of options for diagnosing cancer during pregnancy. And again, thinking about the costs of not doing versus the cost of doing, right? It is really important to make the diagnosis of cancer if that is a consideration or a concern. And sometimes going directly to biopsies or getting definitive studies, even if there is a small risk to the developing fetus, is really essential because if the mom does not survive, of course, the fetus is also not going to survive. And so we need to be thinking first about the patient who is sitting in front of us, the woman who needs to know what is going on in her body so she can make good decisions about her health. So, I think that is a key principle in thinking about this.

Brittany Harvey: Absolutely. So, following that diagnosis of a new or recurrent cancer, what is recommended for oncologic management of patients who are diagnosed with cancer during their pregnancy?

Dr. Ann Partridge: So, I think the general principle is, again, cancer is such a wide number of diseases and even within diseases, a range of stages and risks and associated opportunities for risk reduction and/or treatment depending on the type of cancer. Just by example, in the work that I do, which is breast cancer, once someone has had a surgery in the early-stage setting, a lot of our treatment is about risk reduction. And that is very different than from what Alison does, which is treating people with leukemia, where it is kind of binary. If you do not treat, including with cytotoxic drugs, the patient and an unborn fetus will die, especially early in the pregnancy, obviously.

So this is where cancers are very, very different. So I think taking the approach of what would you do if the patient were not pregnant? And what is the best treatment for that particular patient with that particular kind of cancer? And then applying the pregnancy and where the patient is in that pregnancy in terms of the trimester of the pregnancy, and what is safe and what is unsafe from the options that you would give her if she were not pregnant. And then if the patient is choosing to keep the pregnancy, which in my practice, many people come and they come to me because they want to hold onto their pregnancy and want to figure out how to make it work, coming up with a regimen that tries to give them kind of the best bang for the buck, the best possible breast cancer therapy with the least harm, when possible, to the fetus. It is a bit of a balance, right? And then we cannot always give people the best approach. And sometimes it comes down to making a decision to give up something that may improve their survival so as not to harm the fetus. And sometimes it goes the opposite direction where a patient will say, "Oh, that is going to improve my survival by 5% and you can't give it to me now? I am going to choose to terminate." Even though that is obviously a very, very difficult and challenging decision to make in this setting because they want to optimize their survival and ideally live on to potentially have another pregnancy in the future if that is something that is of interest to her. So these are really, really hard conversations as you can imagine, but that is kind of where we go.

Dr. Alison Loren: Yeah, and I think this is where the need for more research and understanding is really key because sometimes questions come up. I guess I am thinking about like HER2-directed agents, which we know are contraindicated in pregnancy. But what about sequencing? Does it matter when you get it? Can you get it later? I think that is something that we don't really fully understand. And similarly, again, this is obviously like a breast cancer and blood cancer focused discussion because that is what we do, but thinking about managing blood cancers, certainly with acute lymphoblastic leukemia, there is actually a lot of options now that, you know, you could potentially use to temporize or sort of get somebody through a pregnancy relatively safely. I am focusing on the word "relatively" because we do not know what the long-term impact might be of potentially not optimal therapy in the long run. And then thinking about other things like timing of a bone marrow transplant relative to either delivery or termination. I mean, again, we really do not know what are the right sets of sort of timing considerations for those. So there are just a lot of unknowns. And I think trying to be sort of self-aware and humble and honest about those unknowns so that the patient can engage in the conversation in a way that is meaningful to her and make the decisions that make the most sense for her. I think the most important thing is to make sure that the patient feels supported and safe to make those decisions with as little regret as possible.

Brittany Harvey: Yes, I think it is really important that you mentioned that there is a wide range of cancers here, and that means that care really needs to be individualized for each patient. I will also note, just in this section, that I found really informative while reading through the guideline the list of oncologic agents that may be offered in each individual trimester, whether it is contraindicated or it can be used with caution, or if there is relatively good safety data on it for prioritizing maternal treatment needs and balancing fetal safety at the same time. I think that is, that is really key. And I think readers will really like that section of the guideline to provide concrete information for them and their patients.

Dr. Alison Loren: Thank you. We actually spent a lot of time on that table and just thinking about what it should look like, what the format ought to be, what the language ought to be. Because of course, at the end of the day, everything should be used with caution. So what does that actually mean? And we sort of tried to explicate that a little bit in like the footnotes. We really tried to leverage what we know from clinical experience, from package labels, from mechanism of action to try to be as clear and definitive as we could be without overstating or understating what we know.

Dr. Ann Partridge: Yeah, and I think we are focusing on breast and leukemia because that is what we do. But the truth is much of the data comes from those two areas. Leukemia, not because it is so common, but because you do not really have choices to treat or not treat. And so for decades, they have been treating and saying, "We hope the progeny comes out okay." And for many agents it does. The babies are okay. And so, we have reasonable observational data. And then in breast cancer, there have been actually some prospective registry-type studies where people have been followed and treated when pregnant, and the progeny have been accounted for, and so we have some good experience in that way too. Again, not randomized trials, but at least data that suggests certain agents are safe. And increasingly, because of that, when we have had to treat patients, we have said, "Okay, let us do it on this registry so that we can at least learn from every patient that comes in in this situation." And so, I think we will have more and more data given the growing number of young adults with cancer and the delays in childbearing that are happening around the world, and particularly in Westernized countries. I wish we did not. We wish we did not see this problem, but of course, when we do, we have to make sure that we learn from it and try and get patients enrolled in these registries and any kinds of studies that are available.

Dr. Alison Loren: Yeah, I will just underscore that to say that, you know, there is outcomes of pregnancy and then there is outcomes of pregnancy, right? So there is like, "Okay, the baby was born with 10 fingers and 10 toes, and they passed their Apgar, and they are doing all their developmental processes along the way." But what happens when they are 10 or 15 or 20? Are they maturing normally? Are they cognitively intact? And then, of course, it is really inseparable from what is the impact on a family of having the mom with cancer? And how does that impact childhood development and intellectual development? And so these are really, really important questions that are very difficult to answer given the longitudinal information that you need, but it is a really critical question that, you know, patients ask and we do not know the answer.

Dr. Ann Partridge: Yeah, that actually leads me to one of the important principles in the guideline that is a little bit of a change from when I first started practicing, which is we have learned from the wider neonatology literature, as they have followed up on the children that were born prematurely, that it is actually better not to be premature and to keep the baby in utero as long as it is safe for the fetus and the mother as long as possible, ideally to term rather than delivering early and then giving the chemo after that or separating the chemo from before and after. We used to try and deliver early and then give agents, but now we typically will give agents that are safe to be given at the end of pregnancy, ideally close to term, a couple weeks out, to allow for the ability of count recovery, and you do not want to go into preterm labor with chemotherapy on board, but we used to go much earlier and have an argument with our maternal-fetal medicine doctors. "How early can you get them out?" And they would say, "How long can they stay in?" And increasingly, we have been able to try and compromise to go even later and allow the fetus to go to term because of the neonatal outcomes that in longer term there is a suggestion that the children are developing better in the long run if they are kept in utero for as long as possible.

Dr. Alison Loren: Yeah, that is such a great point. I think that is probably the most important thing for people to take away. For anyone who sort of does this, I mean, no one does this regularly because it is a rare event, although I think it is increasing as I mentioned. But this idea that the third trimester is, most of us know, is primarily a time for growth. Most of the critical development has already occurred, and so administering most chemotherapy agents towards the end of the third trimester seems to be preferable long term than delivering them early. So that is a really big change. I think we used to try to sort of, "Oh, get them to 30 or 32 weeks and then deliver," but we really are trying to get them closer to term, 37 weeks or more, and then coordinating the treatment so that they are not nadiring, as Ann said, at the time of planned delivery.

Brittany Harvey: Yes, and that is a really important point related to evidence-based care and why we have changed that practice.

And so then that actually leads nicely into my next question. But as you both mentioned, this is an important collaboration between oncologists and obstetricians. So the next section of the guideline addresses obstetrical practice. And so beyond what is standard, what additional recommendations are there in obstetrical management for pregnant patients with cancer?

Dr. Alison Loren: That is a great question. So I will say we were really struggling with like how much do we cover? Like this is an oncology guideline. We are not obstetricians. We certainly had great representation from our maternal-fetal medicine colleagues on the panel. But really trying to sort of give useful information without overstepping. And so I think that the main recommendations are to increase the frequency of fetal monitoring, make sure that there is close attention to blood counts in the patient. But I think there is really still a gap in terms of what we know about optimal management of a pregnant person who is receiving therapy and how to handle the pregnancy itself. The delivery should be a usual delivery. Our colleagues did not recommend a planned C-section. They recommended usual care in terms of planning for the delivery. Obviously, if a C-section is indicated, then it should be done, but it should not be planned this way because of the cancer diagnosis. And I guess the other thing that we mentioned in the guideline, although we were reluctant to push it too hard because of access to these specialized services, was evaluating the placenta after birth to ensure that there were no metastases in the placenta itself.

Dr. Ann Partridge: Those are the main things, and judicious and prudent obstetrical care, as I think, you know, is trying to be practiced regularly with MFM. Typically these patients should be followed not by your average OB/GYN, but a maternal-fetal medicine specialist because these patients will have special concerns, especially if they are sick. So oftentimes, especially Alison's patients, are actually sick with leukemia. And so you are monitoring them a lot, whereas, you know, a breast cancer patient typically isn't sick, although they could get sick with their chemotherapy. And so we really want to hand-in-hand manage these patients with our MFM colleagues.

Dr. Alison Loren: I think we also highlighted in the guideline just for the refresher purposes of the oncology community, generally which drugs that would be given in a normal oncology setting are safe to be given to a pregnant person. So we talked a little bit about what kinds of steroids are recommended, antiemetics, DVT prophylaxis, peripartum. These are things that we think about a lot in oncology, but just want to make sure that it sort of intersected appropriately with the care of a pregnant patient.

Brittany Harvey: Definitely. That specialized care is really important for patients who are pregnant and have cancer.

And then the last section of the recommendations addresses psychological and social support. As you both mentioned before, this is a highly emotional time and it can be difficult and challenging to make decisions. So what is recommended for the psychological and social support of pregnant patients with cancer?

Dr. Ann Partridge: Well, as I said, it is really something that needs to be considered at the beginning, through the diagnostic period, all the way into survivorship. Ironically, even though it is a highly fraught, emotional situation, I find that my pregnant patients actually are extraordinarily resilient, and what they are really focused on often is the safety of the fetus, because again, many of the people that come to me, it is a highly wanted pregnancy. They are also focused on their own health, of course, and often you need to bring in social work, sometimes a psychologist, professionals who are there just to help manage their emotions while we are focusing on what do they need medically to be as healthy as possible, both for the again, the mother, the patient, and the fetus.

It is very tricky, and I will say also bringing in sometimes people on the ethics team in the hospital to help, both from the "Are you recommending and giving something that is safe?" That is number one. And then number two, sometimes patients want to be treated with drugs that we do not have any safety data for in pregnancy. What are our obligations? I think most of us would say we would not treat someone if we do not have safety data and there is suspicion for concern. But where is that line in terms of the right thing to do by that patient? And so we are all beholden to our ethics colleagues to help us when we make decisions like that. You know, we all want to do right by the patient, but we have to uphold our oaths and legal obligations. I don't know if you have to add on that because it's very tricky.

Dr. Alison Loren: It is, it is very hard. I mean, I think, you know, there is a lot of emotion, obviously any cancer diagnosis is extremely charged and people are already at sort of a heightened, you know, they are anticipating a new baby and planning around that. And so it is just an extremely disruptive is the smallest word I can think of to describe it. And I think that often there is a co-parent, there might be parents and in-laws and other siblings, and then there is care after delivery. And so it is just a very complex set of dynamics. And having both our ethics colleagues and our psychology and social work colleagues to sort of just pitch in and make sure that the patient is being supported. I think there are sometimes really difficult situations where maybe what the patient wants is different from what the father of the baby wants or what the rest of the family wants. And so that can be really challenging. And you never really know where those landmines are going to pop up. So it is good to have the team on board early and often.

Dr. Ann Partridge: Yeah, I would add to that, the other thing here that I think is really important, like in all of medicine but especially in situations like this, this is where we have to be very careful as professionals not to impose our own ethical, moral, emotional, personal views on the patient and to try to reserve judgment as much as possible. We are their navigator with the most important evidence and information that we can provide in the current situation. And that is where this guideline is extraordinarily helpful, we hope, for clinicians in the years to come. And at the same time, we cannot necessarily impose our own views and what we would do on a patient or what we tell our daughters, sisters, friends, family members. It is very tricky in that way. And so sometimes not just support for the patient, but support for the care team may be warranted in some of these very fraught situations.

Dr. Alison Loren: Yeah, that is such a great point. And I was sort of thinking that too. I mean, it is, of course, the patient is front and center, but these are really difficult situations to navigate. And I will just add also that a lot of times these patients end up in academic centers, which I think is that's where the expertise or even just the experience may be. But the downside of that is that, you know, the teams are constantly changing. You have a new resident, you have a new intern, you have a new attending, a new fellow. And so, you know, the patients may be subjected to lots of different ways of communicating and sometimes those perceived differences can be really challenging. So sort of team huddles to sort of make sure that everybody is reading from the same script and everyone is comfortable with how the information is being presented so that the patient does not feel more confused or more overwhelmed, that they are kind of getting a consistent message from the whole team that, "This is what we know, this is what we are recommending, here are your other choices, and here are the pros and cons of each of these options."

Brittany Harvey: Yes, I think you have both touched on this and that bringing in appropriate experts to support both clinicians and patients and their decision-making and their mental health is really important for this section of the guideline.

We have already discussed this a fair bit throughout our conversation, but in your view, what is the importance of this guideline and how will it impact both clinicians and pregnant patients diagnosed with cancer?

Dr. Ann Partridge: I could start with that. We just talked about experts and having them all around, but the fact is most people do not have the experts all around when they are dealing with this. And I think this is, you know, an expert-based, evidence-based guideline where having this in one's back pocket, whether you are in rural Montana or at a major cancer center on either coast, you will be armed with the latest and the greatest in terms of what we know and what we do not know, and some very helpful algorithms for how to think through the process of dealing with a patient who is diagnosed during pregnancy, whichever type of cancer it is. We could not cover every single specific thing about every cancer, although it is a pretty long guideline and there is a lot of nuance in there. So you might find a lot about specific cancers. And I think that that will be very, very helpful for people who are faced with this situation in the clinics just to frame it out, think through. Sometimes there is no answer that is the perfect answer and then, you know, using this as kind of a scaffolding and phoning a friend who may have more experience to help guide you and guide the patient, most importantly. I think it will be very helpful in that regard.

Dr. Alison Loren: Yeah, I think so too. And I have talked about that we are working on this guideline and the anecdotal feedback has been, "This is so helpful." Like there really has not been, I think, an all-in-one place, diagnostic considerations, radiographic considerations, staging, treatment, all the modalities, surgical, radiation, systemic chemotherapy. We tried to include, when we could, novel agents including targeted agents and monoclonal antibodies and bispecifics and cellular immunotherapies and non-cellular immunotherapies. We really, really tried to cover in 2025 what are people using to treat cancer and to try to give the most balanced view of what we think is is safe or reasonably safe and what we think is either unproven or known to be risky, really to have it be kind of a go-to, like all-in-one, as much information as we have about these really challenging cases. We tried to include, Ann mentioned, you know, specific cancers, and I think when there were specific things to shout out with specific cancers, we really tried to highlight that. Like, "Okay, lots of young patients with cancer have Hodgkin's lymphoma, so what is safe and what is not for that specific case?" Or, "What is safe or what is not when you are thinking about colon cancers?" And we have a shout-out in here about considering checking for DPD deficiencies in patients who are pregnant. And I know it is generally recommended nowadays, but certainly for people who are pregnant, you know, you really want to avoid excess toxicity. So I think just really trying to be attentive to specifics about certain cancers in young patients and what would be valuable for a practicing oncologist and obstetrician to know when you are faced with this situation.

Dr. Ann Partridge: Yeah, and I think the other critical thing that is great about this guideline is it's a starting place. And I anticipate that we will be building on this guideline for many years to come. And remember that when first, I was not around then, but probably three or four decades ago, when chemotherapy was just coming out and patients were coming in pregnant, there was a feeling I am sure that was, "We cannot give this to this person because it is purposefully going to destroy cells. And when you destroy cells in a growing fetus, you are going to destroy or harm that fetus." And yet, people did not have great choices. It was get treated or die, especially with things like leukemia early on. And bold patients along with their oncologist said, "Bring it on." And that is how some of this literature has been born. And so moving forward, there will be either purposeful exposures or inadvertent exposures of some of our therapies where we will learn ultimately. And this is a place where we can update these guidelines. That is the beautiful thing about the ASCO guidelines is that they are constantly being thought about to be updated. And then when there is enough of a change in practice, they will be updated such that they will continue to inform how we do this in the years to come for patients who come in pregnant.

Dr. Allison Loren: Yeah, and I will say I have been doing this long enough now, we were just talking about a different guideline, the fertility guideline earlier today, and over the 20 years that the fertility guidelines have been out, just the amount of research has really skyrocketed. And you can see as you look at each guideline how much we have learned, what we can say, "Yes, this is working," "No, this is not working." Like, it is stuff that we used to say, "Oh, we do not really know," and now we have answers.

I think I speak for both of us when I say that we are hopeful that this will serve as, as Ann said, as a starting off point and really inspire people to ask the questions and do the research so that we can give better guidance moving forward, really trying to think about, you know, mechanisms and leaning on our colleagues in pharma and in the government who sort of think about safety and efficacy, to sort of make sure that they are contemplating not just non-pregnant patients, but also pregnant patients or as they are thinking about marking the package inserts with safety guidelines around this.

Brittany Harvey: Yes, this is a critically important first guideline on the management of cancer during pregnancy, and we will look forward to continuing to build on that. I think as you mentioned, this guideline is far-reaching and has a lot of recommendations in it. And so both the full text of the guideline and those at-a-glance algorithms, figures, and tables will be really useful for clinicians in their clinic.

Finally, to wrap us up, we have just been discussing this a little bit, but specifically, what are the outstanding questions on the management of pregnant patients with cancer, and where is this further research needed?

Dr. Alison Loren: There are lots and lots and lots of unanswered questions. And I think if you look at the table, most of what we say is, "We are pretty sure this is okay, we are not so sure about this." I am paraphrasing, but we really just are operating in a paucity of what we would normally consider gold-standard evidence. It is hard to imagine, of course, there would ever be, as we mentioned in the beginning, randomized trials. But I think that preclinical data, mechanistic data, trying to think about including as we go through animal data, making sure that we are looking at female animals and pregnant animals so that we can sort of fully understand what the impact may be. And then I think thinking about more localized therapies around sort of radiation, you know, we are now moving into really hyper-focused radiation treatments like protons. Is that better because there is less scatter? Like I think those are real considerations that we just do not know the answer to.

What do you think?

Dr. Ann Partridge: I think so many unanswered questions, and this is a call to action to continue to and increase the documentation of the experiences and outcomes for patients diagnosed during pregnancy.

Dr. Alison Loren: Yeah, and I think the long-term outcomes too are really going to be critical.

Brittany Harvey: Yes, we will look forward to learning about more evidence across the spectrum of care to inform future updates to this guideline.

So I want to thank you both so much for your work to develop this guideline, to review the extensive amounts of literature that you did, and work to create this guideline. And thank you also for your time today, Dr. Loren and Dr. Partridge.

Dr. Alison Loren: Thanks. It was fun.

Dr. Ann Partridge: Yeah, thank you.

Brittany Harvey: And finally, thank you to all of our listeners for tuning into the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Tanya Thomas and Dr. Aparna Jotwani join the podcast to discuss the new Oncology Nursing Society and American Society of Clinical Oncology evidence-based guideline on the management of antineoplastic extravasation. They discuss recommendations from the expert panel on: management of extravasation of vesicant or irritant with vesicant properties antineoplastic agents, management of extravasation of paclitaxel or docetaxel, use & duration of thermal compress, and escalation of care. They share the importance of this comprehensive interdisciplinary guideline, highlight the algorithm as a useful tool for clinicians, and outline the outstanding questions related to the management of extravasation. Read the full guideline, "ONS/ASCO Guideline on the Management of Antineoplastic Extravasation" at www.asco.org/supportive-care-guidelines

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP-25-00579

My name is Brittany Harvey, and today I'm interviewing Dr. Tanya Thomas, clinical chair of the guideline and clinical nurse specialist from University of Virginia Health, and Dr. Aparna Jotwani, medical oncologist from Baylor College of Medicine, authors on "Management of Antineoplastic Extravasation: Oncology Nursing Society – American Society of Clinical Oncology Guideline." Thank you for being here today, Dr. Thomas and Dr. Jotwani.

Dr. Aparna Jotwani: Thank you.

Dr. Tanya Thomas: Thank you for having us.

Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Thomas and Dr. Jotwani, who have joined us here today, are available online with the publication of the guideline in JCO Oncology Practice, which is linked in the show notes.

So then to dive into the content here, Dr. Thomas, could you start us off by providing an overview of both the scope and the objectives of this guideline?

Dr. Tanya Thomas: Yes, so the objective of this guideline is to provide the evidence-based recommendations to help support our interdisciplinary teams, including the oncologist, the advanced practice providers, pharmacists, and nurses who are involved in the care and management of patients who are experiencing an extravasation of an antineoplastic agent. While rare, the antineoplastic and certain chemotherapy extravasations are oncologic emergencies. The recommendations are to minimize negative consequences and provide a standardized approach to the care when such an event occurs.

Dr. Aparna Jotwani: I would add that our scope is limited to intravenous antineoplastic vesicants, irritants, and irritants with vesicant potential. The scope of the guideline applies to the care team for adult oncology patients receiving treatments through venous access. Outside the scope is management of extravasation during other routes of treatment administration, such as intraperitoneal, intravesical, and hepatic arterial infusion. Our recommendations regarding vascular access for therapy or interventions to prevent extravasations are also outside of the scope for this guideline.

Brittany Harvey: Understood. I appreciate that background and understanding what's in scope and what's out of scope for this guideline.

So then I'd like to pivot and talk about the key recommendations of this guideline across the clinical questions. So first, Dr. Jotwani, what does the panel recommend for patients with extravasation of vesicant or irritant with vesicant properties antineoplastic agents?

Dr. Aparna Jotwani: The panel strongly recommends for all classes where an antidote exists to proceed with using the antidote. Recommendations for paclitaxel and docetaxel are specifically addressed in a recommendation. This is further detailed in Tables 1 and 4 within the guideline. Evidence on the use of antidotes for extravasation is limited to nonrandomized, uncontrolled, observational studies and case series. Placebo-controlled trials on this topic would be unethical. There is also a lack of comparative data for different antidote strategies. However, potential benefits of using the antidotes include tissue preservation and avoiding tissue necrosis. In developing the guidelines, we had an in-person roundtable discussion and weighed risks and benefits to ensure patient safety above all else.

Brittany Harvey: I appreciate that description of the recommendation here. So then you just mentioned that there's a specific recommendation for paclitaxel and docetaxel. So what is recommended for those patients with extravasation of paclitaxel or docetaxel?

Dr. Aparna Jotwani: So here, we conditionally recommended the specific use of hyaluronidase as the antidote. This was based on five studies that all used hyaluronidase as an antidote to lower the risk of tissue necrosis. In the studies included, with a subgroup of patients that experienced taxane-related extravasation, development of necrosis ranged from 0% to 0.83% among the patients who received an antidote. The potential harms associated with this were likely trivial.

Brittany Harvey: Thank you for providing that recommendation as well.

So then the next section of the guideline, Dr. Thomas, what does the expert panel recommend for use and duration of thermal compress?

Dr. Tanya Thomas: So the expert panel actually recommends the use of thermal compresses, and the recommendations are based on the available literature for the various agents and the actual time frames most frequently used for the compress application. The utilization of a thermal compress is recommended for 15 to 20 minutes at a time for 3 to 4 times daily, at least for the first 48 to 72 hours after that extravasation occurs. The actual frequency and duration may vary based on the extent of the extravasation and the agent involved in that extravasation. The intent of the warm compress is to help disperse the agent and reduce the localized accumulation of the agent, whereas the cold compress, it actually helps prevent the dispersion or the spread of the agent while allowing the antidote to help neutralize that agent.

Warm compresses are recommended for extravasations involving the vinca alkaloids, etoposide, oxaliplatin, and the taxanes - paclitaxel and docetaxel - only when coadministering the antidote hyaluronidase. The use of a cold compress is actually recommended for extravasations involving the anthracyclines, antimetabolites, alkylating agents, and taxanes when coadministration of the antidote hyaluronidase does not occur.

Brittany Harvey: Understood. Those specific and actionable recommendations are really key for clinical practice.

So then, following those recommendations, how does the guideline address escalation of care and surgical referral for patients with central line extravasation?

Dr. Tanya Thomas: So this topic actually had a lot of discussion. And while there is not enough evidence to make strong recommendations, the expert panel recognized that surgical referrals should be considered in certain scenarios.

Dr. Aparna Jotwani: We discussed that certain scenarios would include high-risk populations, such as patients that are receiving DNA-binding vesicants, those with high-volume estimated extravasation, and those with CTCAE grade 2, which would be erythema associated with symptoms such as edema, pain, induration, and phlebitis, or grade 3, which would be symptoms of ulceration or necrosis or concern for severe tissue damage, or grade 4, where you would have a life-threatening consequence extravasation, may have a greater likelihood of benefiting from surgical referral and/or escalation of care as deemed appropriate.

Brittany Harvey: Great. And yes, it's really important to provide all of these recommendations that you've both just gone through, even when we're faced with very low evidence.

So then, Dr. Thomas, in your view, what is the importance of this guideline, and how will it impact clinical practice?

Dr. Tanya Thomas: So when extravasations occur in the clinical setting, members of the interdisciplinary team can be faced with barriers related to where to look for the information, how to find all the relevant information in one concise place, how to provide education to the patient about how to care for the site of extravasation in the home setting, and also when to escalate to specialized teams. This can actually cause some added stress and anxiety, and in certain circumstances, may lead to delays in efficient management.

This guideline provides the resource clinicians have been looking for. It includes comprehensive recommendations for antineoplastic extravasations in one guideline while also providing a one-page algorithm with the key information regarding the management of the extravasations. This allows all levels of providers to have evidence-based recommendations regarding initial management of the extravasation, for instance, how to manage the infusion, key site assessment reminders, available antidotes, and the use of thermal compress; the required documentation, recommended follow-up scheduling, in addition to key aspects of the patient education. This type of guidance is not found in any other single document regarding antineoplastic extravasation. Having this document readily available at the point of care potentially can reduce time required for providers to search for management recommendations and also provide consistency in patient education and follow-up management scheduling. It reduces uncertainty within interdisciplinary teams and can help inform policy development for clinicians to approach extravasations with confidence.

Brittany Harvey: Absolutely. I agree that this is an incredible resource for clinicians with the recommendations, the algorithm that you mentioned, and the supporting evidence that underpins these recommendations to really provide both efficient and effective care for patients.

So beyond the impact for clinical practice, Dr. Jotwani, how will these guideline recommendations affect patients receiving antineoplastic treatment for cancer?

Dr. Aparna Jotwani: Exactly. In addition to the clinical care team, we want to help and benefit our patients. So, oncology patients that experience extravasations are at risk for, aside of the side effects of tissue necrosis and infection, they also are at risk for delay of cancer treatment. In making these guidelines, we kept in mind the cost and the efforts for patients, additional visits that they could incur, additional time and supplies for care of the extravasation, as well as cost. Our guideline aims to provide an evidence-based approach to the care of oncology patients receiving antineoplastic intravenous therapy. While there are gaps in the data due to the nature of these events, based on careful literature review, these guidelines serve as a basis for quality, standardized oncology care during extravasation. Personally, I hope our graphics especially can be used across the systems to guide clinical care.

Brittany Harvey: Definitely. We hope that these recommendations improve treatment and treatment outcomes for all patients receiving antineoplastic treatment for cancer.

So then you've also just mentioned some gaps in the literature. So Dr. Thomas, I'd like to turn to you to wrap us up and ask, what are the outstanding questions for the management of antineoplastic extravasation?

Dr. Tanya Thomas: Yes, that's a good question. Two of the main outstanding questions are related to the management of extravasations involving the novel agents and extravasations involving multi-agent regimens. The current literature regarding how to effectively manage the multi-agent regimens, for instance, there is no clear guidance for managing the extravasation for someone who is receiving a regimen that involves simultaneous administration of, let's say, a vinca alkaloid and an anthracycline. One of those agents requires a warm compress while the other requires a cold compress, and there are different antidotes for those two agents.

Additionally, there has not been a lot of published information on the impact of extravasation of those novel agents like the antibody-drug conjugates. With the pace of the drug development, a subgroup of the guideline panelists actually are exploring case reports specific to novel agents to help inform some future work.

Brittany Harvey: Yes, we'll look forward to learning more about how to address these ongoing issues and potentially impact guideline recommendations in the future as well.

So I want to thank you both so much for your work to develop this incredibly important guideline, and thank you for your time today, Dr. Thomas and Dr. Jotwani.

Dr. Aparna Jotwani: Thank you for the opportunity.

Dr. Tanya Thomas: Yes, thank you.

Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. I also encourage you to check out the companion episode on this guideline on the ONS podcast, available on Amazon Music, Apple Podcasts, Spotify, and YouTube Music.

And finally, you can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Kathleen Horst, Dr. Rachel Jimenez, and Dr. Yara Abdou discuss the updated guideline from ASTRO, ASCO, and SSO on postmastectomy radiation therapy. They share new and updated recommendations on topics including PMRT after upfront surgery, PMRT after neoadjuvant systemic therapy, dose and fractionation schedules, and delivery techniques. They comment on the importance of a multidisciplinary approach and providing personalized care based on individual patient characteristics. Finally, they review ongoing research that may impact these evidence-based guidelines in the future. Read the full guideline, "Postmastectomy Radiation Therapy: An ASTRO-ASCO-SSO Clinical Practice Guideline" at www.asco.org/breast-cancer-guidelines"

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-01747

My name is Brittany Harvey, and today I am interviewing Dr. Kathleen Horst, expert panel chair from Stanford University; Dr. Rachel Jimenez, expert panel vice chair from Massachusetts General Hospital; and Dr. Yara Abdou, ASCO representative from the University of North Carolina, authors on "Postmastectomy Radiation Therapy: An American Society for Radiation Oncology, American Society of Clinical Oncology, and Society of Surgical Oncology Clinical Practice Guideline." Thank you for being here today, Dr. Horst, Dr. Jimenez, and Dr. Abdou.

Dr. Kathleen Horst: Thank you for having us.

Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Horst, Dr. Jimenez, and Dr. Abdou who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

Then to dive into the content that we are here today to talk about, Dr. Horst, could you start us off by describing what prompted the update for this joint guideline between ASTRO, ASCO, and SSO, and what is the scope of this 2025 guideline on postmastectomy radiation therapy?

Dr. Kathleen Horst: Thank you. This joint guideline was last updated in 2016. Over the past decade, the treatment of breast cancer has evolved substantially. Newer systemic therapy regimens have increasingly personalized treatment based on tumor biology, and local therapy management has explored both the de-escalation of axillary surgery and more abbreviated courses of radiation therapy. Given these advances, it was important to revisit the role of postmastectomy radiotherapy in this modern era of breast cancer therapy.

This updated guideline addresses four key questions, including postmastectomy radiation therapy after upfront surgery as well as after neoadjuvant systemic therapy. It also reviews the evolving role of various dose and fractionation schedules and optimal treatment techniques and dose constraints.

Brittany Harvey: Excellent. I appreciate that background, Dr. Horst. So then, next, Dr. Jimenez, I would like to review the recommendations of this guideline across those four key questions that Dr. Horst just mentioned. So first, what does the panel recommend for PMRT for patients who received initial treatment with mastectomy?

Dr. Rachel Jimenez: The panel provided pretty strong consensus that patients with positive lymph nodes or patients with large tumors involving the skin or the chest wall should receive postmastectomy radiation. However, the panel also recognized that the omission of postmastectomy radiation may be appropriate for select patients who have positive lymph nodes and have an axillary lymph node dissection if they have a low nodal burden and other favorable clinical or pathologic features. For patients without lymph node involvement at the time of surgery and no involvement of the skin or chest wall, postmastectomy radiation was not advised by the panel.

Brittany Harvey: Understood. It is helpful to understand those recommendations for that patient population. Following that, Dr. Abdou, what are the key recommendations for PMRT for patients who received neoadjuvant systemic therapy before mastectomy?

Dr. Yara Abdou: When we think about PMRT after neoadjuvant treatment, the key point is that the initial stage of presentation still matters a lot. So for example, if a patient comes in with more advanced disease, say a large primary tumor, like a clinical T4, or more extensive nodal disease, like an N2 or N3 disease, those patients should get PMRT, no matter how well they respond to neoadjuvant therapy, because we know it reduces the risk of recurrence and that has been shown pretty consistently.

On the other hand, if there are still positive lymph nodes after neoadjuvant treatment, basically residual nodal disease, PMRT is also strongly recommended because the risk of local-regional recurrence is much higher in that setting. The gray area is the group of patients who start with a lower burden of nodal disease, such as N1 disease, but then become node negative at surgery. For those patients, we tend to individualize the decision. So if the patient is young or has triple-negative disease, or if there is a lot of residual disease in the breast even though the nodes are cleared, then radiation is probably helpful. But if everything has melted away with pCR in both the breast and the nodes, then it may be safe to omit PMRT in those patients.

For patients with smaller tumors and no nodal involvement to begin with, like a clinical T1-T2 N0, if they are still node negative after neoadjuvant treatment, then PMRT is generally not recommended because their baseline recurrence risk is low.

And finally, if the margins are positive and cannot be re-excised, then PMRT is recommended after neoadjuvant therapy.

Brittany Harvey: Yes, those distinctions are important for appropriate patient selection.

So then, Dr. Horst, we have just reviewed the indications for PMRT, but for those patients who receive PMRT, what are the appropriate treatment volumes and dose fractionation regimens?

Dr. Kathleen Horst: The guideline addresses coverage of the chest wall and regional nodes with a specific discussion of the data regarding internal mammary nodal irradiation, which has been an area of controversy over many years. The guideline also reviews the data exploring moderate hypofractionation, or shorter courses of radiation therapy. The task force recommends utilizing moderate hypofractionation for the majority of women requiring postmastectomy radiation, which is likely to have a large impact on clinical practice. This recommendation is based on the evolving data demonstrating that a 3-week course of radiotherapy after mastectomy provides similar oncologic outcomes and minimal toxicity for most patients compared to the standard 5-week treatment course.

Brittany Harvey: Thank you for reviewing that set of recommendations as well.

So then, Dr. Jimenez, to wrap us up on the key questions here, what delivery techniques are recommended for treating patients who receive PMRT?

Dr. Rachel Jimenez: So this portion of the guideline is likely to be most helpful for radiation oncologists because it represents the most technical part of the guideline, but we do believe that it offers some important guidance that has, to this point, been lacking in the postmastectomy radiation setting.

So first, the panel recommends that all patients should undergo 3-dimensional radiation planning using CAT scan based imaging, and this includes contouring. So contouring refers to the explicit identification, using a drawing interface on the CAT scan imaging, by the radiation oncologist to identify the areas that are targeted to receive radiation, as well as all of the nearby normal tissues that could receive unintended radiation exposure. And we also provide radiation oncologists in the guideline with suggestions about how much dose each target tissue should receive and what the dose limits should be for normal tissues.

Additionally, we make some recommendations regarding the manner in which radiation is delivered. So for example, we advise that when conventional radiation methods are not sufficient for covering the areas of the body that are still at risk for cancer, or where too high of a dose of radiation would be anticipated to a normal part of the body, that providers employ a technique called intensity modulated radiation therapy, or IMRT. And if IMRT is going to be used, we also advise regular 3-dimensional imaging assessments of the patient's body relative to the treatment machine to ensure treatment fidelity.

When the treatments are delivered, we further advise using a deep inspiration breath-hold technique, which lowers the exposure to the heart and to the lungs when there is concern for cardiopulmonary radiation exposure, and again, that image guidance be used along with real-time monitoring of the patient's anatomy when those techniques are employed.

And then finally, we advise that patients receiving postmastectomy radiation utilize a bolus, or a synthetic substance placed on the patient's skin to enhance radiation dose to the superficial tissue, only when there is involvement of the skin with cancer or other high-risk features of the cancer, but not for every patient who receives postmastectomy radiation.

Brittany Harvey: Understood. And then, yes, you just mentioned that section of the guideline is probably most helpful for radiation oncologists, but I think you can all comment on this next question. What should all clinicians, including radiation oncologists, surgical oncologists, medical oncologists, and other oncologic professionals, know as they implement all of these updated recommendations?

Dr. Rachel Jimenez: So I think one of the things that is most important when we consider postmastectomy radiation and making recommendations is that this is a multidisciplinary panel and that we would expect and encourage our colleagues, as they interpret the guidelines, to employ a multidisciplinary approach when they are discussing each individual patient with their surgical and medical oncology colleagues, that there is no one size fits all. So these guidelines are intended to provide some general guidance around the most appropriate techniques and approaches and recommendations for the utilization of postmastectomy radiation, but that we recognize that all of these recommendations should be individualized for patients and also represent somewhat of a moving target as additional studies, both in the surgical and radiation oncology realm as well as in the systemic therapy realm, enter our milieu, we have to adjust those recommendations accordingly.

Dr. Kathleen Horst: Yeah, I would agree, and I wanted to comment as a radiation oncologist, we recognize that local-regional considerations are intertwined with systemic therapy considerations. So as the data evolve, it is critical to have these ongoing updates in a cross-disciplinary manner to ensure optimal care for our patients. And as Dr. Jimenez mentioned, these multidisciplinary discussions are critical for all of us to continue to learn and understand the evolving recommendations across disciplines but also to individualize them according to individual patients.

Dr. Yara Abdou: I could not agree more. I think from a medical oncology perspective, systemic therapy has gotten much better with adjuvant CDK4/6 inhibitors, T-DM1, capecitabine, and immune therapy. So these are all newer adjuvant therapies, so the baseline recurrence risks are lower than what they were in the trials that established PMRT. So the absolute benefit of radiation varies more now, so smaller for favorable biology but still relevant in aggressive subtypes or with residual disease. So it is definitely not a one-size-fits-all.

Brittany Harvey: Yes, I think it is important that you have all highlighted that multidisciplinary approach and having individualized, patient-centric care.

So then, expanding on that just a little bit, Dr. Abdou, how will these guideline recommendations affect patients with breast cancer?

Dr. Yara Abdou: So basically, reiterating what we just talked about, these guidelines really move us towards personalized care. So for patients at higher risk, so those with larger tumors, multiple positive nodes, or residual nodal disease after neoadjuvant therapy, PMRT remains essential, consistently lowering local-regional recurrence and improving survival.

But for patients at intermediate or lower risk, the recommendations support a more selective approach. So instead of a blanket rule, we now integrate tumor biology, response to systemic therapy, and individual patient factors to decide when PMRT adds meaningful benefit. So the impact for patients is really important because those at high risk continue to get the survival advantage of radiation while others can be spared the unnecessary treatment and side effects. So in short, we are aligning PMRT with modern systemic therapy and biology, making sure each patient receives the right treatment for their situation.

Brittany Harvey: Absolutely. Individualizing treatment to every patient will make sure that everyone can achieve the best outcomes as possible.

So then, Dr. Jimenez, to wrap us up, I believe Dr. Horst mentioned earlier that data continues to evolve in this field. So in your opinion, what are the outstanding questions regarding the use of PMRT and what are you looking to for the future of research in this space?

Dr. Rachel Jimenez: So there are a number of randomized phase III clinical trials that are either in active accrual or that have reported but not yet published that are exploring further de-escalation of postmastectomy radiation and of axillary surgery. And so we do not yet have sufficient data to understand how those two pieces of information integrate with each other. So for example, if you have a patient who has a positive lymph node at the time of diagnosis and forgoes axillary surgery aside from a sentinel lymph node biopsy, we do not yet know that we can also safely forgo radiation entirely in that setting. So we expect that future studies are going to address these questions and understand when it is appropriate to simultaneously de-escalate surgery and radiation.

Additionally, there is a number of trials that are looking at ways in which radiation could be omitted or shortened. So there is the RT CHARM trial, which has reported but not yet published, looking at a shorter course of radiation. And so we do make recommendations around that shorter course of radiation in this guideline, but we anticipate that the additional data from the RT CHARM study will provide further evidence in support of that.

Additionally, there is a study called the TAILOR RT trial, which looks at forgoing postmastectomy radiation in patients who, to Dr. Abdou's point, have a favorable tumor biology and a low 21-gene recurrence score. And so we are going to anticipate the results from that study to help guide who can selectively forgo postmastectomy radiation when they fall into that favorable risk category.

So there are a number of questions that I think will help flesh out this guideline. And as they publish, we will likely publish a focused update on that information to help provide context for our colleagues in the field and clarify some of these recommendations to suit the latest data.

Brittany Harvey: Absolutely. We will look forward to those de-escalation trials and ongoing research in the field to build on the evidence and look for future updates to this guideline.

So I want to thank you for your work to update these guidelines, and thank you for your time today, Dr. Horst, Dr. Jimenez, and Dr. Abdou.

Dr. Rachel Jimenez: Thank you.

Dr. Yara Abdou: Thank you.

Dr. Kathleen Horst: Thank you.

Brittany Harvey: And then finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Cris Bergerot and Dr. Enrique Soto join the podcast to discuss the new global guideline on geriatric assessment. This guideline provides evidence-based, resource-stratified recommendations across the basic, limited, and enhanced settings. Dr. Bergerot and Dr. Soto discuss who should receive a geriatric assessment, the role of geriatric assessment, which elements of geriatric assessment can help predict adverse outcomes, and how a geriatric assessment is used to guide care and make treatment decisions. They comment on the importance of this guideline worldwide, and the impact of this guideline for a wide range of clinicians, patients, researchers, policymakers, and health administrators. Read the full guideline, "Geriatric Assessment: ASCO Global Guideline" at www.asco.org/global-guidelines."

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/global-guidelines. Read the full text of the guideline, view clinical tools and resources, and review authors' disclosures of potential conflicts of interest in the JCO Global Oncology, https://ascopubs.org/doi/10.1200/GO-25-00276

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Cris Bergerot from OncoClínicas & Co and Dr. Enrique Soto from the University of Colorado, co-chairs on "Geriatric Assessment: ASCO Global Guideline".

Thank you for being here today, Dr. Bergerot and Dr. Soto.

Dr. Cris Bergerot: Thank you.

Dr. Enrique Soto: Thanks for the invitation, Brittany.

Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bergerot and Dr. Soto who have joined us here today, are available online with the publication of the guideline in JCO Global Oncology, which is linked in the show notes.

So then to jump into the guideline here, Dr. Soto, could you start by providing an overview of the scope and the purpose of this global guideline on geriatric assessment?

Dr. Enrique Soto: Of course, Brittany. So, this guideline comes from a request from the global oncology community and from the geriatric oncology community, who is very interested in making sure that geriatric oncology recommendations that are used in the United States can be adopted and used globally. So, this was a very highly rated topic when we had our call for proposals for guidelines, and that's why we decided to do this.

The idea of this guideline is to provide resource-stratified recommendations for the use of geriatric assessments and interventions in older adults with cancer across different settings, right? And that these guidelines can be applied by clinicians working in low- and middle-income countries, but also, in a way, by clinicians working in community settings where the availability of resources may be limited. And the idea of these recommendations is to help clinicians evaluate older people with cancer better and also understand which interventions can be implemented with the resources they have and which interventions have a bigger bang for the buck, so to speak.

And as all evidence-based, stratified guidelines that ASCO conducts, we stratified resources as basic, limited, or enhanced. And that means resources that go from those that provide the greatest benefits for patients in terms of outcomes to those that are evidence-based but provide additional additive benefits. And those resource-stratified recommendations can be found in the ASCO website as to how these guidelines are developed, and that's pretty standard for most resource-stratified guidelines.

Brittany Harvey: Great. I appreciate that background and the impetus for this guideline, and thank you for providing that resource-stratified framework of basic, limited, and enhanced. I think that helps provide context for the guideline recommendations here.

So then, Dr. Bergerot, I'd like to next review the key recommendations of this guideline across the four clinical questions that the guideline addresses. So, across those settings, the basic, limited, and enhanced settings, what is the role of geriatric assessment in older adults with cancer to inform specific interventions?

Dr. Cris Bergerot: I think this is one of the most important points, so let's break it down. First off, who should actually receive the geriatric assessment? And the recommendation is clear. All patients aged 65 and older who are being considered for systemic cancer therapy should undergo a geriatric assessment. Now, depending on the available resources, for example, in basic setting, a quick screening may be enough, but in enhanced setting, a comprehensive geriatric assessment is encouraged.

And for our next question, in which elements of the geriatric assessment can help predict poor outcomes, the core domains to focus on include things like physical function, comorbidities, polypharmacy, cognition, nutrition, social support, and psychological health. And there are also validate tools like the G8, the CGA, and the CARG that can be used depending on the setting and resources available.

Now, talking about how we actually use the geriatric assessment to guide care, the assessment results can guide interventions to reduce treatment-related toxicities and maintain the patient functions. So, even in basic settings, the result can help guide those adjustments or identify the need for supportive care. And in more resource settings, we can implement more tailored intervention based on those findings.

And finally, for our fourth question: How can geriatric assessment help guide treatment decisions? So, GA can influence decisions about how aggressive treatment should be, help clarify goals of care, and determine whether a curative or palliative approach makes the most sense. And again, even in settings with limited resources, a simplified GA can still provide meaningful guidance.

Brittany Harvey: Great. Thank you, Dr. Bergerot, for that high-level overview of the recommendations of this guideline.

So then, following that, Dr. Soto, which geriatric assessment tools and elements should clinicians use to predict adverse outcomes for older patients receiving systemic therapy across the basic, limited, and enhanced settings?

Dr. Enrique Soto: Yeah, so that is an excellent question because it's something that people want to know, right? When people start developing a geriatric oncology clinic, one of the first things they want to know is which tools should I use. And we hope that this guideline will provide some clarity regarding this. So, our overarching recommendation is that every patient, regardless of the level of resources, should receive some sort of geriatric assessment. And that geriatric assessment can go from a simple screening tool, such as the G8 tool, which is available online and very easy to do, and that can be done in basic settings, to a more sophisticated geriatric assessment.

The important thing, and what we emphasize in the guideline, is that regardless of the tool you use, it should include those high-priority domains that are associated with outcomes in older adults with cancer. And those include an assessment of physical function, of cognition, emotional health, comorbidities, polypharmacy, nutrition, and social support. In addition to that, an important thing that the guideline does is endorse the recommendation from our parent guideline, the guideline from high-income settings, the practical geriatric assessment, which is a tool that was actually developed by the ASCO Geriatric Oncology Group, which is a self-administered tool that people can use to evaluate their patients in a prompt and fast manner. And what we actually did for this guideline is include the validation of the various tools included in the practical geriatric assessment in the five most widely spoken languages in the world, including Hindi, Chinese, Spanish, and French, and Portuguese. And so, most of these tools are validated in these languages.

So, we believe that the practical geriatric assessment is a tool that can be utilized across settings and that doesn't require a lot of resources. I think an important future step is making sure that we get the practical geriatric assessment translated into various languages, and we're working with the ASCO team in getting that done.

Brittany Harvey: That's an excellent point. And yes, we'll hope to have the practical geriatric assessment translated into more languages. And that tool is available linked in the guideline itself, and we'll also provide a link for listeners in the show notes of this episode (Practical Geriatric Assessment).

So then, following that, Dr. Bergerot, in resource-constrained settings, what general life expectancy data should clinicians use to estimate mortality and inform treatment decision-making?

Dr. Cris Bergerot: So, in basic and limited resource environments, you might not have access to every tool or specialist, but you can still make informed and thoughtful decisions. So, what the guideline recommends is to start with population-level life expectancy tables. These are available through the WHO Global Health Observatory, and they offer useful starting points. And if available, clinicians should also look for country-specific or regional survival data. That kind of local information can be even more relevant to your patient population. The clinical judgment is also key here, and it becomes even more powerful when it's guided by the patient's geriatric assessment results. And when possible, use age- and comorbidity-adjusted models, like the Lee index or tools from the ePrognosis. This can help refine estimates of mortality risk and also inform how aggressive treatment should be.

Brittany Harvey: Absolutely. I appreciate you providing those specifics as well.

So then, following that, Dr. Bergerot mentioned this a little bit earlier, but Dr. Soto, how should geriatric assessment be used to guide management of older patients with cancer across the basic, limited, and enhanced settings?

Dr. Enrique Soto: Yeah, and again, that's another important focus, right? Because if we assess things and then don't do anything about them, then why even assess them, right? And in many settings, people say, "Well, I don't have the tools to provide the interventions that these patients actually need." And a very significant part of building this guideline was coming up with a resource-stratified and evidence-based way in which to prioritize which interventions provide most benefits for older adults with cancer. And so, for each level and each domain, we have a series of interventions that have been stratified according to importance and evidence base, and that is actually one of the coolest features of the guideline. We included a table, and then we have for each of the domains, including falls, functional status, weight loss, et cetera, what are the interventions that oncologists can do in their clinical visit without needing a lot of resources, including providing some specific information, giving some recommendations to patients, to more high-level things that can be done when the healthcare system allows it, such as working with a nutritionist, providing supplements, testing for particular cognitive impairments, et cetera. So, I encourage people to take a look at that table. It was really a lot of work putting that table together, and that table has specific recommendations for each setting, and I think people will find it very useful.

Brittany Harvey: Absolutely. That table certainly contains a lot of information that's very helpful for clinicians. I think it's important to call out those tailored interventions to improve care and quality of life for every patient.

So then, we've just reviewed all of the recommendations in this guideline. So, I'd like to ask you, Dr. Bergerot, in your opinion, what should clinicians know as they implement these recommendations across resource levels?

Dr. Cris Bergerot: I would say that clinicians should remember that even a brief geriatric assessment can make a meaningful difference. You don't need a full suite of tools to improve quality of care, but clinicians should tailor all the tools that are available in their local context and always keeping in mind the core geriatric domains that we have mentioned in the very beginning of our podcast.

And let's be clear, the goal of the assessment isn't just to gather data, as Enrique mentioned; it's to use this information to guide treatment decision and also to improve outcomes. And whenever possible, clinicians should engage interdisciplinary teams that might include nurse, psychologist, social workers, community health workers, or anyone who can help address the patient's broader needs. And flexibility really matters. So, especially in settings with limited access to specialists or diagnostics, we should prioritize what is feasible and what will truly help our patients during their journey. And above all, we should keep this in mind that equity in care delivery is essential. Just because resources are limited doesn't mean we can't deliver age-sensitive and even patient-centered care.

Brittany Harvey: Definitely. That multidisciplinary care that you mentioned is key, and also thinking about what is feasible across every resource level to provide optimal care for every single patient.

So then, to expand on that just a little bit and to wrap us up, Dr. Soto, what is the impact of this guideline for older adults with cancer globally?

Dr. Enrique Soto: Well, what we hope this guideline will lead to is to a boom in geriatric oncology worldwide, right? That is our final goal. And what we want is for clinicians interested in starting a geriatric oncology program or setting up a geriatric oncology clinic to use these guidelines in order to justify the interventions that they're going to do, to pick the important partners they need for their multidisciplinary team, to choose the tools that they're going to implement. And then, with that, to present this to leaders in their hospitals, leaders in their healthcare system so that they can start these clinics that will ultimately lead to better outcomes for older adults with cancer.

So, I encourage people to view this as high-quality, evidence-based recommendations that are done by a group of experts and with a thorough review of the literature and also based on our parent guidelines. The fact that these guidelines are resource-stratified does not by any mean signify that they're of less quality or that the recommendations that are included in those are not proven to improve outcomes, cancer-specific and also general outcomes, in older adults with cancer.

Another thing that I think these guidelines could do in the future is motivate researchers in low- and middle-income countries to fill in the gaps that we have identified in these guidelines. We've made it very clear across the guidelines where evidence is lacking. And I think that this should prompt researchers across the globe to start trying to fill in these gaps with high-quality research.

And finally, I also think that this is a call for policymakers, health administrators, and people interested in public health to start scaling up resources so that places with basic resources can eventually become places with more sophisticated resources. And I think this does not only apply to low- and middle-income countries, but also to community oncologists in the US who may be facing resource constraints. And I think that these guidelines can help them stratify and understand what things should be implemented first and how to scale up.

So yeah, that's the dream that with this guideline, more people will start implementing geriatric oncology around the globe and that ASCO will continue to be a leader in setting the stage for what should be done in geriatric oncology and for improving care to older adults with cancer, regardless of where they live.

Brittany Harvey: Absolutely. This guideline is wide-reaching and has important impacts worldwide.

So, I want to thank you both so much for the huge amount of work you took to develop this evidence-based guideline, and thank you for joining me on the podcast today, Dr. Bergerot and Dr. Soto.

Dr. Cris Bergerot: Thank you so much.

Dr. Enrique Soto: Thank you for the invitation. It was a pleasure.

Brittany Harvey: And finally, thank you to our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/global-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Ms. Kim Woofter and Dr. John Cox discuss the latest updates to the evidence-based standards on oncology medical homes developed by ASCO and COA. These standards serve as the basis for the ASCO Certified program. They share the new and revised standards around topics including the culture of safety and just culture in oncology practice, geriatric assessment and geriatric assessment-guided management, and multidisciplinary team management. They expand on the importance of these standards for clinicians and oncology practices to ensure every patient receives optimal care.

Read the complete standards, "Oncology Medical Homes: ASCO-Community Oncology Alliance Standards Update" at www.asco.org/standards.

TRANSCRIPT

These standards, clinical tools, and resources are available at www.asco.org/standards. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP-25-00498

My name is Brittany Harvey, and today I'm interviewing Ms. Kim Woofter, a registered nurse in practice leadership and administration from AC3 Inc in South Bend, Indiana, and Dr. John Cox, a medical oncologist and adjunct faculty member from UT Southwestern Medical Center in Dallas, Texas, co-chairs on "Oncology Medical Homes, American Society of Clinical Oncology – Community Oncology Alliance Standards." Thank you for being here today, Ms. Woofter and Dr. Cox.

Dr. John Cox: You bet.

Ms. Kim Woofter: Thank you.

Brittany Harvey: And then before we discuss these standards, I'd just like to note that ASCO takes great care in the development of its standards and ensuring that the ASCO Conflict of Interest Policy is followed for each guidance product. The disclosures of potential conflicts of interest for the expert panel, including Dr. Cox and Ms. Woofter, who have joined us here today, are available online with the publication of the standards in JCO Oncology Practice, which is linked in the show notes.

So then, to dive into what we're here today to talk about, Dr. Cox, could you start us off by explaining what prompted an update to these ASCO-COA standards and what the scope of this update is?

Dr. John Cox: Well, the ASCO-COA standards relative to defining and outlining Oncology Medical Home were initially published four or five years ago. At the time, we planned a regular update of the standards. So, in essence, this is a planned update. The whole program is built on the idea of continuous improvement. So, this update and future updates are prompted and defined by our literature, our science, the science of care delivery, and new developments and insights gained from studies and evaluations of care delivery methods, and informed by the practice. These standards are in place to underpin a program of care delivery by ASCO, the ASCO Certified, and as practices engage in this program, we are learning from them. The whole idea is to enlarge and improve how patients are cared for in practice.

Brittany Harvey: Absolutely. It's great to have this iterative process to continue to review the evidence and update these standards that form the basis for ASCO Certified.

So then, following that background, Ms. Woofter, I'd like to review the key points of the revised standards for our listeners. First, how do the revised standards address the culture of safety and just culture in oncology practice?

Ms. Kim Woofter: I think safety is of utmost importance to all of us. So let me say that first and foremost. And what we know in oncology is our QOPI standards already address safety in the infusion suite process. So, safe delivery of chemotherapy agents and antineoplastics. It also talked about near misses and medication errors - absolutely essential, for sure.

But what we need to do is look at a more systemic approach to safety because we know is processes throughout an organization they'll often cause you trouble. To do that, we know you need what we call a just culture, which is a very common term in today's workplace. But what it really means is it's a culture of open reporting of any potential for error, any potential for malfunction, and it can be in any place in the organization. So, what we are doing in our new standard is to say, look at your entire processes throughout the organization, and approach that in an open-minded way so that people don't feel scared to report things, and it's a really positive approach to intervening early and making sure that errors don't occur anywhere in the workplace.

Brittany Harvey: Taking that systemic approach to look at overarching processes seems really key to ensuring safety in oncology practices.

So then, the next new section, Dr. Cox, what are the new OMH standards surrounding geriatric assessment and geriatric assessment–guided management?

Dr. John Cox: This is a challenging update for our standards. As many folks in practice recognize, there is a deep literature on recognizing the geriatric population in oncology. Geriatric - those in my age group over age 60, 65 - make up the majority of cancer patients in this country. And yet, there are many aspects that should be taken into account as you address treatment decisions in this population.

ASCO's recognized this. There has been a guideline previously on geriatric assessment. It's been updated, and we really felt it's time that it be incorporated in any iteration of what oncology care delivery means, so, within the oncology medical home standards. In short, what the standard outlines is that practices that are using these standards, that are using this benchmark, should have a geriatric assessment for patients within the practice care and use that information to guide management. Now, the standard allows wide exploration of how practices meet this standard, but it really puts on the table that if an oncology practice in the United States, or anywhere in the world really, is adhering to a good practice, that they're going to include and recognize these assessments in practice.

Ms. Kim Woofter: I would like to add that this is a highly discussed and reviewed standard. Many of our community practices were concerned that they would have the time and manpower to perform this assessment. We all know it reduces toxicities if done appropriately at treatment planning, and so the outcomes are better. And we really left it to the practices to define how they're going to implement it, understanding that it will evolve to every single patient, but maybe day one, it was a step approach to be able to implement. So, I was really proud of the team that - the expert panel - that said, okay, let's step into this, but we do think it's essential.

Brittany Harvey: Absolutely. It's important to recognize that practices may have limited resources and time, and implementing it in the way that makes sense for them allows this to be a standard that can be used in practice. And it's great to have this geriatric assessment guideline integrated into these standards to improve care delivery. And we can provide a link to that guideline in the show notes of this episode as well (Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update).

So then, following that section of the standards, Ms. Woofter, how do the updated standards now address multidisciplinary team management?

Ms. Kim Woofter: Well, we address multidisciplinary team management in a more comprehensive way in the updated standard. We always thought that that was a critical piece when doing treatment planning, and we kind of highlighted it in a bigger way, understanding that not everybody has the same resources available at the time of treatment planning. And again, this was a much-discussed standard, in that that multidisciplinary team approach doesn't necessarily have to be in a tumor board or a prospective analysis of every case. It is actually a conversation between specialists, between the surgeon and pathologist and the medical oncologist. And we are saying, do what works for you, but we know that that team approach, every specialty coming to the table at time of treatment planning, truly provides better outcomes for our patients. And so we kind of reiterated that, understanding that again, it doesn't have to be a formal tumor board, but it has to be a dialogue between specialties. And we highlighted that again in the new standard.

Brittany Harvey: Open communication of all team members is really critical to providing optimal care.

Dr. Cox, I'd like to ask you, in your view, how will these updated standards impact both clinicians and oncology practices?

Dr. John Cox: Well, our whole goal with discussing a comprehensive care model for oncology practice is to have a benchmark, to have an iteration of what good oncology care delivery looks like. So, our hope is that practices, all practices, whether you're participating formally in ASCO Certified, the marquee quality program for ASCO, or if you are simply running a practice or a team within an academic environment or institutional environment, these standards are to apply across the board wherever oncology is practiced - that you can look at these standards as a benchmark and compare what you are doing in your practice and where are the gaps. So ideally, we drive improved care across the board.

You know, one thing I've learned over the last couple of years as ASCO Certified is getting spun up and using and implementing these standards, is practices are remarkably innovative. We've learned a lot by seeing how pilot practices have met the standards, and that's gone into informing how we can improve care delivery for all of our practices and, importantly, for the team members who are delivering this care. The fourth rail of burnout and the like is inefficiency that occurs in practice. And when you know you've got a good, spun-up, effective team, less burnout, less stress for practice. I hope clinicians and oncology practices will use this to help drive improvements in their care and gain insight into how they can approach practice problems in a better way.

Kim, you've been leading practices. I have to ask you, your thoughts in leaning into this question.

Ms. Kim Woofter: I think very well said, I will say that first. And what I love about this is for practice leaders who are new to our ecosystem, if you will, they need a playbook. It's "Where do I begin?" And Dr. Cox said it very well, no one does everything perfectly day one, but it's a step-by-step self-assessment approach to say, "How do I get to this gold standard?" I really love the standards because they are very comprehensive, everything from treatment planning to end of life. So it's the spectrum of the care we deliver in the oncology setting.

So as a leader and an administrator, it is the standard I want all of my departments to understand, adhere to, and engage, and be excited about. We now have a baseline approach, and what's even more important, these standards will evolve as our intelligence evolves, as literature evolves. It's a system that will always grow and change, and that's what we love about it. It's not a one-and-done. So, I'm very proud of the fact that it gives them a road map.

Brittany Harvey: Yes, these evidence-based standards provide a critical foundation for practices in ASCO Certified, for those team members you mentioned, and for quality improvement beyond just those individuals and practices as well.

So then finally, to wrap us up, Ms. Woofter, what do these revised standards mean for patients receiving cancer treatment?

Ms. Kim Woofter: Well, I think that's the most exciting part, is we all do this for our patients and the best outcomes for our patients and the best treatment plans for our patients and their families. And these standards, that is their core, their absolute core. So what it's going to do for a patient is they can say, "Am I at a practice that implements ASCO standards?" And if that is a 'yes', there's a confidence that, "I am in an evidence-based medicine thinking practice, I have a team around me, they will care for me not only at time of treatment planning but at the time of end of life, they will help me be part of that decision-making, and they will give me resources available to me in my community." So, it is a true comprehensive approach. As a patient, I have that comfort, that it is bigger than just a great doctor. It is a great team. As a patient, that would be very important to me and important to my family.

That being said, Kim Woofter would love every practice to be ASCO Certified. Understanding that that isn't feasible day one, just to know that the practice is implementing and engaging the standards is the great place to start. Every patient can't go to an ASCO Certified practice day one, but our dream would be that everyone would adhere to those standards, engage those standards, believe them, educate their staff on what they mean, so that patient outcomes and satisfaction will be optimized for everyone.

The other piece to this that we all know is if you give evidence-based medicine, cost-effective, efficient care, it's better for the system as a whole. And I'm not saying that insurance is our driver - certainly patient outcomes are our driver - but the whole ecosystem of oncology benefits when you do the right thing.

Dr. John Cox: It's hard to add anything to Kim's good statements, but I just highlight that this whole area began with the patient-centered medical home, and every time we've met, patients and how we deliver care to patients is top of mind. I think that reflects our community. It reflects oncology as a whole. I don't know any oncologist or practice that is focused on anything else as the prime goal.

Brittany Harvey: That's what I was just going to say. The ultimate goal here is to provide patient-centered care across where every single patient is receiving treatment and at every stage of that treatment.

So, I want to thank you both so much for your work to update these standards, to review the evidence, and discuss with the experts on the panel to come up with the solutions that will help drive quality improvement across care delivery. So, thank you for that, and thank you for your time today, Dr. Cox and Ms. Woofter.

And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the complete standards, go to www.asco.org/standards. You can also find many of our standards and interactive resources in the free ASCO Guidelines app, which is available on the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Joshua Reuss joints that podcast to discuss the latest changes to the living guideline on stage IV NSCLC with driver alterations. He discusses the new evidence for NSCLC with EGFR mutations and NRG1 fusions and how this impacts the latest recommendations from the panel. He shares ongoing research that the panel will review in the future for further updates to this living guideline, and puts the updated recommendations into context for clinicians treating patients with stage IV NSCLC. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2025.1" at www.asco.org/thoracic-cancer-guidelines

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-01061

My name is Brittany Harvey, and today I'm interviewing Dr. Joshua Reuss from Georgetown University, co-chair on "Therapy for Stage IV Non–Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2025.1."

It's great to have you here today, Dr. Reuss.

Dr. Joshua Reuss: Thank you. Happy to be here.

Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Reuss, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So to dive into what we're here today to talk about, Dr. Reuss, this living clinical practice guideline for systemic therapy for patients with stage IV non–small cell lung cancer with driver alterations is updated on an ongoing basis. So what prompted this latest update to the recommendations?

Dr. Joshua Reuss: Yes, thank you. It's very important that we have living guidelines that are continuously updated. We obviously don't live in a static environment where things are non-changing, and we really need to apply the most up-to-date and current evidence to treat our patients with the most effective strategies, the most groundbreaking strategies. And so to have guidelines that can be disseminated, particularly these ASCO guidelines, to treating providers is incredibly important.

So, with any of these updates, we review ongoing studies, published work, for the quality of evidence to see if it's something that warrants making adjustments to our guidelines or at least incorporating the information so that providers can review it and incorporate this into their own personal decision-making.

So in this particular update, we reviewed evidence particularly pertaining to EGFR-mutated non–small cell lung cancer and non–small cell lung cancer harboring an NRG1 fusion.

Brittany Harvey: Yes, certainly there's a lot of new evidence in the advanced non–small cell lung cancer field, and so we appreciate the panel's continuous review of this evidence.

So then you just mentioned two separate areas where the panel reviewed new evidence. So starting with that first one, what updated evidence did the panel review on first-line treatment options for patients with EGFR alterations, and how did this impact the recommendations?

Dr. Joshua Reuss: Yes, so advanced EGFR-mutated non–small cell lung cancer, at least with classical activating alterations - that is our exon 19 deletions and our exon 21 L858R mutations - is something that's really evolved rapidly in the last few years. You know, for many years, we basically, for the frontline treatment setting, were saying, "Okay, we have a targeted therapy, osimertinib. We're going to give that, and we're going to see what effect we can get out of that," with, you know, a median time of duration of treatment response averaging around 18 months, knowing that there are some that that's a lot longer and some that are a lot shorter. But recently, we've seen a lot of data emerging on combination strategies. The guideline has already been updated to incorporate two of these combinations: osimertinib with chemotherapy based off of the FLAURA2 trial, and then the combination of amivantamab with lazertinib based off of the MARIPOSA trial. And that was data on progression-free survival that was published and led to those particular recommendations.

Now, more recently, we've seen data come out in smaller, randomized studies for other combinations. And more recently, we reviewed the RAMOSE study. So this was a phase II, open-label, randomized trial for patients with tyrosine kinase inhibitor–naive and really, treatment-naive advanced EGFR-mutated non–small cell lung cancer harboring one of these two classical EGFR alterations, randomized to either osimertinib alone or osimertinib with the combination of ramucirumab, which is an anti-VEGF agent. There's been a lot of data, preclinical and clinical, for the role of VEGF blockade, particularly in EGFR-mutated non–small cell lung cancer, so exploring the combination of this for synergy in the frontline setting really made a lot of sense.

So again, this was a phase II trial that randomized patients prospectively to one of these two regimens. The population here is really what we typically see with EGFR-mutated non–small cell lung cancer, predominantly a younger population - median age on this study was 65 - predominantly female - 71% female - and predominantly nonsmokers. Now, what this study showed was that at a median follow-up of 16.6 months, the progression-free survival favored the combination arm with a median progression-free survival of 24.8 months with the combination of osimertinib plus ramucirumab versus 15.6 months for osimertinib alone, for a hazard ratio of benefit of 0.55. The landmark one- and two-year endpoints for progression-free survival also favored the combination arm, and response rates were relatively comparable between groups, with overall adverse events being more frequent in the combination group, specifically high blood pressure, proteinuria, and epistaxis, which are our common adverse events related to VEGF-blocking agents.

So, it's good to see data in this space. Now, of note, though, this was a phase II study, so not a phase III level of evidence. In addition, when looking at the population, this was a randomized, multicenter study, but it was a US-only population. There was also some imbalance in the number of visits between arms, so the combination arm was seen more frequently than the arm that got osimertinib alone. Now, the imaging assessments were no different, but obviously this could lead to potential confounding, at least in timing of awareness of potential side effects and and things being brought to the attention of investigators. So very promising data here, but because, you know, of this being a phase II study, this actually led to no changes in the guideline at this time.

Brittany Harvey: Understood. Yes, as you mentioned prior, it's important to understand the full body of evidence and to review the trials even when it doesn't impact the recommendations.

Dr. Joshua Reuss: And I will say that, you know, there is an ongoing phase III study looking at a very similar combination. It's the phase III ECOG-ACRIN trial of the combination of osimertinib plus bevacizumab versus osimertinib alone in this specific population. So, you know, I think we will see phase III–level data for a combination of VEGF with osimertinib, but again, promising phase II data that did not lead to a change in the recommendation at this time.

Brittany Harvey: Absolutely. We'll look forward to that ongoing trial to learn more about combination in this patient population.

So then moving to that second patient population that you mentioned earlier where the panel reviewed evidence, what is the updated evidence and recommendation for patients with NRG1 fusions?

Dr. Joshua Reuss: Yeah, so this was an exciting update that we made more recently with this unique iteration of the living guidelines. So, NRG1 fusions, this is perhaps a newer kid on the block in terms of driver alterations that has been known to be identified in non–small cell lung cancer among other solid tumors. It is very rare, occurring in less than 1% of solid tumors, but something that we know is a unique oncogenic pathway that can lead to oncogenesis and cancer development, including in non–small cell lung cancer.

So up until now, unfortunately, there have not been targeted therapies that target this unique alteration. It's somewhat different than other driver alterations where there's a top-level signaling change in a protein. This is more of a ligand alteration that then alters, that then enables activation of more classical pathways, but again, through upregulation of a unique ligand. So a slightly different pathway but something that we know should be able to be targeted to promote patient survival for those with NRG1 fusions.

So the therapy here is a therapy called zenocutuzumab. It's an IgG1 bispecific antibody against HER2 and HER3. So it prevents the downstream dimerization and signaling that occurs as a result of this NRG1 fusion and upregulation of the NRG1 signal. This was, as you can imagine with a rare alteration, a large phase II registrational study that examined this in advanced solid tumors containing the NRG1 fusion. This is the NRG1 registrational trial.

And this study enrolled patients with advanced solid tumors who had progressed on prior therapy. Patients were treated with zenocutuzumab 750 milligrams IV every two weeks. Among 158 response-evaluable solid tumor patients, the response rate was 30%, median duration of response of 11.1 months, and a median progression-free survival of 6.8 months.

Now, in those with non–small cell lung cancer, that made up 93 response-evaluable patients, very similar outcomes there: a response rate of 29%, median duration of response of 12.7 months, and a median progression-free survival of 6.8 months. This therapy did appear to be well tolerated. The most common higher-grade emergent side effects - grade 3 or higher - were anemia occurring in 5% and elevated liver numbers occurring in 3%.

So this is a subsequent-line study, so this led to the updated recommendation that clinicians may offer zenocutuzumab in the subsequent-line setting for patients with advanced non–small cell lung cancer who harbor NRG1 fusions. So I think this does speak toward the incredible importance of next-generation sequencing and molecular testing for patients, particularly to include testing that looks at the RNA. These large fusions can sometimes be very challenging to detect on DNA sequencing platforms alone, so it's important to, if you have a high level of suspicion for an alteration like this, perhaps some of the mucinous adenocarcinomas where it's been challenging to find a driver alteration, and it's someone who is a never-smoker, really would want to include molecular testing that assesses the RNA level and not just the DNA.

Brittany Harvey: Absolutely. It's important to have all the biomarkers available so that clinicians are able to use that to inform their decision-making.

So then, given these changes in the guideline, what should clinicians know as they implement this latest living guideline update? And how do these changes impact patients?

Dr. Joshua Reuss: Yeah, I think talking in reverse order of what we just discussed here, there is a new guideline update for NRG1 fusions. So I think making sure that that's being evaluated, that clinicians are testing for that and really looking for that result that should be incorporated in in most next-generation large sequencing assays to get that result, but it's very important that that is not overlooked now that we do have a therapy that's available in the subsequent-line setting, though it is important to note that patients with NRG1 fusions, at least the limited data that there is suggests that the efficacy to standard chemoimmunotherapy regimens is overall poor. So physicians unfortunately might be facing this question for second-line therapy in patients with NRG1 fusions sooner rather than later.

For the former, for EGFR-altered non–small cell lung cancer and how do we incorporate VEGF-containing regimens into these patients? Our guideline top-level update did not change based off of review of this new study, but it's important for clinicians to know what other combinations may exist. You know, there are phase III studies looking at this combination in the frontline setting. And of course, there is data on other bispecific molecules that incorporate VEGF in the subsequent-line setting, particularly a combination that includes the VEGF/PD-1 bispecific antibody ivonescimab that's being studied in the HARMONi-A trial for patients with EGFR-mutated advanced non–small cell lung cancer, for which we hope to get some more definitive data in the coming months.

Brittany Harvey: Definitely.

And then you've just mentioned a few ongoing trials where we're looking for evidence to inform future updates. But thinking beyond that, into the future, what is the panel examining for future updates to this living guideline?

Dr. Joshua Reuss: It's a very exciting time to be in the world of treating advanced non–small cell lung cancer, particularly patients with driver alterations, because there is so much evolving data that's changing our practice in real time, again highlighting the importance of these living guideline updates. I'd say there's many things that we're excited to see. You know, a lot of the combination regimens in EGFR-mutated non–small cell lung cancer for which there are approvals and current recommendations in our guideline, particularly osimertinib plus chemotherapy and amivantamab plus lazertinib - those are the two approved combination strategies in the front line - we are now seeing the emergence of overall survival data for those combinations. So obviously that is something that's going to be very important for the committee to review and incorporate into guideline updates.

There are several new therapies coming down the road for other driver populations. We recently saw an approval for taletrectinib for ROS1 fusion–positive non–small cell lung cancer, so it's going to be important that the committee reviews the data and the publications regarding that therapy.

And then there are other novel therapies that we're looking to see updated data on. There are multiple antibody-drug conjugates, which take the potent power of a chemotherapy molecule and attempt to make that targeted with an antibody targeting to a unique feature on the cancer cell. And there are several antibody-drug conjugates that are in development at various levels of promise in this space, particularly in EGFR-mutated non–small cell lung cancer, and I anticipate seeing some emerging data for that coming up in the near future as well. So really, lots to be excited in the space and lots for our committee to review to give guidance on so that these patients can really receive the top-level care wherever they are being treated in the country and throughout the world.

Brittany Harvey: Yes, we'll await this new data to continue to provide optimal options for patients with stage IV non–small cell lung cancer with driver alterations.

So, Dr. Reuss, I want to thank you so much for your work to rapidly and continuously update and review the evidence for this guideline and thank you for your time today.

Dr. Joshua Reuss: Thank you so much.

Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available on the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Lyudmila Bazhenova is back on the podcast to discuss the latest update of the living guideline on therapy for stage IV NSCLC without driver alterations. She shares the studies the Expert Panel reviewed in the first- and second-line settings, including NIPPON, HARMONi-2, and DUBLIN-3. Although these studies do not impact the existing guideline recommendations, Dr. Bazhenova provides context and comments on ongoing trials that will influence the next iteration of the living guideline. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1" at www.asco.org/thoracic-cancer-guidelines

TRANSCRIPT

My name is Brittany Harvey, and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on "Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1."

It's great to have you back on the show today, Dr Bazhenova.

Dr. Lyudmila Bazhenova: It's my pleasure to be here.

Brittany Harvey: And then before we discuss this guideline update, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bazhenova, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then to dive into the content here, Dr. Bazhenova, this living clinical practice guideline for systemic therapy for patients with stage IV non–small cell lung cancer without driver alterations is updated on an ongoing continuous basis. So what prompted this latest update to the recommendations?

Dr. Lyudmila Bazhenova: Living ASCO guidelines are designed to keep pace with rapidly evolving evidence that impacts treatment of our patients with lung cancer. As a committee, we are tasked with regular review of the published literature and determine if the new data warrants changes to existing recommendations. So in this recently published update, we evaluated new trials related to treatment of patients with metastatic lung cancer without driver alterations.

Brittany Harvey: Excellent. Thank you for that explanation of the process.

So, you just mentioned that the panel reviewed new trials for this update. So, which particular updated evidence did the panel review on first-line treatment options for patients with good performance status across histology and PD-L1 expression status, and how did this impact the recommendations?

Dr. Lyudmila Bazhenova: For the first-line treatment option for patients without driver alterations, two studies met our criteria for review. One was the NIPPON trial from Japan, the second was the HARMONi trial. None of those two trials resulted in change in our guidelines, but I think they are giving us some additional information that would be useful for the way we treat patients with non–small cell lung cancer without driver alterations. For example, if we take those patients, we currently have several treatment options as a first line. One is monotherapy immunotherapy. You can give pembrolizumab as an example, and that was based on the KEYNOTE-024 and KEYNOTE-042 trials. Then we have a platinum doublet plus immunotherapy, and there are several trials that did that pathway. And then we have also an option of giving our patients dual IO immunotherapy combination, such as CheckMate 9LA and POSEIDON.

At this point, we do not have any randomized trials comparing those three treatment modalities head-to-head. And the NIPPON trial was interesting to us because it was the first trial to compare CheckMate 9LA regimen, which is again, dual immunotherapy plus chemo, versus KEYNOTE-189 or KEYNOTE-407, which is a chemotherapy plus immunotherapy. And as a result of the study, while chemotherapy plus ipilimumab-nivolumab led to numerically higher overall survival, the difference was not statistically significant. And what is concerning in that trial is that we saw a higher number of treatment-related death occurring in nivolumab and ipilimumab arm compared to the pembrolizumab-chemotherapy arm. As a matter of fact, the trial was terminated early because of the increased risk of death. If you look at the treatment-related death in CheckMate 9LA, the 9LA study reported the treatment-related death to be 2%, and then in the NIPPON trial, the treatment-related death was 7%. Why is that happening? It's really difficult to say. The study was done in Japan. Maybe there is some pharmacogenomic differences between global population and Japan population. But certainly the higher rate of adverse events needs to be taken into account.

Another interesting thing about this trial is that it did not show any differences in a subset analysis for patients with squamous histology as well as PD-L1 negative tumor. So while this does not change our current guidelines and CheckMate 9LA treatment still remains an appropriate treatment option, it kind of raises the possibility that this combination could be associated with a higher toxicity. And we do have a randomized US-based trial that is ongoing, and we are hoping that eventually we will be able to answer that question after the trial will be completed.

The second trial we reviewed is HARMONi-2. So HARMONi-2 was a randomized, double-blind study which is conducted primarily in China, looking at bispecific PD-L1 and VEGF antibody called ivonescimab. And that took patients who were PD-L1 positive, as defined as more than 1% expression, and patients were randomized to pembrolizumab versus bispecific ivonescimab. And the study was positive. It showed improvement in median progression-free survival of 11 months versus almost 6 months in bispecific versus pembrolizumab. There were, however, higher grade 3 events in the ivonescimab arm. At this point, we are not changing our recommendations because this trial was done in an ex-US population, and we are awaiting a similar trial ongoing in the United States before we change recommendations and decide if ivonescimab needs to be included in our guidelines.

Brittany Harvey: This context is very helpful when clinicians think through the data behind these options. And it's important that the panel reviews this evidence, even if it doesn't prompt a change to the recommendations. And we'll await results of those trials that you mentioned to further inform this guideline.

So then beyond those studies for first line, what updated evidence did the panel review for second-line and subsequent treatment options for patients with good performance status, and how did this impact the recommendations?

Dr. Lyudmila Bazhenova: So for second line, only one trial met the criteria, and that was DUBLIN-3. DUBLIN-3 is a phase 3 single-blind randomized trial comparing docetaxel versus docetaxel plus plinabulin. And the study enrolled patients with second or third line. They have to have had platinum-based chemotherapy and progressed. Plinabulin is an interesting compound. It's a small molecule tubulin binder that prevents polymerization of tubulin and appears to impact dendritic cell maturation and T-cell activation. This study enrolled 559 patients, randomly assigned them to two groups. And one important information about this study is that was a study that was envisioned before immunotherapy became a standard mainstream treatment for first-line therapy. And only 20% of patients had prior PD-1 exposure. So therefore, the results of that study need to be taken into context of this population no longer existing in the United States because we use PD-L1 inhibitors in the first line.

And we saw that interesting in the plinabulin arm had lower rates of neutropenia but higher rates of serious adverse events. And at this point, we are not changing our guidelines for mainly two reasons. Number one, low number of patients that received prior treatment with first-line immune checkpoint inhibitors, as well as a modest overall survival benefit of this trial.

Brittany Harvey: Understood. I appreciate you describing that study as well and why that evidence didn't prompt a change to those particular recommendations.

So then, what should clinicians know as they implement this living guideline, and how does this new evidence impact clinicians and patients?

Dr. Lyudmila Bazhenova: At this point, none of the studies that we reviewed resulted in a change in guidelines. We are still waiting for more global results from some of the studies that I highlighted. It shows that there's still a lot of questions we need to be answering in those patients. And I'm hoping that with future clinical trials, we will be able to definitively maybe recommend one treatment over another. But at this point, all the treatments that I mentioned before remain appropriate for patients with stage IV non–small cell lung cancer without driver alterations.

Brittany Harvey: Definitely. And then you just mentioned that there's still a lot of outstanding questions in this field. You've mentioned a couple different studies where we're awaiting evidence. Beyond those that you already mentioned, what is the panel examining for future updates to this living guideline?

Dr. Lyudmila Bazhenova: Right now, our next task is to come up with a full guidelines update. ASCO have certain rules for the guidelines committee members. And so we are gearing for a full guideline update, which hopefully will be ready by the end of 2025.

Brittany Harvey: Excellent. We'll look forward to that full update of the living guideline, and we'll still await results of these ongoing trials to further inform this living guideline.

So I want to thank you so much for your work to rapidly and continuously update this living guideline, and thank you for the time today, Dr. Bazhenova.

Dr. Lyudmila Bazhenova: My pleasure.

Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store.

If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Luis Raez and Michael Reff share the newest update to the medically integrated dispensing pharmacy standards from NCODA and ASCO. They review updates to domain one, on key patient-centered quality standards on health equity and social determinants of health, drug access, patient safety, education, and adherence to maximize treatment outcomes and domain two, on key operational quality standards on logistics, care coordination, and waste prevention. We also cover the impact of these updated standards for clinicians, oncology practices, and people receiving oral anti-cancer medications.

Read the complete standards, “Medically Integrated Dispensing Pharmacy: ASCO-NCODA Standards.”

Transcript These standards, clinical tools, and resources are available on ASCO.org.  Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the JCO Oncology Practice.

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO’s podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Michael Reff from the Network of Collaborative Oncology Development and Advancement and Dr. Luis Raez from Memorial Cancer Institute and Florida Atlantic University, co-chairs on "Medically Integrated Dispensing Pharmacy: American Society of Clinical Oncology – Network of Collaborative Oncology Development and Advancement Association Standards Update." Thank you for being here, Michael and Dr. Raez.

Dr. Luis Raez: Thanks for inviting us.

Michael Reff: Thank you for having us.

Brittany Harvey: Then, before we discuss these standards, I'd like to note that ASCO takes great care in the development of its standards and ensuring that the ASCO Conflict of Interest policy is followed for each guidance product. The disclosures of potential conflicts of interest for the expert panel, including Michael and Dr. Luis Raez who have joined us here today, are available online with the publication of the standards in JCO Oncology Practice, which is linked in the show notes.

So then, to dive into the content here, Michael, I'd like to start with what prompted an update to these ASCO-NCODA standards and what is the scope of this update?

Michael Reff: Thank you, Brittany. What led NCODA and ASCO to endeavor in this, and it started back in 2019 as the amount of oral anticancer medications became more and more prevalent in cancer treatment, we saw the need providing a blueprint for excellence in care for patients prescribed oral anticancer medications, specifically in the outpatient setting. And the update was driven by the rapid growth of these oral oncolytics starting back in the mid to late 2015 through 2019 or so, and then continued on into the 2020s where we are today. We saw the increase in the complexity of the management of these patients with these therapies basically outside the traditional clinical settings. And we wanted to make sure that with more cancer treatments that are taken at home than just at the clinic, like in the oral setting, new challenges had emerged around patient safety, access, adherence, and overall treatment success. The updates now address patient-centered and operational interventions designed to improve access, safety, quality, accountability, and outcomes of oral anticancer and other supportive care medications prescribed for the cancer patient.

Dr. Luis Raez: As Mike said, these guidelines help improve patient care tremendously, but also help us a lot as an oncologist, you know, community oncologists that- now that we have opportunity to dispense these oral oncolytics, we need help to create our medical integrated pharmacies, and NCODA is providing here a way that, how to do this safely, efficaciously, good quality, you know? So that's why I think we always do everything for the patients, but also this helps a lot to the doctors. And there are a lot of what we call specialty pharmacies or medical integrated pharmacies now nationwide.

Michael Reff: I'll build on what Dr. Raez had mentioned. This is the impetus. If you looked at the innovation that was coming from the pharmaceutical companies, many of it coming in the oral form for anticancer medications, and based on that, taking a look at the infrastructure that is in place in these practices, whether it's in the community or the IDN or health system settings, this amount of innovation that was coming needed to be addressed by taking a look at the medically integrated oncology team. And these standards address not just the pharmacy component, but also the whole continuum of care, starting with a medical oncologist or the hematologist, with the pharmacists, nurses, the pharmacy technicians, others that are involved in the care of the patient. And there were no standards involved. And when we approached ASCO back in 2018 to eventually publish the first version of these standards, the need was identified, and we worked collaboratively with ASCO to create the first set and then the revisions as we talked about.

One thing to note regarding the revision plus the original standards, we had a cross-section of the care team on the committee, and we did that very purposefully. So, the ASCO-NCODA team curated a committee to help develop these original standards and the revision of these standards with medical oncologists both from community and health systems, pharmacists from both community and health systems, and also nurses. And we also included a patient that currently has and currently receives oral anticancer medication. And so NCODA and ASCO are very proud of the committee that we put together because of the experts in their field, but also extended the invitation to a current patient. And we embedded everybody's expertise in the curation of these standards.

Brittany Harvey: Absolutely. I appreciate that background and context and how it's critical to improve patient care. And these standards really help oncologists, and we're looking across the continuum of care to provide optimal care for our patients.

So then next, Dr. Raez, I'd like to review the key points of the revised standards for our listeners. So for Domain 1, what are the key patient-centered quality standards on health equity and social determinants of health, drug access, patient safety, education, and adherence to maximize treatment outcomes?

Dr. Luis Raez: Yeah, this was a great effort, you know, at the multidisciplinary team. And as you can read in the standard, there were more than 240 publications reviewed; more than 55 of them are quoted here. And the standards are in two groups, as you said. With the group one, I'll briefly mention some of them. For example, SDOH, social determinants of health, is very important because as doctors, we prescribe, and sometimes patients don't get the medication, you know? And we prescribe assuming that 100% of the patients will get the medication. But something simple like the patient doesn't have insurance, the patient is underinsured. I have a patient that we didn't have an address to send the medication because he's homeless. Something that as a doctor you say, "Oh, oh my God, this is outside my realm," but it's not outside reality. So that's why, even if we don't think that this is part of our expertise dealing with social determinants of health, the fact that the patients have food insecurity, they don't have transportation, they don't have insurance, they don't have a caregiver, impact tremendously in the outcomes of the therapy. So that's why, basically, in this standard, we want to call attention that SDOH, social determinants of health, needs to be identified.

There are in the literature countless examples of why this is important. For example, in the guidelines, we quote two or three examples of prostate cancer studies that, for example, we quote a study of 27,000 people with prostate cancer that were taking oral oncolytics, and how come the fact that the elderly, seniors, the fact that they have high prescription costs, and how all of this affected the adherence to the medication. And that's why it's important to identify the SDOH. And in other sections of the guidelines, we said how to address them, no?

Another important thing in this domain is the cultural, you know, we need to be culturally sensitive and to take care of all of these social factors. For example, here in South Florida, we deal with the Haitian culture, Filipino culture, Latin culture, and American culture, and it's a blend, but it's not easy to go from one to the other.

Another one is the fact that we have to include new technologies. A lot of patients, for example, we use EMR, EMR Epic, and now Epic has everything in the phone. The fact that we can have now the patient can see her prescription medication over the phone, the fact that they can use the phone to request from you a refill, and from your phone, you send the refill to the pharmacy, and you notify from your phone to the patient that the refill is sent, and the patient can check in his phone that the refill is ready. These things are amazing because that's why it's important that we incorporate these technologies to the patient care, and in this specific case, of dispensation of oral therapies, no?

Another crucial point is education. You cannot be sending a patient a package of 300 pills without education. So that's why in our guidelines, mainly pharmacy, clinical pharmacies, or in some centers like mine, we have advanced practice providers, it's mandatory in our centers to have like a one hour of education before you send the prescription. So the patient is aware about side effects and contraindications, all of these things. They provide them also materials and also consent. You know, in the old times, you don't give chemo without a consent. Now, a lot of people say, "Oh, it's only a pill." There is a lot of benefits or side effects that can come from the pill, so you need to consent everybody, you know?

So, another aspect is adherence. I already told about that, but we need to provide patients with a baseline assessment, no? So, you cannot send again the prescription and hope, "Oh, I'll figure it out what happened next month when the patient comes back." I tell you, the patient is homeless, where are you going to send it? If the patient is telling you, "I don't have insurance," what good is it for you to send a prescription? The patient will not get it. So that's why you need to do a baseline assessment of adherence. You need to do a calendar. You need to do electronic support, I mentioned already with the EMR and the phones. For example, my MIP, my specialty pharmacist, sends me a message in the EMR, "Dr. Raez, the insurance is not covering, the patient has a high copayment, we are going to delay the dispensation of the medication." So there needs to be a communication. Or sometimes there is a confusion with the insurance, and I cannot wait for the poor patient to call three, four weeks later, "Oh, I didn't get the medication," to know what happened, no? My MIP is very good. They send the clinical pharmacist a message, "Hey, you know, the insurance doesn't believe that the pill is adequate, or you need to provide more documentation. You need to prove the mutation, the genetic aberration." So if you provide us that, the insurance may approve. So that communication with the doctor is very important to improve adherence.

And one important thing that we have in this one that we didn't have in the anterior is the tracking of outside medications. A lot of times you say, "Okay, the insurance allowed us to provide the medication it’s 100% responsible." But then the insurance says, "Oh, no, no, don't worry. CVS will provide the medication." So it says, "Well, it's you know, it's not my responsibility. CVS will provide the medication, they have to take care." But we know that outside our specialty pharmacies or MIPs, the care is not very good. So that's why we are taking our ownership that, "Okay, the insurance said the patient will get the medication from some outside pharmacy." But our clinical pharmacists track that. What happened? Did the patient get it? The patient didn't get it. The copayment is still high. So even if you get the medication from somewhere else, if the copayment is high, we, our clinical pharmacists, help the patient to navigate and get the foundation or the copayment or finally the maker, the industry partner, provides the drug for free, but somebody needs to do the paperwork. And that's why this is very important. We cannot abort our responsibility because, "Oh, the insurance said somebody else will give it." I work for the public healthcare system, so my patients, some of them don't have insurance, they are underinsured. So we see these problems every day.

And finally, the standards talk about the importance of safety, documentation, verification, monitoring, refills, you know, you need to keep track of refills. We already mentioned how important is the technology to facilitate the refills, and the quality.

Brittany Harvey: Yes, thank you for touching on those highlights for Domain 1. It's important that all patients have access to care and these oral anticancer medications, and not only just access to care, but safe and effective care. It's really important, as you mentioned, Dr. Raez, to meet patients where they're at and incorporate technology. And I also want to note the coordination with external pharmacies that you mentioned in tracking outside medications as well. It's not only important for multidisciplinary care within the oncology practice itself, but also external to the oncology practice. That's why we put together this multidisciplinary panel to develop these standards.

So then, expanding on that, Dr. Raez, for Domain 2, what are the key operational quality standards? Those on logistics, care coordination, and waste prevention.

Dr. Luis Raez: Yeah, we have a lot of standards here, but maybe we can summarize in five or six points, no? For example, financial toxicity in cost and waste are very important because the patients, yeah, you put them on therapy, but as you can understand, if there is disease progression, the patient don't need the medications. And sometimes you get refills even if the patient has disease progression. If you do a dose reduction, the same problem. Or you discontinue medication and the patient keeps getting the drugs. So, you're talking about drugs that are between 20 and 30 thousand dollars per month. This is a lot of money. There are studies that we're quoting in the standards that the waste could be from 1 to 3 or 4 thousand per patient, no?

Another aspect is dispensing. When you dispense the medication, this is not as easy as, "I'll ship to your house a bag of medications." You know, there needs to be a diagram, a decision tree. You need to train the staff to know what we're doing. There needs to be an auditing of the process. They need to be even packaging and shipping, you know? For example, I'm in Florida today and outside in summer it's going to be 95 degrees. So, everybody leaves the package outside your house, and sometimes you go the whole day until when you come at 6:00 p.m. There are medications that cannot be left outside there, you know? I don't know, it sounds like a joke, but I have a patient that the medication used to be stolen because people thought that that was something important, you know? And of course, it's important because it's a $20,000 medication. So, the poor patient, because he lives in an area that is not safe, has to come and pick up in person. All of these things sound very trivial, but that's real life that affects adherence.

Another important thing is shortage. This is something that we just suffered two or three years ago, and we have to think about what happens in the next shortage. What happens if there's going to be a shortage? What do we do or how are we going to do that? Now we know it's something that is happening probably very soon again, and something that we have to consider.

Another standard is the care coordination. You need to have probably, if it's possible, a coordinator. I know that for small practices it's very hard, but for big cancer centers, you should have a coordinator of this. I already mentioned before, the communication between the physicians and the doctors to coordinate the care, no? You need to write the prescription again, you need to provide more information, or to be notified, "Hey, you know, the patient is throwing up in the first week, you need to see the patient, please," no? So, this type of communication needs to exist so we can serve the patient better.

It's also important, you know, we're improving quality and we're improving care. It's important to try to collect patient-reported outcomes. This is something that now we have the opportunity, if we do things well, to do it and show that we're providing a better care. The other thing is that we already mentioned SDOH in the other standard. In this standard, we mention mainly SDOH to partner. For example, we collect in my center SDOH, and I always get frustrated when the patient doesn't have transportation. But I didn't know that there are local institutions that provide free Uber rides, free Lyft rides. So that's why it's important to partner with these institutions. I have a local grocery chain that provides free food for the patients, and I didn't know that. It's important to be aware what the patient needs and what resources do you have to fulfill the SDOH. That's the part that we mention in here. So that's why, in summary, those are the six probably most important points here. I'll ask Mike for some comments.

Michael Reff: Thank you, Dr. Raez. Brittany, to answer your question, and as was pointed out on logistics, care coordination, and prevention of waste, certainly that is an aspect that has changed in the revision that we're here to talk about. There's really two components to waste, and it's cost avoidance and then waste prevention. And as Dr. Raez mentioned several times, the importance of the medically integrated team and having the ability for that practice to fill that prescription internally and have robust documentation. Cost avoidance is a critical component that the medically integrated pharmacy, or the MIP, can help the total cost of care. And that is by preventing errant fills or waste that can occur by intervening in the care of the cancer patient, as we do every day. But when the practice has access to the medication and can fill that prescription in-house in the medically integrated pharmacy, that team, that care coordination that takes place, can prevent those errant fills or additional fills when there's dose reductions, there's holidays, there's things that happen in real time. And it's impossible for a mail-order pharmacy that's in another state that has lead times, when a prescription needs to be mailed 7 days or 10 days before the patient will run out of the medication, it's impossible for them to logistically coordinate that care like we can internally within the medically integrated pharmacy.

So, we prevent waste and overall cost of care by cost avoidance and having that coordination or that continuity of care that we talk about. And we prevent waste from the mail-order pharmacies by taking that prescription internally and filling it, but also doing it in a way that's more sustainable and cost-effective for all stakeholders in the oncology ecosystem.

Brittany Harvey: Absolutely. Thank you both for reviewing those key standards for Domain 2 and touching on the importance of distribution logistics and all the things that a medically integrated pharmacy needs to think through in getting oral anticancer agents to patients.

Following that, Michael, we've touched on this a little bit earlier, but how will these updated standards impact clinicians and oncology practices?

Michael Reff: Yes, and as Dr. Raez and I have discussed throughout this podcast, these additional standards are there to help support that continuity of care by educating the clinicians that are in the oral anticancer medication space to elevate their provision for these oral therapies. What I mean by that is the practice has to perform at a certain level in order for them to, as I call it, deserve the right to fill that prescription by having the processes and procedures in place. And these standards, these updated or revised standards, are the blueprint for better patient care and to help the practices execute on that journey of continuous improvement.

Dr. Luis Raez: Yeah, I only want to add, we have practical examples in the guidelines. We quote a couple of studies that have been successful. And this year, for example, I am a lung cancer doctor, we are presenting in World Lung our standards of adherence to oral oncolytics for EGFR therapy, following the NCODA-ASCO standards. We're around 95% of adherence. We are a healthcare system that is public. We have people with no insurance and a lot of social determinants of health. We are trying to show that it's feasible, even in the most difficult circumstance, when you follow the standards, to be successful.

Brittany Harvey: Definitely, these standards can help clinicians and oncology practices succeed in providing these medications.

So then beyond that, and to wrap us up, Michael, what do these revised standards mean for patients who are receiving oral anticancer medications?

Michael Reff: Yes, great point and question, Brittany, because we have covered the benefits to the clinicians and the practices themselves. But how is this going to support better patient care? And it does it in a whole host of ways. I'll cover just a few of them. What I'm about to share with you relates back to what we call at NCODA the "core claims." Like, what's the core claims of having a medically integrated pharmacy within the practice? And there are seven different core claims that we feel practices that are focused on the continuity of care can deliver better outcomes that are embedded in these standards. And it's talking about abandonment, adherence, access and affordability, speed to therapy or time to fill, as we call it, education, patient satisfaction, and cost avoidance that we covered earlier. So those are the core claims that a practice that follows these revised standards can help elevate.

So, faster and more affordable access to the oral cancer medications; individualized support to address barriers like transportation, finance, language, or health literacy, and so on; clear, patient-friendly education; something that is near and dear to all clinicians' hearts, and of course, the patient that was on our panel or on our committee, to empower them to manage side effects and recognize when to seek help; and a stronger partnership with a care team, with regular follow-ups focused on their experience, challenges, and successes; and then, greater overall safety through proactive monitoring for medication errors or complications. So all of these aspects, or tenets, as I'll call them, are baked into these quality standards that are totally aligned with NCODA's core claims document that, again, talks about abandonment, adherence, access and affordability, speed to therapy, education, satisfaction for the patients, and also cost avoidance.

Dr. Luis Raez: I only want to add and invite the community to adhere to these standards, to practice the standards. You will be providing the best patient care that we can nowadays.

Brittany Harvey: Definitely. I think these standards are very important. And Michael, I thank you for touching on those key claims from NCODA. I think those, along with these updated standards, will improve outcomes for patients everywhere.

So I want to thank you both so much for your work to update these standards and all the time you put into it. And thank you for your time today too, Michael and Dr. Raez.

Michael Reff: I'd like to thank not only the committee, my esteemed committee that helped support the standards and the revision. Many of the original healthcare providers and patient that were on the first go of the standards were part of the second standards. We revised it, of course, and we got additional support from the new committee. And certainly ASCO and their partnership and collaboration with NCODA has been tremendous. And we look forward to the oncology community at large adopting these standards, again, to work together, we do become stronger, and it will improve cancer care for patients receiving oral anticancer medications. So thank you, Brittany.

Dr. Luis Raez: I only want to say the same thing. Actually, there is probably more people in NCODA that is not in the publication that has helped. Same in ASCO. Also, we want to give thanks to Dr. Stephen Grubbs, our leader in quality. He's retiring. We're going to miss him, but he has been a key collaborator with Mike organizing these standards for the last five or six years. So, looking forward to these standards in practice.

Brittany Harvey: Absolutely. A big thank you to the entire panel and everyone who contributed to this, and NCODA as well.

And then finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the complete standards, go to www.asco.org/standards. I also encourage you to check out the companion episode on these standards on the PQI podcast by NCODA, which you can find on Apple Podcasts and Spotify. You can also find many of our standards and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Kimberly Perez and Dr. Jaydira Del Rivero discuss the new guideline from ASCO on symptom management for well-differentiated GEP-NETs. They share the latest recommendations on managing symptoms related to hormone excess, including carcinoid syndrome and carcinoid heart disease, managing symptoms of functioning pancreatic neuroendocrine tumors, and also palliative interventions. Dr. Perez and Del Rivero share how to use this guideline in concert with the systemic therapy for tumor control in metastatic well-differentiated GEP-NETs guideline, and hope for the future for the treatment of gastroenteropancreatic neuroendocrine tumors.

Read the full guideline, “Symptom Management for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.”

Transcript This guideline, clinical tools, and resources are available on ASCO.org. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in JCO Oncology Practice.

My name is Brittany Harvey and today I'm interviewing Dr. Kim Perez from Dana-Farber Cancer Institute and Dr. Jaydira Del Rivero from the Center for Cancer Research at the National Cancer Institute, co-chairs on “Symptom Management for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.”

Thank you for being here today, Dr. Del Rivero and Dr. Perez.

Dr. Kim Perez: Thank you.

Dr. Jaydira Del Rivero: Thank you so much for the invitation.

Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Perez and Dr. Del Rivero, who have joined us here today, are available online with the publication of the guideline in JCO Oncology Practice, which is linked in the show notes.

So then to jump into the content here, first Dr. Del Rivero, could you provide an overview of the scope and purpose of this guideline?

Dr. Jaydira Del Rivero: Yeah. Thank you so much. Well, first, we really wanted to thank ASCO for allowing us to develop these guidelines for the management of gastroenteropancreatic neuroendocrine tumors. I do want to mention that there is also another set of guidelines that I was very fortunate also to co-chair with Dr. Perez on the systemic management of gastroenteropancreatic neuroendocrine tumors. But when discussing these guidelines as well as with the different panelists, experts in this type of disease, we also realized that the management of these tumors are quite complex, not only from the management of the disease progression, but at the same time, management of the symptoms related to the hormone excess. And because of that, we like to thank ASCO for allowing us to then not only have a discussion on the systemic management of these tumors, but at the same time develop recommendations for the symptoms related to the different hormones that these neuroendocrine tumors may produce.

These guidelines are for the management of grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors. These guidelines include the management of the different aspects and the symptoms related to hormone excess, such as carcinoid syndrome, carcinoid heart disease, how to manage carcinoid crisis, as well as the different symptoms and how to manage the functional pancreatic neuroendocrine tumors and as well as provide recommendations in the different treatments for these tumor types, not only from the systemic management but also from the surgical management as well as for liver-directed therapy options and the different aspects in terms of the palliative care of these patients to improve not only the symptoms related to the hormone excess caused by these tumors, but as well as to improve the quality of life.

Brittany Harvey: Absolutely. And I appreciate that overview. And yes, we'll link the guideline on the Systemic Therapy for Tumor Control for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors in the show notes for our listeners so that they can refer to that companion guideline as well.

So then you just described the several different categories of recommendations that this guideline covers on symptom management. So, Dr. Perez, I'd like to start reviewing some of those key recommendations of that guideline. So, starting with what are the key recommendations for carcinoid syndrome and carcinoid heart disease?

Dr. Kim Perez: Thank you Brittany. Yeah, I also want to thank ASCO for inviting us to do this podcast today. Just to start, I think these guidelines will really add to what's available in the literature to provide a kind of a quick look for the community provider to manage carcinoid-related symptoms. I think the highlights that I would point out are we've all been using somatostatin analogs for the last few decades to manage symptoms, but with the newer treatments that are now available, we tried to highlight what does the literature support in regards to PRRT, what does the literature support in regards to using systemic therapy for disease management, but also the benefits that you will get from a symptom management perspective using other modalities. I think the highlight really is it's a multidisciplinary approach. We are now considering surgery and embolization or interventional radiology as a critical piece.

And I think the third that I'd highlight is the fact that sometimes we get too focused on carcinoid syndrome and the symptoms will actually, may result from other things. And the highlight in the algorithms that we've provided is what other things cause carcinoid-related diarrhea. And let's not forget about that because we will find ourselves treating and patients getting very frustrated with persistence of symptoms when in actuality, we should be treating something else that is causing a very similar symptom.

For carcinoid heart disease, I think there are more and more guidelines that are now available to provide guidance there, but I think the major advances are that we should be utilizing heart assessment with echocardiogram with lab values such as BMP. But also critical to this is consulting with our cardiology colleagues and making sure that we're identifying heart related issues that are resulting from hormone excess sooner than later because interventions on the earlier side can really make a significant impact on quality of life and associated comorbidities and mortality.

Brittany Harvey: Thank you for reviewing those key points for both carcinoid syndrome and carcinoid heart disease symptom management.

So then the next set of recommendations. Dr. Del Rivero, what are the key highlights for symptom management of functioning pancreatic neuroendocrine tumors?

Dr. Jaydira Del Rivero: Yes, it's very important to recognize the symptoms related to hormone excess due to pancreas neuroendocrine tumors. Up to 10% of pancreas neuroendocrine tumors may produce different hormones. Among those hormones can be insulin, gastrin, glucagon, somatostatin. So it's important to know and understand that based on what a neuroendocrine tumor is, they may produce different types of hormones. The importance of these guidelines is to also recognize some of these symptoms and how to address that, because it's not necessarily in these tumor types besides the management of metastatic disease, and know the different options that we recommend for metastatic disease from the systemic therapy, such as chemotherapy or targeted therapies or PRRT. It's important to recognize the symptoms because based on the symptoms we may recommend a different approach. That's something that is important to acknowledge and recognize. Moreover, in certain functional pancreas neuroendocrine tumors, as Dr. Perez mentioned, is a multidisciplinary approach. And it's important to also discuss these different cases with your endocrinologist. You may need to have an experienced endocrinologist to manage, for example, the excess of insulin. And also discuss your cases with a surgeon and interventional radiologist because some of these approaches can certainly improve the symptoms related to hormone excess.

I understand that sometimes medical oncologists in the communities may not have access to the multidisciplinary approach or have the different teams that can manage these tumors, and that's the reason why with these guidelines we wanted to establish the understanding of different symptoms associated with the hormone excess to these neuroendocrine tumors as well as how to manage this. For example, in the case of insulinoma, I think for the medical oncologist it is important to know that the everolimus is an option to be used for these tumors, not only to manage tumor progressions related to this tumor type at the same time, because everolimus as a side effect causes hyperglycemia, that can also improve some of the symptoms related to the excess of insulin besides the somatostatin agonist. I think these recommendations will allow the medical oncologist to recognize the symptoms and based on what the symptoms cause, then you can have a different approach that could be added to the systemic therapies options as well.

Brittany Harvey: Yes, beyond systemic therapy, it's important to be recognizing symptoms to provide an individualized approach for every single patient.

So then, following that overview of symptom management for functioning pancreatic neuroendocrine tumors, Dr. Perez, what is recommended regarding palliative interventions for patients with gastroenteropancreatic neuroendocrine tumors?

Dr. Kim Perez: Yeah, great question. So I think what's unique to neuroendocrine tumors is that the palliative approach really mirrors what we would be doing for symptom management. Some of these patients are living a very long time with carcinoid related symptoms. And so the approach that we take for the carcinoid symptom control is going to mirror the palliative piece of it. I think for those who develop a burden of disease related symptoms, I think it mirrors what we do across the board for all cancer-related complications. And so I think what we attempted to highlight here and included one of our colleagues who focuses specifically on the field of palliative care and neuroendocrine tumors, was to never really lose sight of what we've been doing to care for symptom management throughout the patient's journey and to always rereview the etiology of the symptoms, ensure that we don't focus solely on carcinoid-related issues, but also the symptom management that we would apply to all patients with cancer-related burden symptoms.

Brittany Harvey: Definitely. I think that's a helpful approach to consider when thinking about how to manage these palliative interventions as well.

So then Dr. Del Rivero, what should clinicians know as they implement these symptom management recommendations?

Dr. Jaydira Del Rivero: Yes, thank you so much for that question. As we have discussed in the last 10 or 15 minutes, we have discussed the different approaches on the management of gastroenteropancreatic neuroendocrine tumors. Clinicians, I think it's important to know that neuroendocrine tumors is a quite complex disease because we're not only addressing the management of tumor growth, but we're also addressing the management of the symptoms related to hormone excess and the complexity associated with that. When medical oncologists or clinicians implement these recommendations it’s to understand what symptoms these tumors may cause related to the hormone excess but at the same time, how do we approach those symptoms? As Dr. Perez said that I think is very important is to recognize the different types of diarrhea. It doesn't mean that if the patient has worsening diarrhea, it doesn't mean that this is related to disease progression. So it's important to recognize so that way you can address that, because the type of diarrheas can be related because of the lanreotide or somatostatin agonist, it could be because of the prior surgery. I think it's important to recognize those in order to address the symptom. And the same with the gastroenteropancreatic neuroendocrine tumors. It's important to know what hormones they produce because there are different measurements that may be added to the systemic management of these tumors.

I think that there are two aspects here, and that's the reason why these guidelines were implemented in the sense that not only we're going to manage disease progression of these tumors, or how do we manage the metastatic disease of these tumors, but at the same time, how do we manage the symptoms related to the hormone excess and the different complications. Moreover, I think, as we discussed earlier, we need to manage these tumors in a multidisciplinary approach. And something very important is not like one size fits all, because the treatment recommendations, it will depend on different characteristics in terms of the tumor presentations. And hormone excess is one of the important aspects to recognize so that way we can implement these recommendations that will definitely help the quality of life of these patients.

Brittany Harvey: Absolutely. And using these guidelines in concert with the systemic therapy guidelines is key.

And then beyond this impact for clinicians that Dr. Del Rivero has just outlined, Dr. Perez, what does this new guideline mean for patients with gastroenteropancreatic neuroendocrine tumors?

Dr. Kim Perez: Yeah, I think that's an important highlight of this guideline. It really gives patients a voice. I think it recognizes the fact that these symptoms can go unmanaged or mismanaged or just missed, and patients commonly will come in feeling very frustrated and feeling very ill. And I think it will provide them a means to open up a conversation with their providers and say, “Hey, this is what I'm experiencing. Let's talk about what's available. How does this apply to me?” And I think that can be very empowering. I think it's really hard nowadays with so many sources and resources online and patients are really left wondering what are the bullet points that they should be bringing to their clinician appointments? And I think that these guidelines provide them a good framework for those discussions.

Brittany Harvey: Yes, bringing these discussion points for patients is very important to be able to have those resources. And we have some patient resources and information available on the website for this guideline and we can link that in the show notes for listeners.

So then you've both touched on the importance of this guideline for improving quality of life and we continue to see advancements in this field. So Dr. Del Rivera, what are the outstanding questions regarding symptom management and tumor control for gastroenteropancreatic neuroendocrine tumors?

Dr. Jaydira Del Rivero: I have to say whenever somebody asks me that question, the word that I will say is I feel hopeful, because more than 10 years ago we didn't have that many options for gastroenteropancreatic neuroendocrine tumors. And it has been in the last decade or so that there has been more developments in the management of these tumors as well as the understanding of the symptoms related to these tumors. But that said, yes, we do need more therapies for gastroenteropancreatic neuroendocrine tumors. Of the treatment options that we have, we all know in the field that even though we have disease control by using the different options for the systemic management of gastroenteropancreatic neuroendocrine tumors, we need options where we can achieve an objective response, especially for these tumor types. But there is a significant volume of disease and we see a lot of these patients with gastroenteropancreatic neuroendocrine tumors. And now where the field is going is to make some of these therapies more effective, to develop more therapies as well. For example, immunotherapies, a different type of immunotherapy understand the tumor immune microenvironment of these tumors in order to develop therapies as well. From the antibody drug conjugates, I think that's a new way to also address or treat these tumor types, understanding about the different markers found on these tumors that way they can be addressed in different ways. Now with the development of new therapies, I think that's something that can help us as well not only have disease control and as well as having an objective response, but having a better objective response can certainly also help with the symptoms related to hormone excess too.

In terms of other therapies, I think some of the issues that we encounter are like the refractory carcinoid diarrhea and how do we manage this. We do have therapies that can help us control the diarrhea in the refractory settings, such as telotristat. Telotristat is one of the newer medications that can help us control the refractory diarrhea. But that said, despite this, that we still encounter situations where it's sometimes difficult to control. I think in those situations it will be good to understand more about the biology of these tumors as well and how we manage. If there is a different time or how do we implement these options. I think there is so much to learn. But that said, I feel we're in hopeful times. We're understanding more about these tumors so that way we can help us develop better therapies not only to have control of the tumor growth as well having control of the symptoms. And it's the same with the pancreas neuroendocrine tumors in the metastatic setting. Sometimes it may be difficult to control this hormone excess. But understanding these and having therapies that can achieve more of an objective response, I think that will definitely help us more and manage these patients.

But one aspect I want to mention, and Dr. Perez also mentioned as well, the fact that we have these guidelines that help us understand about the different symptoms related to hormone excess and how to address it, I think is very important because having symptoms related to hormone excess can be detrimental to the quality of life on patients with neuroendocrine tumors that may necessarily be related to disease progression and having this information is so important. And I'm hopeful for the different therapies. There's different clinical trials ongoing for neuroendocrine tumors and especially in the field of PRRT. And a lot of more information will come with the different alpha-PRRT and combination therapy. So more information to come in the next couple of years. So this is, in my opinion, hopeful times for this field.

Brittany Harvey: It's great to hear that you're hopeful for all the developments in this field and we'll look forward to the development and discovery of new therapies and further research and then, hopefully incorporate those updates into guidelines in the future.

So I want to thank you both so much for your work to develop these guidelines and thank you for your time today. Dr. Del Rivero and Dr. Perez.

Dr. Jaydira Del Rivero: Thank you so much for having us.

Dr. Kim Perez: Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Rohan Garje shares the updated recommendations for the ASCO guideline on systemic therapy for patients with metastatic castration-resistant prostate cancer. He discusses the systemic therapy options for patients based on prior therapy received in the castration-sensitive and non-metastatic castration-resistant settings. He emphasizes personalizing treatment choices for each individual, considering patient-specific symptoms and signs, treatment-related toxicities, potential drug interactions, cost, and access. He also reviews recommendations on response assessment. The conversation wraps up with a discussion of potential future updates to this guideline, as the guideline transitions into a “living guideline” on mCRPC.

Read the full guideline update, “Systemic Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Update”.

Transcript This guideline, clinical tools, and resources are available at www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology.

My name is Brittany Harvey and today I'm interviewing Dr. Rohan Garje from Miami Cancer Institute Baptist Health South Florida, lead author on, “Systemic Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Update.”

Thank you for being here today, Dr. Garje.

Dr. Rohan Garje: Absolutely. Thank you so much for having me, Brittany.

Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Garje, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to start on the content of this guideline, first, could you provide us an overview of the purpose of this guideline update?

Dr. Rohan Garje: Sure. So ASCO has guidelines for prostate cancer and the specific guideline which we have updated for metastatic castrate-resistant prostate cancer was originally published in 2014. It's almost a decade. It's been a long time due for an update. Over the last decade, we have seen a lot of advances in the treatment of prostate cancer, specifically with regards to genomic testing, newer imaging modalities, and also the treatment landscape. Now we have newer options based on genomic targets such as PARP inhibitors, we have radiopharmaceuticals, a newer variant of chemotherapy, and also some specific indications for immunotherapy which were not addressed previously. Because all these advances have been new, it was really important for us to make an update. In 2022, we did make a rapid update with lutetium-177, but these additional changes which we have seen made it an appropriate time frame for us to proceed with a newer guideline.

Brittany Harvey: Absolutely. It's great to hear about all these advances in the field to provide new options.

So I'd like to next review the key recommendations from this guideline. So let's start with the overarching principles of practice that the panel outlined. What are these key principles?

Dr. Rohan Garje: As a group, all the panel members came up with some ground rules: What are necessary for all our patients who are being treated for metastatic CRPC? First, the founding aspect was a definition for what is metastatic CRPC. So we defined metastatic CRPC as castrate level of testosterone with evidence of either new or progressive metastatic disease on radiological assessments or patients who have two consecutive rising PSAs in the setting of existing metastatic disease. We also emphasized on the need for germline and somatic testing for patients with metastatic prostate cancer at an earliest available opportunity because it is critical to select appropriate treatment and also right treatment for patients at the right time. And we actually have a concurrent guideline which addresses what genes to be tested and the timing. The other principles are patients should continue to receive androgen deprivation therapy or undergo surgical castration to maintain castrate level of testosterone.

Now the key aspect with these guidelines is personalizing treatment choices. As you can see the evolution of treatment options for prostate cancer, the drugs that were initially developed and approved for prostate cancer were primarily in castrate-resistant settings, but now most of these drugs are being utilized in castrate-sensitive. So, when these patients develop castration resistance, the challenges are there are no appropriate particular drug-specific guidelines they meet. So, it's very important for the clinicians to be aware of what treatments have been received so far prior to castration resistance so that they can tailor the treatment to patient specific situations. In addition, prior to choosing a therapy, it is important for the physicians to consider patient specific symptoms or signs, treatment-related toxicities, potential drug interactions, cost, and also access to the drugs. There may be multiple treatment options available for the patients, but for a patient specific scenario, there may be a drug that may be more promising than the others. So, it is important to tailor the drug choices based on patients' unique circumstances.

The panel also recommends to early integrate palliative and supportive care teams for symptom management and also discuss goals of care with the patient as each patient may have unique needs and it's important for physicians to address those concerns upfront in the care. The panel also suggests patients to receive RANK ligand inhibitors such as denosumab or bisphosphonates such as zoledronic acid to maintain the bone strength to prevent skeletal-related events.

Finally, I would like to also emphasize this point about the lack of randomized clinical trial data for optimal sequencing of therapies for patients with metastatic CRPC. As I previously alluded, we have taken into account all ongoing clinical trials, prior published data, and came up with a format of preferred drugs based on prior treatments and, I think, by following these several clinical principles which I just mentioned, we can optimally choose and utilize best treatments for patients with metastatic CRPC.

Brittany Harvey: Absolutely. These principles that you just outlined are important for optimal patient care, and then I want to touch on one of those things. You talked importantly about the treatments received so far. So in the next set of recommendations, the role of systemic therapy was stratified by the prior therapy received in the castration-sensitive and non-metastatic castration-resistant setting. So starting with what does the panel recommend for patients who are previously treated with androgen deprivation therapy alone in these previous settings and whose disease has now progressed to metastatic castration-resistant prostate cancer?

Dr. Rohan Garje: There are multiple treatment options based on prior treatment received. So for patients who received only ADT for their castration-sensitive disease, the panel strongly urges to get HRR testing to check for homologous recombinant repair related changes, specifically for BRCA1 and BRCA2 mutations, because we have three studies which have really shown significant clinical benefit for patients who have BRCA1 and BRCA2 mutations with drugs such as the combination of talazoparib and enzalutamide or olaparib with abiraterone or niraparib with abiraterone. Unless we test for those mutations, we'll not be able to give these agents upfront for the patients. In the HRR testing, if patients have HRR alterations but they are in genes which are non-BRCA, the guideline panel recommends to utilize talazoparib and enzalutamide based combination therapies. Now, if they don't have HRR alterations then there are multiple treatment choices available. It could either include androgen receptor pathway inhibitors such as abiraterone with prednisone. We could also consider docetaxel chemotherapy. The alternate choices for androgen receptor pathways include enzalutamide or the newer agents such as apalutamide and docetaxel. So, as you can see there are multiple options available, but the panel definitely emphasizes to test for HRR testing because this gives patients access to more precision therapies at this point.

There may be various scenarios where a unique drug may be available for a specific patient situation. For example, patients who have very limited disease burden and may have one or two metastatic lesions, after a multidisciplinary discussion, targeted local therapies such as radiation or potentially surgery could also be offered. In select patients who have very indolent disease where they are castrate-resistant based on slow rising PSA, low-volume disease or asymptomatic disease can consider sipuleucel-T. And in patients who have bone-only metastatic disease, we could also consider radium-223, which is primarily now utilized for patients who have symptomatic bone disease.

Brittany Harvey: Great. I appreciate you reviewing all those options and talking about how important it is to tailor treatment to the individual patient.

So then the next category of patients, what is recommended for those who have been previously treated with ADT and an androgen receptor pathway inhibitor and whose disease has now progressed to metastatic castration-resistant prostate cancer?

Dr. Rohan Garje: So for patients who received ADT along with an androgen receptor pathway inhibitor, which we consider would be a most common cohort because most patients now in castration-sensitive setting are receiving androgen receptor pathway inhibitor. It was different in the past where five or six years back ADT alone was the most common treatment, but fortunately, with enough awareness and education, treatment choices have improved. Patients are now receiving ADT and ARPI as the most common choice of drug. Once again, at this point the panel emphasizes to consider HRR testing in there is enough data for us to suggest that patients who have alterations in the HRR pathway definitely will benefit with the PARP inhibitor. You know the multiple options, but specifically we speak about olaparib. And then if they are HRR-negative, we prefer patients receive agents such as docetaxel or if they are intolerant to docetaxel, consider cabazitaxel chemotherapy, options such as radium-223, and if they have a specific scenario such as MSI-high or mismatch repair deficiency, pembrolizumab could also be considered.

The panel also discussed about the role of a second ARPI agent. For example, if patients progressed on one androgen receptor pathway inhibitor, the second androgen receptor pathway inhibitor may not be effective and the panel suggests to utilize alternate options before considering androgen receptor pathway inhibitor. There may be specific scenarios where a second ARPI may be meaningful, specifically, if alternate choices are not feasible for the concern of side effects or toxicities or lack of access, then a potential ARPI could be considered after progression on ARPI, but the panel definitely encourages to utilize alternate options first.

Brittany Harvey: Great. Thank you for outlining those options as well for those patients.

So then the next category, what is recommended for patients who have been previously treated with ADT and docetaxel?

Dr. Rohan Garje: For patients who received ADT and docetaxel and were never treated with androgen receptor pathway inhibitors, the panel again emphasizes on HRR testing. If they have BRCA1 and 2 mutations, the combination therapies of talazoparib with enzalutamide, olaparib with abiraterone, or niraparib with abiraterone are all good choices. If they don't have BRCA mutations but they have other HRR mutations, the panel suggests to potentially utilize talazoparib with enzalutamide. And if they do not have any HRR alterations, the options could include androgen receptor pathway inhibitors such as abiraterone or enzalutamide.

I want to emphasize that these are preferred options, but not the only options. As you can see, there are multiple options available for a particular clinical situation - so the ability of the physicians to access particular combinations, the familiarity of those drugs or the patient's unique situation where they have other medications which can potentially interact with a choice of agents. So I think based on access, based on cost and patients' concurrent illness with potential drug interactions can make one particular combination of therapy better over the other options.

Brittany Harvey: Absolutely. That's key to keep in mind that access, contraindications, and cost all play a role here.

So then the next set of recommendations. What are the key recommendations for patients who have previously been treated with ADT, an androgen receptor pathway inhibitor, and docetaxel who now have mCRPC?

Dr. Rohan Garje: Yes. In this group, the options remain, again, broad. We utilize PSMA imaging here specifically and if they are positive on PSMA imaging, lutetium-177 is a good option. If they do not have PSMA-positive disease on PSMA imaging but if they have HRR alterations, olaparib could be utilized. And if they are negative on PSA imaging, they don't have HRR alterations, then alternate options could include cabazitaxel, radium-223. And if they have MSI-high or deficiency in mismatch repair, pembrolizumab could be utilized in this setting.

Brittany Harvey: Thank you for outlining those options as well.

So then next the panel addressed treatment options for de novo or treatment emergent small cell neuroendocrine carcinoma of the prostate. What are those key recommendations?

Dr. Rohan Garje: Yes. This is a very high unmet need group because there are limited clinical trials, especially prospective clinical trials addressing treatment options for this group. Most of our current guidelines are always an extrapolation from lung small cell cancer based guidelines, but the panel recommends to utilize cisplatin or carboplatin along with etoposide as a preferred choice for this group. Also, an alternate option of carboplatin along with cabazitaxel could be considered for this cohort.

The panel also encourages participation in clinical trials. There are numerous trials ongoing now in smaller phase studies and I think it's important for patients to consider these trials as well, because this will give them access to newer agents with potential biological targets. In addition to these agents in specific scenarios or potentially case by case basis, because we don't have prospective data, so we have made it as a select case by case basis to consider adding immunotherapy along with platinum-based chemotherapy followed by maintenance immunotherapy, which is currently a standard of care in small cell lung cancer. But the data is so limited in prostate cancer, so the panel suggested that it has to be a case by case basis only. The alternate options also include lurbinectedin, topotecan, tarlatamab upon progression on platinum-based chemotherapy.

Brittany Harvey: Yes. It's important to have these recommendations in these unique situations where there is really a lack of data.

So then the final set of recommendations I'd like to cover, what does the panel recommend for how clinicians should assess for response while patients are on systemic therapy and what scans are recommended for this response assessment?

Dr. Rohan Garje: Yes. Again, this is another strong emphasis of the panel for global assessment of the patients. Traditionally, patients and physicians per se are heavily reliant on PSA as an accurate marker for response. This is in fact true in earlier phases of prostate cancer either in castrate-sensitive setting or localized prostate cancer setting. But as patients evolve into castrate-resistant, we don't want to heavily rely on PSA alone as a marker of response. The panel suggests to incorporate clinical response, radiological response, and also include PSA as a component, but not just rely primarily on PSA. So the panel also suggests that patients should get a bone scan and a CT scan every three to six months while on treatment to assess for appropriate response or for progression.

And now one key important aspect, we are all aware about the evolving role of PSMA-based imaging with several of these new agents that are currently available. We do acknowledge these scans definitely have an important role in the care for patients with metastatic prostate cancer. Currently, the utility is primarily to select patients for lutetium-based therapy and also in situations where the traditional scans such as technitium 99 bone scan or CT scan are equivocal, then a PSMA-based imaging can be helpful. Now we are also aware that there are newer studies coming up, prospective data coming up for the role of PSMA-based imaging for response assessment. We are hoping to update the guidelines if we get access to newer data, but currently we have not recommended the utility of PSMA-based imaging for response assessments.

Brittany Harvey: Understood. And I appreciate you describing where there is data here and where there's a lack of data to currently recommend. And we'll look forward to future updates of this guideline.

Coming back to – at the start you mentioned how much has changed since the last guideline update. So Dr. Garje, in your view, what is the importance of this update and how will it impact both clinicians and patients with metastatic castration-resistant prostate cancer?

Dr. Rohan Garje: The updated guidelines are designed to have a significant impact on clinical practice and also patient outcomes by providing clinicians with a comprehensive evidence-based framework for managing patients with metastatic CRPC. And also, by using these guidelines can make informed decisions, can select therapies tailored to patients’ unique genomic status, clinical situation, where they are in the course of the cancer based on what they received previously. Also utilizing these guidelines, we can potentially improve patient outcomes, improve survival, and importantly have efficient use of healthcare resources.

Brittany Harvey: Absolutely. We're always looking for ways to improve patient outcomes and survival.

I want to wrap us up by talking a little bit about the outstanding questions in this field. So earlier you had mentioned about prospective data to come about PSMA PET scans, but what other outstanding questions are there for patients with metastatic castration-resistant prostate cancer? And what evidence is the panel looking forward to for future updates?

Dr. Rohan Garje: We do have now rapidly evolving data specifically about the utility of the radiopharmaceutical lutetium-177 prior to chemotherapy. We are hoping that with newer data we can make some changes to the guideline based on that. We are also looking at newer drugs that are coming up in the pipeline, for example, androgen receptor degraders. We are looking at data that might potentially help based on bispecific T-cell engagers and newer radiopharmaceuticals.

So I think in the next few years, we will definitely update all the guidelines again. But this time we are trying to do it more proactively. We are following a newer model. We are calling it as ‘living guidelines’ where we are actually utilizing week by week updates where we look at the literature and see if there is any potential practice impacting change or publication that comes up. And we are trying to incorporate those changes as soon as they are available. That way patients and practicing physicians can get the latest information available through the guidelines as well.

Brittany Harvey: That's great to hear. Yes, we'll await this data that you mentioned to continuously update this guideline and continue to improve patient outcomes for the future.

So Dr. Garje, I want to thank you so much for your time to update this guideline. It was certainly a large amount of recommendations, and thank you for your time today, too.

Dr. Rohan Garje: Thank you so much for having me here. And it's always nice talking to you.

Brittany Harvey: And finally, thank you to our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Nimish Mohile and Dr. Jaishri Blakeley share the new rapid recommendation update to the therapy for diffuse astrocytic and oligodendroglial tumors in adults guideline. They review the evidence from the INDIGO trial that prompted this update, and how to incorporate the use of vorasidenib into clinical practice. They discuss the importance of molecular testing, particularly for IDH1 or IDH2 mutations and outstanding questions for treatment of patients with oligodendrogliomas and astrocytomas.

Read the latest update, “Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline Rapid Recommendation Update.”

Transcript This guideline, clinical tools, and resources are available at http://www.asco.org/neurooncology-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in Journal of Clinical Oncology.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Jaishri Blakeley from Johns Hopkins University School of Medicine and Dr. Nimish Mohile from the Department of Neurology and Wilmot Cancer Institute at the University of Rochester Medical Center, co-chairs on “Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: American Society of Clinical Oncology-Society for Neuro-Oncology Guideline Rapid Recommendation Update.”

Thank you for being here today, Dr. Blakeley and Dr. Mohile.

Dr. Jaishri Blakeley: Thank you.

Dr. Nimish Mohile: Thank you for having us.

Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Blakeley and Dr. Mohile who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to jump into the content here, Dr. Mohile, could you start us off by describing what prompted this rapid update to the ASCO-SNO therapy for diffuse astrocytic and oligodendroglial tumors in adults guideline, which was previously published in 2021?

Dr. Nimish Mohile: Yeah. So the key reason for this update is the publication of a study in 2023. And this was a study called the INDIGO study that looked at a new class of therapies, something called IDH inhibitors. And in this study with a drug called vorasidenib, changed how we think about the treatment of oligodendrogliomas and astrocytomas, so particularly the grade 2 oligodendrogliomas and grade 2 astrocytomas. Because of the results of that study, we decided that we needed to do an update to inform clinicians about some of these changes and how we might approach these tumors differently today.

Brittany Harvey: Great. I appreciate that background. So then, based off the new data from the INDIGO study, what are the updated and new recommendations from the expert panel?

Dr. Nimish Mohile: So the key findings from the INDIGO study involved people who had grade 2 astrocytomas and grade 2 oligodendrogliomas. And in the setting after surgery, they were treated with vorasidenib, and what they found is that this delayed the time to next intervention. And the key aspect of that is that it delayed when we could start radiation and chemotherapy in these patients.

So what we did in the guidelines is that for both low grade oligodendrogliomas and low grade astrocytomas, we added one additional guideline statement. Our previous guideline in 2021 offered the options for observation or treatment with radiation and chemotherapy. And now in this guideline, we have options for observation, treatment with vorasidenib in those in whom we feel it is safe to defer radiation and chemotherapy, and then treatment with radiation and chemotherapy. So we've added in an additional option here. And the key message of the guideline is really on how, as clinicians, we think about using the vorasidenib and what the ideal setting for using the vorasidenib is.

Brittany Harvey: Excellent. It's great to hear about this new option for patients. So then you were just talking about how we think about who to offer this IDH inhibitor to. So, Dr. Blakeley, what should clinicians know as they implement these new recommendations into practice?

Dr. Jaishri Blakeley: Yes. So, first and foremost, let's go back to 2021, and a key note from those guidelines was the importance of molecular testing. And at that point, the importance of molecular testing, which in large part was focused on IDH1 or IDH2 mutations, was prognostic. We could say there's a difference in an IDH1 mutant astrocytoma and an IDH1 wild type astrocytoma, but we didn't have a specific therapeutic recommendation attached to that, like Dr. Mohile just said. And the big shift here is now we have a specific therapeutic for that population with IDH1 or IDH2 mutant glioma.

So for clinicians, we hope that they've been getting molecular testing on newly diagnosed glioma already, but now there's an additional motivation to do so because it may change your treatment plan in the right circumstance. So since the publication of the phase III INDIGO study that Dr. Mohile mentioned, and the FDA approval of vorasidenib, if you meet the specified criteria in the clinical trial - which the guidelines point out is a little different than what's on the FDA label, so clinicians might want to dig into that a little bit - then there is a treatment option that is new and different than combined chemoradiation or radiation alone or observation.

Brittany Harvey: I appreciate those clarifications there.

So then also, Dr. Blakeley, how does this update impact patients with astrocytic or oligodendroglial tumors?

Dr. Jaishri Blakeley: So first, patients also should know if they have IDH mutant gliomas. And this update only applies to people with IDH1/2 mutant glioma. Perhaps, we're not sure, it might only apply to people who are in the newly or newly-ish diagnosed category because the INDIGO study required that people were within the first five years of their surgical diagnosis and had not had other treatment. So there are a lot of people who have astrocytoma or oligodendroglioma who may or may not know their IDH1/2 status and may have already had another therapy - this update doesn't apply to them. We hope that future research will teach us about that. This update is for people who are newly diagnosed and just starting the journey to figure out the best therapy. It does say that if you do have that IDH1/2 alteration in your tumor, there is a drug therapy that is different from the drug therapies we would offer gliomas that do not have the IDH1/2 mutation.

Brittany Harvey: Absolutely. I think both that emphasis on molecular testing is very important and also thinking about that study inclusion criteria and how it impacts who's eligible for this treatment.

So then finally, Dr. Mohile, what are the outstanding questions about vorasidenib or other interventions for gliomas in adults?

Dr. Nimish Mohile: I think the key question for clinicians is exactly who we're going to use this in. The challenges with inclusion criteria in clinical trials is they don't actually always match what we're seeing in the clinic. And I think it brings up the question of, in low grade oligodendrogliomas which we think of as very slow growing tumors, do we have the option outside of the strict inclusion criteria to use that drug in other settings? I think it brings up the question for some clinicians in some of the higher grade tumors, in the grade 3 tumors, we don't yet have data in that area and our guideline doesn't address that. But I think some will be asking what the clinical activity of vorasidenib is in that setting. There are some suggestions that the IDH inhibitors may impact seizure control, and I think that that's data that we're continuing to wait on.

So I think that there's several outstanding questions there that we will have answers for hopefully in the next several years. I think the big question that we don't have an answer for and that will take a long time to know is whether the addition of vorasidenib in this setting actually improves how long people live. And given how long people with low grade oligodendrogliomas and low grade astrocytomas live today, we probably won't have an answer to that question for more than a decade.

Brittany Harvey: Definitely. We'll look forward to these ongoing developments and eventually longer term data on overall survival on these agents.

So, I want to thank you both so much for your work to rapidly include this information from this new trial. And thank you for your time today, Dr. Blakeley and Dr. Mohile.

Dr. Jaishri Blakeley: Thank you so much.

Dr. Nimish Mohile: Thank you Brittany.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/neurooncology-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Ko Un “Clara” Park and Dr. Mylin Torres present the latest evidence-based changes to the SLNB in early-stage breast cancer guideline. They discuss the practice-changing trials that led to the updated recommendations and topics such as when SLNB can be omitted, when ALND is indicated, radiation and systemic treatment decisions after SLNB omission, and the role of SLNB in special circumstances. We discuss the importance of shared decision-making and other ongoing and future de-escalation trials that will expand knowledge in this space. Read the full guideline update, “Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: ASCO Guideline Update” at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-00099

My name is Brittany Harvey and today I'm interviewing Dr. Ko Un "Clara" Park from Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Dr. Mylin Torres from Glenn Family Breast Center at Winship Cancer Institute of Emory University, co-chairs on “Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: ASCO Guideline Update.”

Thank you for being here today, Dr. Park and Dr. Torres.

Dr. Mylin Torres: Thank you, it's a pleasure to be here.

Brittany Harvey: And before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Torres and Dr. Park, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

To start us off, Dr. Torres, what is the scope and purpose of this guideline update on the use of sentinel lymph node biopsy in early-stage breast cancer?

Dr. Mylin Torres: The update includes recommendations incorporating findings from trials released since our last published guideline in 2017. It includes data from nine randomized trials comparing sentinel lymph node biopsy alone versus sentinel lymph node biopsy with a completion axillary lymph node dissection. And notably, and probably the primary reason for motivating this update, are two trials comparing sentinel lymph node biopsy with no axillary surgery, all of which were published from 2016 to 2024. We believe these latter two trials are practice changing and are important for our community to know about so that it can be implemented and essentially represent a change in treatment paradigms.

Brittany Harvey: It's great to hear about these practice changing trials and how that will impact these recommendation updates.

So Dr. Park, I’d like to start by reviewing the key recommendations across all of these six overarching clinical questions that the guideline addressed. So first, are there patients where sentinel lymph node biopsy can be omitted?

Dr. Ko Un "Clara" Park: Yes. The key change in the current management of early-stage breast cancer is the inclusion of omission of sentinel lymph node biopsy in patients with small, less than 2 cm breast cancer and a negative finding on preoperative axillary ultrasound. The patients who are eligible for omission of sentinel lymph node biopsy according to the SOUND and INSEMA trial are patients with invasive ductal carcinoma that is size smaller than 2 cm, Nottingham grades 1 and 2, hormone receptor-positive, HER2-negative in patients intending to receive adjuvant endocrine therapy, and no suspicious lymph nodes on axillary ultrasound or if they have only one suspicious lymph node, then the biopsy of that lymph node is benign and concordant according to the axillary ultrasound findings. The patients who are eligible for sentinel lymph node biopsy omission according to the SOUND and INSEMA trials were patients who are undergoing lumpectomy followed by whole breast radiation, especially in patients who are younger than 65 years of age. For patients who are 65 years or older, they also qualify for omission of sentinel lymph node biopsy in addition to consideration for radiation therapy omission according to the PRIME II and CALGB 9343 clinical trials. And so in those patients, a more shared decision-making approach with the radiation oncologist is encouraged.

Brittany Harvey: Understood. I appreciate you outlining that criteria for when sentinel lymph node biopsy can be omitted and when shared decision making is appropriate as well.

So then, Dr. Torres, in those patients where sentinel lymph node biopsy is omitted, how are radiation and systemic treatment decisions impacted?

Dr. Mylin Torres: Thank you for that question. I think there will be a lot of consternation brought up as far as sentinel lymph node biopsy and the value it could provide in terms of knowing whether that lymph node is involved or not. But as stated, sentinel lymph node biopsy actually can be safely omitted in patients with low risk disease and therefore the reason we state this is that in both SOUND and INSEMA trial, 85% of patients who had a preoperative axillary ultrasound that did not show any signs of a suspicious lymph node also had no lymph nodes involved at the time of sentinel node biopsy. So 85% of the time the preoperative ultrasound is correct. So given the number of patients where preoperative ultrasound predicts for no sentinel node involvement, we have stated within the guideline that radiation and systemic treatment decisions should not be altered in the select patients with low risk disease where sentinel lymph node biopsy can be omitted. Those are the patients who are postmenopausal and age 50 or older who have negative findings on preoperative ultrasound with grade 1 or 2 disease, small tumors less than or equal to 2 cm, hormone receptor-positive, HER2-negative breast cancer who undergo breast conserving therapy.

Now, it's important to note in both the INSEMA and SOUND trials, the vast majority of patients received whole breast radiation. In fact, within the INSEMA trial, partial breast irradiation was not allowed. The SOUND trial did allow partial breast irradiation, but in that study, 80% of patients still received whole breast treatment. Therefore, the preponderance of data does support whole breast irradiation when you go strictly by the way the SOUND and INSEMA trials were conducted. Notably, however, most of the patients in these studies had node-negative disease and had low risk features to their primary tumors and would have been eligible for partial breast irradiation by the ASTRO Guidelines for partial breast treatment. So, given the fact that 85% of patients will have node-negative disease after a preoperative ultrasound, essentially what we're saying is that partial breast irradiation may be offered in these patients where omission of sentinel node biopsy is felt to be safe, which is in these low risk patients.

Additionally, regional nodal irradiation is something that is not indicated in the vast majority of patients where omission of sentinel lymph node biopsy is prescribed and recommended, and that is because very few of these patients will actually end up having pathologic N2 disease, which is four or more positive lymph nodes. If you look at the numbers from both the INSEMA and the SOUND trial, the number of patients with pathologic N2 disease who did have their axilla surgically staged, it was less than 1% in both trials. So, in these patients, regional nodal irradiation, there would be no clear indication for that more aggressive and more extensive radiation treatment.

The same principles apply to systemic therapy. As the vast majority of these patients are going to have node-negative disease with a low risk primary tumor, we know that postmenopausal women, even if they're found to have one to three positive lymph nodes, a lot of the systemic cytotoxic chemotherapy decisions are driven by genomic assay score which is taken from the primary tumor. And therefore nodal information in patients who have N1 disease may not be gained in patients where omission of sentinel lymph node biopsy is indicated in these low risk patients. 14% of patients have 1 to 3 positive lymph nodes in the SOUND trial and that number is about 15% in the INSEMA trial. Really only the clinically actionable information to be gained is if a patient has four or more lymph nodes or N2 disease in this low risk patient population. So, essentially when that occurs it's less than 1% of the time in these patients with very favorable primary tumors. And therefore we thought it was acceptable to stand by a recommendation of not altering systemic therapy or radiation recommendations based on omission of sentinel nodes because the likelihood of having four more lymph nodes is so low.

Dr. Ko Un "Clara" Park: I think one thing to add is the use of CDK4/6 inhibitors to that and when we look at the NATALEE criteria for ribociclib in particular, where node-negative patients were included, the bulk majority of the patients who were actually represented in the NATALEE study were stage III disease. And for stage I disease to upstage into anatomic stage III, that patient would need to have pathologic N2 disease. And as Dr. Torres stated, the rate of having pathologic N2 disease in both SOUND and INSEMA studies were less than 1%. And therefore it would be highly unlikely that these patients would be eligible just based on tumor size and characteristics for ribociclib. So we think that it is still safe to omit sentinel lymph node biopsy and they would not miss out, if you will, on the opportunity for CDK4/6 inhibitors.

Brittany Harvey: Absolutely. I appreciate you describing those recommendations and then also the nuances of the evidence that's underpinning those recommendations, I think that's important for listeners.

So Dr. Park, the next clinical question addresses patients with clinically node negative early stage breast cancer who have 1 or 2 sentinel lymph node metastases and who will receive breast conserving surgery with whole breast radiation therapy. For these patients, is axillary lymph node dissection needed?

Dr. Ko Un "Clara" Park: No. And this is confirmed based on the ACOSOG Z0011 study that demonstrated in patients with 1 to 3 positive sentinel lymph node biopsy when the study compared completion axillary lymph node dissection to no completion axillary lymph node dissection, there was no difference. And actually, the 10-year overall survival as reported out in 2017 and at a median follow up of 9.3 years, the overall survival again for patients treated with sentinel lymph node biopsy alone versus those who were treated with axillary lymph node dissection was no different. It was 86.3% in sentinel lymph node biopsy versus 83.6% and the p-value was non-inferior at 0.02. And so we believe that it is safe for the select patients who are early stage with 1 to 2 positive lymph nodes on sentinel lymph node biopsy, undergoing whole breast radiation therapy to omit completion of axillary lymph node dissection.

Brittany Harvey: Great, I appreciate you detailing what's recommended there as well.

So then, to continue our discussion of axillary lymph node dissection, Dr. Torres, for patients with nodal metastases who will undergo mastectomy, is axillary lymph node dissection indicated?

Dr. Mylin Torres: It's actually not and this is confirmed by two trials, the AMAROS study as well as the SENOMAC trial. And in both studies, they compared a full lymph node dissection versus sentinel lymph node biopsy alone in patients who are found to have 1 to 2 positive lymph nodes and confirmed that there was no difference in axillary recurrence rates, overall survival or disease-free survival. What was shown is that with more aggressive surgery completion axillary lymph node dissection, there were higher rates of morbidity including lymphedema, shoulder pain and paresthesias and arm numbness, decreased functioning of the arm and so there was only downside to doing a full lymph node dissection.

Importantly, in both trials, if a full lymph node dissection was not done in the arm that where sentinel lymph node biopsy was done alone, all patients were prescribed post mastectomy radiation and regional nodal treatment and therefore both studies currently support the use of post mastectomy radiation and regional nodal treatment when a full lymph node dissection is not performed in these patients who are found to have N1 disease after a sentinel node biopsy.

Brittany Harvey: Thank you.

And then Dr. Park, for patients with early-stage breast cancer who do not have nodal metastases, can completion axillary lymph node dissection be omitted?

Dr. Ko Un "Clara" Park: Yes, and this is an unchanged recommendation from the earlier ASCO Guidelines from 2017 as well as the 2021 joint guideline with Ontario Health, wherein patients with clinically node-negative early stage breast cancer, the staging of the axilla can be performed through sentinel lymph nodal biopsy and not completion axillary lymph node dissection.

Brittany Harvey: Understood.

So then, to wrap us up on the clinical questions here, Dr. Park, what is recommended regarding sentinel lymph node biopsy in special circumstances in populations?

Dr. Ko Un "Clara" Park: One key highlight of the special populations is the use of sentinel lymph node biopsy for evaluation of the axilla in clinically node negative multicentric tumors. While there are no randomized clinical trials evaluating specifically the role of sentinel lymph nodal biopsy in multicentric tumors, in the guideline, we highlight this as one of the safe options for staging of the axilla and also for pregnant patients, these special circumstances, it is safe to perform sentinel lymph node biopsy in pregnant patients with the use of technetium - blue dye should be avoided in this population.

In particular, I want to highlight where sentinel lymph node biopsy should not be used for staging of the axilla and that is in the population with inflammatory breast cancer. There are currently no studies demonstrating that sentinel lymph node biopsy is oncologically safe or accurate in patients with inflammatory breast cancer. And so, unfortunately, in this population, even after neoadjuvant systemic therapy, if they have a great response, the current guideline recommends mastectomy with axillary lymph node dissection.

Brittany Harvey: Absolutely. I appreciate your viewing both where sentinel lymph node can be offered in these special circumstances in populations and where it really should not be used.

So then, Dr. Torres, you talked at the beginning about how there's been these new practice changing trials that really impacted these recommendations. So in your view, what is the importance of this guideline update and how does it impact both clinicians and patients?

Dr. Mylin Torres: Thank you for that question. This update and these trials that inform the update represent a significant shift in the treatment paradigm and standard of care for breast cancer patients with early-stage breast cancer. When you think about it, it seems almost counterintuitive that physicians and patients would not want to know if a lymph node is involved with cancer or not through sentinel lymph node biopsy procedure. But what these studies show is that preoperative axillary ultrasound, 85% of the time when it's negative, will correctly predict whether a sentinel lymph node is involved with cancer or not and will also be negative. So if you have imaging that's negative, your surgery is likely going to be negative.

Some people might ask, what's the harm in doing a sentinel lymph node biopsy? It's important to recognize that upwards of 10% of patients, even after sentinel lymph node biopsy will develop lymphedema, chronic arm pain, shoulder immobility and arm immobility. And these can have a profound impact on quality of life. And if there is not a significant benefit to assessing lymph nodes, particularly in someone who has a preoperative axillary ultrasound that's negative, then why put a patient at risk for these morbidities that can impact them lifelong? Ideally, the adoption of omission of sentinel lymph node biopsy will lead to more multidisciplinary discussion and collaboration in the preoperative setting especially with our diagnostic physicians, radiology to assure that these patients are getting an axillary ultrasound and determine how omission of sentinel lymph node biopsy may impact the downstream treatments after surgery, particularly radiation and systemic therapy decisions, and will be adopted in real world patients, and how clinically we can develop a workflow where together we can make the best decisions for our patients in collaboration with them through shared decision making.

Brittany Harvey: Absolutely. It's great to have these evidence-based updates for clinicians and patients to review and refer back to.

So then finally, Dr. Park, looking to the future, what are the outstanding questions and ongoing trials regarding sentinel lymph node biopsy in early-stage breast cancer?

Dr. Ko Un "Clara" Park: I think to toggle on Dr. Torres’s comment about shared decision making, the emphasis on that I think will become even more evident in the future as we incorporate different types of de-escalation clinical studies. In particular, because as you saw in the SOUND and INSEMA studies, when we de-escalate one modality of the multimodality therapy, i.e., surgery, the other modalities such as radiation therapy and systemic therapy were “controlled” where we were not de-escalating multiple different modalities. However, as the audience may be familiar with, there are other types of de-escalation studies in particular radiation therapy, partial breast irradiation or omission of radiation therapy, and in those studies, the surgery is now controlled where oftentimes the patients are undergoing surgical axillary staging.

And conversely when we're looking at endocrine therapy versus radiation therapy clinical trials, in those studies also the majority of the patients are undergoing surgical axillary staging. And so now as those studies demonstrate the oncologic safety of omission of a particular therapy, we will be in a position of more balancing of the data of trying to select which patients are the safe patients for omission of certain types of modality, and how do we balance whether it's surgery, radiation therapy, systemic therapy, endocrine therapy. And that's where as Dr. Torres stated, the shared decision making will become critically important.

I'm a surgeon and so as a surgeon, I get to see the patients oftentimes first, especially when they have early-stage breast cancer. And so I could I guess be “selfish” and just do whatever I think is correct. But whatever the surgeon does, the decision does have consequences in the downstream decision making. And so the field really needs to, as Dr. Torres stated earlier, rethink the workflow of how early-stage breast cancer patients are brought forth and managed as a multidisciplinary team.

I also think in future studies the expansion of the data to larger tumors, T3, in particular,reater than 5 cm and also how do we incorporate omission in that population will become more evident as we learn more about the oncologic safety of omitting sentinel lymph node biopsy.

Dr. Mylin Torres: In addition, there are other outstanding ongoing clinical trials that are accruing patients right now. They include the BOOG 2013-08 study, SOAPET, NAUTILUS and the VENUS trials, all looking at patients with clinical T1, T2N0 disease and whether omission of sentinel lymph node biopsy is safe with various endpoints including regional recurrence, invasive disease-free survival and distant disease-free survival.

I expect in addition to these studies there will be more studies ongoing even looking at the omission of sentinel lymph node biopsy in the post-neoadjuvant chemotherapy setting. And as our imaging improves in the future, there will be more studies improving other imaging modalities, probably in addition to axillary ultrasound in an attempt to accurately characterize whether lymph nodes within axilla contain cancer or not, and in that context whether omission of sentinel lymph node biopsy even in patients with larger tumors post-neoadjuvant chemotherapy may be done safely and could eventually become another shift in our treatment paradigm.

Brittany Harvey: Yes. The shared decision making is key as we think about these updates to improve quality of life and we'll await data from these ongoing trials to inform future updates to this guideline.

So I want to thank you both so much for your extensive work to update this guideline and thank you for your time today. Dr. Park and Dr. Torres.

Dr. Mylin Torres: Thank you.

Dr. Ko Un "Clara" Park: Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Irene Su and Dr. Alison Loren present the latest evidence-based recommendations on fertility preservation for people with cancer. They discuss established, emerging, and investigational methods of fertility preservation for adults and children, and the role of clinicians including discussing the risk of infertility with all patients. Dr. Su and Dr. Loren also touch on other important aspects of fertility preservation, including the logistics of referral to reproductive specialists, navigating health insurance, and costs. They also discuss ongoing research and future areas to explore, including risk stratification, implementing screening, referral, and navigation processes in lower resource settings, fertility measurements, and health care policy impacts. Read the full guideline update, “Fertility Preservation in People with Cancer: ASCO Guideline Update” at www.asco.org/survivorship-guidelines."

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02782

In this guideline, the terms "male" and "female" were defined based on biological sex, specifically focusing on reproductive anatomy at birth. "Male" refers to individuals born with testes, while "female" refers to those born with ovaries. The guideline, and this podcast episode, we will refer to individuals as "males" or "females" based on this definition.

Brittany Harvey Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Irene Su from the University of California, San Diego, and Dr. Alison Loren from the University of Pennsylvania, co-chairs on “Fertility Preservation in People With Cancer: ASCO Guideline Update.”

Thank you for being here today, Dr. Su and Dr. Loren.

Dr. Irene Su: Thanks for having us.

Dr. Alison Loren: Thanks for having us.

Brittany Harvey: Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Su and Dr. Loren, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to jump into the content here, Dr. Loren, this is an update of a previous ASCO guideline. So what prompted this update to the 2018 guideline on fertility preservation? And what is the scope of this particular update?

Dr. Alison Loren: Yeah, thanks, Brittany. So, yeah, a couple of things, actually. I would say the biggest motivation was the recognition that the field was really moving forward in several different directions. And we felt that the previous guidelines really hadn't adequately covered the need for ongoing reproductive health care in survivorship, including the fact that fertility preservation methods can be engaged in even after treatment is finished. And then also recognizing that there is increasing data supporting various novel forms of fertility preservation in both male and female patients. And we wanted to be able to educate the community about the wide array of options that are available to people with cancer, because it really has changed quite a bit even in the last six years. And then lastly, as I'm sure this audience, and you definitely know, ASCO tries to update the guidelines periodically to make sure that they're current. So it sort of is due anyhow, but I would say motivated largely by those changes in the field.

Brittany Harvey: Great. I appreciate that background information.

So then I'd like to dive a little bit more into those updates that you discussed. So, Dr. Su, I'd like to review the key recommendations across the main topics of this guideline. So starting with what are the recommendations regarding discussing the risk of infertility with patients undergoing cancer treatment?

Dr. Irene Su: Thanks, Brittany. So for every child, adolescent, and adult of reproductive age who's been diagnosed with cancer, the recommendation remains that healthcare clinicians should discuss this possibility of infertility as early as possible before treatment starts, because that allows us, as reproductive endocrinologists and fertility specialists, to preserve the full range of options for fertility preservation for these young people. Where it's possible, I think risk stratification should be a part of the clinical infertility risk counseling and then the decision making. And then for patients and families who have an expressed interest in fertility preservation, and for those who are uncertain, the recommendation is to refer these individuals to reproductive specialists. And it turns out this is because fertility preservation treatments are medically effective for improving post-treatment fertility and counseling can ultimately reduce stress and improve quality of life, even for those who don't undergo fertility preservation. And as Dr. Loren said, a change in the guideline is specifically about continuing these discussions post-treatment yearly or when cancer treatments change because that changes their infertility risk or when pregnancy is being considered.

Brittany Harvey: Absolutely. Discussing that risk of infertility at the beginning, before any treatment is initiated, and when treatment changes, is key.

So then talking about the options for patients, Dr. Loren, what are the recommended fertility preservation options for males?

Dr. Alison Loren: There has been a little bit of an evolution in options for male patients. The standard of care option which is always recommended is cryopreservation of sperm, or otherwise known as sperm banking. And this is something that should be offered ideally prior to initiating cancer directed therapy. The guideline does reflect the fact that we're starting to understand in a little bit more depth the impact of cancer-directed treatments on the health and quantity of sperm. And so trying to understand when, if ever, it's appropriate to collect sperm after initiation of treatment, but before completion of treatment remains an area of active research. But the current understanding of the data and the evidence is that sperm banking should be offered prior to initiating cancer-directed therapy. And all healthcare clinicians should feel empowered to discuss this option with all pubertal and post-pubertal male patients prior to receiving their treatment.

We do offer a little bit more information about the ideal circumstances around sperm banking, including a minimum of three ejaculates of sufficient quality, if possible, but that any collections are better than no collections. We also talk about the fact that there is a relatively new procedure known as testicular sperm extraction, which can be offered to pubertal and post-pubertal males who can't produce a semen sample before cancer treatment begins. There remains no evidence for hormonal protection of testicular function - that has been a long-standing statement of fact and that remains the case. And then we also begin to address some of the potential risk of genetic damage in sperm that are collected soon after initiation of cancer-directed therapy. We are starting to understand that there is a degradation in the number and DNA integrity of sperm that can occur even after a single treatment. And so, really highlighting the fact that collecting samples, again, to Dr. Su's point, as early as possible and as many as possible to try to optimize biological parenthood after treatment.

Brittany Harvey: Yes. Thank you for reviewing those options and what is both recommended and not recommended in this scenario.

So then, following those recommendations, Dr. Su, what are the recommended fertility preservation options for female patients?

Dr. Irene Su: There are a number of established and effective methods for fertility preservation for people with ovaries, and this includes freezing embryos, freezing oocytes, freezing ovarian tissue. For some patients, it may be appropriate to do ovarian transposition, which is to surgically move ovaries out of the field of radiation in a conservative gynecologic surgery, for example, preserving ovaries or preserving the uterus in people with gynecologic cancers. We do recommend that the choice between embryo and oocyte cryopreservation should be guided by patient preference and clinical considerations, their individual circumstances, including future flexibility, the success rates of embryo versus egg freezing that we detail more in the guideline, and legal considerations.

And what is new in this guideline, as Dr. Loren alluded to earlier, is consideration of post-treatment fertility preservation for oocyte and embryo freezing. And this is going to be because, for some females, there's going to be a shortened but residual window of ovarian function that may not match when they are in their life ready to complete their families. And so for those individuals, there may be an indication to consider post-treatment fertility preservation. We clarify that gonadotropin releasing hormone agonists, GNRH agonists, while they shouldn't be used in the place of established fertility preservation methods, e.g., oocyte and embryo freezing, they can definitely be offered as an adjunct to females with breast cancer. Beyond breast cancer, we don't really understand the benefits and risks of GNRH agonists and feel that clinical trials in this area are highly encouraged. And also, that for patients who have oncologic emergencies that require urgent chemotherapy, these agonists can be offered because they can provide additional benefits like menstrual suppression.

What's emerging is in vitro maturation of oocytes. It's feasible in specialized labs. It may take a little bit shorter time to retrieve these oocytes. There are cases of live births following IVM, in vitro maturation, that have been reported. But these processes remain inefficient compared to standard controlled ovarian stimulation. And therefore, it's really being treated as an emerging method.

Finally, uterine transposition. It's experimental, but it's a novel technique for us. It's really moving the uterus out of the field of radiation surgically. We recommend that this is done under research protocols.

So taken together, there are improvements in fertility preservation technology, and consideration of which of any of these methods really depends on tailoring to what is that patient's risk, what is the time that they have, what is feasible for them, and what is the effectiveness comparatively among these methods for them.

Brittany Harvey: I appreciate you reviewing those recommendations and considerations of patient preferences, the clarification on GNRH agonists, and then those emerging and experimental methods as well.

So then the next category of recommendations, Dr. Loren, what are the recommended fertility preservation options for children?

Dr. Alison Loren: Thanks, Brittany. This remains a very challenging area. Certainly for older children and adolescents who have begun to initiate puberty changes, we support proceeding with previously outlined standard methods of either sperm or oocyte collection and cryopreservation. For younger children who are felt to be at substantial risk for harm to fertility, the really only options available to them are gonadal tissue cryopreservation, so ovarian tissue or testicular tissue cryopreservation. As Dr. Su mentioned, the ovarian tissue cryopreservation methods are quite effective and well established. There's less data in children, but we know that in adults and older adolescents that this is an effective method. Testicular cryopreservation remains experimental, and we suggest that if it is performed, that strong consideration should be given to doing this as an investigational research protocol. However, because these are the only options available to children, we understand there may be reasons why there might need to be some flexibility around this in the proper setting of informed consent and ascent when appropriate for children.

Brittany Harvey: Absolutely. And so we've discussed a lot of recommendations on fertility preservation options. So, Dr. Loren, what is recommended regarding the role of clinicians in advising people about these fertility preservation options?

Dr. Alison Loren: Yeah, this is a really important question, Brittany, and I think that we really hope to empower the entire oncology clinical team to bring these issues to the forefront for patients. We know from qualitative studies that oncology providers sometimes feel uncomfortable bringing these issues up because they feel inexpert in dealing with them or because it's so overwhelming. Obviously, these are usually younger patients who are not expecting a cancer diagnosis, and there can be quite a lot of distress, understandably, around the diagnosis itself and the treatment plan, and it can be sometimes overwhelming to also bring up fertility as a potential risk of therapy. We are seeing that as patients are becoming more familiar and comfortable kind of speaking up, I think, social media and lots of sort of online communities have raised this issue, that we're seeing that young people with cancer do spontaneously bring this up in their visits, which we really appreciate and encourage. But I think sometimes clinicians feel it's sometimes described as a dual crisis of both the cancer diagnosis and a risk to future fertility and it can be a really challenging conversation to initiate.

I feel, and we hope that the guidelines convey, that the whole point is just to bring it up. We do not expect an oncology clinician of any kind, including social workers, nurses, to be able to outline all of the very complex options that are articulated in this guideline. And in fact, the reason that the co-chairs include myself, a hematologist oncologist, and Dr. Su, who's a reproductive specialist, is because we understand that the complex reproductive options for our patients with cancer require expert conversations. So we do not expect the oncology team to go into all the guideline options with their patients. We really just want to empower everyone on the team to bring up the issue so that we can then get them the care that they need from our colleagues in reproductive endocrinology so that they can be fully apprised of all of their options with enough time before initiation of treatment to be able to embark on whichever therapies they feel are most suited to their family planning wishes.

Brittany Harvey: Absolutely. And then jumping off of that, as a reproductive endocrinologist, Dr. Su, what do you think clinicians should know as they implement these updated recommendations?

Dr. Irene Su: I wholly echo what Dr. Loren has said about- this is a team effort and it's been really fun to work as a team of various specialties on this guideline, so we hope that the guideline really reflects all of the partnerships that have occurred. I think that what clinicians should know is it may be well worth spending some time in identifying a pathway for our patients. So that starts off with the oncology team. How are we going to screen? How are we going to screen with fidelity? And then from the time of screening, really anybody who has an interest or potentially is unsure about their future fertility needs, who are the reproductive specialists, male and female, that you are in the community with to refer to? What is that referral process going to be like? Is it emails? Is it a phone? Is it a best practice advisory in your electronic health record system?

From our standpoint as fertility specialists, we need to spend some time implementing in this system a way to receive these referrals urgently and also be able to support insurance navigation. Because actually, what is really exciting in this field is for the purpose of equitable access, there is increasing insurance coverage, whether it is because employers feel that this is the right thing to do to offer, or 17 states and the District of Columbia also have state mandates requiring fertility preservation coverage by many insurances, as well as, for example, federal employees and active military members. So more than ever, there is a decreased cost barrier for patients and still early days, so navigating health insurance is a little bit challenging. And that is the role, in part, of navigators and fertility clinic teams to help support these patients to do that.

Dr. Alison Loren: Forming these relationships and reinforcing them so early and often is really key. Because although these patients come up with some infrequency, when they occur, they're really emergencies and we want to make sure that there's a well-established path for these patients to get from their oncology clinicians to the reproductive specialists. And as Dr. Su said, whatever works best for your system - there's a lot of different ways that people have tackled these challenging referrals - but it is really important to have an expedited path and for the receiving reproductive specialist office to understand that these are urgent patients that need to be expedited and that the oncology clinician's responsibility is to make sure that that's communicated appropriately.

Brittany Harvey: Definitely. Thinking in advance about those logistics of referral and navigating health insurance and cost is key to making sure that patients receive the care that they want and that they'd like to discuss with clinicians.

So then, Dr. Loren, you touched on this a little bit earlier in talking about the dual crisis, but how does this guideline impact people diagnosed with cancer?

Dr. Alison Loren: Well, what we're hoping is that this is sort of a refresher. I think that many or hopefully most or all oncology clinicians are aware that this is a potential concern. And so part of our hope is that, as this guideline rolls out, it'll sort of bring to the top of people's memories and action items that this is an important part of oncology care is the reproductive health care of our patients. And it's a critical component of survivorship care as well. We want to remind people that the field continues to advance and progress. In oncology, we're very aware of oncologic progress, but we may not be so aware of reproductive healthcare progress. And so letting people know, “Hey, there's all these new cool things we can do for people that open up options, even in situations where we might have thought there were no options before.” It's a reminder to refer, because we're not going to be able to keep up with all the advances in the field. But Dr. Su and her colleagues will be able to know what might be an option for patients. I want to highlight that communication piece again because our reproductive colleagues need to know what treatments are going to be given, what the urgency is, what the risks are. And so part of our responsibility as part of the team is to make sure that it's clear to both our patients and our reproductive specialist colleagues what the risks are.

And Dr. Su mentioned this earlier, but one really important open question is risk stratification. We know that not all cancer treatments are created equal. There are some treatments, such as high dose alkylating agents, such as cyclophosphamide or busulfan, or high doses of radiation directly to the gonadal tissue, that are extremely high risk for causing permanent gonadal harm very immediately after exposure. And there are other therapies, particularly emerging or novel therapies, that we really just have no idea what the reproductive impact will be. And in particular, as patients are living longer, which is wonderful for our patients, how do we integrate reproductive care and family building into the management of perhaps a younger person who's on some chronic maintenance therapies, some of which we know can harm either the developing fetus or reproductive health, and some of which we really don't know at all. And so there's a very large open question around emerging therapies and how to counsel our patients. And so we hope that this guideline will also raise to the forefront the importance of addressing these questions moving forward and helping our patients to understand that we don't necessarily have all the answers either, which we hope will enrich the discussion and really have it be a good example of shared decision making between the clinical teams and the patient, so that ultimately the patients are able to make decisions that make the most sense for them and reduce the potential for decision regret in the future.

Dr. Su, I know you have spent a lot of time thinking about this.

Dr. Irene Su: Yeah. I really echo this notion that not all cancer treatments are going to be toxic to future reproductive function. And as clinicians, I and colleagues know that patients want to know as much when there is no effect on their fertility, because that feels reassuring in that that prevents them from having to go through the many hoops that sometimes it can be to undergo fertility preservation, as it is to know high risk, as it is to know we don't know. This is key and central, and we need more data. So, for example, we often chat about, wouldn't it be great if from the time of preclinical drug development all the way to clinical trials, that reproductive health in terms of ovarian function, testicular function, fertility potential, is measured regularly so that we are not having to look back 30, 40, 50 years later to understand what happened. And so this is one of our key research questions that we hope the field takes note of going forward.

Dr. Alison Loren: This is an important point. We focus greatly, as we should, on potential harms to fertility, making sure that there's access to all the reproductive options for young people with cancer. But to Dr. Su's point, not all therapies are created equal, and there are some therapies that are somewhat lower risk or even much lower risk, including, I'm a blood cancer specialist and so certainly in the patients that I take care of, the treatments related to AML, ALL, and some lymphomas are actually fairly low risk, which is why the post-treatment fertility preservation options are so important. And particularly for patients who potentially present acutely ill with acute leukemia do not have the time or the ability to engage in fertility preservation because of their medical circumstances, it's important to have that conversation. I want to emphasize to oncology clinicians that even if you know medically that this patient is unable to undergo fertility preservation techniques at the time of diagnosis of their cancer, that it's still appropriate to talk about it and to say, “We're going to keep talking about this, this is something that we're going to raise again once you're through this initial therapy. I'm not forgetting about this. It may not be something we can engage in now, but it's a future conversation that's important in your ongoing care.” And then to think about pursuing options when possible, particularly for patients who may require a bone marrow transplant in their future, either due to higher risk disease at presentation or in the event of a relapse, we know that generally bone marrow transplants, because of the high intensity conditioning that they require for most patients who are young, that permanent gonadal insufficiency will be a fixture. And so there can be a window of time in between initial therapy and transplant where a referral might be appropriate.

So my public service announcement is that it's never the wrong time to refer to a reproductive specialist. And sometimes people make assumptions about chemotherapy that, “Oh, they've already been treated, so there's nothing we can do,” and I want to make sure that people know that that's not true and that it's always appropriate to explore options.

Dr. Irene Su: I think we talk a lot about how important screening and referral is and I can imagine that it's hard to actually know how to implement that. One of our other research questions to look out for is that we see a lot of tertiary care centers that have put together big teams, big resources, and that's not always feasible to scale out to all kinds of settings. And so what's emerging is: What are the key processes that have to happen and how can we adapt this screening, referral, financial navigation process from larger centers to smaller centers to less resource settings.

So I guess my public service announcement is there's research in this area, there's focus in this area, so keep an eye out because there will be hopefully better tools to be able to fit in different types of settings. And more research is actually needed to be able to trial these different screening, referral, navigation processes in lower resource settings as well.

Brittany Harvey: Absolutely. It's important to think about the research questions on how to improve both the delivery of fertility preservation options and the discussion of it, and it's important to recognize, as you mentioned, the different fertility risks of different cancer directed treatment options and the importance to have the conversations around this.

So then just to expand on this notion a little bit, Dr. Su, we've touched on the research needed here in terms of discussing fertility options with patients and referring and then also in some of the experimental and emerging treatment options. So, what are the other outstanding research questions regarding fertility preservation for people with cancer?

Dr. Irene Su: A couple others I'd like to add and then have Dr. Loren chime in in case I missed anything in all of our discussions, there's so many wants. So head to head comparisons of which method is best for which patient and what the long term outcomes are: How many kiddos? Do we complete family building? That is still missing. Being able to invest in novel methods from - there’s fertoprotective agents that are being tested, potentially spermatogonial stem cell transplant. These are closer to clinical trials to really early research on ovarian, testicular, uterine biology. This is needed in order to inform downstream interventions. One of the questions that is unanswered is: After treatment starts, when is it safe to retrieve oocytes? And so this is a question because, for example, for our leukemia patients who are in the middle of treatment, when is it safe to retrieve eggs? And we don't know. And then post-treatment, for people who have a reduced window, when do you optimally have the most number of eggs or embryos that you can cryopreserve? That's unknown. But I think the question around once treatment has started, is recent exposure of anti-cancer treatments somehow mutagenic or somehow toxic to the oocytes with regard to long term offspring health? That is unanswered.

I'm going to scope out a little bit and maybe policy nerd this a little bit. It's been very exciting to see advocacy, advocacy from our patients, from our clinicians on trying to improve health care policy. Like how can we use mandates to improve this delivery? But we actually don't know because actually the mandates from states that require health insurance coverage for fertility preservation, they vary. And so actually what are the key ingredients and policies that will ultimately get the most patients to the care they need? That is in question and would be really interesting. And so what is a part of this guideline which is not often seen in clinical guidelines, is a call for what we think are best practices for health insurance plans to help patients be able to access. And so this means that we recommend being specific and comprehensive in the coverage of these established fertility preservation services that have been recommended. And this means, for example, an egg freezing covering the whole process from consultation to office visits, to ultrasounds and laboratories, to medicines, to the retrieval, and then to long term storage. Because particularly for the youngest of our patients, these gametes could be frozen for a number of years and may not always be so affordable without health insurance coverage.

We think that fertility preservation benefits really should be at parity, that you should not be having more cost sharing on the patient compared to other medical services that are covered. This is an inequity and where possible we should eliminate prior authorization because that timing is so short between diagnosis and needing to start anti-cancer treatment. And so prior authorization having to go through multiple layers of health insurance is really a key barrier because we all know that health insurance literacy is limited for all of us. And so whatever we can do to support our patient for the intent of these benefits would be recommended.

Dr. Alison Loren: That was so well said, Dr. Su. I'll take the oncology perspective and say that from our side, really being able to understand the risks of infertility and understanding better measurements of fertility capacity, understanding where our patients are - every patient is different. These conversations are very different for a 37-year-old than they are for a 17-year-old. And so what we haven't really talked about is the fact that certainly at least female patients, as they age, their reproductive potential declines naturally. And so their infertility trajectory may be accelerated, they may have a shorter timeline or have less reserve than younger patients. And so being able to tailor our risk discussions not just based on the specific treatments, but on the reproductive age of the patient sitting in front of us and really being able to tailor those to very personalized risks would be really helpful. Because, as Dr. Su mentioned, and I think, as many people know, undergoing fertility preservation techniques can be really arduous. Even if they're covered and paid for, and all of those logistics are easy, which they seldom are, the physical drain of having to do injections, go for labs, all of the parts of those therapies can be really difficult for patients. And so being able to really understand who needs to have these interventions and who could pass, and understanding what the risks are, as I mentioned earlier, for these novel and emerging therapies would be really helpful.

Another really important aspect of future research questions is we would like to encourage all clinicians, both reproductive specialists and oncology clinicians, and also our young people with cancer, to participate in clinical studies pertaining to fertility measurements and preservation. We also exhort our industry colleagues to consider including important reproductive endpoints, including biomarkers of ovarian and testicular reserve, if possible, in clinical trials. It will enhance our ability to provide counseling and support for these therapies in the future to be able to understand what the true impact of infertility, family building and health of offspring to be able to include these data in prospective databases and trials.

Brittany Harvey: Definitely. And I want to thank you both for raising those really important points. So we'll look forward to this ongoing research and optimizing policies for covering fertility preservation benefits for all patients with cancer.

I want to thank you both so much for your work to update this critical guideline and talk about these important needs of people with cancer. And thank you for your time today, Dr. Su and Dr. Loren.

Dr. Alison Loren: Thanks so much for having us.

Dr. Irene Su: You're welcome. This was really fun.

Dr. Alison Loren: It was fun. And I just will add that the team at ASCO is amazing and really made this a pleasure.

Dr. Irene Su: I couldn't agree more. And from the point of being a fertility specialist, being invited to be a part of this with ASCO and with all of our colleagues, it's been really amazing. And so thanks for allowing us to contribute.

Brittany Harvey: Definitely. And a big thanks to the entire panel as well.

And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Mellar Davis discusses the joint guideline from MASCC, ASCO, AAHPM, HPNA, and NICSO on opioid conversion in adults with cancer. He reviews the limited evidence, and the formal consensus process used to develop the guideline. He shares the key recommendations on pre-conversion assessment, how opioid conversion should be conducted, including opioid conversion ratios, and post-conversion assessment. We touch on gaps and questions in the field and the impact of these new recommendations.

Read the full guideline, “Opioid Conversion in Adults with Cancer: MASCC-ASCO-AAHPM-HPNA-NICSO Guideline” at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline in the Supportive Care in Cancer, https://link.springer.com/article/10.1007/s00520-025-09286-z

My name is Brittany Harvey and today I'm interviewing Dr. Mellar Davis from Geisinger Medical Center, lead author on “Opioid Conversion in Adults with Cancer: Multinational Association of Supportive Care and Cancer, American Society of Clinical Oncology, American Academy of Hospice and Palliative Medicine, Hospice and Palliative Nurses Association, Network Italiano Cure di Supporto and Oncologia Guideline.”

Thank you for being here today, Dr. Davis.

Dr. Mellar Davis: Thank you. I'm glad to be here.

Brittany Harvey Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Davis, who has joined us here today, are available online with the publication of the guideline, which is linked in our show notes.

So then, to dive into the content here, Dr. Davis, can you provide an overview of both the scope and purpose of this guideline on opioid conversion in people with cancer?

Dr. Mellar Davis: This is an important topic in management of cancer pain and this topic came up as a result of a survey that MASCC had done, which involved 370 physicians in 53 countries. They were queried about how they change or convert one opioid to another, which is a common practice, and we found that there was quite a divergence in opioid conversion ratios. To step back a little bit, about two thirds of patients with advanced cancer have moderate to severe pain and most of the time they're managed by opioids. But about 20% or 40% require a switch either because they have an adverse reaction to it or they don't respond to it, or the combination of both. Rarely, it may be that they need a route change, perhaps because they have nausea or vomiting. So, the opioid conversion works basically because of the complexity of the new opioid receptor which has at least four exons to it as a result of that non-cross tolerance between opioids.

As a result of the survey, we convened a group of specialists, 14 international specialists, to look to see if we could develop an international guideline. And we did a systematic review which involved viewing 21,000 abstracts and we came up with 140 randomized trials and 68 non-randomized trials. And after reviewing the data, we found that the data was really not strong enough to provide a guideline. As a result, ASCO, MASCC, the AAHPM, the HPNA and the Italian Group formed a supportive network that allowed us then to do a Delphi guideline based upon ASCO modified criteria for doing Delphi guidelines.

And so we then involved 27 additional international experts informing the guideline to it. And this guideline is then the result of the Delphi process. It consists basically of a pre-conversion ratio recommendations, conversion ratios, which is actually a major contribution of this guideline, and then what to do after converting someone to another opioid. Our target audience was not only oncologists, but also we wanted to target nurses, pharmacists, hospitalists, primary care physicians, patients and caregivers.

Brittany Harvey: I appreciate that background information, particularly on the evidence that is underpinning this and the lack of quality of evidence there, which really transformed this into a formal consensus guideline. We're glad to have all of these organizations coming together to collaborate on this guideline.

So then next I'd like to review the key recommendations. So starting with, what is recommended for pre-conversion assessment?

Dr. Mellar Davis: In regards to pre-conversion, physicians and clinicians need to be aware of pain phenotypes. That is, there are pains that are more opioid refractory than others, such as neuropathic pain, hence, they may be more resistant to the opioid that you're converting to. One needs to be aware of the fact that patients may not be compliant, they're either afraid of opioids not taking what was prescribed, so it's important to query patients about whether they are taking their opioid as prescribed. Occasionally, there are patients who will divert their medication for various reasons. Pain may be poorly controlled also because of dosing strategies that are poorly conceived, in other words, giving only ‘as needed’ opioids for continuous cancer pain. And there are rare circumstances where an opioid actually induces pain and simply reducing the opioid actually may improve the pain. The other issue may be cancer progression. So that poorly controlled pain or rapidly increasing pain may actually be a result of progressive cancer and changing treatment obviously will be important. And you need to assess the pain severity, the quality of the pain, the radiating localizing effects, which does require not only a physical exam but also radiographic examinations.

But the other thing that's very important in opioid conversions are pain scales with function. A significant number of patients don't quite understand a numerical scale which we commonly use: 0 to 10, with 10 being severe pain and 0 being no pain. They may in fact focus more on function rather than on pain severity or pain interference with daily activities or roles. Sometimes patients will say, “Oh, my pain is manageable,” or “It's tolerable,” rather than using a numerical scale. Choices of opioids may be based on cost, drug-drug interactions, organ function, personal history or substance use disorder so that one will want to choose an opioid that's safe when converting from one to another. And obviously social support and having caregivers present and understanding the strategy in managing pain will be important.

Brittany Harvey: Thank you, Dr. Davis, for reviewing those pre-conversion assessment considerations and particularly the challenges around some of those.

So, following this pre-conversion assessment, what are the recommendations on how opioid conversion should be conducted?

Dr. Mellar Davis: Opioid conversions are basically the safe dose. People have used the term ‘equianalgesia’, but the panel and the consensus group felt that that would be inappropriate. So a conversion ratio is the dose at which the majority of patients will not experience withdrawal or adverse effect. It would be the safe dose. Thereafter, the dose will need to be adjusted. So, in converting, that's only the first step in managing pain, the doses need to be adjusted to the individual thereafter. There are a significant number of conversions that are done indirectly, that is that there has not been a study that has looked at a direct conversion from one opioid to another in which one needs to convert through another opioid. We call that a ‘morphine equivalent daily dose’. So, most of the time a third opioid is used in the conversion. It allows you then to convert when there hasn't been a direct study that has looked at conversion between those two opioids, but it is less accurate and so one has to be a little bit more careful when using morphine daily equivalents.

We found, and I think this is the major advantage to the guideline, is that commonly used opioids - oxycodone, morphine, hydromorphone - we did establish conversion ratios to which we found in the MASCC guideline they were widely divergent and hope that actually, internationally, they will be adopted. We also found some conversion ratios for second-line opioids. However, we felt also that an opioid like methadone, which has a unique pharmacology, should be left to experts and that experts should know at least several ways of converting from morphine usually to methadone. There is what appears to be a dose-related increased potency of methadone relative to morphine, which makes it more difficult, particularly at higher doses, to have an accurate conversion ratio. Most patients will have transient flares of pain. We came up with two suggestions. One is using a 10 or 15% of the around-the-clock dose for the breakthrough dose, but we also realized that there was a poor correlation between the around-the-clock dose and the dose used for transient flares of pain. And so the breakthrough dose really needs to be adjusted to the individual responses.

There was also a mention of buprenorphine. One of the unique things about buprenorphine is that if you go from high doses of a drug like morphine to buprenorphine in a stop-start dosing strategy, you can precipitate withdrawal. And so one has to be careful and have some experience in using buprenorphine, which can be an effective analgesic.

Brittany Harvey: Yes, I think that the conversion ratios that you mentioned that are in Table 3 in the full guideline are a really useful tool for clinicians in practice. And I appreciate the time that the panel and the additional consensus panel went through to develop these. I think it's also really key what you mentioned about these not being equianalgesic doses and the difficulties in some of these conversions and when people need to really look to specialists in the field.

So then, following opioid conversion, what assessments are recommended post-conversion?

Dr. Mellar Davis: Post-conversion, probably the cardinal recommendation is close observation for response and for toxicity. And I think that probably summarizes the important parts of post-conversion follow up. So assessment should be done 24-48 hours after conversion and patients followed closely. Assessment scales should include patient personalized goals. Now, it used to be in the past that we had this hard stop about a response being below 4 on a 0 to 10 scale, but each patient has their own personal goals. So they gauge the pain severity and their function based upon response. So a patient may function very well at “a severity of 5” and feel that that is their personal goal. So I think the other thing is to make sure that your assessment is just not rote, but it's based upon what patients really want to achieve with the opioid conversion. The average number of doses per day should be assessed in the around-the-clock dose so those should be followed closely. Adverse effects can occur and sometimes can be subtle. In other words, a mild withdrawal may produce fatigue, irritability, insomnia and depression. And clinicians may not pick up on the fact that they may be actually a bit under what patients have or they're experiencing withdrawal syndrome.

It's important to look for other symptoms which may be subtle but indicating, for instance, neurotoxicity from an opioid. For instance, visual hallucinations may not be volunteered by patients. They may transiently see things but either don't associate with the opioid or are afraid to mention them. So I think it's important to directly query them, for instance, about visual hallucinations or about nightmares at night. Nausea can occur. It may be temporary, mild, and doesn't necessarily mean that one needs to stop the second opioid. It may actually resolve in several days and can be treated symptomatically. Pruritus can occur and can be significant. So close observation for the purposes of close adjustments are also necessary. As we mentioned, you want to start them on an around-the-clock of breakthrough dose, but then assess to see what their response is and if it’s suboptimal then you'll need to adjust the doses based both upon the around-the-clock and the breakthrough dose or the dose that's used for breakthrough pain. Also looking at how patients are functioning, because remember that patients frequently look at pain in terms of function or interference with their roles during the day. So, if patients are able to do more things, that may, in fact, be the goal.

Brittany Harvey: Thank you for reviewing all of these recommendations across pre-conversion assessment, how opioid conversion should be conducted, including conversion ratios, and what assessments are recommended after opioid conversion. I think it's really important to be watching for these adverse events and assessing for response and keeping in mind patient goals. So, along those lines, how will these guideline recommendations impact both clinicians and people with cancer? And what are the outstanding questions we're thinking about regarding opioid conversion?

Dr. Mellar Davis: I think it's important to have a basic knowledge of opioid pharmacology. There's, for instance, drugs that are safer in liver disease, such as morphine, hydromorphone, which are glucuronidated. And there are opioids that are safer in renal failure, such as methadone and buprenorphine, which aren't dependent upon renal clearance. I think knowing drug-drug interactions are important to know. And sometimes, for instance, there may be multiple prescribers for a patient. The family physician's prescribing a certain medication and the oncologist is another, so being aware of what patients are on, and particularly over-the-counter medications which may influence opioid pharmacokinetics. So complementary medications, for instance, being aware of cannabis, if patients are using cannabis or other things, I think, are important in this.

There are large gaps and questions and that's the last part of the guideline that we approach or that we mentioned that I think are important to know. And one is there may be ethnic differences in population in regards to clearance or cytochrome frequencies within communities or countries, which may actually alter the conversion ratios. This has not been explored to a great extent. There's opioid stigmata. So we are in the middle of an opioid crisis and so people have a great fear of addiction and they may not take an opioid for that reason, or they may have a relative who's been addicted or had a poor experience. And this may be particularly true for methadone and buprenorphine, which are excellent analgesics and are increasingly being used but may in fact have the stigmata.

There are health inequalities that occur related to minority groups that may in fact not get the full benefit of opioid conversions due to access to opioids or to medical care. Age, for instance, will cause perhaps differences in responses to opioids and may in fact affect conversion ratios. And this may be particularly true for methadone, which we have not really explored to a great extent. And finally, the disease itself may influence the clearance or absorption of an opioid. So for a sick patient, the opioid conversion ratio may be distinctly different than in a healthy individual. This is particularly seen with transdermal fentanyl, which is less well absorbed in a cachectic patient, but once given IV or intravenously has a much longer half life due to alterations in the cytochrome that clears it. And so conversion ratios have frequently been reported in relatively healthy individuals with good organ function and not that frequently in older patient populations. So just remember that the conversion ratios may be different in those particular populations.

Brittany Harvey: Yes. So I think a lot of these are very important things to consider and that managing cancer pain is key to quality of life for a lot of patients and it's important to consider these patient factors while offering opioid conversion.

I want to thank you so much for your work to review the existing literature here, develop these consensus-based recommendations and thank you for your time today, Dr. Davis.

Dr. Mellar Davis: Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Jyoti Patel is back on the podcast to discuss the updates to the living guideline on therapy for stage IV NSCLC with driver alterations. She shares updated recommendations in the first- and second-line settings for patients with stage IV NSCLC and classical EGFR mutations, and the impact of these updates for clinicians and patients. We also look to the future to discuss ongoing developments in the field. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02785

Brittany Harvey: Welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.”

It's great to have you back on the show today, Dr. Patel.

Dr. Jyoti Patel: Thanks so much. Happy to be here.

Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline and in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content of this update, Dr. Patel, this clinical practice guideline for systemic therapy for patients with stage IV non small cell lung cancer with driver alterations is living, meaning that it's continuously reviewed and updated. So what data prompted this latest change to the recommendations?

Dr. Jyoti Patel: Thanks so much. So it's really been an exciting time in the treatment of EGFR lung cancer, particularly this past year has required us to rethink approaches to front- and second-line therapy. In this particular update, we examined what patients in the front-line setting may be offered by their clinicians. And so we're talking about the population of classical EGFR mutations, so exon 19 and exon 21 L858R substitution. And so certainly for this population, osimertinib has a high level of evidence and should be offered to all patients at the time of diagnosis when they present with advanced disease. Our last update included a recommendation that patients could also get platinum doublet chemotherapy with osimertinib or osimertinib alone. This current recommendation also introduces another alternative therapy and that's the combination of amivantamab plus lazertinib. And so now, clinicians are faced with three really good options for their patients with EGFR exon19 deletion or L858R.

Brittany Harvey: It's great to hear that there's this advance in the space, particularly for patients with these classical EGFR mutations that you mentioned.

So what should clinicians know as they implement these new first-line recommendations?

Dr. Jyoti Patel: I think it's become more complex than ever. Certainly, we know again that patients should get osimertinib in the frontline setting. But we've been kind of stuck at progression-free survival that's between a year and a half and two years. And so we've really been looking at opportunities to intensify therapy. So one could certainly be with chemotherapy or switching over to amivantamab, the bispecific antibody that targets EGFR and MET plus lazertinib, an oral TKI that's very similar in structure to osimertinib. And when you're talking to a patient, it's really a conversation about balancing efficacy with toxicity. Unfortunately, as we know, there aren't that many free lunches. And so if we think about what a patient is hoping for in their therapy and how we can further personalize treatment options, really is important to look at some of the analyses for this study.

So in the study of amivantamab plus lazertinib, we know that there were increased toxicities with a combination of both therapies. In fact, up to 75% of patients had over grade 3 toxicities, versus about 43% of patients with osimertinib monotherapy. And we know if we look back at FLAURA2, almost two thirds of patients with osimertinib and chemotherapy had grade 3 toxicities, compared to 27% of patients with osimertinib alone. So we certainly see an increase in toxicities. Then we have to ask ourselves, are those paper toxicities or ones that really impact patients? And we know that amivantamab, for example, causes significant cutaneous toxicities. With both of these therapies, whether it's chemotherapy or adding amivantamab, there's the burden of infusional visits and increased time in the doctor's office. Certainly with chemotherapy, there can be an increased incidence of myelosuppression. And so when we're thinking about advising our patients, certainly we need to talk about the toxicities.

But one thing that we've been able to do is to look at the patients that were included in this trial. And what we really find is that in higher risk cohorts, particularly those that we know historically have done less well with standard osimertinib, so patients, for example, with CNS metastasis, for those patients with co-mutations, it may be that that additive benefit is significant. And so one example I think would be from the MARIPOSA study, again, the study of amivantamab and lazertinib versus chemotherapy. What we can say is that patients who had co-mutations, so patients with EGFR mutations as well as TP53, lazertinib and amivantamab led to a hazard ratio of 0.65 compared to osimertinib alone. So that was 18.2 months versus 12.9 months. And so this may be really important to patients. And we also see conversely that patients with wild type TP53, so those patients who didn't have the mutation, probably had equivalent survival regardless of therapy.

So certainly, we need to prospectively study some of these high-risk cohorts. We've only seen progression-free survival in these studies. And so at this juncture, we can advise our patients about toxicity, the improvements in certain categories of progression-free survival, but we really still don't know how this pans out in overall survival. In many of these studies, all patients do not necessarily cross over to the study arm and so they may have lost the benefit of subsequent therapy.

Brittany Harvey: Absolutely. It's very important to talk about that balance of benefits and risks and particularly those toxicities that you discussed.

So I appreciate reviewing that recommendation and the considerations for clinicians for first-line therapy. This update also included a second-line treatment update. What is that update for patients with EGFR alterations?

Dr. Jyoti Patel: So this is where it gets super tricky because we have a frontline option with amivantamab and now we've had an update in the second line option. So what we said is that for patients who have progressed on an EGFR TKI, and in the United States, certainly that's predominantly osimertinib, or those in other parts of the world that may have gotten an earlier generation TKI, but do not have evidence of T790M or other targetable mutations, we can offer patients chemotherapy with or without amivantamab. And so certainly we have seen that this again leads to improved survival.

There have also been a number of studies looking at incorporation of PD-L1 and anti-VEGF therapies. And what we can say, I think pretty clearly is that multiple phase 3 trials have really shown no benefit of the addition of PD-1 to platinum chemotherapy. But there are some emerging bispecific antibodies that may target PD-1 as well as VEGF, or combinations of antibodies that target both of those pathways that may improve outcome. At this juncture, I think we feel that the evidence surrounding chemotherapy plus amivantamab is strongest, but there is certainly work in this space that will be of interest.

Now, what happens if your patient received amivantamab and lazertinib in the frontline setting and then has progression? And so we're trying to understand resistance mechanisms and opportunities for treatment. What the panel decided to recommend, based on the available evidence, was that certainly those patients should get platinum-based chemotherapy, but there may also be a role for antivascular endothelial growth factor targeting therapy such as bevacizumab in patients in whom it would be safe.

Brittany Harvey: Great. I appreciate you detailing those recommendations when it gets complicated in the second-line setting.

So what should clinicians know as they implement these second-line recommendations too?

Dr. Jyoti Patel: So certainly the frontline setting matters significantly. So if a patient gets osimertinib in the frontline setting, we generally suggest that patients undergo repeat testing to see if they have another targetable mutation. If they don't, then I think preferred therapy would be chemotherapy with or without amivantamab. And amivantamab leads to a significant improvement in progression-free survival and response rate at the cost of increased risk of toxicity. For patients who get FLAURA2 in the frontline setting, chemotherapy plus osimertinib, it's a little bit of an unclear space. Those patients most likely would get docetaxel with or without ramucirumab. But there are other agents that we hope to have available to our patients in the near future.

For patients who receive amivantamab and osimertinib, we recommend that those patients get chemotherapy probably with anti-VEGF as demonstrated by multiple trials that have shown the improved progression-free survival with introduction of an anti-VEGF agent. And we've seen evidence of amivantamab in the third line setting, so it is likely that this question about sequencing really takes center stage in our next set of trials. When you're talking to a patient, I think again, it's absolutely important to discuss: What are their goals? How symptomatic or how fast is their progression? Are there ways in which patients may benefit from spot treatment oligoprogression such as radiation? When is the right time for introduction of amivantamab and when do we think patients need chemotherapy? Is it up front or predominantly in the second-line setting?

Brittany Harvey: Definitely. And then you've just touched on the goals of treatment for individual patients. So in your view, what does this update mean for patients with stage IV non-small cell lung cancer and an EGFR alteration?

Dr. Jyoti Patel: For patients, this is a time in which shared decision making really needs to take center stage. So our best patients are those patients that are best informed not only about their disease but also have a good understanding about what is important to them and their families in terms of care. And so bringing that shared understanding to the table again helps us think about this particular cancer as more of a journey rather than just a one off treatment. Therapy will hopefully be prolonged, and so it's absolutely important that we address toxicities, make therapies more tolerable, again, with the shared goal of living long and living well.

Brittany Harvey: Absolutely. Those are key points to making sure that patients are living both longer and have a good quality of life during that time as well.

So then, before you mentioned the possibility of future sequencing trials and other ongoing developments. What additional studies or future directions is the panel examining for future updates to this living guideline?

Dr. Jyoti Patel: So certainly we're thinking about trials that look at, for example, cfDNA clearance. So are there patients that do well and can we detect that early on without having to intensify therapy on day 1 so it may be that we add chemotherapy a little bit later. I think really exciting are some of the new bispecific. The HARMONi-A trial was a trial in China of a novel bispecific, ivonescimab. And this drug targets both PD-1 and VEGF and it was combined with chemotherapy. And this trial found almost a doubling of progression-free survival with this drug in combination chemotherapy in an EGFR patient population. That study is being planned and being run in the United States to see if we have similar outcomes with a more diverse population. So certainly that's exciting.

There are a number of antibody drug conjugates that are being studied in the post-chemotherapy setting as well. And I think we'll likely soon see a better understanding of what co-mutations and burden of disease really mean when we're thinking about assigning treatment. So which patients, again, need intensification of therapy and which patients may do really well on just an oral agent that they're taking at home with more tolerable toxicity than dual treatment.

Brittany Harvey: Yes, we'll look forward to continued developments in these fields and seeing some of those studies come to fruition.

So with that, I want to thank you for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Patel.

Dr. Jyoti Patel: Thanks so much, Brittany. It's really an exciting time for lung cancer and we hope that these updates really help physicians decide the best treatments for their patients. Again, it's a rapidly evolving landscape which is fantastic, but it does become more cumbersome to stay ahead of the literature.

Brittany Harvey: Definitely. And so we appreciate your time and the panel's time spent reviewing this literature and providing this much needed information to clinicians everywhere.

So finally, thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Lyudmila Bazhenova joins us again to share the newest changes to the living guideline on therapy for stage IV NSCLC without driver alterations. She discusses new evidence reviewed by the panel and changes to second-line recommendations for patients with good performance status and HER2 overexpression, and what these updates mean in practice. We discuss ongoing evidence generation as we await further updates to these living guidelines.

Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on “Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3.”

It's great to have you back on the show today, Dr. Bazhenova.

Dr. Lyudmila Bazhenova: It's my pleasure to be here as always.

Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline panel, including Dr. Bazhenova, who has joined us here today, are available online with the publication of the guide in the Journal of Clinical Oncology, which is linked in the show notes.

So then to dive into the content here, first, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations has frequent updates to the recommendations. What prompted this latest update?

Dr. Lyudmila Bazhenova: Living ASCO guidelines are created to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. As a committee, we review published literature on a specific topic at the regular intervals and determine if it alters any recommendations. This time, upon our literature review, we felt that there are new data that requires an update in the guidelines and therefore the guidelines were updated.

Brittany Harvey: Great. Thank you for that updated information.

So then it looks like the panel updated recommendations for second line and subsequent treatment options for patients with good performance status and HER2 overexpression. What is that updated recommendation from the panel?

Dr. Lyudmila Bazhenova: Yes, this is correct. We now added an extra recommendation for patients with stage IV non-small cell lung cancer who have overexpression of the protein called HER2. HER2 overexpression with 2+/3+ level via immunohistochemistry is seen in approximately 8% to 20% of patients with lung cancer. And the data behind our recommendation comes from the DESTINY-Lung01 trial where patients with HER2 overexpression were treated with trastuzumab deruxtecan. And we saw that if patients with stage IV non-small cell lung cancer had a HER2 IHC score of 3+, overall response rate was seen at 53% and median duration of response was 6.9 months and, therefore, that in our opinion qualified for updated recommendation. We are still waiting for additional results that will be released later on another clinical trial where we see preliminary data presented at the World Conference of Lung Cancer in 2024. They looked at 36 patients also with HER2 overexpression and saw the overall response rate of almost 45%. It is important to highlight in this smaller study that a majority of the patients in the study were actually having EGFR mutation and the response rate in those patients who had an EGFR mutation was higher than the response rate in patients without EGFR mutations who just had a HER2 overexpression. So for now this is updated in the guidelines, but we will wait for additional data or formal publication of a World Lung Conference presentation and see if those recommendations need to be changed.

Brittany Harvey: Understood, and I appreciate you providing the context of some of those ongoing developments as well.

So then what should clinicians know as they implement this updated recommendation?

Dr. Lyudmila Bazhenova: Number one, we should all start from remembering to test for HER2 via immunohistochemistry. There is a slight difference in what considers HER2 positive in lung versus breast. In lung, we use what's called the gastric scoring and the difference is the circumferential versus non circumferential staining of the membrane. And number two, immunohistochemistry is not always included in next generation sequencing panels. So when you order your next generation sequencing, I think it's important to know if your company that you're using is testing for HER2 via immunohistochemistry. And if it's not, make sure that you find a company that does or work with your local pathology department to make sure that this testing is offered. It is also important to know the difference between HER2 overexpression and HER2 exon 20 insertion mutation even though the treatment for those two abnormalities is the same, which is trastuzumab deruxtecan. But the benefit that you can cite your patients and the rigor of the literature supporting the usage of trastuzumab deruxtecan in mutation versus overexpression is different.

Brittany Harvey: Yes. And as you mentioned, it's essential that, in the first place, patients are actually receiving the testing so that we know if they're eligible for these treatment options.

So what additionally does this change mean for patients with stage IV non-small cell lung cancer and HER2 overexpression?

Dr. Lyudmila Bazhenova: So for patients, it adds another treatment modality which is now FDA approved. So if there are patients listening to me, make sure that your physician has tested your tumor for HER2 overexpression. So I think proactive asking of your physician would be very appropriate in this situation.

Brittany Harvey: Absolutely. And then earlier you mentioned an ongoing trial that the panel was looking to for the future. But what other additional trials did the panel review during this guideline update and what is the panel examining for future updates to this living guideline?

Dr. Lyudmila Bazhenova: So at this point we reviewed three additional studies. The results of those studies did not make it into a change in guidelines. So we reviewed the HARMONi-2 trial. HARMONi-2 trial so far does not have an official publication and, as per our strategy on how we come up with ASCO guidelines, we need to wait for an official publication. So this is one thing we're going to be expecting in the future. Once this is published, we will review it and decide if we need to make an additional change in recommendations. For those of you who are not aware, HARMONi-2 trial used bispecific monoclonal antibody against VEGF and PD-1 and was a phase III randomized trial comparing their investigational product which is called ivonescimab over pembrolizumab for patients with PD-L1 more than 50. And again, we are waiting for the final publication to make our recommendation.

The second trial we reviewed was a LUNAR trial and the LUNAR trial looked at addition of tumor treating fields to chemotherapy or immunotherapy in patients whose cancer progressed with platinum doublet. The key point about this study is that immunotherapy was not required to be administered in a first line setting which is a current standard of care in the United States. And even though the study met their primary endpoint of overall survival, there were more benefits in patients who were immunotherapy naive in the second line. And we felt that given the potential lifestyle implication of wearing a device for 18 hours per day, and the lack of evidence in immunotherapy-pretreated population, and the absence of data in the first-line setting where we currently using immunotherapy in the United States, we felt that there is insufficient data to definitely recommend addition of tumor treating fields to systemic chemotherapy for most patients. And we are waiting for additional trials that are ongoing in this setting to formalize or change our recommendations.

And we also reviewed- the final study that we reviewed was TROPION-Lung01. TROPION-Lung01 study was a phase III study in post platinum doublet setting which compared efficacy of Dato-DXd and docetaxel and trials showed improvement in progression free survival but not in overall survival. And progression free survival benefit was more pronounced in non-squamous carcinoma histology subgroup and we felt that the results do appear promising, but the strength of evidence which was based on unplanned subgroup analysis was not sufficient enough to make a change in treatment recommendation at this time.

Brittany Harvey: I appreciate your transparency on why some of that data did not prompt a change to recommendations at this time. And additionally, we'll look forward to those future published results and potential incorporation of new data into future versions of this living guideline.

So, I want to thank you so much for your work to rapidly and continuously update this guideline and for your time today, Dr. Bazhenova.

Dr. Lyudmila Bazhenova: It is my pleasure. Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Chris Holsinger shares the new guideline from ASCO on transoral robotic surgery (TORS) for patients with oropharyngeal squamous cell carcinoma. He reviews the evidence-based recommendations on baseline assessment, the role of TORS in HPV-positive and HPV-negative disease and in the salvage/recurrent setting, which patients are eligible or ineligible for TORS, and the role of adjuvant therapy. He discusses the importance of multidisciplinary collaboration and shared decision-making between patients and their clinicians. Read the full guideline, “Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline.”

TRANSCRIPT

This guideline, clinical tools, and resources are available at asco.org. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Chris Holsinger from Stanford University, lead author on “Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline.”

Thank you for being here today, Dr. Holsinger.

Dr. Chris Holsinger: Thanks, Brittany. We've been working together for years on these guidelines and what a pleasure to get to meet you at least virtually today.

Brittany Harvey: Yes, it's great to have you on. And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Holsinger, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So let's jump into this important guideline. Dr. Holsinger, to start us off, can you provide an overview of both the scope and purpose of this guideline?

Dr. Chris Holsinger: Absolutely. And again, thanks for the opportunity to be here, Brittany. I appreciate the invitation to participate in the ASCO Guidelines and to work with the great people on this paper that's now out there.

I think it's a really important guideline to be published because it really talks about surgery, specifically transoral robotic surgery, a minimally invasive technique, as a new way to treat head and neck cancer. Why that's so important is that what is now known as head and neck cancer is completely different than what we saw even 25 years ago. Around the turn of the century, some really thoughtful epidemiologists working at Hopkins and UW in Seattle started to see this connection between the human papillomavirus and head and neck cancer. And since then we've seen this precipitous rise in the number of throat cancers specifically due to HPV. The results from the American Cancer Society showed last year that head neck cancer, in particular these cancers of the oropharynx, actually were one of the few cancers that still had an increasing incidence, I think it was around 2.5% per year. And other studies have shown that almost 50% of the cases we're seeing across the United States now are actually HPV-mediated throat cancers. That's bad news because we're seeing this rise in cases, but it's good news in the sense that this is a cancer that is highly curable and I think opens up a lot of different treatment avenues that we didn't have a couple of decades ago. And when patients are facing a mortality risk that's two or three times lower than the formerly HPV-negative smoking-driven cancers, it really behooves us as clinicians, as oncologists to think about treatment selection in a completely different way. And for years, the only function-sparing option, surgery certainly was not, was radiation therapy with concurrent cisplatin chemotherapy.

In 2009, the FDA approved the use of surgical robotics using a transoral approach, a minimally invasive approach to resect the primary tumors and to perform neck dissection. And so now when patients walk in the door, they not only have this gold standard option in the path of radiation therapy with chemo, but also frontline surgery. And with some recent publications, especially the ECOG 3311 study, there's some really good evidence that for HPV-mediated throat cancers, we can actually de-escalate the intensity of adjuvant therapy when we start with surgery first. So who we choose that option for, which patients want that option - these are all really important new questions that we try to grapple with in these guidelines.

Brittany Harvey: That background is really key for setting the stage for what we're about to talk about today.

And so next I'd like to review the key recommendations across the clinical questions that the panel addressed. So you just talked about the importance of treatment selection. So to start that off, first, what is recommended for baseline assessment for patients with oropharyngeal squamous cell carcinoma who are being considered for transoral robotic surgery?

Dr. Chris Holsinger: So I think here we tried in the guidelines to really standardize the workup and approach of this disease, in general, but with a strong focus on who might be a good surgical candidate. As I mentioned in the introduction, I mean, this is a disease that is very new. Our workup is in flux. And so what we tried to do, especially in items 1.2 and 1.3, is to really standardize and confirm that the tumor that we're dealing with, which oftentimes presents in a metastatic lymph node, is in fact associated with the human papillomavirus. So how biopsy is done, how high risk HPV testing is performed, whether you're doing that with an in situ hybridization, a DNA based study, or a p16 immunohistochemical study. And we try to tackle these issues first to really make sure that the patient population we're considering is actually indeed eligible for this kind of treatment de-escalation with surgery.

Brittany Harvey: Understood. So it's important to consider which patients could be eligible for TORS upfront.

So what is the role of TORS in patients with HPV-positive oropharyngeal squamous cell carcinoma?

Dr. Chris Holsinger: Yeah, exactly. So I think first of all, surgery is ideally suited, and the robot is FDA approved for early-stage cancers - T1 and T2 cancers that are amenable to a minimally invasive approach. And we really try to emphasize, especially in our patient selection section of the guideline, who is really an ideal candidate for this. It's not just the T1 and T2 tumor. It's a tumor that is lateralized so that we can maybe consider managing the neck concurrently just on the side of the tumor, rather than doing bilateral neck dissection for most patients. Which patients might get the best functional outcome is a really critical component of this. And in fact, that actually goes back to a guideline that we didn't have time to chat about earlier, which is that we think every head neck cancer patient, whether or not they're being considered for transoral robotic surgery or frontline radiation therapy with cisplatin, every patient should have a pre-treatment assessment by a speech and swallowing expert. They're called different names across the country: speech language pathologists, speech pathologists, etc. But having a really good functional assessment of the patient's ability to swallow before treatment selection is really critical. And why that's important with frontline surgery is that there's a period of about one or two weeks after which that patient really needs intensive rehabilitation. And so for every patient being considered by TORS, we want to work really hand in hand with that speech pathologist to do pre-habilitation and then immediate post-operative rehab and then long longitudinal rehabilitation so that if radiation is needed down the road in a month, that patient just hopefully sails through this de-escalated treatment that we're offering.

Brittany Harvey: Great. I appreciate you describing which patients can be considered for transoral robotic surgery.

So beyond that, which patients with HPV-positive oropharyngeal squamous cell carcinoma aren't really good candidates for TORS?

Dr. Chris Holsinger: We talked about that sort of ideal patient, but you know, we're not always living in an ideal world. And so I think it's important, and I'm really happy about the multidisciplinary discussions that led to these final guidelines because I think it helped engage radiation oncologists, medical oncologists, and surgeons around who’s maybe not a good candidate for this because radiation therapy, with or without cisplatin chemotherapy, remains a good option for many of these patients. But I think the consensus, especially among the surgeons in this group, were that patients with tumors were more endophytic - that's the old fashioned oncology and surgical oncology term that refers to tumors that seem to not be as evident on the surface and have more of an infiltrative deep growth pattern - these are not ideal tumors. Whereas an exophytic tumor that's growing upwards, that's more readily seen on flexible endoscopy during a routine clinic assessment, or frankly, better seen on imaging, those exophytic tumors are better suited to a surgical approach because the surgeon has a better chance when he or she sees the tumor to get a good margin. When we can appreciate not just the surface mucosal margins that need to be taken, but also have a better chance to appreciate their depth. And with those infiltrative tumors, it's much harder to really understand how to get that deep margin, which in many cases is always the hardest. And so that's a long way to say that surgical decision making, patient selection is really critical when it comes to offering TORS as a multidisciplinary group.

And then there are a few other things that we can quickly talk about before we move on to discussing adjuvant therapy. But I think there are some relative contraindications to patients who might have tumors arising in a palatine tonsil or tonsillar pillar, but which might grow significantly into the soft palate, such that a major palatal resection would be needed to get a good margin. For T1 and T2 tumors, we're not sure that that is an ideal candidate. And the other relative contraindication, but it's a hard and fast contraindication in my personal practice, is patients with extensive nodal disease. I think a patient who has preoperative extranodal extension, matted nodes, clinically and on MRI, you know pre-op they're going to need intensive post operative concurrent chemoradiation post-op that's maybe not the best patient for TORS, although there are some select cases where that that might make sense. But that's a quick overview of patient selection for TORS, Brittany. Hopefully, that's helpful.

Brittany Harvey: That's definitely helpful. I think it's really important to consider not only who is eligible, but who isn't eligible for this de-escalation of treatment, and I appreciate you clarifying some of that.

So then you've just also mentioned adjuvant therapy along with multidisciplinary discussion. So what is recommended regarding adjuvant therapy for patients who have resected HPV-positive oropharyngeal squamous cell carcinoma?

Dr. Chris Holsinger: Definitely. And I think the post-operative discussion has to begin with great pre-op planning. And pre-op planning is really anchored in a really robust multidisciplinary team. So, we spoke earlier about the critical importance of getting speech language pathology involved initially, but they're part of a much larger team that includes not just a surgeon, but medical oncologist, a radiation oncologist and a dental oncologist - all of these specialties, and I could think of several others if we had time to chat further - this should also be really engaged in the care of these patients. But great decision making regarding adjuvant therapy really begins with a robust multidisciplinary consultation pre-op and we try to emphasize that in the guidelines.

But just to return and answer your question very directly, I think adjuvant therapy is really the critical piece in getting that great functional outcome for a patient with HPV-mediated throat cancer. And I think traditionally patients who have a variety of different risks, based on a large study done again by the ECOG group, ECOG 3311, we showed that by stratifying patients based on their surgical pathology rather than on an estimate of disease extent, we can better stratify adjuvant therapy. And so the low risk patient is a patient with good margins and of course, good margin, we could spend another two hours discussing that. But good margins are greater than at least 1 to 3 millimeters superficially and a clear deep margin. Patients with lymph node metastases that are less than 3 cm and a single lymph node can sometimes be observed but most patients don't fall into that low risk category. Most patients fall into an intermediate risk where the margin is good and it's clear, but it might be close. That depends if you're talking about the superficial mucosal margin or the deep. But more often than not, we spend a lot of time considering the extent of lymph node involvement as it pertains to how adjuvant therapy is delivered.

And I think for patients with less than 4 lymph nodes traditionally without extranodal extension, radiation therapy will suffice for adjuvant therapy after TORS. And the question of dose then comes up. Are we talking 50 Gray, the experimental arm that showed real promise in the ECOG 3311 trial, or 60 Gray or more traditional dose? And that is a topic definitely for another podcast, which we should do with a radiation oncologist online. I don't want to get into the weeds with that, but I refer you to our guidelines and Bob Ferris and Barbara Burtness’ paper from JCO in 2021 for further details about that.

But then for patients with positive margins with more than four lymph nodes, but especially patients with extranodal extension, the role of radiation therapy and chemotherapy is really absolutely critical. Because these patients and while they only accounted for around 20% to 30% of patients that we're seeing in this new era of TORS, they're the ones that we’re really focusing on how can we do better because their overall survival is still good, it's 90%, but it's not as good as the patients we're seeing with a low and intermediate risk. So that's a brief overview there.

Brittany Harvey: I appreciate that overview. And yes, we'll refer listeners to the full guideline, which is linked in the show notes of this episode to learn more about the intricacies of the radiation therapy that you mentioned.

So then we've talked a lot about patients with HPV-positive disease, but what is the role of TORS in patients with HPV-negative disease?

Dr. Chris Holsinger: I think TORS still has a role for these patients. Our colleague in India, Surender Dabas, has a really nice series that shows that for HPV-negative patients, this is a way for early stage cancers to potentially escalate the intensity of treatment for a disease that does worse than this new HPV-positive we're seeing in the US. So I think there's a good signal there. I think more study needs to be done and I think those studies, in fact, are underway in India and other countries. I hope that we can, as an oncology community here in the United States, also tackle this disease, which is still a significant part of the disease we face in head and neck oncology.

Brittany Harvey: Yes, we'll look forward to more data coming out for HPV-negative disease.

So then, the last clinical question that the guideline panel addressed: What is the role of TORS in the salvage or recurrent setting?

Dr. Chris Holsinger: So we wrap up the guidelines tackling this topic. It's definitely something for the experienced TORS surgeon in consultation with that multidisciplinary team. Oftentimes, we are still seeing many patients who need salvage surgery and I think, while TORS alone could be a really effective treatment option, TORS with a microvascular reconstruction is oftentimes what is needed for these patients who, with recurrence, do often present with an RT 2, 3, 4 tumor.

In my own practice, I found that using TORS as a way to minimize the superficial mucosal extent and then delivering that tumor through a traditional lateral pharyngotomy, then neck dissection and then having a microvascular flap inset done after that really provides the best possible chance for good long term function and of course control of the tumor. Here, I definitely refer the listener to some great work done out of the Royal Marsden with Vin Paleri, who we're happy to have on our TORS guideline panel for his RECUT study that really grapples in some detail with these very issues.

Brittany Harvey: Excellent. And so we've covered a lot of the recommendations here that were made by the panel and you've touched a little bit about how this changes things for clinicians in practice. But what should clinicians know as they implement these new recommendations?

Dr. Chris Holsinger: One thing as we close, I hope that in the future we can really start to grapple with this concept of patient selection. I think these guidelines help establish that TORS is a great oncologic option with - really the only option for treatment de-escalation in the here and now. Radiation therapy and cisplatin concurrent chemotherapy is going to be an option that is such an important choice for patients. And I think where I hope the field goes in the future is figuring out which patient wants one of these options. And I think certain patients really want that tumor taken out and others just the idea of surgery is not something that makes sense for them. How we in the context of a multidisciplinary team, really engage that patient, elicit their treatment preferences and then through considering treatment eligibility criteria that we've spelled out here for surgery and can be spelled out for chemo RT, bringing all that together in a formal shared decision making process is really where I hope the field will be going in the next few years. And hopefully these guidelines help to pave the way there.

Brittany Harvey: Definitely the aspect of care by a multidisciplinary team and talking with patients to go through shared decision making is key to implementing these guidelines. So then, in that same vein, what do these recommendations mean for patients with oropharyngeal squamous cell carcinoma?

Dr. Chris Holsinger: I think the central take home message for patients should be that especially if you have a T1 and T2 tumor, it’s really important to have that consultation with a surgeon who knows how to do TORS and has a busy practice, but then also having an honest discussion up front about what the functional outcomes would be both with surgery and also chemo RT. And I think just knowing all those different options, that multidisciplinary treatment selection process is going to be that much more robust. And I think more right decisions will get made and we'll see less decisional regret down the road, which I think is a long term goal of our field.

Brittany Harvey: Absolutely. That discussion of preferences is key.

So then to wrap us up, you touched on this a little bit earlier in talking about ongoing research and data, particularly in the field of HPV-negative disease, but what are the outstanding questions regarding TORS in this patient population?

Dr. Chris Holsinger: Yeah, I think that in addition to this work around shared decision making, I really hope that we'll embrace shared decision making in the context of future clinical trial. I think where we are now is you have surgeons saying, “Hey, TORS and 50 gray is a great option. Why aren't we doing that?” And then our colleagues, perhaps across the aisle, if I can use a political metaphor, are saying, “Well, where's the comparative data? Can we even do a randomized clinical trial between surgery and radiation?” Well, Christian Simon in Lausanne in Switzerland is trying to do this in a small pilot study being led by the EORTC, and I would encourage American investigators to consider something analogous. But I think how we solve this question of I think treatment choice is going to be pivotal for any such trial to ever be done.

And then finally, I think, how will the changing treatment landscape around immunotherapy change this? There's some really provocative data that dates back to 1996 in a JCO paper from Ollivier Laccourreye and the University of Paris experience that showed induction chemotherapy followed by function preserving surgery in the larynx was a really powerful strategy for organ preservation, and that has never been followed up in the United States. And so especially with the upcoming presentation of KEYNOTE-689, will we be doing neoadjuvant approaches for patients and then following them by minimally invasive surgery or lower dose radiation? I think these are going to be some exciting new areas of study and I can't wait to see how this might evolve so we can refine the treatment - still get those great outcomes, but reduce those late toxicity.

Brittany Harvey: Yes. We'll look forward to this ongoing research to continue to move the field forward.

So, Dr. Holsinger, I want to thank you so much for your time to develop this important guideline. It's been great to have you on the podcast to discuss it today.

Dr. Chris Holsinger: Well, thanks a lot Brittany. It's nice to finally meet you.

Brittany Harvey: Likewise.

And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Stéphanie Gaillard and Dr. Bill Tew share updates to the evidence-based guideline on neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer. They highlight recommendations across ten clinical questions, addressing initial assessment, primary cytoreductive surgery, neoadjuvant chemotherapy (NACT), tests and/or procedures that should be completed before NACT, preferred chemotherapy regimens, timing of interval cytoreductive surgery (ICS), hyperthermic intraperitoneal chemotherapy (HIPEC), post ICS-chemotherapy, maintenance therapy, and options for those without a clinical response to NACT. They highlight the evidence supporting these recommendations and emphasize the importance of this guideline for clinicians and patients.

Read the full guideline update, “Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update” at www.asco.org/gynecologic-cancer-guidelines."

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Stéphanie Gaillard from Johns Hopkins University and Dr. Bill Tew from Memorial Sloan Kettering Cancer Center, co-chairs on “Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update.” Thank you for being here today, Dr. Gaillard and Dr. Tew.

Dr. Bill Tew: Thank you for having us.

Dr. Stéphanie Gaillard: Yeah, thank you. It's great to be here.

Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Gaillard and Dr. Tew, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then to dive into the content here, first, Dr. Tew, could you describe what prompted this update to the neoadjuvant chemotherapy for ovarian cancer guideline? And what is the scope of this update?

Dr. Bill Tew: Yeah. It's been almost a decade since ASCO first published its neoadjuvant chemotherapy guidelines for women with newly diagnosed ovarian cancer, and over that 10-year period, there's really been a major shift in how oncologists treat patients in the U.S. If you look at the National Cancer Database, between 2010 and 2021, the proportion of patients with advanced ovarian cancer who underwent primary surgery fell from about 70% to about 37%. And there's been a doubling in the amount of neoadjuvant chemotherapy used. So we wanted to take a look at that and really both highlight the appropriate patient populations for primary surgery versus new adjuvant chemotherapy, as well as review any studies that have been published since then. There's been, I think, about 61 trials published, nine randomized trials alone in the last 10 years. And the scope of the guideline was really not only the neoadjuvant chemotherapy and surgical questions, but also to touch upon some new treatments that have come to the forefront in newly diagnosed ovarian cancer, including heated intraperitoneal chemotherapy or HIPEC, as well as the integration of maintenance therapy, particularly bevacizumab and PARP inhibitors.

Brittany Harvey: Understood. That's a large amount of new evidence to review in this Update.

Then, next, Dr. Gaillard, I'd like to review the key recommendations across the 10 clinical questions that the guideline addressed. So, starting with: What is recommended regarding initial assessment for patients with newly diagnosed pelvic masses and/or upper abdominal or peritoneal disease?

Dr. Stéphanie Gaillard: Sure. So in talking about the first guidelines, the first one that we addressed was how to do the initial assessment for these patients. And first, and probably most critically, it's important to recognize that these patients really should be evaluated by a gynecologic oncologist prior to initiation of any therapy, whether that means a primary cytoreductive surgery or neoadjuvant chemotherapy, because really, they are the best ones to determine the pathway that the patient should take. The initial assessment should involve a CA-125, a CT of the abdomen and pelvis with oral and IV contrast, if not contraindicated, and then also chest imaging, in which a CT is really the preferred modality. And that helps to evaluate the extent of disease and the feasibility of the surgical resection.

Now, there may be some other tools that could be helpful to also refine this assessment. So, for example, a laparoscopy can really help to determine the feasibility of surgical resection as well as the extent of disease. Further imaging, such as diffusion-weighted MRI or FDG-PET scans can be helpful, as well as ultrasounds. And then also an endometrial biopsy. And that was newly added because there really has been a divergence of treatment for endometrial cancer versus ovarian cancer. And so it's really important to determine upfront where the source of the disease is coming from.

Brittany Harvey: I appreciate you describing those recommendations surrounding initial assessment.

So following this assessment, Dr. Tew, which patients with newly diagnosed advanced epithelial ovarian cancer should be recommended primary cytoreductive surgery?

Dr. Bill Tew: The key thing here is if the GYN oncology surgeon feels that they have a high likelihood of achieving a complete cytoreduction with acceptable morbidity, the panel overwhelmingly agrees that primary cytoreduction surgery should be recommended over chemotherapy. And we know that surgery is really the cornerstone to achieving clinical remission. And our concern is that neoadjuvant chemotherapy may be overused in this fit population. Sometimes it is challenging to determine truly if a patient has a high likelihood of complete cytoreduction or what is acceptable morbidity. But an evaluation with performance status, fitness, looking at age or frailty, nutritional status, as well as a review of imaging studies to plan and determine for who is the right patient for primary surgery is key.

Brittany Harvey: And then the title of this guideline, Dr. Gaillard, for which patients is neoadjuvant chemotherapy recommended?

Dr. Stéphanie Gaillard: Yeah. So there's really two patient populations that we think are best suited to receive neoadjuvant chemotherapy. Those may be patients who are fit for a primary cytoreductive surgery, but they're unlikely to have a complete cytoreduction if they were to go to surgery directly. And so that's where neoadjuvant chemotherapy can be very helpful in terms of increasing the ability to obtain a complete cytoreduction.

The second population is those who are newly diagnosed who have a high perioperative risk, and so they're not fit to go to surgery directly. And so it may be better to start with neoadjuvant chemotherapy and then do an interval cytoreductive surgery. Again, I just want to emphasize the importance of including a gynecologic oncologist when making these determinations for patients.

Brittany Harvey: Absolutely. So then the next clinical question. Dr. Tew, for those patients with newly diagnosed stage 3 to 4 epithelial ovarian cancer, what tests and or procedures are recommended before neoadjuvant chemotherapy is delivered?

Dr. Bill Tew: The key test is to confirm the proper diagnosis, and that requires histological confirmation with a core biopsy. And this was a point the panel strongly emphasized, which is a core biopsy is a much better diagnostic tool compared to cytology alone. But there will be cases, exceptional cases, where a core biopsy cannot be performed. And in those settings, cytology combined with serum CA-125 and CEA is acceptable to exclude a non-gynecologic cancer.

The other reason why cord biopsy is strongly preferred is because we already need to start thinking about germline and somatic testing for BRCA1 and 2. This information is important as we start to think about maintenance strategies for our patients. And so having that information early can help tailor the first-line chemotherapy regimen.

Brittany Harvey: So then you've described who should be receiving neoadjuvant chemotherapy, but Dr. Gaillard, for those who are receiving neoadjuvant chemo, what is the preferred chemotherapy regimen? And then what does the expert panel recommend regarding timing of interval cytoreductive surgery?

Dr. Stéphanie Gaillard: Sure. So for neoadjuvant chemotherapy, we generally recommend a platinum taxane doublet. This is especially important for patients with high grade serous or endometrioid ovarian cancers, and that's really because this is what the studies had used in the neoadjuvant trials. We recognize, however, that sometimes there are individual patient factors, such as advanced age or frailty, or certain disease factors such as the stage or rare histology that may shift what is used in terms of chemotherapy, but the recommendation is to try to stick as much as possible to the platinum taxane doublet.

And then in terms of the timing of interval cytoreductive surgery, this was something that the panel discussed quite a bit and really felt that it should be performed after four or fewer cycles of neoadjuvant chemotherapy, especially in patients who've had a response to chemotherapy or stable disease. Sometimes alternative timing of surgery can be considered based on some patient centered factors, but those really haven't been prospectively evaluated. The studies that looked at neoadjuvant chemotherapy usually did the interval cytoreductive surgery after three or four cycles of chemotherapy.

Brittany Harvey: For those patients who are receiving interval cytoreductive surgery, Dr. Tew, earlier in the podcast episode, you mentioned a new therapy. What is recommended regarding hyperthermic intraperitoneal chemotherapy?

Dr. Bill Tew: Yeah, or simply HIPEC as everyone refers to it. You know, HIPEC isn't really a new therapy. HIPEC is a one-time perfusion of cisplatin, which is a chemotherapy that has been a standard treatment for ovarian cancer for decades. But the chemotherapy is heated and used as a wash during the interval cytoreductive surgery. And since our last guideline, there has been a publication of a randomized trial that looked at the use of HIPEC in this setting. And in that study there was improved disease-free and overall survival among the patients that underwent HIPEC versus those that did not. So we wanted to at least emphasize this data. But we also wanted to recognize that HIPEC may not be available at all sites. It's resource-intensive. It requires a patient to be medically fit for it, particularly renal function and performance status. And so it's something that could be discussed with the patient as an option in the interval cytoreductive surgery. One other point, the use of HIPEC during primary surgery or later lines of therapy still is unknown. And the other point is this HIPEC trial came prior to the introduction of maintenance PARP inhibitors. So there's still a lot of unknowns, but it is a reasonable option to discuss with appropriate patients.

Brittany Harvey: I appreciate you reviewing that data and what that updated recommendation is from the panel. So then, Dr. Gaillard, after patients have received neoadjuvant chemotherapy and interval cytoreductive surgery, what is the post ICS chemotherapy recommended?

Dr. Stéphanie Gaillard: The panel recommends some post ICS chemotherapy, as you mentioned. This is typically to continue the same chemotherapy that was done as neoadjuvant chemotherapy and so preferably platinum and taxane. And typically we recommend a total of six cycles of treatment, although the exact number of cycles that is given post-surgery can be adjusted based on different patient factors and their response to treatment. Importantly, also, timing is a factor, and we recommend that postoperative chemotherapy begin within four to six weeks after surgery, if at all feasible.

Brittany Harvey: Absolutely. Those timing recommendations are key as well.

So then, Dr. Tew, you mentioned this briefly earlier, but what is the role of maintenance therapy?

Dr. Bill Tew: Maintenance therapy could be a full podcast plus of discussion, and it's complicated, but we did want to include it in this guideline in part because the determination of whether to continue treatment after completion of surgery and platinum based therapy is key as one is delivering care in the upfront setting.

So first off, when we say maintenance therapy, we are typically referring to PARP inhibitors or bevacizumab. And I would refer listeners to the “ASCO PARP Inhibitor Guideline” that was updated about two years ago, as well as look at the FDA-approved label indications. But in general, PARP inhibitors, whether it's olaparib or niraparib, single agent or olaparib with bevacizumab, are standard treatments as maintenance, particularly in those patients with a germline or somatic BRCA mutation or those with an HRD score positive. And so it's really important that we emphasize germline and somatic BRCA testing for all patients with newly diagnosed ovarian cancer so that one can prepare for the use of maintenance therapy or not. And the other point is, as far as bevacizumab, bevacizumab is typically initiated during the chemotherapy section of first-line treatment. And in the guidelines we gave specific recommendations as far as when to start bevacizumab and in what patient population.

Brittany Harvey: Great. Yes. And the PARP inhibitors guideline you mentioned is available on the ASCO guidelines website and we can provide a link in the show notes for our listeners.

So then, the last clinical question, Dr. Gaillard, what treatment options are available for patients without a clinical response to neoadjuvant chemotherapy?

Dr. Stéphanie Gaillard: Yeah, this is a tough situation. And so it's important to remember that ovarian cancer typically does respond to chemotherapy initially. And so it's unusual to have progressive disease to neoadjuvant chemotherapy. So it's really important that if someone has progressive disease that we question whether we really have the right diagnosis. And so it's important to, I think at that point, obtain another biopsy and make sure that we know what we're really dealing with. In addition, this is where Dr. Tew mentioned getting the molecular profiling and genetic testing early in the course of disease. If that hasn't been done at this point in time, it's worth doing that in this setting so that that can also potentially help guide options for patients. And patients who are in those situations, really, the options are other chemotherapy regimens, clinical trials may be an option, or in some situations, if they have really rapidly progressing disease that isn't amenable to further therapy, then initiation of end-of-life care would be appropriate.

Brittany Harvey: I appreciate you both for reviewing all of these recommendations and options for patients with advanced ovarian cancer.

So then to wrap us up, in your view, what is both the importance of this guideline update and how will it impact clinicians and patients with advanced ovarian cancer?

Dr. Bill Tew: Well, first off, I'm very proud of this guideline and the panel that I work with and Dr. Gaillard, my co-chair. The guideline really pulls together nicely all the evidence in a simple format for oncologists to generate a plan and determine what's the best step for patients. The treatment of ovarian cancer, newly diagnosed, is really a team approach - surgeons, medical oncologists, and sometimes even general gynecologists - and understanding the data is key, as well as the advances in maintenance therapy and HIPEC.

Dr. Stéphanie Gaillard: For my part, I'd say we hope that the update really provides physicians with best practice recommendations as they navigate neoadjuvant chemotherapy decisions for their patients who are newly diagnosed with ovarian cancer. There is a lot of data out there and so we hope that we've synthesized it in a way that makes it easier to digest. And along that regard, I really wanted to give a special shout out to Christina Lacchetti, who just put in a tremendous effort in putting these guidelines together and in helping to coordinate the panel. And so we really owe a lot to her in this effort.

Dr. Bill Tew: Indeed. And ASCO, as always, helps guide and build a great resource for the oncology community.

Brittany Harvey: Absolutely. Yes, we hope this is a useful tool for clinicians. And I want to thank you both for the large amount of work you put in to update this evidence-based guideline. And thank you for your time today, Dr. Gaillard and Dr. Tew.

Dr. Stéphanie Gaillard: Thank you.

Dr. Bill Tew: Thank you for having us.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Evan Yu presents the new evidence-based guideline on genetic testing for metastatic prostate cancer. He discusses who should receive germline and somatic testing with next-generation sequencing technologies, what samples are preferred for testing, and the therapeutic & prognosistc impacts of genetic testing. Dr. Yu emphasizes the need for awareness and refers to areas of active investigation and future research to improve personalized therapies for patients with metastatic prostate cancer.

Read the full guideline, “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline” at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

My name is Brittany Harvey and today I'm interviewing Dr. Evan Yu from the University of Washington and Fred Hutchinson Cancer Center, lead author on “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline”. Thank you for being here today, Dr. Yu.

Dr. Evan Yu: Thanks for having me on.

Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline, including Dr. Yu, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, Dr. Yu, to start us off on the content of this guideline, could you first provide an overview of both the purpose and scope of this guideline?

Dr. Evan Yu: Yeah, absolutely. So I think the one key thing to recognize is that prostate cancer is the highest incidence of all cancers in males. Additionally, it's the second highest cause of mortality in males, and that's about 35,000 deaths in 2024. So with that being said and done, it's a disease where we need to do better. And part of that is recognizing that we now have many targeted therapies, precision medicine type of therapies, but unlike a lot of other cancers out there, prostate cancer patients are not always getting sequencing, next generation DNA sequencing, let's say, to identify both inherited and also spontaneously develop what we call somatic mutations in their tumor. And I suspect that's partially because other cancers like breast cancer, we're so used to- in the first line, you present the patient, you throw out their estrogen receptor status, progesterone receptor status, HER2, ER/PR HER2; in lung cancer it’s EGFR, ALK, ROS1, etc. In things like prostate cancer, things like BRCA2 have major important patient treatment implications and potentially family counseling and downstream cascade testing implications. But it hasn't made their way into that first-line presentation yet. And for that reason, there are some studies out there that show that testing in the community may be as low as 15% of patients with metastatic prostate cancer. We want to bring awareness to that and hopefully increase testing down the road so that we can better help our patients with metastatic prostate cancer.

Brittany Harvey: Absolutely. It's important to get these targeted therapies to the patients who can benefit most. Using that context, I'd like to next review the key recommendations of this guideline across the six clinical questions that the panel addressed. So, starting with: Who should receive germline testing with next generation sequencing technologies?

Dr. Evan Yu: Yeah. We think that it's common enough that everyone with metastatic prostate cancer should receive germline genetic testing. And the reason for that is there have been studies that have looked at this and have shown that 12% of men with metastatic prostate cancer have some sort of inherited germline mutation in a gene, mostly DNA repair genes. But 12% have something that is inherited and that loved ones, first degree relatives, siblings, offspring might have also inherited. Now, most of these are in the DNA repair genes, but that being said and done, there's not only treatment implications for the patient, where there are newer drugs that that patient could get treated with, but other loved ones that might have inherited these gene mutations, that these things can cause other cancers as well - not just prostate cancer, but breast cancer, endometrial cancer, ovarian cancer, pancreatic cancer. So, it's very important to test, with as high of an incidence as 12%, to test, and if you identify it in a patient, it's our job to talk to the patient about it and talk to them about the pros and cons of family counseling and talking to their loved ones and potentially having their loved ones get tested. Because if they test positive, then their doctors may want to know and may screen them very, very aggressively and differently for a whole host of other cancers. And the whole idea is you find the cancer very early and cure the patients before the cancer really takes hold and has the ability to spread so we can save a lot of lives down the road.

Brittany Harvey: Absolutely. This germline testing is important not just for the patient, but has wider implications for their families as well, as you mentioned.

So then, beyond those recommendations for germline testing, which patients should receive somatic testing with next-generation sequencing technologies?

Dr. Evan Yu: So let's talk a little bit about somatic testing. So germline again, as we know, is inherited. The patient inherited it in every single cell in their body, then it becomes very easy, many of these are cancer predispositions for them to lose the other allele and then to have biallelic loss and then develop the cancer. Now, somatic just means it spontaneously occurred. Certainly, it's not going to occur in every cell in the body, but you can get one hit, lose one allele and then lose the other allele. And if that gene is truly carcinogenic and leading to that cancer, then that can have implications potentially for treatment as well. So we recommend that all patients with metastatic prostate cancer also undergo somatic next-generation sequencing testing. We recognize that at this point in time it's only those with metastatic castration-resistant prostate cancer or hormone-resistant prostate cancer, which is a later disease state where there are drugs that may target those mutations, for instance, like PARP inhibitors, but that early identification for a patient population that's fit and that can benefit from these therapies makes sense so that you know it's in place already and you have your treatments outlined and mapped out for the future. So we recommend it for everybody - somatic testing also for everyone with metastatic prostate cancer.

Brittany Harvey: Understood. And then when patients are receiving that somatic testing, what is recommended for somatic testing? Primary tumor archival tissue? Fresh metastatic biopsy tissue? Or circulating tumor DNA testing?

Dr. Evan Yu: We recommend that in the initial setting when you're first diagnosed, that archival tissue samples are fine and preferred. But circulating tumor DNA is good when there's no accessible archival tissue, or if the archival tissue, let's say, is very old and it's been sitting around for a long time, or you can't get it anymore because it's many years back when maybe a patient had a prostate needle biopsy. So if it's not accessible, then we recommend ctDNA. We believe that is preferred and also that ctDNA is recommended in a situation where you can't easily biopsy a metastatic site. Sometimes it's just not in a safe area to go after. Sometimes it's just a small lesion. So in general, we recommend tissue when available, and when we think that the tissue sample will yield clean results, if not, then we recommend doing ctDNA at that point in time.

Brittany Harvey: So you have described who should get germline and somatic genomic testing. But what are the therapeutic impacts of this germline or somatic testing for single gene genetic variants?

Dr. Evan Yu: We pulled this panel together and we met like every single month for like 12 months straight, and part of it was to review the literature. And as part of this literature review, we were able to pull a whole bunch of different trials. I think there was like 1713 papers we identified in the literature search. Eventually, we narrowed it down because with ASCO, we want to present the data with the highest level evidence, level 1 evidence, randomized controlled prospective data. And after reviewing 1713 papers, we narrowed it down to 14 papers. With those 14 papers, if you look at it, there are a lot of things that we think may have implications for treatment or prognosis, but we didn't feel was the highest level of evidence that we could support. So the things that have the highest level of evidence that we can support are certain DNA repair gene alterations, especially BRCA2, and treatment with PARP inhibitors because there are many PARP inhibitor prospective trials that show progression-free survival benefit and even overall survival benefit. And so that's the type of study that achieved the level of evidence that we could include. So I would say BRCA1 and BRCA2 highest level of evidence and PARP inhibitor use also is included in that.

Brittany Harvey: Understood. I appreciate you reviewing those therapeutic options. So then, the last clinical question, which you just touched on briefly, but what are the prognostic impacts of germline and/or somatic testing?

Dr. Evan Yu: Whenever you do testing, especially if you use panel testing, you find a lot of information. There's a lot of different mutations and some of which are VUSs (variants of unknown significance) where we don't quite know what it means yet, but we can track that, especially if it's germline. But with somatic, we find lots of things that have implications, but maybe just not treatment implications. A perfect example is p53. p53 is one of the most common tumor suppressor gene mutations on all cancers, but in prostate cancer they can occur and they can usually occur late, although there can even be germline inherited p53 alterations. There's no treatment that targets p53 right now, but we know that if you have a p53 mutation that those patients may have more aggressive disease and that prognostic information is important to give to the patient. And I think it's important for future clinical trial design and direction. So we do not recommend making treatment recommendations or changes based on these prognostic only biomarkers at this point in time. But we do recommend that, based on this, we can design intensification trials for those patients who have these poor risk biomarkers and de-intensification trials for patients who may have a good risk biomarker. So for instance, SPOP is a gene where we think these patients may have better outcomes, they might respond better to certain hormonal therapies like abiraterone. I say might because the level of evidence isn't quite there. But what I would say is that these prognostic only biomarkers, we just don't think they cut the mustard yet to be able to make treatment decisions. But we do think that they can drive counseling for the patient and potential selection and trial design for the future to say, “Okay. This is a patient population that has a more aggressive cancer. We need to be more aggressive in treating these patients.” “This patient population might have a less aggressive cancer. Maybe we can de-intensify and say side effects and quality of life may be better for the patients.”

Brittany Harvey: Definitely. It's important for thinking through how to personalize care for these patients.

So then you've talked about this a little bit in talking through the recommendations, but could you expand on what is the importance of this guideline and how it will impact both clinicians and patients with metastatic prostate cancer?

Dr. Evan Yu: Yeah, I think the number one thing is awareness. I think the data's out there and people that are in my field, they know this. But by evidence of the fact that it's not first-line presentation lingo that everyone's talking about things like BRCA status, it means it hasn't necessarily disseminated all the way through. So it's increasing awareness of the fact that both germline and somatic alterations can occur and that these may have impacts on the patient for their treatment and their prognosis, and basically to increase testing for the future. I really think that in the future, there'll be other reasons that we may want to serially even retest and we may find that there may be mutations that develop as mechanisms of resistance that might guide therapy down the road. So we need to get people to start doing this for everyone with metastatic prostate cancer, because someday we might be doing it not just once, but over and over again.

Brittany Harvey. Absolutely. We hope this guideline reaches a wide audience and that these recommendations can be put into practice.

Finally, you've talked about how not all the data in the field has yet risen to the level of evidence that made it into the guidelines. So what are the outstanding questions in future research areas for both germline and somatic genomic testing for metastatic prostate cancer?

Dr. Evan Yu: It was in our discussion, but it clearly- it's not common enough for there to be randomized prospective trials that would reach that level of evidence to make it in this guideline recommendation. But we all know that for any solid tumor, you can get mismatched repair deficiency, microsatellite instability leading to hypermutation or high tumor mutational burden. And that happens in maybe 3 to 5% of patients with metastatic prostate cancer as well. There is evidence and data that these patients can potentially benefit from immunotherapies like pembrolizumab. But again, it's just not common enough for there to be those randomized prospective controlled trials out there. But we mention it because we know it's FDA-approved across all the tumor types, so we felt like we have to mention it because that's something that has treatment implications for the patient.

But also, I alluded to this earlier, I think an area of active investigation is the tried and true number one driver of prostate cancer, which is androgen receptor. Testosterone binds to androgen receptors, stimulates it. That's how androgen deprivation therapy works. That's how abiraterone and the amides like enzalutamide, apalutamide, darolutamide, that's how they all work. But even beyond that, we're starting to identify that maybe 15%, 20% of patients with metastatic castration resistant prostate cancer have androgen receptor mutations. And there are newer classes of therapies like androgen receptor degraders like CYP11A1 antagonist that lead to complete adrenal annihilation of other steroid hormones that might promiscuously stimulate these androgen receptor mutants. These things develop as mechanisms of resistance, and in the future, we might want to serially test- and that's an active area of investigation in the future, to say you've been treated, let's say, with androgen deprivation therapy and abiraterone for years. There are certain mutations that might develop as a resistance mechanism. We might need to serially test somebody because you didn't have that mutation earlier on, but later in the disease course you might. And then there might be a new drug X out there that we would want to use. Again, we need the data, we need the randomized prospective controlled trials, but they're happening out there. And somewhere down the road we may rewrite this guideline and have a lot more recommendations to add to it.

Brittany Harvey: Yes, we'll look forward to more research in this field to better provide targeted therapies for patients with metastatic prostate cancer across the treatment paradigm. And we'll look forward to report outs from those trials that you mentioned.

So I want to thank you so much for your work to develop this guideline and thank you for your time today, Dr. Yu.

Dr. Evan Yu: Thank you so much. It's wonderful to be here today.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Hedy Kindler joins us on the podcast to discuss the latest update to the treatment of pleural mesothelioma guideline. She discusses the latest changes to the updated recommendations across topics including surgery, immunotherapy, chemotherapy, pathology, and germline testing. Dr. Kindler describes the impact of this guideline and the need for ongoing research in the field.

Read the full guideline update, “Treatment of Pleural Mesothelioma: ASCO Guideline Update” at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02425

My name is Brittany Harvey and today I'm interviewing Dr. Hedy Kindler from the University of Chicago, lead author on “Treatment of Pleural Mesothelioma: ASCO Guideline Update.”

Thank you for being here today, Dr. Kindler.

Dr. Hedy Kindler: Thank you so much.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kindler, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to jump into the content of this podcast episode, first, Dr. Kindler, can you provide an overview of the purpose and scope of this guideline update on pleural mesothelioma?

Dr. Hedy Kindler: The initial ASCO practice guideline on mesothelioma, which we published in 2018, was quite comprehensive, but since that time incredible progress has been made which has truly transformed the management of this disease. So we felt it was really important to update the guideline now, focusing on four key areas: the role of surgery, new systemic treatments, pathologic insights, and germline testing.

Brittany Harvey: Great. Thank you for highlighting those key areas of the guideline. And so I'd like to next review the key updated recommendations for our listeners. So starting with what are the new updates for surgery?

Dr. Hedy Kindler: So surgery has always been controversial in meso, with significant geographic variation in its use. Now, it's even more controversial. Recent randomized data from the MARS 2 trial, placed in the context of other data we also reviewed in this update, suggest that surgical cytoreduction should not be routinely offered to all patients based solely on anatomic resectability. Surgery should only be offered to highly selected patients with favorable prognostic characteristics. This includes comprehensively staged patients with early-stage epithelioid tumors. Patients should preferably be treated at centers of excellence which have documented low morbidity and mortality, and this should also be done in the context of multimodality therapy and preferably within clinical trials.

Brittany Harvey: Understood. I appreciate you reviewing those recommendations for who surgery should be offered to. So following those, what are the main recommendations for immunotherapy for treating pleural mesothelioma?

Dr. Hedy Kindler: So for a disease in which for 16 years there was only one FDA-approved regimen, pemetrexed and platinum, the pace of recent changes in systemic therapy has been a welcome change with the FDA approval of doublet immunotherapy in October of 2020 and the approval of chemo immunotherapy just a few months ago in September of 2024. Now that we have choices, we've tried to help clinicians determine the optimal treatment regimen for the individual patient. Doublet immunotherapy with ipilimumab and nivolumab should be offered as a first-line systemic option to any mesothelioma patient. For patients with non-epithelioid histology, doublet immunotherapy is hands down the recommended regimen based on the dramatic improvement in survival from 8.8 to 18.1 months for immunotherapy compared with chemo. For patients with previously untreated epithelioid mesothelioma, either ipilimumab-nivolumab immunotherapy or platinum-pemetrexed chemotherapy are reasonable options. Therapy can be individualized based on the patient's comorbidities, acceptance of differing toxicities. and treatment goals. Chemoimmunotherapy with pembrolizumab, pemetrexed, and carboplatin is a newer treatment option for patients with newly diagnosed pleural mesothelioma. This regimen is noteworthy for its very high objective response rate of 62%.

Brittany Harvey: It's great to have those new options to improve outcomes for patients.

Beyond the chemoimmunotherapy recommendation that you just described, what are the highlights for chemotherapy recommendations?

Dr. Hedy Kindler: So pemetrexed platinum-based chemotherapy with or without bevacizumab still plays a role in this disease and should be offered as a first-line treatment option in patients with epithelioid histology. This regimen is not recommended in patients with non-epithelioid disease unless they have medical contraindications to immunotherapy. Pemetrexed maintenance chemotherapy following pemetrexed-platinum chemotherapy is not recommended.

Brittany Harvey: Thank you for reviewing those recommendations as well.

So then next, what are the important changes regarding pathology?

Dr. Hedy Kindler: Well, one fun fact is that we've changed the name of the disease. It's no longer malignant mesothelioma. Now it's just mesothelioma. Since the non-malignant mesothelial entities have been renamed, all mesos are now considered malignant, so there's no need to use the prefix malignant in the disease name. Mesothelioma should be reported as epithelioid, sarcomatoid, or biphasic because these subtypes have a clear prognostic and predictive value. Knowing the subtype helps us decide on whether chemotherapy or immunotherapy is the optimal treatment for a patient, so it must be reported. Additionally, within the epithelioid subtype, histologic features, including nuclear grade, some cytologic features, and architectural patterns should be reported by pathology because they have prognostic significance. Pathologists have recently identified a premalignant entity, mesothelioma in situ, which can be found in patients with long standing pleural effusions and should be considered in the differential diagnosis. In the appropriate clinical setting, additional testing, including BAP1 and MTAP IHC should be performed.

Brittany Harvey: Definitely. These pathologic recommendations are important for treatment selection. So in that same vein, in the final section of the recommendations, what are the updated recommendations from the panel regarding germline testing?

Dr. Hedy Kindler: This is one of our most important recommendations, that universal germline testing should be offered to all mesothelioma patients. The proportion of patients with mesothelioma who have pathogenic or likely pathogenic germline variants is similar to other diseases in which universal germline genetic testing and counseling are now the standard of care. This is most commonly observed in the tumor suppressor gene BAP1 and this not only affects cancer risk in patients and their family members, but also has key prognostic significance. For example, pleural mesothelioma patients with BAP1 germline mutations who receive platinum-based chemotherapy live significantly longer, 7.9 years compared to 2.4 years for those without these mutations. Thus, we recommend that all patients with mesothelioma should be offered universal germline genetic counseling and/or germline testing.

Brittany Harvey: So there were a large amount of new and updated recommendations in this update. So in your view Dr. Kindler, what is the both importance of this update and how will it impact both clinicians and patients with pleural mesothelioma?

Dr. Hedy Kindler: Even as we were researching and writing this update, new data kept emerging which we needed to include. So it's clearly a time of great progress in the management of this disease. We've comprehensively reviewed and analyzed the extensive emerging data and provided clinicians with a roadmap for how to incorporate these new advances into their management of this disease.

Brittany Harvey: Absolutely, that is key for optimal patient care.

So you've just mentioned emerging data and rapid evidence generation, so what future research developments are being monitored for changes in the treatment of pleural mesothelioma?

Dr. Hedy Kindler: Despite these recent advances in disease management, mesothelioma continues to be a lethal cancer, and there's clearly a need to develop better treatments. This includes ongoing studies of novel immunotherapeutic agents such as bispecific antibodies, cell therapy using chimeric antigen receptors targeting mesothelioma tumor antigens, and precision medicine approaches to target tumor suppressor genes.

Finally, strategies for early cancer detection and prevention are vital for individuals predisposed to develop mesothelioma due to BAP1 and other germline mutations, as well as for those who are occupationally or environmentally exposed to asbestos.

Brittany Harvey: Absolutely. We'll look forward to these new updates to continue development in the field.

So thank you so much for this mountain of work to update this guideline, and thank you for your time today, Dr. Kindler.

Dr. Hedy Kindler: Thank you so much. It's been a pleasure. Thank you for asking me to do this.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Van Morris presents the new evidence-based guideline on systemic therapy for localized anal squamous cell carcinoma. Dr. Morris discusses the key recommendations from the Expert Panel, including recommended radiosensitizing chemotherapy agents, dosing and schedule recommendations, the role of induction chemotherapy and ongoing adjuvant chemotherapy, and considerations for special populations. He emphasizes the importance of this first guideline from ASCO on anal squamous cell carcinoma for both clinicians and patients with stage I-III anal cancer, and ongoing research the panel is looking to for the future.

Read the full guideline, “Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02120

My name is Brittany Harvey and today I'm interviewing Dr. Van Morris from MD Anderson Cancer Center, co-chair on “Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline.”

Thank you for being here today, Dr. Morris.

Dr. Van Morris: Thank you for having me. On behalf of our committee who put together the guidelines, I'm really excited to be here and talk with you today.

Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Morris, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to jump into the content of this guideline, Dr. Morris, can you provide an overview of both the purpose and the scope of this guideline on stage I to III anal squamous cell carcinoma?

Dr. Van Morris: So anal cancer is considered a rare malignancy for patients in the United States and across the world as well. Even though it's not something we see as commonly, for example, as the adjacent colorectal cancer, this still is a cancer that is rising in incidence every year in the United States. And really, despite the presence of the preventative HPV vaccines, which we hope will ultimately prevent and eradicate this cancer, we still expect the incidence to continue to rise in the coming decades before we really start seeing numbers begin to decrease as a result of the vaccine. So this is an alarming trend for which oncologists will continue to see likely more and more cases and new diagnoses every year. So we wanted to review the most recent literature and provide oncologists up to date recommendations for how they can best take care of patients with a new diagnosis of localized anal cancer.

Brittany Harvey: Absolutely. I appreciate that background and context to set the stage for this guideline.

So then next I'd like to review the key recommendations of this guideline. So starting from the first clinical question, what are the recommended radiosensitizing, doublet or single chemotherapy agents for patients with stage I to III anal cancer?

Dr. Van Morris: It's true that really the standard treatment for patients with localized anal cancer has not changed over the last literally half century. When the Nigro regimen was first reported back in 1974, 50 years ago, the standard of care for patients with a new diagnosis of localized anal cancer centers around concurrent chemotherapy and radiotherapy. And we looked at the various randomized control trials and the highest level of evidence which has been reported over the past decades, and really for most patients, the standard of care continues to remain doublet cytotoxic chemotherapy in combination with radiation. We reported that the most commonly, and I think most accepted, regimen here is a combination regimen of 5-FU, intravenous 5-fluorouracil with mitomycin C. And this most commonly is given on a week 1 to 5 regimen. The 5-FU, we recommended a dose of 1000 milligrams per meter squared per day on days 1 to 4 and then on days 29 to 32 of the radiation treatment. And then the mitomycin C, looking at various trials, has been given at a dose of 10 milligrams per meter squared on day 1 and day 29, or alternatively a single dose of mitomycin C at 12 milligrams per meter squared on day 1.

I think that the thing that's important for clinicians and patients alike to remember is that this chemotherapy can be very toxic in patients who are undergoing a curative-intent therapy for this diagnosis of localized anal cancer. I think it's just important for oncologists to be watching closely the blood counts for the patients to make sure that the myelosuppression doesn't get too bad. And then in select cases, if that is the case, when the oncologist opts to go for the day 1 and day 29 dosing, it may be prudent, if the myelosuppression is too excessive, to consider withholding that day 29 dose.

Brittany Harvey: Great. Thank you for providing those recommendations along with some of those dosing and the schedule recommendations from the expert panel.

So are there any other alternate dose or schedule recommendations from the expert panel?

Dr. Van Morris: Yeah, but I think that we saw with the ACT II data that was a randomized trial that was done out of the UK that compared 5-FU mitomycin with 5-FU cisplatin as two different doublet cytotoxic regimens, that overall outcomes were very similar between the two regimens in terms of curative outcomes for patients treated whether 5-FU mitomycin or 5-FU cisplatin. So certainly there is evidence supporting the use of cisplatin as a second cytotoxic agent with 5-fluorouracil. In the ACT II study that was given at a dose of 60 milligrams per meter squared on days 1 and 29 along with the 5-FU at the regimen I talked about previously. There is other lower level of evidence data suggesting that even the 5-FU and cisplatin can be given on a weekly schedule and that that can be safe. Actually, at my institution at MD Anderson, that is our standard practice pattern as well.

There's also the option when we're thinking about giving pelvic radiation for patients with lower GI cancers, many oncologists in the treatment of localized rectal adenocarcinoma are accustomed to using capecitabine as a chemosensitizer in patients with localized rectal cancer. If I'm giving chemoradiation for a patient with localized anal cancer, can I substitute the intravenous 5-FU with oral capecitabine? And although the evidence is not as strong in terms of available data with regards to randomized controlled trials, there certainly is data that suggests that capecitabine may be an acceptable alternative in lieu of intravenous 5-fluorouracil that would be given at a dose of 825 milligrams per meter squared on days of radiation. But certainly, I think that that's a feasible approach as well and maybe even associated with less hematologic toxicity than intravenous 5-FU would be.

Brittany Harvey: Great. It's important to understand all the options that are out there for patients with early-stage anal squamous cell carcinoma.

So in addition to those chemoradiation recommendations, what is recommended from the expert panel regarding induction chemotherapy or ongoing adjuvant chemotherapy for this patient population?

Dr. Van Morris: When we think about treating patients with lower GI cancers with curative intent therapies, when we think about the more common rectal adenocarcinoma, oncologists may be used to giving chemoradiation followed by subsequent cytotoxic chemotherapy. But actually when you look at the data for anal cancer, really there's not any data that strongly supports the use of either induction chemotherapy prior to chemoradiation or adjuvant post-chemoradiation chemotherapy. The RTOG 98-11 study was a trial which evaluated the role of induction 5-fluorouracil prior to chemoradiation and did not show any survival benefit or improved outcomes with the use of induction chemotherapy in a randomized control trial setting.

The ACT II trial, which I referenced earlier, was a 2 x 2 design where patients were either randomized to concurrent chemoradiation with 5-FU mitomycin C or concurrent chemoradiation with 5-FU cisplatin. But then there was a second randomization after chemoradiation where half of the study participants received adjuvant cisplatin 5-fluorouracil after completion of their chemo radiation, or the other half were randomized to the standard of care, which of course would be observation. And what that trial showed was that there was no added benefit with the addition of post-chemoradiation cytotoxic chemotherapy. So we look at these data and say that in general, for the general population of patients with localized stages I to III anal cancer, there really is no supporting data suggesting benefit of either induction chemotherapy or adjuvant chemotherapy. And to that end, really it's concurrent chemoradiation remains the standard of care at this time for patients with a new diagnosis of localized anal cancer.

Brittany Harvey: Absolutely. It's just as important to know what is not recommended as it is to know what is recommended for these patients. And so I thank you for explaining the evidence behind that decision from the panel as well.

So then, are there any other considerations for special populations that oncologists should consider?

Dr. Van Morris: I think so. I think that anal cancer is a disease where we don't see that many patients being diagnosed earlier at a younger age, especially in relation to the alarming trend of early onset colorectal cancer that we're currently seeing right now. So there may be patients who come with a new diagnosis of localized anal cancer who are an octogenarian at an advanced age or may have other significant medical comorbidities. And if that is the case, we get called about this quite frequently from outside institutions. I have an 85 year old who is coming to my clinic with this diagnosis. I don't feel comfortable giving this patient doublet cytotoxics, what options do I have? Especially given other organ dysfunction that may precede this diagnosis. And I think that in that case, there are times when it's okay safely to drop the mitomycin C and opt for single agent 5-fluorouracil as a single cytotoxic agent. So I think that that would be something that we've certainly incorporated into our practice at our institution. There's also an association between various autoimmune disorders, patients on immunosuppression, even persons living with HIV being at higher risk for this virally associated cancer. So I think that, again, if the patient is coming with baseline immunosuppression for these reasons prior to treatment, certainly kind of being in tune to the potential for hematologic toxicity. And watching these patients very closely as they're getting chemoradiation remains really important.

Brittany Harvey: Definitely. So, you've just discussed some of those comorbidities and patient characteristics that are important for clinicians to consider when deciding which regimens to offer. So in addition to those, in your view, what is the importance of this guideline and how will it impact clinical practice for clinicians who are reading this guideline.

Dr. Van Morris: Chemoradiation remains a very effective option and most patients will be cured with this diagnosis and with this treatment. So it's important to make sure that these patients are able to safely get through their treatment, minimizing treatment delays due to toxicities which may come about because of the treatment, and really help to carry them over the finish line so that they have the best likelihood for achieving cure. So we really hope that these data will provide oncologists with a readily available summary of the existing data that they can refer to and continue to help as many patients as possible achieve and experience a cure.

Brittany Harvey: Absolutely. So then to build on that, it's great to have this first guideline from ASCO on anal squamous cell carcinoma. But how will these new recommendations affect patients with stage I to III anal cancer?

Dr. Van Morris: I certainly hope it will allow patients and oncologists to know what their options are. It certainly is not a one size fits all treatment approach with regards to the options which are available. Depending on the patient, depending on the various medical conditions that may accompany them, these treatments may need to be tailored to most safely get them through their treatment.

Brittany Harvey: I appreciate you describing the importance of this guideline for both clinicians and patients.

So what other outstanding questions and future research do you anticipate seeing in this field?

Dr. Van Morris: It's a really good question and I think that there is a lot coming on the horizon. Even though the standard treatment has really not changed over the last half century, I think it still remains true that not all patients will achieve cure with a chemoradiation treatment. So a recent trial has completed enrollment in the United States, this is the EA2165 trial led by one of our committee members, Dr. Rajdev and Dr. Eng as well, that's looking at the use of nivolumab anti PD-1 immunotherapy after completion of concurrent chemo adiation. So in that trial, patients were randomized to concurrent chemoradiation followed by either observation or six months of adjuvant anti PD-1 therapy. We're really awaiting the results of that. Hopefully if we see an improvement with the addition of nivolumab following concurrent chemoradiation, our hope would be that more patients would be able to achieve a cure. So we're certainly looking forward to the outcomes of that EA2165 study.

And then I think one question that we often get from our patients in the clinics is, “What is the role of circulating tumor DNA in the management of my disease?” And really, to date there have been some series which have shown that we can assess patients or circulating tumor DNA after completion of their concurrent chemo radiation that may need to start about three months after to give time for the radiation to wear off and most accurately prognosticate that. But I think that this will be a powerful tool moving forward, hopefully, not only in the surveillance to identify patients who may be at high risk for recurrence, but ultimately to translate that into next generation clinical trials which would treat patients at higher risk for recurrence by virtue of a detectable circulating tumor DNA result. In doing so, hopefully cure even more patients with this diagnosis.

Brittany Harvey: Yes, we'll look forward to these developments and hope to add more options for potential treatment and surveillance for patients with anal cancer.

So, I want to thank you so much for your work to develop these guidelines and share these recommendations with us and everything that the expert panel did to put this guideline together. Thank you for your time today, Dr. Morris.

Dr. Van Morris: Thank you. And thank you to ASCO for helping to keep this information out there and ready for oncologists for this rare cancer.

Brittany Harvey: Absolutely.

And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Greg Kalemkerian reviews the latest evidence-based rapid update from the Expert Panel on systemic therapy for small cell lung cancer. He discusses the updated recommendations for patients with limited-stage SCLC based on the ADRIATIC trial, and for patients with relapsed SCLC based on the DeLLphi-301 trial. Dr. Kalemkerian shares insights on what these changes mean for clinicians and patients, and highlights new trials in progress to provide more options for patients diagnosed with SCLC.

Read the full rapid update, “Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02245

My name is Brittany Harvey and today I'm interviewing Dr. Greg Kalemkerian from the University of Michigan, lead author on, “Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update”.

Thank you for being here today, Dr. Kalemkerian.

Dr. Greg Kalemkerian: Thank you. Thank you for the invitation.

Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kalemkerian, who has joined us here today, are available online with the publication of the update in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content of this rapid update, Dr. Kalemkerian, what prompted this update to the Systemic Therapy for Small Cell Lung Cancer Guideline, which was previously published in 2023?

Dr. Greg Kalemkerian: So even though the original guideline only came out a year ago, the past year we've seen two significant advances in small cell lung cancer with two reports, one in limited stage with the addition of immunotherapy, the other in the addition of a new immunotherapeutic agent in relapsed small cell lung cancer.

Brittany Harvey: It's great to have this new data in the small cell lung cancer space. So based on these new changes, what are the updated recommendations from the expert panel?

Dr. Greg Kalemkerian: So the first recommendations have to do with patients with limited-stage small cell lung cancer based on the ADRIATIC trial which added consolidation durvalumab for patients who had not had progression after standard chemotherapy and radiotherapy. And this study demonstrated a significant improvement in overall survival with about a 10% improvement in both 2- and 3-year overall survival, up to a 57% overall survival at 3 years for the patients receiving consolidation durvalumab. And based on those findings, we updated the recommendation for the standard treatment for limited-stage small cell lung cancer such that it included the use of consolidation immunotherapy with durvalumab for up to two years in patients who had had no disease progression, and completion of concurrent chemoradiotherapy for limited-stage small cell lung cancer. Of course, those patients would be those who do not have contraindications to the use of immunotherapy.

As a corollary to that recommendation, for patients who have poorer performance status, so performance status of 3 or 4, who had had initial treatment perhaps with sequential chemotherapy and radiotherapy, if their performance status improves with their initial treatment, then it would also be reasonable to add consolidation immunotherapy for those patients as long as their performance status maintains improvement and they have no evidence of progression.

The other update of the guidelines had to do with patients with relapsed small cell lung cancer and that was based on the DeLLphi-301 trial which was a phase II study looking at the use of tarlatamab, a bispecific T cell engager, binds to both DLL3 and CD3 in order to increase the immune killing of small cell lung cancer cells. So what this study did was it treated patients who had had at least two prior regimens. So this is third-line or beyond was what the population that this study looked at. And the majority of these patients had already had some immune checkpoint therapy. They all had good performance status and it did allow patients with brain metastases to be included in the study. When we look at the patients who received the approved 10 milligram dose of the drug, the response rate was about 40%. Responses were seen in both patients with sensitive and refractory based on the time since their prior treatment and the median duration of response was 10 months, which is much better than anything we've seen before with relapsed small cell lung cancer patients, remembering that all these patients were also third-line or beyond.

So based on the results of the DeLLphi-301 trial, we updated two of the recommendations regarding relapsed small cell lung cancer. In the first one, we stated that in patients with relapsed small cell lung cancer with a chemotherapy free interval of less than 90 days, single agent systemic therapy would be considered standard of care, and that the preferred agents would include topotecan, lurbinectedin, or, now, tarlatamab. We did mention as a qualifying statement that single-agent chemotherapy is preferred over multi-agent chemotherapy. And the second recommendation was that, in patients with relapsed small cell lung cancer with a chemotherapy interval longer than 90 days, the rechallenge with a platinum-based regimen or single-agent chemotherapy was considered standard and the preferred agents for single agent therapy would be topotecan, lurbinectedin, or tarlatamab being added in the recent study. Tarlatamab was approved by the FDA for use in patients with relapsed small cell lung cancer with no stipulations with regard to the treatment.

Brittany Harvey: Understood. I appreciate you describing those updated recommendations along with the supporting data for both limited stage small cell lung cancer and relapsed small cell lung cancer.

So then, what should clinicians know as they implement these new and updated recommendations into practice?

Dr. Greg Kalemkerian: So with regard to the ADRIATIC trial or the consolidation durvalumab being added for limite- stage small cell lung cancer patients, I think the important considerations are that this was done after patients had demonstrated no progression of disease after chemotherapy and radiotherapy, so the initial treatment does not change with platinum-etoposide plus definitive radiotherapy being recommended. The addition of durvalumab is going to be potentially useful in patients generally with good performance status, so performance statuses 0 to 1, and we still have to pay attention to the patients who may have contraindications to immunotherapy, things like interstitial lung disease, autoimmune problems that do occur in patients with small cell lung cancer where they develop paraneoplastic autoimmune syndromes such as Lambert-Eaton myasthenic syndrome. Those patients with those types of preexisting conditions would not be good candidates for immunotherapy use. So still having the tailored treatment to the individual patient is what's most important. The duration of the durvalumab was up to two years and not beyond that, so following those specific guidelines for the use of durvalumab in patients with limited-stage small cell lung cancer.

With regard to tarlatamab, tarlatamab is an immunotherapy treatment. So we still do have the exclusions of people who have had prior severe immune-related adverse events, people who have pneumonitis, people who have interstitial lung disease, people with autoimmune neurologic problems we can see with small cell lung cancer, these patients should not be considered good candidates for the use of tarlatamab. The study did include patients who had had treated and asymptomatic brain metastases and there is some evidence that tarlatamab can have some control of brain metastases. So that's not necessarily an exclusion.

Tarlatamab does have some other specific considerations to it in that 51% of patients had some evidence of cytokine release syndrome (CRS). Only 1% of those patients had grade 3 CRS. So even though they had frequent fevers and hypotension and hypoxia, it was generally not severe. But this concern for CRS and also for neurologic complications after treatment does require that patients be admitted to the hospital for a 24-hour observation period during the first and second doses. Subsequent to that, patients can be observed for some time after the infusion in the outpatient setting. But they also need to have very clear and strict guidance for when they go home about what things to look for. Looking for fevers, looking for shortness of breath, looking for any neurologic changes. It's a good idea for them to have a caregiver with them in order to observe them during that time. Most of these complications occur during the first or second cycles, but it is a drug that is going to require significant education not only of our staff, but also of the patients in order to ensure that the drug's used safely.

Brittany Harvey: Absolutely. For these new options, it's important to tailor cancer treatment to the individual patient and the factors that you mentioned and be mindful of these potential toxicities.

So, it's always great to learn of new options for patients. But in your view, how will this update impact patients with small cell lung cancer?

Dr. Greg Kalemkerian: Well, clearly we need longer term follow up. So, with regard to the limited-stage small cell lung cancer situation, that's a curative situation. We have been curing patients with limited-stage disease with chemotherapy and radiotherapy for several decades now, but the cure rates were relatively low with about 25%, 30% of people becoming long term survivors. Now the hope is with the durvalumab being added on, that we can increase that number. Thus far, we have three-year survival data with a three-year survival of 57% overall survival and we're hoping that that is maintained over time and that we're not just delaying recurrences, but that we're actually preventing recurrences and helping people live longer, as has been seen with non-small cell lung cancer in stage III disease with the addition of durvalumab to chemoradiotherapy. So hopefully, we will be improving the cure rate of people with limited-stage small cell lung cancer.

There are several other trials with immunotherapy in this space coming down the line and we're anxiously awaiting not only long term follow up from ADRIATIC, but also initial data from studies such as KEYLYNK and ACHILLES and NRG-LU005. So all of these studies in the next few years are hopefully going to guide treatment for limited-stage small cell lung cancer and hopefully improve the long term survival outcomes. With regard to tarlatamab, unclear at this point what the long term outcomes are going to be. Is a 40% response rate substantially better than what we've seen before? Well, lurbinectedin also had about a 40% response rate in patients who had sensitive disease, but the duration of response does look longer. And there are some patients now who have been on this study that are doing very well for quite long periods of time with the drug. So, the hope here also is that we will have some small subset of patients who continue to do better for long periods of time. Whether that'll translate into a cure or not, way too early to know, clearly hoping to add another brick in the wall so that we can keep the disease at bay, at least for a longer period of time for these patients.

How we will integrate tarlatamab into the regimens is a bit unclear. Whether most of us will start using it as second-line therapy or whether we will use perhaps lurbinectedin or topotecan as second-line and tarlatamab as third-line, we're all going to have to work that out based on the potential toxicities, the logistical complications of using the drug at this point in time. But I do think that it's nice to have more options to add to our armamentarium to treat this very, very challenging and difficult disease.

Brittany Harvey: Definitely. So, you've just discussed the need for both longer term follow up here along with some important ongoing trials in this space. So we'll look forward to future readouts of those trials to learn more about caring for patients in small cell lung cancer.

So, I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Kalemkerian.

Dr. Greg Kalemkerian: Okay. Again, thank you for the invitation, Brittany, and thanks to ASCO for developing the whole guideline structure to help all of us take better care of our patients.

Brittany Harvey: Absolutely. And also thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full update, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Lyudmila Bazheova share the latest updates to the ASCO living guideline on therapy for stage IV non-small cell lung cancer with driver alterations. She discusses changes for patients with EGFR driver alterations in both the first- and second-line setting, and reviews the evidence supporting these updated recommendations, from trials such as MARIPOSA, MARIPOSA-2, CheckMate 722, and KEYNOTE-789. Stay tuned for future updates to this continuously updated guideline.

Read the full update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2.” at www.asco.org/living-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02133

My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, lead author on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2.”

Thank you for being here, Dr. Bazhenova.

Dr. Lyudmila Bazhenova: It is my pleasure.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bazhenova, who has joined us on this episode today, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to kick us off on the content here, Dr. Bazhenova, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is being updated routinely as a living guideline. So what prompted the update to the recommendations in this latest version?

Dr. Lyudmila Bazhenova: Living ASCO Guidelines are developed to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. In this recently published guideline, we reviewed new evidence for patients with metastatic lung cancer harboring driver alterations. We reviewed evidence from four published studies, MARIPOSA, MARIPOSA-2, CheckMate 722 and KEYNOTE-789 that resulted in updated guidelines.

Brittany Harvey: Great. And then based off those four trials that you just mentioned, what are the updated recommendations for patients with stage IV non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution?

Dr. Lyudmila Bazhenova: In the previous guideline, we detailed FLAURA 2 study which was presented and published in the past. In this guideline, we specifically highlighted a phase 3 MARIPOSA trial which took patients with untreated advanced non-small cell lung cancer which harbored classical EGFR mutations such as EGFR deletion 19 and L858R. In this study, patients were randomly assigned to receive amivantamab plus lazertinib or osimertinib or lazertinib alone. And the study showed that the primary endpoint which was progression-free survival was longer with amivantamab plus lazertinib compared to osimertinib, and numerically the progression free survival was 23.7 months with ami-lazertinib versus 16.6 months with osimertinib which was statistically significant. The challenge that we have to face when discussing that option with our patients is increased toxicity with amivantamab and lazertinib combination. For example grade 3 treatment adverse events were 75% with amivantamab and lazertinib and 43% with osimertinib. So this will require shared decision making between our patients and ourselves. We also noticed in the guidelines that there was a subgroup analysis of that study showing that the patients with a higher disease burden, central nervous metastasis or brain metastasis as well as disease which considered to be a higher risk such as commutation, for example, p53 and liver metastasis, they might benefit from intensified therapy. However, another thing that we are highlighting in the guideline is that at this point we do not know how the intensification of therapy will change overall survival of our patients. So one needs to take into account increased toxicity with that combination.

Brittany Harvey: So then Dr. Bazhenova, in addition to those updates for first line therapy, what are the updated recommendations for second line therapy?

Dr. Lyudmila Bazhenova: For patients who have progressive disease on osimertinib or other EGFR tyrosine kinase inhibitors, we also updated our guidelines highlighting MARIPOSA 2 study. In the MARIPOSA 2 study, patients were assigned to chemotherapy versus amivantamab plus lazertinib plus chemotherapy versus amivantamab plus chemotherapy. And both of the amivantamab arms showed superiority in progression-free survival compared to chemotherapy alone arm and therefore this becomes an additional treatment option for our patients who develop resistance to osimertinib. In addition, we also updated the results which highlight the lack of efficacy of immunotherapy in the patients who progressed on osimertinib.

There were two studies that we highlighted. One of them was a CheckMate 722 which randomly assigned patients with metastatic non-small cell lung cancer whose cancer has progressed on EGFR tyrosine kinase inhibitor to receive either chemotherapy or chemotherapy plus nivolumab which is an immune checkpoint inhibitor.

And the second study was KEYNOTE-789 which had a very similar study design. Again, patients who progressed on EGFR TKI also were assigned to receive chemotherapy plus pembrolizumab or chemotherapy alone and in both of those studies there was no improvement in progression-free survival when adding immunotherapy to chemotherapy. So for all your patients who are progressing on EGFR tyrosine kinase inhibitors and you’re thinking if additional immunotherapy is necessary, we now have two randomized phase 3 studies telling us that immunotherapy should not be used in addition to chemotherapy for patients who develop progression on osimertinib.

Brittany Harvey: Understood. I appreciate you talking about the evidence that supports these latest recommendations from the expert panel.

So then you've already touched on this a little bit in mentioning shared decision making and discussing toxicity with these new therapies, but what should clinicians know as they implement these new recommendations and how do these new recommendations fit into the previous recommendations made by the panel?

Dr. Lyudmila Bazhenova: Our previous recommendations did not include a MARIPOSA trial, so did not include amivantamab and lazertinib. So in our current guidelines for patients with newly diagnosed treatment-naive EGFR classical mutations, we have three options. Number one is osimertinib, number two is osimertinib plus chemotherapy based on the FLAURA study that we highlighted in the prior version of the guidelines. And the third is amivantamab plus lazertinib. At this point, we do not have any randomized head-to-head studies of those combinations with an exception of FLAURA 2 which is osimertinib plus chemo versus osimertinib. And so the decisions will have to be made on a cross-trial comparison, taking into account patient wishes if they would like to receive chemotherapy or amivantamab plus lazertinib, understanding that this combination will result in increased toxicity.

Brittany Harvey: Absolutely. I appreciate you detailing those considerations.

So then finally, what do these new options mean for patients with non-small cell lung cancer and an EGFR alteration?

Dr. Lyudmila Bazhenova: As a patient, it is important to also be aware of what options we have and have a direct dialogue with the physician, with the treating physician, trying to understand what option will fit with each individual patient's goals, life goals, as well as toxicity concerns.

Brittany Harvey: Definitely. It's always great to have more options for patients and it's also important to discuss all of those options with their clinician as well.

So I want to thank you so much for your work on this update and thank you for your time today, Dr. Bazhenova.

Dr. Lyudmila Bazhenova: My pleasure.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Sepideh Gholami and Dr. Aaron Scott join us to discuss the latest evidence-based guideline from ASCO on the management of locally advanced rectal cancer. They review the recommendation highlights on topics including assessment, total neoadjuvant therapy, timing of chemotherapy, nonoperative management, and immunotherapy. Additionally, we discuss the importance of this guideline for both clinicians and patients, and the outstanding research questions in the management of locally advanced rectal cancer.

Read the full guideline, “Management of Locally Advanced Rectail Cancer: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.01160

My name is Brittany Harvey, and today I'm interviewing Dr. Aaron Scott from the University of Arizona Cancer Center and Dr. Sepideh Gholami from Northwell Health, co-chairs on, “Management of Locally Advanced Rectal Cancer: ASCO Guideline.” Thank you for being here, Dr. Scott and Dr. Gholami.

Dr. Sepideh Gholami: Thank you for having us.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Scott and Dr. Gholami, who have joined us here today, are available online with a publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to kick us off on the content of this episode, Dr. Gholami, first, what is the purpose and scope of this guideline on locally advanced rectal cancer?

Dr. Sepideh Gholami: Well, I think, historically, this is the group of patients with locally advanced rectal cancer for which we've used multiple therapies to address their management. And with the advent of the total neoadjuvant approach, we really have seen tremendous changes. So the purpose really of these guidelines was to consolidate the various approaches that we've had in several clinical trials and to provide the oncology community a general management recommendation guideline to really optimize the outcomes for these patients. And I would further notice that with the specifics to like which patients are included for these, so we define patients with locally advanced rectal cancer as any of those patients with T3 or T4 tumors and/or lymph node positive disease.

Brittany Harvey: Great. I appreciate you providing that background and context of this guideline.

So then, next, I'd like to review the key recommendations of this guideline. So, Dr. Scott, starting with the first section of the guideline, what are the recommendations for assessment of locally advanced rectal cancer?

Dr. Aaron Scott: Yeah, thank you. So really, we were charged with trying to answer, I think, several very important questions as it comes to the treatment of locally advanced rectal cancer. And the first step in doing so is to define the patient group. So, as far as the first section goes in the assessment, we were really charged with defining what locally advanced rectal cancer means. We think that this is best done with a high resolution pelvic MRI, dedicated rectal sequence prior to any treatment for risk assessment and proper staging, and the use of standardized synaptic MRI is recommended that includes relation of the primary tumor to the anal verge, sphincter complex, pelvic lymph nodes, the mesorectal fascia, otherwise known as the MRF, and includes assessment of the EMVI tumor deposits and lymph nodes.

Brittany Harvey: I appreciate you reviewing those highlights for assessment of locally advanced rectal cancer.

So following that, Dr. Gholami, what does the panel recommend regarding total neoadjuvant therapy and standard neoadjuvant chemotherapy for patients with proficient mismatch repair or microsatellite stable tumors?

Dr. Sepideh Gholami: Yeah, thanks so much for that question, Brittany. I would say that the guidelines really provide a lot more details, but in general, the consensus was that TNT should be offered as really initial treatment for patients with low rectal locally advanced rectal cancers or those who have higher risk for local and distant metastases. Those risk factors included anyone with either T4 disease, extramural vascular invasion and/or tumor deposits identified on the MRI for any threatening of the mesorectal fascia or the intersphincteric plane.

Brittany Harvey: Excellent. So then, Dr. Gholami just discussed who should be offered TNT. But Dr. Scott, what are the recommendations regarding timing of TNT?

Dr. Aaron Scott: So the way I take this question, think about this question, is a lot of the work that we put toward defining whether chemoradiation plus consolidation versus induction chemotherapy is the right choice, and there are a lot of implications to consider in this situation. The panel recognizes that the decision to proceed with chemoradiation followed by chemo versus chemotherapy followed by chemoradiation often depends on logistics regarding the time to treatment start, concern for distant metastases, and desire for local control that may impact surgical decision making.

When we look at the subgroup analysis for overall survival of patients treated with TNT, it doesn't seem to matter which approach you take. Either induction or consolidation doesn't seem to have an impact on overall survival. However, there are other outcomes that may be of importance. Based on the CAO/ARO/AIO-12 randomized phase II trial, both pathologic complete response rates and sphincter sparing surgery were numerically higher with consolidation chemo. That said, there was no difference in disease free survival. So if you have a patient that really wants to consider some sort of sphincter sparing surgery, or a patient has a highly symptomatic disease burden, etc., these are patients that we would recommend starting with chemoradiation followed by consolidation chemotherapy.

Brittany Harvey: Understood. And so you have both mentioned radiation included in treatment regimens. So Dr. Gholami, what is recommended in the neoadjuvant setting? Short course radiation or long course chemoradiation?

Dr. Sepideh Gholami: Yeah, we actually had a really long discussion about this, but I think in general the consensus was that if radiation is included in any patient's treatment plan, neoadjuvant long course chemoradiation is preferred over short course RT for patients with locally advanced rectal cancer. And really the recommendation was based on the long term results that we've seen from the RAPIDO phase 3 clinical trial, which showed a significant higher rate of five year local regional failure with a total neoadjuvant approach with short course of 10% compared to the standard chemo RT with only 6% of the local recurrence rate. So that's why they opted for the long course, if the patients can actually tolerate it.

Brittany Harvey: Excellent. I appreciate reviewing the recommendation and the supporting evidence that the panel reviewed to come to those recommendations.

Then following that, Dr. Scott, for those patients who have a complete clinical response after initial therapy, what is recommended regarding nonoperative management?

Dr. Aaron Scott: First, I would like to just say that this is really an area that still remains somewhat controversial and needs more investigation to best select patients for this approach. This topic was not systematically reviewed for the ASCO guideline. However, the expert panel was surveyed and most agreed with the time interval used in the OPRA phase 2 trial, which assessed patients for clinical complete response within eight weeks plus or minus four weeks after completion of TNT. Expert panel members and reviewers noted that if the radiation therapy component of TNT is delivered first, then an eight week interval following subsequent chemotherapy may result in a prolonged period of no treatment and therefore a first assessment of this response in this scenario would occur on the earlier side of the recommended interval. If a near clinical complete response is noted, then reevaluation within eight weeks is recommended to assess for developing a clinical complete response.

Brittany Harvey: Absolutely. That information is helpful to understand what is recommended regarding nonoperative management and clinical complete responses.

Then the final clinical question, Dr. Gholami, for patients with tumors that are microsatellite instability high or mismatch repair deficient, which treatment strategy is recommended?

Dr. Sepideh Gholami: Yeah, I think we really came up to summarize that in general, when there is no contraindication to immunotherapy, then patients with MSI high tumors should be really offered immunotherapy. The evidence for this recommendation was relatively low, though, just due to the small sample size of the data that's currently available. But we did want to highlight that the data is very promising, but a definitive recommendation by the committee should be validated in future larger clinical trials.

Brittany Harvey: Absolutely. Well, thank you both for reviewing the highlights of these recommendations for each clinical question.

Moving on, Dr. Scott, in your view, what is the importance of this guideline and how will it impact both clinicians and patients with locally advanced rectal cancer?

Dr. Aaron Scott: This would be the first guideline through ASCO to spell out management options for locally advanced rectal cancer. This has largely been needed due to the increased number of phase II and III trials investigating the specific patient population that have investigated a variety of different TNT approaches and treatment combinations utilizing systemic therapy, radiation, and surgical treatment. So, in this guideline, we really set out to define what locally advanced rectal cancer is, have organized and analyzed impactful large randomized studies to address multimodality therapy, and have consolidated this information into what we consider a concise and generalizable approach to help clinicians and patients individualize their management based on specific clinical pathologic features of their cancer.

Brittany Harvey: Yes, this has been a mountain of work to review all the evidence, consolidate it into a concise review of that evidence, and develop recommendations for best clinical practice for management of locally advanced rectal cancer.

So then, finally, to wrap us up, Dr. Gholami, what are the outstanding questions regarding management of locally advanced rectal cancer?

Dr. Sepideh Gholami: Yeah, I think I just want to reiterate, Brittany, what you mentioned, this was a tremendous amount of body work, and we really would like to thank the committee and everyone from ASCO to help us with creating these general guidelines. I think one of the outstanding questions really still remains is the use of circulating tumor DNA as a management tool for patients with rectal, locally advanced rectal cancer. And also, I think outside of what we can think of the straightforward populations to deduce from PROSPECT, be really interested to see what other patient populations, for example, could also potentially maybe avoid radiation therapy. And lastly, I think we really wanted to highlight that this guideline really focuses on the locally advanced, and it would be great to see future guidelines for early stage rectal cancer which will be forthcoming.

Brittany Harvey: Definitely. We'll look forward to answering those outstanding questions and for upcoming guidelines on earlier stage rectal cancer. So, I want to thank you both so much for, as you said, the tremendous amount of work that went into these guidelines and thank you for taking the time to speak with me today, Dr. Scott and Dr. Gholami.

Dr. Aaron Scott: Thank you.

Dr. Sepideh Gholami: Thank you so much for having us. Appreciate it.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please read and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Megan Daly presents the latest rapid recommendation update to the ASCO management of stage III NSCLC guideline, based on data from the phase III randomized LAURA trial, presented at the 2024 ASCO Annual Meeting, and subsequently published. She discusses the results of the trial, shares the updated recommendation from the expert panel, and the impact for both clinicians and patients. We also discuss future research in the area and exciting new developments to watch out for in the field. Read the full rapid update, “Management of Stage III Non-Small Cell Lung Cancer: ASCO Rapid Guideline Update” at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-01324.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO’s podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Megan Daly from the University of California Davis Comprehensive Cancer Center, lead author on, “Management of Stage III Non–Small-Cell Lung Cancer: ASCO Rapid Guideline Update.”

Thank you for being here today, Dr. Daly.

Dr. Megan Daly: Thanks for having me, Brittany.

Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Daly, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to start us off on the content of this update, first, this guideline was updated based off new evidence presented at the 2024 ASCO Annual Meeting. Dr. Daly, could you describe the trial that prompted this rapid update to the management of stage III non-small cell lung cancer guideline?

Dr. Megan Daly: The trial that prompted this update is the LAURA trial. The LAURA trial was a phase III randomized trial conducted in patients with unresectable stage III non-small cell lung cancer harboring EGFR mutations, either exon 19 deletions or L858R insertions. Patients in this trial were randomized 2:1 between the third generation EGFR tyrosine kinase inhibitor osimertinib or placebo, and osimertinib or placebo were continued until progression or other reasons for discontinuation. Osimertinib was found to provide a considerable benefit in progression free survival, with a hazard ratio of 0.16. The median progression free survival for patients randomized to osimertinib was 39.1 months, and for patients on the placebo arm, it was 5.6 months. We did not yet have overall survival data from the LAURA trial. The data is not mature, but the considerable progression free survival benefit noted with osimertinib has drawn a lot of interest to this trial.

Brittany Harvey: Absolutely. Thank you for describing the results of those trials and the endpoints. So then, based on this new evidence, what is the updated recommendation from the guideline expert panel?

Dr. Megan Daly: The updated recommendation from the panel is that patients with unresectable stage III non-small cell lung cancer with an EGFR exon 19 deletion or exon 21 L858R mutation may be offered consolidation osimertinib after definitive chemoradiotherapy, which can be either platinum-based chemotherapy and thoracic radiation given either concurrently or sequentially. Our evidence quality is moderate and the strength of the recommendation is strong.

Brittany Harvey: Great. And thank you for reviewing both the strength of the recommendation there as well as the evidence quality rating. So it's great to have this new option for patients. So what should clinicians know as they implement this new recommendation?

Dr. Megan Daly: I think it's important for clinicians to know when they're counseling patients about considering osimertinib to understand that first, the LAURA trial enrolled patients who had common EGFR mutations. So exon 19 deletions or L858R mutations. Patients with other uncommon EGFR mutations were not included in the trial. It's important to know that overall survival data is not yet mature. We do not know yet whether the use of consolidation osimertinib leads to a survival benefit at this time. We only know that it leads to a progression-free survival benefit as compared to placebo. I think it's also important to know that there was increased toxicity noted on the experimental arm. Grade 3 or higher adverse events was significantly higher with the use of osimertinib. So these are all important considerations when counseling patients and considering the use of osimertinib.

Brittany Harvey: Absolutely. Those are definitely key points, as you mentioned, to consider. And you've already touched on this a little bit. But how does this change impact patients living with stage III non-small cell lung cancer?

Dr. Megan Daly: We do see in the LAURA trial a rather remarkable benefit for progression-free survival. The progression-free survival, as I already mentioned, increased from 5.6 months median on the control arm to 39.1 months on the experimental arm with consolidation osimertinib. So this is an exciting new option for patients with unresectable stage III non-small cell lung cancer who have one of these mutations to extend their progression-free survival by almost three years. And we hope that this progression-free survival benefit will end up translating into a considerable overall survival benefit as well. So, certainly, the overall survival data is eagerly awaited.

Brittany Harvey: Definitely, this is a promising option for patients, and we look forward to future readouts of long-term data on this trial. So that's one of the outstanding questions here. But what other outstanding questions are there regarding the management of stage III non-small cell lung cancer?

Dr. Megan Daly: I think what many of us question when we look at this data is whether we could extrapolate to the use of other targeted agents with other less common oncogenic driver mutations. Unfortunately, the answer is we simply don't know yet. We hope to see some ongoing data in the resectable setting. Doing randomized trials with rare oncogenic drivers in unresectable stage III lung cancer is very difficult, unfortunately, and there's always a degree of extrapolation for clinicians when trying to figure out how to best manage our patients. But for me, that's one of the biggest outstanding questions I think specifically ties into interpreting the LAURA trial and other related trials in patients with oncogenic driver mutations.

I think there's still many outstanding questions about how we continue to improve outcomes for our patients with unresectable stage III non-small cell lung cancer, questions about how we optimize our radiation regimens to have the best possible local control while reducing toxicity. We still need to continue to have randomized trials looking at questions on optimizing radiation, optimizing concurrent chemotherapy, whether there are any settings where we might be able to reduce or omit chemotherapy in place of some of these newer agents. These are all outstanding questions that hopefully will be answered over the next several years. We also continue to have open questions about when patients are more appropriate for surgery and more appropriate for non-surgical options, those borderline patients with N2 nodes who may technically be surgical candidates or could potentially be downstaged with neoadjuvant therapy. So, I think there's a lot of exciting work going on in stage III right now.

Brittany Harvey: Absolutely. We'll look forward to that more data that you mentioned for more optimal individualized options for these patients with stage III non-small cell lung cancer.

And I want to thank you so much for your time to rapidly update this guideline based off new evidence presented and then published. And thank you for your time today, Dr. Daly.

Dr. Megan Daly: Thank you, Brittany. It's great to be on here.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions

View Details

Ms. Charité Ricker, MS, CGC and Dr. Nadine Tung, MD, FASCO share updates from the new ASCO guideline on selection of germline genetic testing panels in patients with cancer. They discuss highlights on family history collection, when and how multigene panel germline genetic testing should be used, which genes are generally recommended for testing, and how germline genetic testing interfaces with somatic genetic testing. Ms. Ricker and Dr. Tung also note the importance of the guideline and the impact of these new recommendations on clinicians and patients with cancer. Read the full guideline, “Selection of Germline Genetic Testing Panels in Patients with Cancer: ASCO Guideline” at www.asco.org/molecular-testing-and-biomarkers-guidelines.

TRANSCRIPT

GDL 24E13

This guideline, clinical tools, and resources are available at www.asco.org/molecular-testing-and-biomarkers-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00662

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO’s podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts

My name is Brittany Harvey, and today I'm interviewing Dr. Nadine Tung, a medical oncologist from Beth Israel Deaconess Medical Center in Boston, and Ms. Charité Ricker, a cancer genetic counselor with the Norris Comprehensive Cancer Center at the University of Southern California and Los Angeles General Medical Center, co-chairs on, “Selection of Germline Genetic Testing Panels in Patients with Cancer: ASCO Guideline.”

Thank you for being here, Ms. Ricker and Dr. Tung.

Dr. Nadine Tung: Pleasure.

Ms. Charité Ricker: Thank you.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Tung and Ms. Ricker, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to start us off first, Dr. Tung, could you provide us a broad overview of both the purpose and scope of this guideline?

Dr. Nadine Tung: Sure. A main impetus for creating the guideline is that oncologists are increasingly being tasked with ordering genetic testing for hereditary cancer risk for their cancer patients. More and more now, they may find themselves sending the test and then seeking guidance from genetic experts to interpret the result. And these panels range from focused tests with just a few genes to comprehensive ones that include over 100 genes. So it can be very overwhelming for an oncologist to be able to understand ordering these tests and explaining them to their patients. So, we believe that it was important to offer some guidance and direction on the use of these multigene panels.

Brittany Harvey: Thank you for setting the stage for this guideline and the recommendations that come from it.

So then, Ms. Ricker, this guideline addresses four overarching clinical questions. I'd like to review the recommendations based on each of those questions for our listeners. So starting with that first question, what is the importance of family history collection in the setting of germline multigene panel testing and which elements of family history are the most important?

Ms. Charité Ricker: Thanks. As a genetic counselor, this is probably one of my favorite questions. I love the opportunity we have to sit with families and really dig into family history. But family history collection can be overwhelming and a big lift sometimes in busy clinics where genetics is not the focus. So, what we tried to do was to break down the key elements of what components of family history are most relevant to informing which test to do, and also the interpretation of those test results. And I like to think about the key pieces of family history as being the who, what, and when of somebody's family cancer history. Who was diagnosed with cancer within their close relatives? And usually we're most focused on first and second degree relatives. So parents, siblings, grandparents, aunts, and uncles. But sometimes relevant history might go into third degree relatives like cousins or more distant. So the who being who has cancer on both sides of the family? And then the what: what kind of cancer was it? Or where did that cancer begin? And the when: how old was that individual at the time they were diagnosed? Often we ask patients maybe not to fixate on the exact age, but to give us a sense. So was this somebody who was diagnosed young, in their 20s or 30s or older, in their 60s or 70s? Because that at least gives us a ballpark around what might be relevant for understanding the genes that should be included on somebody's test.

When we are thinking about the purpose of this history, as Dr. Tung said, often the range of multigene panels might be from a few very focused genes to a very broad panel. Family history can help us understand if we need to step beyond the very focused genes that might be relevant for the patient's history of cancer and include other genes that might be indicated based on that family history. So I think about the role that family history has at the time of identifying which test to do and then its role when interpreting what those results mean for the patient and their family. Again, Dr. Tung touched on the fact that we are often testing very large panels. However, we still don't know everything. And so a negative genetic test result does not mean that somebody does not have additional cancer risk. And family history becomes our kind of guiding star for understanding if there is still a need to change the cancer screening and prevention management for that individual and their family members.

Brittany Harvey: Absolutely. Those are key points to understanding the important role of family history for each individual patient.

So then moving to the next clinical question, Dr. Tung, what does the panel recommend regarding when and how multigene panel germline testing should be used, when germline genetic testing is indicated?

Dr. Nadine Tung: Well, anytime multiple genes need to be tested, as Ms. Ricker said, because of the patient's own personal cancer history, or their family history of cancer and close relatives, it's appropriate to consider a multi-gene panel. And in truth, we rarely ever just order one gene these days. Perhaps we do if there's a known gene like a BRCA gene in the family, and a relative just wants to know if they have that. But it's not all that common. And to be clear, as Ms. Ricker is going to cover a bit later, we are recommending that the appropriate minimal panel at least include the genes relevant to the patient's own cancer and the cancers in their relatives.

But it's worth thinking about what are some of the pros and cons of ordering genes beyond that, beyond the patient's own cancer or their relatives? Well, for pros, since a patient's awareness of their family history may be incomplete, testing for a larger number of cancer risk genes does ensure that significant pathogenic variants won't be overlooked. And sometimes, even if the family history is well known, pathogenic variants in important cancer risk genes can be found even when the family history would not have prompted testing for them. But it is important for clinicians to appreciate that bigger isn't necessarily better. Some larger panels may include genes for which management of pathogenic variants is not entirely clear and that can create anxiety or unnecessary screening. And if the clinician receiving the information is not well informed about the significance of the finding, that can lead to unnecessary treatment and sometimes even unnecessary surgeries.

And I'd add one final point that clinicians must have a system for communicating reclassification of these variants, the ones with uncertain significance that we call VUS. Because as the number of genes tested increases, so does the likelihood of encountering these VUS. So I would say those are some of the main points about when to use the panel and when to think about larger or smaller panels.

Brittany Harvey: Yes, I appreciate you reviewing both the pros and cons of expanding the genes included in multi-gene panel testing and the importance of variants of uncertain significance.

So then Dr. Tung just touched on this, but speaking of minimal panels and which genes should be included, Ms. Ricker, what are the recommendations on which genes are generally recommended for germline genetic testing?

Ms. Charité Ricker: I think this is one of the harder questions that our group took on as we were working on this guideline. I don't think there is a one size fits all and one easy answer to this question. However, we chose to approach it by selecting the more common solid tumors that oncologists see in their clinics and the ones where the role of genetic testing is most well defined, as well as some very rare tumors where they're kind of easy. So we know that all individuals with certain types of cancers, even though they are rare, should merit genetic testing regardless of age of diagnosis, family history.

And so as we approached it, and I really appreciate ASCO’s support in helping us develop some tools and tables that hopefully will be important aids for clinicians who are trying to make these decisions, we took the approach of, as Dr. Tung mentioned, selecting kind of a minimal set of recommended genes where most individuals who are informed in this area would agree that if nothing else was done, these genes should be done, but then also acknowledged that there is an expanding understanding about the impact of certain genes on cancer risk, and so then also provided a kind of a next level if somebody wanted to be more expansive, what we would recommend less strongly, but would be reasonable to consider. Then I think the other last piece that the committee felt was important to acknowledge is that given how common, in comparison to some of these genetic conditions that we work with, pathogenic variants in BRCA1 and BRCA2 can be, and also the important clinical impact of those genes along with the genes associated with Lynch syndrome, we felt that those were important to think about in the setting of all cancer patients. So if you're approaching a panel and thinking about what genes to include, looking at that kind of minimally recommended based on the patient's personal and family history, maybe the next level, which might include some additional genes that we have included in kind of the less strongly recommended category for those tumor types. And then consideration of the BRCA1 and 2 genes and genes associated with lynch syndrome, if they weren't already encapsulated by your other personal and family history considerations.

Brittany Harvey: Definitely. This was a big lift for the panel to tackle, and the tools and tables that you mentioned are all available online with the publication in the Journal of Clinical Oncology. So listeners who are looking for more specifics on that can definitely refer to those tools and tables there.

Dr. Tung, the last clinical question: which patient should be offered germline genetic testing, who will have or who have previously had somatic genetic testing?

Dr. Nadine Tung: Identifying which genes identified through the tumor testing should trigger germline testing is really important for assessing our patients’ future risk of cancer and their relatives. So during the development of our guidelines, the ASCO expert panel became aware that the ESMO Precision Medicine Working group had updated their recommendations for this topic, namely germline testing in response to tumor test findings. And these recommendations were based on the Memorial Sloan Kettering IMPACT registry, which consists of nearly 50,000 tumors and paired germline testing. Given the sheer volume of that data and the methods that ESMO used, our group decided to use that as a framework to develop our recommendations. The ASCO guideline provides a list of genes that, if found in the tumor, a pathogenic variant in those genes may prompt germline testing.

And we offered or proposed two different approaches. The first approach, which is broad and perhaps simplest, involves doing germline testing if a pathogenic variant is found in any of the genes listed. But then we offer a conservative approach to test the germline for all highly actionable genes, like BRCA1 and 2, or lynch genes that are found in a tumor, but for less actionable genes, testing the germline only if the pathogenic variant is found in a tumor relevant to that gene. So, for example, ATM, if found in breast cancer or pancreatic cancer, would trigger germline testing with this approach, but not if found in lung cancer, whereas with the permissive first approach, you would simply test the germline if any pathogenic variant is found in any of the genes on the list. This latter, more conservative approach, while less sensitive for identifying every germline pathogenic variant, increases the likelihood that a pathogenic variant found in the tumor will actually be germline. That approach considers the limited resources available, such as genetic counselors, and respects trying not to overwhelm a system already stressed.

Brittany Harvey: Thank you for reviewing both of those approaches and to you both for discussing all of the recommendations included in this guideline.

Finally, to wrap us up, in your view, Ms. Ricker, what is the importance of this guideline and how will it impact both clinicians and patients with cancer?

Ms. Charité Ricker: I hope that this guideline can open the door for more expansive and appropriate utilization of germline genetic testing. For me, I think about, from both the clinical and patient side, for example, all ovarian cancer patients have had a recommendation for germline genetic testing for many years. Nonetheless, data from multiple research studies has shown us that ovarian cancer patients still are not being tested universally, and this has important implications for their treatment plans and for their family members. And so even in the setting where genetic testing, if I can use the phrase, has been simple in that it didn't require family history, it didn't require even a specific age criteria, it was just broad, testing is not utilized as much as it should be, and then you step into the world of more complex decision making around genetic testing for other tumor types. And so we hope that this provides a framework to simplify that decision making process for providers to increase appropriate utilization.

And then from the patient perspective, I also think about the lack of access of genetic testing in underrepresented communities and minoritized patient populations where there's many barriers that patients face in accessing genetic services. And so if we can help reduce the barriers for this piece of the genetic testing process, my hope is that that opens up better avenues for access to testing, not just for patients with certain tumor types, but for all patients from all communities and backgrounds.

Brittany Harvey: Yes, those are key points. We hope that this guideline helps all patients access the appropriate testing to better inform their cancer prevention and treatment.

So I want to thank you both so much for your work on this comprehensive guideline on germline genetic testing and all of the work that you put into it. And thank you for your time today. Ms. Ricker and Dr. Tung,

Dr. Nadine Tung: Thank you.

Ms. Charité Ricker: It was a pleasure to be here. Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/molecular-testing-and-biomarkers-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Jyoti Patel discusses the latest update to the stage IV NSCLC with driver alterations living guideline, specifically for patients with EGFR or ROS1 alterations. She shares the latest recommendations based on recently published evidence, such as the FLAURA2, MARIPOSA-2, and TRIDENT-1 trials. Dr. Patel talks about how to choose between these new options and the impact for patients living with stage IV NSCLC, as well as novel drugs the panel is monitoring for future guideline updates.

Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1” at www.asco.org/living-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00762

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO’s podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1.”

Thank you for being here today, Dr. Patel.

Dr. Jyoti Patel: Thanks so much.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then to dive into the content of why we're here today, Dr. Patel, this living clinical practice guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being updated on a regular basis. So what prompted the update to the recommendations in this latest update?

Dr. Jyoti Patel: This recent update, I think, absolutely reflects how quickly the science is changing. The landscape of treatment options for patients with advanced non-small cell lung cancer is evolving so rapidly, and guidelines from even six months ago don't address some of the newest approvals and newest data and the newest clinical scenarios that we're presented with when we see patients. I think it's harder because before there was usually a single answer, and now there are a number of scenarios, and we hope that the guideline addresses this.

Brittany Harvey: Absolutely. The panel's had a lot of data to review as you keep this guideline up to date.

So then this latest update addresses updates to both EGFR and ROS1 alterations. So starting with EGFR, what are the updated recommendations for patients with stage four non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution?

Dr. Jyoti Patel: So for patients with classical driver mutations in EGFR, our recommendation remains that patients should be offered osimertinib. We now also have data to support intensification of therapy with osimertinib and chemotherapy. The FLAURA2 trial was a global randomized study in which patients with classical mutations were assigned to receive either osimertinib or osimertinib with doublet chemotherapy. The trial showed that progression free survival was longer with osimertinib plus chemotherapy with a hazard ratio that was pretty profound, 0.62. In patients who had CNS metastasis as well as patients with L858R mutations, this benefit remained and was perhaps even greater. Now the study remains immature in terms of OS. What we can say is that chemotherapy adds toxicity, so the inconvenience of 13 weekly infusions, expected toxicities from chemotherapy of myelosuppression and fatigue. I think this- we’ll continue to watch as the study matures to really see the OS benefit, but certainly intensification in the frontline setting is an option for patients.

The other major update was for second and subsequent line therapy for these patients with EGFR mutations. Another important trial, a study called MARIPOSA-2, was published in the interim, and this was for patients who had received osimertinib in the frontline setting. Patients were randomized to one of three arms. The two arms that are most relevant for us to discuss are chemotherapy with amivantamab or chemotherapy alone. Chemotherapy with amivantamab was associated with an improvement in progression free survival with a hazard ratio of 0.48 as well as improvements in response rate with almost a doubling of response rate to the mid 60%. There was certainly an increase in AEs associated with amivantamab, primarily rash and lower extremity edema and importantly infusion reaction. Based on this data, though in the superior PFS and response rate, we've said that patients after osimertinib should be offered chemotherapy plus amivantamab. Patients may opt for chemotherapy alone because of the toxicity profile, but this recent update is reflective of that data.

Brittany Harvey: Excellent. Thank you for reviewing those updated recommendations and the supporting evidence behind those recommendations. I think that's important to the nuance and the toxicity associated with these new recommendations as well.

So then, following those recommendations, what are the updated recommendations for patients with stage four non-small cell lung cancer and a ROS1 rearrangement?

Dr. Jyoti Patel: ROS1 fusions have been noted in a small but important subset of patients. We now reflect multiple new options for patients. Traditionally, crizotinib was the primary drug that was recommended, but we now have two very active drugs, repotrectinib, and entrectinib, that have both been FDA approved. Repotrectinib was approved based on a study called the TRIDENT-1 trial. In this study, patients who were treatment naive, who had not received a prior TKI, had a response rate of 79% and a long duration of response over 34 months. For patients who had received prior TKIs, so primarily crizotinib, the response rate was lower at 38%. But again, very clinically meaningful. Repotrectinib has known CNS activity, so it would be the favored drug over crizotinib, which doesn't have CNS penetration. The decision between entrectinib and repotrectinib is one, I think, based on toxicity. Repotrectinib can cause things like dizziness and hypotension. Entrectinib can cause weight gain, and also has CNS effects.

Brittany Harvey: Appreciate you reviewing those recommendations as well.

So then you've already talked a little bit about this in terms of deciding between some of the options. But in your view, what should clinicians know as they implement these new recommendations, and how do these new recommendations fit into the previous recommendations?

Dr. Jyoti Patel: So there's an onslaught of new data, and certainly many of us want to remain at the front of our fields and prescribe the newest drug, our most effective drug, to all of our patients. But for the person living with cancer and in the practice of medicine, I think it's much more nuanced than that. For example, for a patient with an EGFR mutation exon deletion 19, the expectation is that osimertinib will have a deep and durable response. Certainly a patient will eventually have progression. I think the decision about intensification of therapy and chemotherapy on the onset really has to do with how much the patient is willing to deal with the inconvenience of ongoing chemotherapy, the uncertainty about what comes next after progression on chemotherapy. It may be, though, that a patient may very much fear progressive disease, and so that inconvenience is lessened because anxiety around feeling like they're doing everything for their cancer is diminished by intensification of therapy. Others who may have a large volume of disease or profoundly symptomatic, or who have L858R or brain metastasis it may make sense to give chemotherapy again, we're improving the time until progression significantly by combination therapy.

Brittany Harvey: Definitely those nuances are important as we think about which options that patients should receive, along with shared decision making as well.

So then what do these new options mean for patients with EGFR or ROS1 alterations?

Dr. Jyoti Patel: It's fantastic for patients that there are multiple options. It's also really hard for patients that there are multiple options, because then again, we have to really clarify aims of therapy, identify what's really important in patient experience and the lived importance of treatment delivery and the burden of treatment delivery. Now more than ever, oncologists have to know what's new and exciting. But patients have to be willing to ask and participate in the shared decision making - understanding their cancer and understanding that their options are absolutely important. As patients start making their decisions, we have the data just in terms of trial outcomes. I think we're now trying to understand the burden of treatment for patients. And so that piece of communicating financial toxicity, long term cumulative lower grade toxicity is going to be more important than ever.

Brittany Harvey: Absolutely. It's great to have these new options, and those elements of communication are key to ensuring that patients meet their goals of care.

So then finally, as this is a living guideline, what ongoing research is the panel monitoring for future updates to these recommendations for patients with stage four non-small cell lung cancer with driver alterations?

Dr. Jyoti Patel: It's certainly been an exciting time, and that's primarily because we've been able to build on years of foundational science and we have new drugs. Patients have been willing to volunteer to go on clinical trials and to think about what treatment options may be best. Now, the work really comes on seeing the longer term outcomes from these trials. So looking at these trials for overall survival, we want to also better identify which patients will benefit the most from these treatments and so that might be additional biomarker analysis. So it may be that we can identify patients that may need intensification of therapy based on tumor factors as well as patient factors as well in those patients in whom we can de-escalate treatment. I think there are a number of new compounds that are in the pipeline. So fourth generation EGFR TKIs are certainly interesting. They may be able to overcome resistance for a subset of patients who progress on osimertinib. We also think about novel drugs such as antibody drug conjugates and how they'll fit into our paradigm with osimertinib or after carboplatin-based doublets.

Brittany Harvey: Definitely. We'll look forward to both longer term readouts from the current trials and new trials in this field to look at additional options for patients.

So I want to thank you so much for your time today, Dr. Patel, and thank you for all of your work to keep this living guideline up to date.

Dr. Jyoti Patel: Great. Thanks so much, Brittany. It really is an exciting time for people who treat lung cancer and for patients who have lung cancer. We certainly have a long way to go, but certainly the rapid uptake of these guidelines reflect the progress that's being made.

Brittany Harvey: Absolutely. And just a final thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Bradley Hunter, MD, MPH and Ms. Amy Evers, BSN, RN, OCN, MBA join us on the latest episode of the ASCO Guidelines Podcast to share key points and insights on the updated ASCO-ONS antineoplastic therapy administration safety standards for adult and pediatric oncology standards. They highlight key updates across the four standards domains: (1) creating a safe environment, (2) patient consent and patient education, (3) ordering, preparing, dispensing, and administering oral and parenteral antineoplastic therapies in a health care facility, organization, or in the home, and (4) monitoring during and after antineoplastic therapy is administered, including adherence, toxicity, and complications. They also comment on the importance of these standards to provide a framework for optimal safe and effective care for all patients. Read the standards, “Antineoplastic Therapy Administration Safety Standards for Adult and Pediatric Oncology: ASCO-ONS Standards” at www.asco.org/standards.

TRANSCRIPT

These standards, clinical tools, and resources are available at www.asco.org/standards. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP.24.00216

My name is Brittany Harvey, and today I'm interviewing Dr. Bradley Hunter from Intermountain Health and Amy Evers from the University of Pennsylvania, authors on “Antineoplastic Therapy Administration Safety Standards for Adult and Pediatric Oncology: American Society of Clinical Oncology – Oncology Nursing Society Standards.” Thank you both for being here.

Dr. Bradley Hunter: Yeah, thanks. Good to be with you.

Amy Evers: Thank you.

Brittany Harvey: Now, before we discuss these standards, I'd like to note that ASCO takes great care in the development of its guidance products and ensuring that the ASCO Conflict of Interest Policy is followed for all standards. The disclosures of potential conflicts of interest for the expert panel are available online with the publication of the standards in the JCO Oncology Practice, which is linked in the show notes.

So then to start us off, Dr. Hunter, what prompted an update to the ASCO-ONS standards? And what is the scope of this update?

Dr. Bradley Hunter: The last guidelines were published in 2016. And just thinking about in the world of oncology, so much has changed since that time. There are a lot of therapies that have become commonplace now that were really not used too much before, including oral genomically determined targeted therapies, immunomodulatory agents, CAR T cell therapy, bispecific antibodies, etc. So there's really been a need to just talk about how do we navigate those therapies and how do we create systems of care in which they are delivered safely. Additionally, the sites of care have changed. I think all of us, eight years ago, wouldn’t have imagined a global pandemic, and how that would have changed the way that we needed to deliver oncology care. So there's been a huge influx of telehealth, including tele-oncology centers, where the oncologist and the patient may never even meet face to face, but just by video. And so it relies on a team approach for that sort of an outreach setting. Intermountain Health spans seven states, there are so many sites like this that we have and I know that we are not unique. This is an issue and a global thing now. Additionally, patients are even getting chemo in their own homes, so that has changed and we need to figure out how to address that so that everyone could be able to have that site of care so they can get there and they can get their therapy in a safe manner.

So, these varied care settings present a challenge to us as oncology providers to ensure that a standard of quality of care is maintained, and that the therapies can be given to patients no matter where they live and that we maximize benefit while minimizing risk to the patient. So I mean, just thinking where we are now, I can't imagine where we're going to be eight years from now or the next time these guidelines are updated.

Brittany Harvey: Absolutely. Thank you for setting the stage and the impetus for this update. It sounds like a lot has changed in the last few years to impact these standards.

So then I'd like to review the key points of the standards and the key updates for our listeners. There are four domains of standards. Starting with domain one, Amy, what are the key points of the standards for creating a safe environment for all routes of antineoplastic therapy?

Amy Evers: So domain one is all about who can write chemotherapy orders, who can prepare chemotherapy and then who can administer that chemotherapy and then what their competencies are both initial and then ongoing. So looking at the existing standards, we did end up making a few updates mainly on how providers discuss and document pregnancy status and fertility preservation with patients. And I think this is really timely given that we're seeing a big uptick in younger patients that are being diagnosed with cancers that were typically considered “old person diseases”. And I think we can and we should do better in ensuring that patients who want to preserve their ability to have a family one day can do so before they start treatment.

The update also included the addition of an assessment for social determinants of health, calling out financial and logistical constraints that patients may face as part of their cancer journey, which I think is extremely important making sure that we have equitable access to care regardless of a patient's background, their financial status, everybody's receiving the highest quality of care they can in their community.

And the last change that we made was to highlight an accurate measurement of height and weight using metric units, which is important when we're calculating the doses of drugs for some of these very high risk medications.

Brittany Harvey: Excellent. Thank you for reviewing those important points for our listeners.

So following those standards, for domain two, Dr. Hunter, what are the key standards for patient consent and patient education?

Dr. Bradley Hunter: In domain two, we’re really seeking to figure out what policies around treatment planning, patient consent and patient's education are shown to result in fewer medical errors and reduce preventable harm? But one of the big things we've found is having a really detailed understanding of exactly what a patient is taking in terms of medications, including over the counters and supplements and herbal remedies, really helps reduce medical errors. You know, some of the research and literature we came across suggest that upwards of 80% of the time when you see a patient's medication there are discrepancies between what's on that list and what patients are actually taking. So being able to sit down as part of a consent discussion and ongoing care and talk about everything that a patient's taking is really important.

My background, I am a bone marrow transplant, stem cell transplant and cellular therapist. Just this last weekend I was on the inpatient service and a patient had brought in food from home which we completely are supportive of. The patient brought in a bunch of superfood shakes that she had bought at Costco and then some CBD tea and she asked us if it was okay if she could take those. And as we reviewed them and what was in all of those shakes and then what was in the CBD tea, there were major interactions between those supplements or those herbal remedies, and then what was in the medications we were giving in the hospital, so it was important. And she told us - it wasn't like I sat down and and was the shining example here, but it was helpful that we were able to take her global picture of what she was taking from a medication standpoint and be able to make sure that we were treating her in a safe manner and making sure that we weren't inadvertently causing harm.

So, those are some of the things that we talked about. So, at every patient visit, and especially the first time you meet a patient you’re going to start therapy to be able to go over all of the different substances that patients are taking to make sure that they're safe.

Brittany Harvey: Thank you so much for reviewing those key standards and key updates and that example of how important it is to review all of medications and herbal supplements that patients are taking to ensure safe care for our patients.

So then following that, Amy, for domain three, what are the key points regarding ordering, preparing, dispensing and administering oral and parenteral antineoplastic therapy in a healthcare facility organization or in the home?

Amy Evers: So, domain three, actually, it was the domain that had probably the biggest discussion and fruitful debate between the panel members, but I think that we had some really great discussions and I think we had brought some really good changes and updates to the standards here. So domain three is where all of the verification standards live. So this is for practices who would either have been through the QOPI certification process or have been QOPI certified. This is where the surveyor actually will observe in real time how the clinical orders are reviewed by staff, how the drugs are prepared by pharmacy, and then how the drugs are checked one final time at the chair side or bedside immediately prior to administration.

So as I mentioned earlier, antineoplastic therapies are being given more frequently in the home or in settings where there may not be two clinical staff members present. In this post-COVID world, we're finding patients can be treated safely in the home, but the standards didn't really reflect kind of these changes in where patients are receiving treatment. And often, more and more practices are relying on technology to supplement the verification process both either in the pharmacy setting where there may be a centralized pharmacist verifying the drug mixing process for multiple sites, or in the actual home setting where a nurse can connect virtually with another clinician to verify a drug immediately or administration. So the standards were updated to include these workflows. And I think it's becoming more and more commonplace, but how do we do this in a safe and effective way where we're ensuring that all of these same safe handling processes are completed, regardless of where the patient may be seeking treatment?

So previous versions of the standards had three verifications. The first was before the actual preparation of the drug that someone other than the provider who wrote the order is verifying the order for all of the correct elements. The second verification is what usually happens in the pharmacy, upon preparation, what's being checked by the pharmacist or pharmacy technician who's preparing the drug. And then a third verification is done at, generally, the chair side where they're doing one final check of the orders to the drug to the patient.

So with this update, we actually broke out that third verification into a fourth verification. So the third verification is that check with the drug in the order by the administering and then a second verifier. And then the fourth verification is actually the one where the patient’s involved in the verification. So there are two clinicians making that final double check with the patient immediately upon preparation, which I think is important and is reflective of this change that we're seeing more drugs being administered in the home setting. The chair side or bedside final verification was also expanded to include a visual inspection of the administration tubing, this is sometimes referred to as tracing the lines, which ensures that the drug is being accurately infused, that there aren't any loose connections, that the clamps are open etc. And I think this is something that most nurses do in their normal clinical practice, but I think adding this as an actual check in the verification process, is really important. And I know personally, I was really happy to see this added in as a formal check.

Dr. Bradley Hunter: Yes, thanks, Amy. One other new standard within domain three is regarding immunomodulatory or immune effector cell therapies that have the risk of cytokine release syndrome and how we build a framework to try to mitigate those toxicities. We really wanted to try to make a set of standards that would apply whether or not you’re at a coronary care center, like Penn or whether you were at a center, like within Intermountain Health, it's a small rural outreach center that you're trying to be able to get patients to care. So really, the main thing within dealing with therapies that have the risk of cytokine release syndrome is really just building a framework that there's a management policy that's present from the institution, and that it's up to date, it's following what we know will work for these therapies in order to mitigate their toxicity, and then also making sure that adequate antidote therapy, whether for example, for cytokine release syndrome, it could be tocilizumab or anakinra or other therapies, and that order sets are present to be able to follow along with the policy guidelines to guide clinicians wherever they are practicing to help mitigate cytokine release syndrome, neurologic toxicity, ICANS, or other sorts of therapies that are associated with these novel agents.

Brittany Harvey: So for or the last domain, domain four, what are the key points for monitoring during and after antineoplastic therapy is administered, including adherence, toxicity, and complications?

Amy Evers: So domain four is pretty straightforward. It discusses the importance of assessing adherence and toxicities related to antineoplastic treatments. There wasn’t a whole lot of updates here. We did include having emerging treatment plans or equipment in the home and the healthcare setting. But what I really think is important and we need to underscore both with patients and clinicians, particularly as we've seen this rise in oral chemotherapy agents, is that a lot of times patients forget that this is the same chemotherapy that they're getting in the infusion suite. They're just taking it in a pill form. And I think patients forget that their adherence is just as important in taking that pill regularly and as prescribed. Financial toxicity is a real problem for most of our patients. Some of these drugs cost hundreds if not thousands of dollars for one treatment plan. As clinicians we've all heard stories of these patients who try to extend their prescription so they'll take a pill every other day instead of daily as prescribed, which really doesn't let the drug do what it's supposed to do. So I think when we talk about adherence, it's not just asking a patient whether they've taken their drug, it's about whether or not oral therapy is even appropriate for that particular patient. Do they have memory problems? Do they have metastatic disease to the brain where they may not be able to follow a complicated oral regimen? Do they have arthritis where opening a pill container is difficult? So having these conversations before a drug is even prescribed and making sure that it's the right route of administration for a patient is just as important as ensuring that they're maintaining their adherence to that drug.

And oftentimes, the toxicities of these oral drugs are worse than what's actually being administered in some of the infusion clinics, and so making sure that we're checking in on these patients regularly to ensure that they're not having any toxicities that aren't being managed appropriately. Or if there may be toxicities that would require a dose reduction, or perhaps switching to a different drug entirely. So, even though it's a pretty simple and straightforward domain, I think it's really important that we're educating our clinicians and our patients about the importance of adherence.

Dr. Bradley Hunter: I completely agree with what Amy said. She said it so well. I just want to echo back a couple of things that she said. Historically, we use the word non-compliant, which I think kind of sounds terrible to describe the patient's adherence to medication. I think part of this domain is recognizing that there is an entire environment that has to do with the patient that influences the way they're able to take their medication whether that's financial toxicity; we were talking to two people in our clinic who are professional financial toxicologists, and their entire job description is to help people get drugs for less so that they can actually take the side effects. If a patient feels terrible at that time, they’re not going to take it. So, understanding these barriers and really understanding the patient's entire picture, when you're figuring out how is the treatment plan going to match up with their reality, I think is super important.

When it comes to site of care, we just want to make sure also that whether you're getting chemo at home or you’re getting chemo in the clinic down the street, or in a coronary care center, that there is a policy in place to respond to an emergency, but also the equipment available in all of those sites of care that you can respond. And that's another aspect that we wanted to make sure we hit in the domain as there's been so many changes in how patients get care in the last eight years.

Brittany Harvey: Absolutely. Recognizing the barriers and factors that impact the ability of an individual to receive the right therapy is crucial. And I want to thank you both for reviewing all of the standards and updates through all four domains.

So then following that, in your view, how will these updated standards impact clinicians?

Dr. Bradley Hunter: It's our hope that these standards will guide the development of treatment infrastructure and help clinicians avoid error prone environments. We hope they're going to guide training efforts and that they will help clinicians ensure that they have relevant and accurate information about their patients and are able to respond appropriately when emergencies or even urgencies arise. Because of COVID, there's been such high staff turnover. And in the midst of all of this change, it's difficult to maintain a culture of safety when you've lost a lot of institutional knowledge of how to deal with that. And so, really trying to help bring people together again to have an infrastructure in place that makes training as seamless as possible and deal with the historical high staff turnover we’ve had.

So we're again, hopeful that we're helping to create a framework that cancer centers, treatment centers can use, whether they are a coronary care center in a large academic space, or whether they're in a rural tele-oncology space to be able to use the standards to create a space and a place and experience for cancer patients in which they’re kept safe and we’re maximizing the benefit of their chemotherapy, their antineoplastic agents, and also minimizing the risk just to optimize benefits for the patient.

Brittany Harvey: Definitely. Those are key points to provide a framework for clinicians.

So then along those same lines, finally, what does this update mean for patients receiving antineoplastic therapy?

Amy Evers: So while these standards are not necessarily patient facing, what I hope that this update will do, or actually not do, is that a patient shouldn't recognize any change in how they are cared for, regardless of what setting that they're receiving treatment. So whether it's at home, whether it's an ambulatory infusion center or in the hospital, they're still going to receive that same level of high quality care while they're receiving treatment. And I think that that's the most important thing that they should take away from this.

Brittany Harvey: Absolutely.

So I want to thank you both so much for all of your work on these standards to ensure patients receive optimal safe and effective care. And I want to thank you both so much for your time today.

Amy Evers: Thank you so much.

Dr. Bradley Hunter: Yeah, thank you. It’s really great to talk about this stuff.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the complete standards go to www.asco.org/standards. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Rachel Freedman and Dr. Sharon Giordano share the latest rapid guideline update from ASCO on the adjuvant use of the CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer. They share details on the impetus for the update, supporting evidence, and considerations of benefits and harms for individuals. Additionally, Drs. Freedman and Giordano discuss what these options mean for clinicians and patients, and outstanding questions regarding optimal adjuvant chemotherapy and targeted therapy for patients with early breast cancer. Read the full rapid update, “Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer – CDK4/6 Inhibitors: ASCO Rapid Guideline Update” at www.asco.org/breast-cancer-guidelines."

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00886

My name is Brittany Harvey, and today I'm interviewing Dr. Rachel Freedman from Dana Farber Cancer Institute and Dr. Sharon Giordano from MD Anderson Cancer Center, co-chairs on “Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer – CDK 4/6 Inhibitors: ASCO Rapid Guideline Update.” Thank you for being here, Dr. Freedman and Dr. Giordano.

Dr. Rachel Freedman: Hi. It's great to be here, thank you.

Dr. Sharon Giordano: Yeah, thank you for having us.

Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Freedman and Dr. Giordano, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content here. First, Dr. Freedman, what prompted this update to the “Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer Guideline”, which was previously updated in 2021?

Dr. Rachel Freedman: Yeah, at that time, we published guidelines which were part of an amendment to the previously published 2020 early breast cancer guidelines to include consideration of adjuvant CDK4/6 inhibitor use, because the first data for adjuvant abemaciclib became available from the monarchE trial, and because the FDA had acted to grant approval for the use of abemaciclib in those with node positive disease and a Ki-67 score of at least 20%. Our recommendation at that time was to apply abemaciclib in the greater context of the intention-to-treat population included on the monarchE study.

But since that time, the FDA in 2023 expanded its approval for adjuvant abemaciclib for a broader population, removing that Ki-67 requirement that was a part of their initial approval. With this change, the recently published longer term data from the monarchE study and the recently published data from the NATALEE trial and adjuvant ribociclib study, we felt that it was time to update our guidelines to be more relevant to the most current data available.

Brittany Harvey: I appreciate you providing that background information on the impetus for this latest update.

So then, Dr. Giordano, based on this new data, what are the updated recommendations in the latest version of this guideline?

Dr. Sharon Giordano: So we really have two updated recommendations and then two qualifying statements that go with the new recommendations. So the first recommendation focuses on the use of adjuvant abemaciclib, which, as Rachel noted, was included in our previous guideline. So this recommendation is that abemaciclib for two years plus endocrine therapy for five or more years may be offered to patients who meet the criteria of the intent-to-treat analysis in the monarchE study. These are patients with resected, hormone receptor-positive, HER2-negative, node-positive breast cancer at high risk of recurrence. The way the study defined the high risk of recurrence was having either four or more lymph nodes involved, axillary lymph nodes involved, or having one to three lymph nodes, plus other high risk features, which included having a grade three tumor the size of 5 cm or greater, or having a Ki-67 of more than 20%. And so, although the FDA has dropped the requirement for the Ki-67 testing, and the language is quite broad now, the panel recommends the use of abemaciclib, really in that subgroup of patients that would have been eligible for the original monarchE study. That's the first recommendation, kind of a long one, but that was the update.

The second recommendation focuses on the use of adjuvant ribociclib, and this is based on the data from the phase three NATALEE trial that was recently published. This recommendation is that ribociclib for three years plus endocrine therapy, may be offered to patients with stage two or three breast cancer who would have met criteria for study entry and have a high risk of recurrence. I would note with this one, I think it's important to remember that the ribociclib that's used in the adjuvant setting is a different dosing. So it's 400 milligrams daily, three weeks on, one week off, as compared to the 600 milligrams we're using in the metastatic setting. That was the second new recommendation.

As I previously mentioned, however, there were two qualifying statements. The first qualifying statement was really the panel wanted to make, because they felt that CDK4/6 therapy in the adjuvant setting may not provide meaningful clinical benefit to every single patient who would have been eligible for these two trials. The concern was especially around lower risk patients. So the early stage two breast cancer patients who were included in the NATALEE trial, and in that situation, the panel felt for some patients, the risks may outweigh the benefits. The challenge here really was that there was not a great way to pick a very specific subgroup of patient that would benefit or wouldn't benefit. So based on that, the panel really recommended taking a broad approach and considering the benefits of therapy, the risks, the costs, and of course, patient preference when making the decision about whether or not to offer these drugs in the adjuvant setting.

Then the second qualifying statement was really around how to pick between the two drugs. What the panel stated was that for patients that met the criteria for both studies, they could have been in either monarchE or NATALEE, for those patients, that abemaciclib has longer follow up, has a deepening benefit over time, it's more convenient because it's two years versus three years, and it has FDA approval. So for patients, again, that would have met criteria for either study, the panel favored using abemaciclib, except if patients had some contraindication or intolerance. That is the update, both the recommendations and the qualifying statements in this updated guideline.

Brittany Harvey: Understood. Thank you for reviewing both of those recommendations and the nuances between choosing between some of those options as detailed in the qualifying statements.

So then, Dr. Freedman, I think Dr. Giordano has talked about this already a little bit, but what should clinicians know as they implement these new recommendations into practice?

Dr. Rachel Freedman: Yeah, in the guidelines, as Sharon said, we've really tried to offer recommendations that balance the available efficacy data along with the toxicity data and even some mention of cost consideration, although we purposely can't address that in the guideline. And we just feel that all of these need to be considered in combination for the individual patient. And just like you heard, our panel felt that for those meeting criteria for both the monarchE and NATALEE trials, given all the reasons that Sharon explained, that abemaciclib may be the preferred agent for now, but we all look forward to the evolving data in this space. It's great to have another evidence-based option with ribociclib at this time, but we really acknowledge that longer term follow up will evolve these recommendations further.

Brittany Harvey: Absolutely. As you mentioned, it's great to have another option in this space.

So then, in your view, Dr. Giordano, how will these recommendations impact patients with early breast cancer?

Dr. Sharon Giordano: I think that, overall, this is really good news for patients who are at high risk because there's now two new available therapies that they can use to help prevent recurrence. I will note, as we mentioned before, though, they do come with a price, both the cost of the drug and the additional side effects of having two or three years of an additional drug that they're taking. But having said that, I think it's always good to have new options for therapy, and we can discuss these options with the individual patients, weigh the risks and the benefits, and ultimately, we hope with longer follow up, it would be great to see if these drugs would actually improve overall survival, which is ultimately our biggest goal.

Brittany Harvey: Definitely, those are key for shared decision making between patients and their clinicians.

Then finally, looking forward, Dr. Freedman, what are the outstanding questions regarding the optimal adjuvant chemotherapy and targeted therapy for early breast cancer?

Dr. Rachel Freedman: Well, there are a lot of outstanding questions with regard to chemotherapy. We have a lot of questions. We still have insufficient data to specify which subgroups, who may have a higher degree of nodal involvement, or what we call anatomical risk, but perhaps a favorable biology or genomics. And we don't know which subgroups still need chemotherapy. And I think this is a group many of us are struggling with in the clinic, is what to do when you have high anatomical risk, but a well behaving cancer, so to speak. And I think that's a burning question for many of us.

I still think we have room to improve our adjuvant regimens and figuring out who needs more and who needs less therapy when we are going to move forward with chemotherapy. And we also, with regard to CDK4/6 inhibition, have a lot of ongoing questions. There are a lot of patients who may not benefit from CDK4/6 inhibition as much as others, and the broader population on the NATALEE trial allows us to explore this a little bit, but we're cautious about interpretation of subgroups. But the lowest risk patients on the NATALEE trial may be a group of patients that it's really important to think about when it comes to balancing that toxicity and efficacy risk, as opposed to that higher risk patient where you're sure you want to move ahead.

And I think we really await the survival data from both NATALEE and monarchE, neither of which have shown a statistically significant survival advantage to date. We really need ongoing follow up of these studies, and we look forward to learning more in the years to come.

Dr. Sharon Giordano: Yeah, I completely agree. It's very well said. I mean, I think one of the biggest challenges, as Rachel said, it's really hard to figure out which subset of patients are truly going to benefit and have the benefit of the drug outweigh the side effects. I hope as we get longer follow up on the studies and additional data come out, we're able to get more information so that we can really give the best therapies to the patients that need it, but also spare patients who don't need it from the additional side effects.

Brittany Harvey: Absolutely. We'll await the longer term follow up of these trials and then future updates to these guidelines.

So I want to thank you so much for your work to rapidly update this breast cancer guideline. And thank you so much for your time today, Dr. Giordano and Dr. Freedman.

Dr. Rachel Freedman: Thanks so much.

Dr. Sharon Giordano: Yeah, thank you very much, our pleasure.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full rapid recommendation update, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Karen Mustian joins us to share the latest update to the management of fatigue in adult survivors of cancer guideline from the American Society of Clinical Oncology and the Society for Integrative Oncology. Dr. Mustian highlights the recommendations across the continuum of care, including recommendations for patients with cancer-related fatigue during active treatment, after treatment, and for patients with advanced cancer or at the end of life. She also discusses interventions that are not recommended for treating cancer-related fatigue. The episode wraps up discussing the importance of this guideline for clinicians and patients, and a call for more research both on interventions and on dissemination and implementation to improve symptom management for cancer-related fatigue. Read the full guideline update, “Management of Fatigue in Adult Survivors of Cancer: ASCO-SIO Guideline Update” at www.asco.org/survivorship-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00541

My name is Brittany Harvey, and today I'm interviewing Dr. Karen Mustian from the University of Rochester School of Medicine and Wilmot Cancer Institute in New York, co-chair on “Management of Fatigue in Adult Survivors of Cancer: American Society of Clinical Oncology –Society for Integrative Oncology Guideline.” Thank you for being here, Dr. Mustian.

Dr. Karen Mustian: Thank you for having me, Brittany.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Mustian, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content of this episode, Dr. Mustian, what is the purpose and scope of this updated guideline on fatigue in adult survivors of cancer?

Dr. Karen Mustian: Cancer-related fatigue is one of the most common and debilitating consequences that patients experience when they go through treatment, and it can actually interfere with their ability to complete treatment and their recovery along the way. And it's not the same as a typical fatigue that you might experience from physical activity, let's say, where you can come back in and rest for a little while or take a nap or sleep, and you wake up refreshed and not feeling fatigued anymore. This type of fatigue actually needs special attention and needs to be treated with therapies.

So, this particular guideline is developed in a manner to help clinicians when patients present with fatigue, especially moderate to severe fatigue, that can be very debilitating, help patients decide what kinds of treatments they can use to reduce this fatigue. It's really important that this fatigue be reduced for a number of reasons. But some of the reasons we think of as being really critical are so that they can actually get their full treatment as prescribed, and then when finished with treatment, so they can actually resume their normal daily activities. They can keep working, they can keep engaging with their families, they can resume all those wonderful normal life activities that we hope for and that their prognosis will be a good one.

Brittany Harvey: Absolutely. It's critical to address cancer-related fatigue for all adults with cancer.

Then, this guideline covers three distinct patient populations and provides recommendations for each. Starting with the first section, what are the key recommendations for patients with cancer-related fatigue during active treatment?

Dr. Karen Mustian: Well, one of the things I want to mention about this guideline before I answer that question is this guideline encompasses the entire cancer trajectory. In previous guidelines for treating fatigue, we really focused on how to work with patients once they had completed their primary treatments for their cancer. This time, we're able, because the research and the literature have advanced more, to really now address what we should be doing to help patients with their fatigue while they're receiving active treatment. This can be primary treatment and/or maintenance therapies, but then also once they're done with treatment and they are in the recovery stage. And then also the third area is how should we help patients with advanced cancers with their fatigue that they are experiencing?

And I believe that you just asked me how we should be working with patients really during active treatment. This guideline, when we reviewed the literature, there's really good evidence to suggest that for people undergoing cancer treatment, clinicians should recommend exercise, cognitive-behavioral therapy, mindfulness-based programs, and Tai Chi or Qigong as first-line therapy to reduce the severity of fatigue that patients can experience during treatment. We also found that the literature suggests that psychoeducation and American ginseng may also be recommended in adults undergoing cancer treatment.

Brittany Harvey: Understood. Thank you for providing those key recommendations for patients with cancer-related fatigue during active treatment.

Then, following those recommendations, at the next point in the cancer trajectory, what does the expert panel recommend for patients with cancer-related fatigue after treatment?

Dr. Karen Mustian: Well, for survivors after treatment, the literature is also strong in that clinicians should be recommending also exercise, again, cognitive-behavioral therapy, and mindfulness-based interventions and programs. There's also a good amount of data to suggest that we should be recommending yoga, acupressure, and moxibustion for cancer-related fatigue after completion of treatment.

Brittany Harvey: I appreciate you reviewing those recommendations as well.

Then that final third population that you previously mentioned, what are the key points for the management of cancer-related fatigue for patients with advanced cancer or at the end of life?

Dr. Karen Mustian: For patients at the end of life, we should be offering those individuals cognitive-behavioral therapy and corticosteroids.

Brittany Harvey: Thank you for reviewing all of those recommendations for patients with cancer-related fatigue during active treatment, after their treatment, and for patients with advanced cancer.

Are there additional recommendations that were made by the expert panel that we should know about treating cancer-related fatigue? Recommendations for things that we should not be doing to treat cancer-related fatigue?

Dr. Karen Mustian: One of the things that's also characteristically different about this particular guideline update for ASCO is that this time we actually have research to suggest that there are some interventions that historically may have been used, but the research is actually suggesting that they should not be recommended at this time. The guidelines now state that clinicians should not recommend L-carnitine or antidepressants, wakefulness agents, or routinely recommend psychostimulants to manage symptoms of cancer-related fatigue. One of the things that this really highlights is the recommendation to pull back on the use of pharmaceutical products as a first-line therapy for treating fatigue and to really look at behavioral interventions which are showing the strongest evidence in the research in terms of effectiveness, both during treatment, after treatment, and for our patients with advanced cancer, and to really promote these behavioral interventions for patients rather than just reaching right for that pharmaceutical product.

There are still instances where pharmaceuticals may be really important for patients, such as if someone tries behavioral therapies and they fail, for example, or if someone has fatigue that is just absolutely so severe that they cannot even give a good effort or attempt to trying something like exercise or cognitive-behavioral therapy or mindfulness-based programs. You know, even considering that most of the cognitive-behavioral therapy and mindfulness-based programs don't require physical activity, they're very low intensity types of behavior change. And that's really a big area where these guidelines also differ in the update from previous guidelines.

Brittany Harvey: Absolutely. I appreciate you reviewing those so that we know what strategies and treatments also should not be used and how we need to tailor our interventions to specific patients and their needs.

So then, in your view, Dr. Mustian, what is the importance of this guideline and how will it impact both clinicians and patients with cancer-related fatigue?

Dr. Karen Mustian: I've seen a lot of ASCO guidelines and helped with a lot of ASCO guidelines, and one of the things that I think is really great about this particular guideline for cancer-related fatigue is, I'll reiterate, this is one of the most prevalent, debilitating toxicities experienced by virtually all cancer patients at some point during their time being treated or in recovery. And I'm really pleased to see that the research has come far enough that we now actually have interventions that we can recommend strongly, and then we also have other interventions that we recommend that the evidence is still growing for.

What's also nice about this, and what's really going to be impactful for patients, as I just said, is that the recommendations are not focused on pharmaceuticals. Patients already take a lot of pharmaceutical products, we have to worry about polypharmacy and all the side effects associated with that, especially in our elderly populations. This guideline gives clinicians and patients not just one or two, but several behavioral interventions that they can use that, if used in the correct way, as stated in the guidelines, stand an excellent chance of reducing the amount of fatigue that they experience. So, it really is going to change the landscape of care for patients. It's also going to change the landscape of what clinicians have to offer in their toolkit for treating patients.

And I know that oftentimes we think it's easy for a physician to recommend a pharmaceutical product. But I also know that a lot of oncologists love being able to recommend lifestyle interventions to really help their patients with side effects and toxicities. And that's exactly what this guideline is offering. And I think it's just going to provide a wonderful place for a clinician and patients to come together to have conversations about what the guidelines say is effective, and to allow them to have a conversation surrounding choice. Which one seems to be the best fit? Which one would a patient actually like to try? Which of these lifestyle interventions does the patient think they have the best chance of succeeding with both in terms of accessing it in their community, adhering to it, being able to do it so that they can actually derive the benefits that we expect to see. That's really one of the key components of the efficacy of these interventions as well, is what really is going to determine, ultimately, how well these interventions work is working together to pick the one that the patient feels that they can actually do and accomplish in order to receive the benefits. It really is going to change the landscape of how we work with symptom management surrounding fatigue.

Brittany Harvey: Yes. As you mentioned, it's great to have these multiple evidence-based recommendations to have a real impact for patients. You also just noted that evidence is still growing in some areas. So what future research is needed regarding the management of cancer-related fatigue in adult survivors of cancer?

Dr. Karen Mustian: I think oftentimes when we see a guideline come out, many times people say, “Well, we have the answers now, so we don't need to fund any more research in that area.” Or maybe it becomes less of a priority. For all that we do have these treatments to recommend now, we're still really very in the early stages of being able to identify, characterize and accurately provide therapies and treatments for cancer-related fatigue. When I look back at the history of nausea and vomiting and where we've come in the decades of research that has ensued since the first initial findings on that. I think fatigue is still very much in its early years.

Some of the things that we still don't necessarily know when it comes to these kinds of interventions, and I can tell you we struggled with in the guideline committee, is what is the actual dose of some of these behavioral interventions? I think when we prescribe a medicine, we think, “Oh, you need this particular dosage of this particular agent. You take it this many times a day, this many times a week for x number of weeks, and there you go.” With behavioral interventions, it's a little more complex. And so really getting down to the nitty-gritty of defining exactly what type of exercise, the intensity of that exercise, exactly how many minutes a day, exactly how many minutes a week do you have to do? We weren't really able to get our recommendations refined to that degree, and I think future research that really wants to be in service of clinicians and patients should work towards defining specific prescriptions of these interventions.

Exercise, I just gave that example, but it's the similar kind of approach for cognitive-behavioral therapy. What are the specific components that need to be included? What does the ratio of focus on those different components need to look like? Also, the same with Tai Chi, Qigong moxibustion, acupressure that we mentioned - really refining those specific prescriptions, I think, is something that we need research on, and that will take us to the next step, where we have patients doing enough that they get the effect that they want, but not wasting their time, effort, energy, and finances doing too much that they don't need to do in order to achieve the benefit that we hope for.

For some of the recommendations that are not strong, we still need large, definitive, randomized clinical trials on those interventions. So, for example, we talk about that we may recommend psychoeducation and American Ginseng for patients undergoing cancer treatment. We need more research in that area in order to be able to really say whether or not we should be offering that for patients undergoing treatment. And specifically, those large, definitive, phase III randomized clinical trials, talking about trials that also could be done across multiple centers where we can have more generalizable populations, different kinds of communities where those interventions are being delivered, rural dwelling communities, for example. And then, of course, there's always the need for newer and better interventions. Some of these interventions have very decent effect sizes in terms of their outcome, but it would be wonderful to actually find an intervention that completely mitigated cancer-related fatigue, and it was completely gone, never to return. I think we're still in some ways waiting for that intervention to be developed. And I also would say, even though we're not recommending pharmaceuticals quite a lot in this guideline, they're not our first-line therapy, there's still always the opportunity to identify molecular targets that really could help with remediating cancer-related fatigue. So there's still a plethora of research to be done out there and things that we don't know.

And then lastly, and very much importantly, we need to do research and dissemination and implementation. Behavioral interventions are really challenging to deliver. So unlike a doctor recommending a pharmaceutical product where they can write a prescription, and then the patient gets the prescription from the pharmacy and they have what they need, supposedly understanding how to prescribe these interventions for patients, or even understanding how to refer them to places in communities where they can actually get a credible practitioner that is using an evidence-based approach that is known for being one of the types of yoga or exercise, or mindfulness-based stress reduction or CBT, that will actually have a positive influence on fatigue is also challenging. And so we need that dissemination and implementation research - that I do believe is going to be also really key in the next decade at changing the landscape of what this toxicity looks like in the patient experience of cancer.

Brittany Harvey: Definitely, these all will be key to understanding the best options for all patients, and we'll look forward to continued research in these areas to fuel future guideline updates and improve management of cancer-related fatigue in all adults with cancer.

So, I want to thank you so much for your work developing this guideline, and thank you for your time today, Dr. Mustian.

Dr. Karen Mustian: Oh, it's such a pleasure. I did not develop this guideline alone. I definitely want to say thank you to all my colleagues who worked very diligently and very hard on digesting the research and making these recommendations. They are representative from institutions all across the United States. A very wonderful expert panel. Thank all of them very much and give them the credit that they are due for all their hard work. And thank ASCO for supporting these efforts for clinicians and patients. And Brittany, thank you very much for having me.

Brittany Harvey: Absolutely. A big thank you to the whole panel.

And thank you also to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Debra Lundquist, PhD, RN and Dr. Arun Ghoshal, MD, MBBS discuss the new update to the palliative care for patients with cancer guideline developed by an interdisciplinary Expert Panel. They share the key updated recommendations on the most effective palliative care interventions, how these recommendations relate to other supportive care services, interventions for family caregivers, care partners, and communities, referrals to specialist palliative care services, and specific strategies for the integration of palliative care for patients with hematologic malignancies and those on early phase clinical trials. Dr. Lunquist and Dr. Ghoshal also discuss the contextual factors that affect equity at the intersection of palliative and oncology care, the impact of this guideline refresh for clinicians and patients, and future innovations in the field of palliative care. Read the full guideline update, “Palliative Care for Patients with Cancer: ASCO Guideline Update” at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00542

My name is Brittany Harvey, and today I'm interviewing Dr. Arun Ghoshal from Princess Margaret Cancer Center and Dr. Debra Lundquist from Massachusetts General Hospital, authors on, “Palliative Care for Patients with Cancer: ASCO Guideline Update.” Thank you for being here, Dr. Ghoshal and Dr. Lundquist.

Dr. Ghoshal: Thanks, Brittany. Thank you for having us here.

Dr. Lundquist: Yes, it's a pleasure.

Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Lundquist and Dr. Ghoshal, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to start us off, Dr. Lundquist, what prompted this guideline update, and what is the scope of the current update for palliative care for patients with cancer?

Dr. Lundquist: Sure. So the goal of this refresh is really to provide oncology professionals with current recommendations regarding palliative care and assess which of the 2016 recommendations remain valid. The scope did increase to also include hematologic malignancies and participants of early phase clinical trials. In addition, this was an opportunity to reflect more recent evidence around the understanding of linguistic, geographic, ethical, and contextual factors that affect equity at the intersection of palliative and oncology care. This update also increased discussion about the inclusion of palliative care, as I mentioned earlier, for the enrollment of patients in clinical trials. And also, in terms of the equity piece, there is also a companion manuscript with the guidelines that focused on the health equity in the oncology palliative care setting.

Brittany Harvey: Excellent. Thank you for setting the stage for this update, Dr. Lundquist.

So then next, I'd like to review the key updated recommendations for our listeners. So starting with clinical question one, Dr. Ghoshal, what are the key recommendations regarding the most effective interventions to provide palliative care to patients with cancer?

Dr. Ghoshal: As we know, healthcare providers should proactively engage in the early integration of specialized, interdisciplinary palliative care teams for patients diagnosed with advanced solid tumors, and as mentioned, not only solid but also hematological malignancies. The most important thing is that palliative care should be offered not only for inpatients but also for outpatients, and oftentimes, when we talk about early palliative care, it is in concurrence with active cancer treatment. So if you want to talk about the core components of such an effective palliative care practice that would encompass establishing a nurturing rapport and relationships with patients and their family caregivers to foster trust and open communication. And obviously, it will encompass symptoms, distress, and functional limitations comprehensively, including but not only limited to pain, dyspnea, fatigue, sleep disturbances, mood disorders, nausea, and constipation.

Another important part is providing education and facilitating discussions to enhance patients' understanding of their illness and prognosis. That means we need to play an active part in clarifying the treatment goals through a shared decision-making process that aligns the patient's values and preferences with their physicians. And apart from that, in this revised guideline, the key evidence about question number one, which is from 2016, and updated to the present is mainly based on three trials with a low risk of bias. These three studies actually demonstrated that early referral to specialized palliative care of patients with advanced cancer led to improvement in the quality of life and also mood, which was a secondary outcome in that study and the higher likelihood of discussing or documenting end-of-life care preferences. I know that the link to the full documents are in the show notes, and I would encourage the listeners to refer to the supplement to the paper that is coming out in the Journal of Clinical Oncology for understanding and getting a detailed insight into the studies which are included in these recommendations.

Brittany Harvey: Absolutely. Early integration of all those aspects of palliative care that you just detailed are imperative. And as you just mentioned, the listeners can find a link to the full guideline in the show notes of this episode to refer back to the more detailed aspects of the guideline.

So following those recommendations, Dr. Lundquist, what does the expert panel recommend regarding how palliative care services should relate in practice to other supportive care services?

Dr. Lundquist: The panel examined the role of the use of additional supportive care services that focus on services including nurse navigation, lay navigation, community and home health care, as well as geriatric oncology, psycho-oncology, pain services, and telehealth services. And findings supported that models of delivering palliative care with the use of other services as well can really improve the patient experience. And one of the ways of doing that, more utilization of standardized assessments of symptoms, certainly, but also encompassing the multidimensions of distress, spirituality, and psychosocial factors. And then emphasizing discussions around prognostic and treatment options to really get a better sense about the patients' understanding of their prognostic awareness, which may also lead to more improved communications around advanced care planning.

And the studies around this guideline supported that most pragmatic approaches to ensuring that patients benefit from palliative care is really through the involvement of this interdisciplinary team and looking from a broad lens, looking at all their potential palliative care needs that may need to be met. But certainly, referral to a specialized interdisciplinary palliative care team is also very important. But it really is where that step before is really looking at the whole experience of the patient and where they are in their cancer trajectory.

Brittany Harvey: Excellent. Yes, incorporating all of those additional supportive care services really benefit patients.

So then beyond these recommendations for patients with cancer, Dr. Ghoshal, what are the recommendations for interventions that are helpful for family caregivers, care partners, and communities?

Dr. Ghoshal: This is a very pertinent question for palliative care practitioners. So, interesting to note that the panel found that there is limited data that exist on how best to support the caregivers of patients with advanced cancer, and especially so in under-resourced settings. And also, most of the evidence that came from the literature is from data which was collected in studies before the COVID-19 pandemic. So the previous guideline stressed the option of phone interventions for those in rural or under-resourced areas. But as we know, with the growth of telehealth and telemedicine related to the pandemic, especially after the pandemic, more people are used to such interventions, more people probably could access and feel comfortable with virtual care. So telehealth, app-based support, and virtual care options, which are probably available and largely familiar to many people, could potentially allow increased access to support services.

Talking about these support services, the focus that has been mostly seen in literature are about education and training programs to empower the caregivers of these patients with advanced cancer, psychosocial support services for emotional well-being of the carer as we know that it can be pretty tough for someone to deal with cancer and also for their caregivers. Also sometimes practical assistance with daily tasks, if possible, to ease the burden of caregiving. Sometimes importance is there on respite care to provide temporary relief for these caregivers. Community supports can play a big role for sharing the resources. Social connections can also play an important part when it’s available. And also very important and we all know that advance care planning discussions to ensure patients' wishes are known to their caregivers. And of course, we must keep this in our mind that cultural sensitivity in caregiving practices is very important to accommodate people from diverse backgrounds. So mostly these are interventions, as mentioned in the guideline, which are aimed at supporting caregivers in their role to alleviate their stress, and to improve the overall caregiving experience for both caregivers and patients with cancer.

Brittany Harvey: Thank you for reviewing the recommendations for support services for both caregivers and care partners in addition to patients with cancer.

So then Dr. Lundquist, you previously mentioned referral to specialist palliative care services. Who does the expert panel recommend should be offered or referred to palliative care services, and when should those referrals occur?

Dr. Debra Lundquist: And as the panel looked at referral to palliative care services, we looked at essentially patients with advanced solid tumors or hematologic malignancies, particularly, those patients with cancer who have unaddressed physical needs, psychosocial needs, and spiritual distress, and as we just heard, the importance of including the caregivers in care and offering palliative care. And the caregivers may include family members, chosen family, friends of individuals who have advanced cancer. And then also looking at including patients that we’ll talk a little bit later about the patients that are on phase one clinical trials as well and why they might be another population to be considering.

But certainly, as we’ve mentioned a little bit already, early in the course of the advanced cancer diagnosis is a very important time to initiate the palliative care. The panel recommends not waiting for the discontinuation of antineoplastic therapy or treatments around the cancer diagnosis, but rather focusing on the specific palliative needs of the individual and really thinking more about it occurring when the patient is getting their active treatment as well in a way to better support them while they potentially may be experiencing side effects from their treatments, from their disease, and thinking about this earlier in the disease continuum. Ideally, clinicians and organizations really need to prioritize the assessment of these dimensions of the patient experience for earlier recognition of their needs at the time of diagnosis of their advanced cancer, but to also really be thinking about while the patients are still receiving active treatment, to really be identifying and determining what other palliative care needs may need to be addressed.

Brittany Harvey: Definitely, those are key considerations for clinicians, and I thank you for defining what early referral means in these circumstances.

So, you both mentioned that this guideline expanded to patients with hematologic malignancies. Dr. Ghoshal, what strategies are recommended for the integration of palliative care into the care of patients with hematologic malignancies?

Dr. Arun Ghoshal: The updated review this time identified three publications. Actually, two of those publications are randomized controlled trials including patients with hematologic malignancies, especially those with acute myelogenous leukemia and those receiving hematopoietic stem cell transplantation. It is important because the trajectory of illness for hematologic cancers and solid tumors can be a bit different. Patients with hematologic malignancies, despite newer therapies offering long-term survival, often face significant side effects. Compared to the solid tumor patients, those with hematologic cancers experience higher hospitalization rates, frequent intensive care unit admissions, and unfortunately, the rates of in-hospital deaths are also more in these patients. And as a result of that, the typical length of stay in hospice is shorter for these patients. Regardless of prognosis, the recommendations state that proactive palliative care should begin at diagnosis and continue throughout the illness trajectory and survivorship of these patients with hematologic cancers.

Historically, integrating specialist palliative care has been infrequent in this group of patients due to misconceptions, and obviously, limitations. However, the latest evidence that we’re talking about supports the benefits of palliative care for patients with hematological cancers, especially, improving their quality of life and psychological outcomes. However, given the paucity of studies in this domain, further research is needed to expand the recommendations beyond the studied population.

Brittany Harvey: Thank you for highlighting the specific needs and recommendations for this patient population.

So then, Dr. Lundquist, for the final clinical question, you’ve already touched on this a little bit. But what is the role of palliative care for patients with cancer participating in early phase cancer clinical trials?

Dr. Debra Lundquist: As I mentioned earlier, the panel this year included this patient population in the refresh of the guidelines. And the early phase clinical trial population is a population of patients who present functionally well, however, most present with advanced disease and have frequently received multiple lines of therapy prior to coming to the clinical trial. They may experience a distinct set of symptoms and concerns with unique supportive and palliative care needs. When we looked at the literature, there is a growing body of research around this, although it is still quite small at this time. Certainly an area for future research.

Patients who are participating on early phase clinical trials come to the trial and they may be struggling to cope with the uncertainty regarding their future, as well as symptoms they may be experiencing and really not knowing what that clinical trial experience is going to look like. So the panel, as we were looking through the literature, it’s becoming more clear that this is a patient population who may have existing physical and psychosocial concerns who would possibly benefit from earlier identification of their palliative care needs as well as intervention with palliative care support coming on to the clinical trial. With the research being limited, the focus on better understanding their palliative care needs is an area for the future that we really may want to be considering more in terms of improving the patient experience. This is a patient population who, I think, in terms of ongoing research, we’re starting to see the benefits and looking at their unique dimensions of their care as they come onto the trial. But then providing the opportunity to enhance their experience and also better identify their distinct supportive care needs may, in fact, enhance their quality of life while they're on the early phase clinical trial.

Brittany Harvey: I appreciate you both reviewing all of this updated and expanded recommendations from the expert panel.

In your view, Dr. Ghoshal, what is the importance of this update and how will it impact both clinicians and patients?

Dr. Arun Ghoshal: So 2015 to 2023, the time and the duration that the update took into consideration, you won’t believe, we got 52 randomized control trials on the subject, and one systematic review, which is the evidentiary basis for the guideline recommendations. So the ASCO guideline update on palliative care for patients with cancer underscores the importance of a comprehensive, patient-centered approach to care that prioritizes symptom management, communication, and support for not only patients but also their families. It distinguishes itself through its rigorous methodology, the expert consensus from a wide array of people who take part in these updates, and also, there is a special section for all the recommendations as far as clinical relevance is considered. The updates are very timely and also comprehensive for sure. So all of these features make it a valuable resource for clinicians who want to seek guidance on providing optimal palliative care to patients with cancer.

I believe that the uptake, as far as possible, by institutions and physicians, factoring physicians all around the world, these guidelines would benefit the patients by providing evidence-based recommendations that improve symptom management, enhance care communication, and shared decision making, ultimately ensuring timely access to palliative and supportive care services. The uptake will support the caregivers and hopefully will help a long way in optimizing the end-of-life care for these patients suffering from cancer.

Brittany Harvey: Definitely, we hope that these updated guidelines are a useful resource for clinicians, as you pointed out, to provide better end-of-life care for all patients with cancer.

So, you both touched a little bit on the limited evidence and some future research opportunities. So finally, to wrap us up, Dr. Lundquist, what are the outstanding questions and future research needed on palliative care in patients with cancer?

Dr. Debra Lundquist: As we’ve been hearing about in our conversation today, the findings and the benefits of palliative care, they’re well known. We know the difference palliative care makes in the life of patients that are experiencing or living with advanced cancer as well as their caregivers and their families. But certainly, more studies are needed to explore more innovative and other models of care. Because we also need to acknowledge that as much as we want every single person to have the opportunity to get palliative care, the workforce is not going to support that. So this is an important time to think about innovative, potentially scalable, and compelling strategies to address the unmet needs of patients in order to deliver palliative care.

Innovative approaches are needed, particularly, to overcome the shortage of the workforce in order to better support the unique needs of our patient population. So as we’re thinking forward, novel application of interventions to address unmet needs tailored to the unique needs of patients across the disease trajectory, and that may include collaborative care models, telehealth, additional training and resources, for example, nurses; advanced practice providers. But as we’re doing that, we really need to be thinking about how we’re going to design, develop, and test these interventions in order for them to be scaled appropriately. And then how do we implement and disseminate across different settings, rural, urban, different locations, in order to best meet the needs of this patient population.

Brittany Harvey: Absolutely. Those are important questions for us all to consider moving forward, and we'll look forward to future research in these areas to continue to provide optimal palliative care to all patients.

So I want to thank you both so much for all of your work on this guideline update, and thank you for taking the time to share the important nuances of this guideline with our listeners today, Dr. Lundquist and Dr. Ghoshal.

Dr. Arun Ghoshal: It's been a pleasure being here.

Dr. Debra Lundquist: Thank you very much, Brittany. It was a wonderful opportunity.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Douglas Peterson presents the latest evidence-based guideline from ISOO, MASCC, and ASCO on the prevention and management of osteoradionecrosis (ORN) in patients with head and neck cancer treated with radiation therapy. He covers topics such as recommended initial workup, best practices for prevention of ORN of the head and neck before and after radiation therapy, nonsurgical and surgical management of ORN, and management of adverse events associated with ORN. Dr. Peterson also comments on the importance of this guideline and what researchers should address moving forward. Read the full guideline, “Prevention and Management of Osteoradionecrosis in Patients with Head and Neck Cancer Treated with Radiation Therapy: ISOO-MASCC-ASCO Guideline” at www.asco.org/head-neck-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/head-neck-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02750.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, bringing you timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all our shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey and today, I'm interviewing Dr. Douglas Peterson from UConn Health, lead author on “Prevention and Management of Osteoradionecrosis in Patients with Head and Neck Cancer Treated with Radiation Therapy: International Society of Oral Oncology, Multinational Association for Supportive Care in Cancer, American Society of Clinical Oncology Guideline.” Thank you for being here, Dr. Peterson.

Dr. Douglas Peterson: Thank you, Brittany. My pleasure to be here.

Brittany Harvey: Before we discuss the guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Peterson, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the topic we're here to discuss, Dr. Peterson, could you first provide an overview of the scope and purpose of this joint ISOO-MASCC-ASCO guideline?

Dr. Douglas Peterson: I'll be pleased to do so, Brittany. Again, thank you for the opportunity to represent the panel in this guideline. The panel has strived to present a guideline that brings consistency in clinical practice regarding prevention and management of osteoradionecrosis of the jaw (ORN) based on the highest quality contemporary science. Given the mechanistic and clinical complexity of ORN, we also stress the importance of interprofessional oncology care of these patients. The team includes, but is not limited to, clinicians representing radiation oncology, head and neck surgery, medical oncology, otolaryngology, dental medicine, oral medicine, oral oncology, oral and maxillofacial surgery, and patient advocacy organizations. So it really is a collective enterprise that we bring to bear in the guideline.

In some cases, the panel has been fortunate to be able to utilize a high quality evidence base in the literature upon which we could build strong recommendations. In selected other cases, however, we utilized informal consensus given the low evidence quality in the field. The recommendations presented have been carefully framed in this context, with the goal of providing state-of-the-science guidelines in clinical decision making and management of ORN. I'd also like to point out that the guideline brings linkage to other guidelines published by ASCO and other major oncology organizations, regarding management of symptoms and other supportive care needs associated with ORN. These companion guidelines include addressing pain, dysphagia, oral care, trismus, and psychosocial impact and survivorship, to name a few. I'd also like to say that combining the expertise of ISOO, MASCC, and ASCO has provided an important opportunity to produce this guideline. This has been a comprehensive effort by many experts. In addition to the outstanding input from the panel, I am also personally so very grateful for the expert input from ASCO's Evidence-Based Medicine Committee, as well as endorsements from other key organizations, including the American Head and Neck Society, the American Society for Radiation Oncology, and the American Academy of Oral Medicine as endorsees of the guideline. Finally in addition, Dr. Nofisat Ismaila’s leadership as ASCO staff has been absolutely invaluable as well.

Brittany Harvey: Excellent. I appreciate you providing that background on the development of this evidence-based guideline, which was developed by a multi-organizational and multidisciplinary panel.

So to dive into the key recommendations of this guideline, this guideline addresses six clinical questions. So, starting with question one, what key points would you like to highlight regarding how ORN is characterized, graded, and reported, and what is the recommended initial workup for patients?

Dr. Douglas Peterson: Osteoradionecrosis of the jaw of the mandible and maxilla should be characterized in the view of the panel as a radiographic, lytic, or mixed sclerotic lesion of bone, and/or visibly exposed bone, and/or, importantly, bone probed through a periodontal pocket or fistula. In the latter case, the clinical appearance of exposed bone may be extremely subtle. ORN is occurring within an anatomical site previously exposed to a therapeutic dose of head and neck radiation therapy. So we have a combined radiographic/clinical approach characterizing the lesion in the context of the patient having received previously a therapeutic dose of head/neck radiation therapy. We do recommend that clinicians evaluate ORN based on the most contemporary staging system, the ClinRad system, which is cited in the publication itself. We also advocate for the use of the ClinRad staging system not only in clinical assessment of patients, but also in clinical trials moving forward. We’ll touch a little bit later on future research opportunities as well.

Finally, the initial evaluation of ORN should include a clinical intraoral examination, and again, the appearance of exposed bone may be extremely subtle, and/or a formal radiographic examination. The guideline delineates the various types of radiographic examinations that we recommend.

Brittany Harvey: Understood. Thank you for reviewing those recommendations regarding reporting and characterization of ORN, as well as the workup.

The next section of the guideline, it focuses on best practices to prevent ORN of the head and neck prior to radiation therapy. What are the key recommendations of that section?

Dr. Douglas Peterson: As with other adverse events in oncology patients, prevention is key. Prevention of ORN does require interprofessional management. The guideline lists several key recommendations along these lines. Now, an important caveat in what the guideline presents is that the target coverage of the tumor should not be compromised in order to avoid radiation dose to bone. So that’s a very important caveat. Now having said that, focused effort should be made to reduce the mean dose to the jaw and the volume of bone receiving above 50 Gy whenever possible. So it’s really a balance between maximizing target coverage of the tumor while limiting exposure to normal bone. In addition, a dental assessment by a dentist and dental specialist, if possible, is strongly advised prior to therapeutic-intent radiation therapy. The purpose of this assessment by the dental team is to identify and remove teeth which will place the patient at risk of developing ORN during the patient’s lifetime, and to comprehensively educate the patient about the lifelong risk of ORN. Dental extraction in advance of radiation is often a consideration to these patients, and if clinically indicated, should occur at least two weeks prior to the commencement of radiation therapy. Now having said that, in the setting of a rapidly progressive tumor, extraction should be deferred and not cause delay in the initiation of radiation therapy.

Brittany Harvey: So you just touched on key points of prevention prior to radiation therapy. Following those recommendations, what does the expert panel recommend regarding best practices to prevent ORN after radiation therapy?

Dr. Douglas Peterson: This can be a challenging clinical issue. So the panel recommends that before finalizing dental treatment plans that may include extractions in patients with a history of head and neck radiation therapy, a review of the radiation therapy plan should be performed with particular attention focused on dose to the mandible and maxilla. For teeth in areas of high-risk for ORN, alternatives to dental extraction may be possible, for example, root canal or endodontic procedures, crowns, or dental restorations, or dental filling should be offered unless the patient has recurrent infections, intractable pain, or other symptoms that cannot be alleviated without extraction. So it really becomes a combined clinical decision making effort between the dental team and oncology team.

One controversial area has been hyperbaric oxygen being administered prior to dental extractions in patients who have received head and neck radiation therapy previously. The panel does not recommend routine use of prophylactic HBO prior to dental extractions in these patients who have received prior head and neck radiation therapy. However, the evidence base here is limited with low quality and we offer a weak strength of recommendation. It is a controversial area, so we did also include a qualifying statement that prophylactic HBO may be offered to patients undergoing invasive dental procedures at oral sites where a substantial volume of the mandible and/or maxilla receive at least 50 Gy. This is an area of controversy. We can talk about this in the future research directions, but clearly, new high quality research related to the role of HBO in the management of these patients is needed.

Brittany Harvey: Definitely. Thank you for touching on those points and that area of controversy. We can definitely touch on that a bit later as we talk about future research in this field.

As you mentioned, Dr. Peterson, this guideline addresses both prevention and management. So, in moving into the management of ORN, how should ORN be managed nonsurgically?

Dr. Douglas Peterson: The guideline relative to nonsurgical management of ORN is focused on the use of pentoxifylline. Now this maybe used in, and this is important, in cancer-free patients with mild, moderate, and severe cases of ORN. But pentoxifylline, the guideline also notes, is most likely to have a beneficial effect if the treatment is combined with tocopherol, antibiotics, and prednisolone as well. So there’s clinical judgment involved in the nonsurgical management of ORN, centered with pentoxifylline in combination with tocopherol, antibiotics, and prednisolone.

Brittany Harvey: Understood. And then expanding on the management of ORN, what are the key points for surgical management of ORN?

Dr. Douglas Peterson: The panel offered several recommendations for which the strength of the recommendations was strong. Just to cite a few, in partial thickness ORN as defined by the ClinRad stage one and two that we talked about earlier, surgical management can start with transoral minor interventions which can lead to resolution over time. It may take time. It may take weeks or even a few months. Now this minimally invasive surgery may include debridement, sequestrectomy, alveolectomy, and/or soft tissue flap closure. Furthermore, small defects, clinically, for example, less than 2.5 cm in length, may heal spontaneously with local topical measures such as we described. It is recommended that larger defects, larger than 2.5 cm, in general be covered with vascularized tissue.

Brittany Harvey: Appreciate you reviewing those recommendations regarding surgical management of ORN. So to wrap up our discussion of the recommendations with the final clinical question, what is recommended for assessment and management of adverse events associated with ORN?

Dr. Douglas Peterson: This is a really important area as well in addition to prevention and management of ORN per se. The panel recommends that patients should be assessed by their healthcare providers for the presence of adverse events at the time of ORN diagnosis and periodically thereafter until the adverse event resolves based on patient status including any interventions or the adverse events that are clinically indicated. The panel and its literature evaluation learned that there is a relative lack of data specifically directed to the management of adverse events associated with ORN. However, this is such an important area that we wanted to address it head on. And so the management we recommend should be informed by pertinent available other guidelines that had been developed for analogous symptoms and/or disease states. The guideline provides links to these companion guidelines developed by ASCO as well as by MASCC and ISOO, the European Society of Medical Oncology, and NCCN. And so in the guideline we provide links on management of adverse events as produced by these other organizations. Table 3 presents a summary of the guidelines that address symptoms and supportive care needs associated with ORN.

Brittany Harvey: Thank you for reviewing all of these recommendations. It's clear that the panel put a lot of work and thought into these recommendations and provided needed guidance in areas with limited evidence. We’ll have links available in the show notes for listeners to be able to go and read these recommendations for themselves and refer to the tables that you mentioned.

So in your view, Dr. Peterson, what is the importance of this guideline and how will it impact clinicians and patients with head and neck cancer?

Dr. Douglas Peterson: As we talked about throughout this podcast, the guideline is designed to synthesize the contemporary science regarding ORN and translate that into recommendations for clinical practice in both prevention and management. As noted in the guideline, oncologists plus other interprofessional healthcare providers have been directly involved in the creation of the guideline, that interprofessional theme, which we believe is so essential given the mechanistic and clinical complexity of ORN.

Now, in addition to the expertise of the panel, the pending widespread distribution of the guideline represents an additional important opportunity for extending the impact across clinical oncology. So in addition to the publication in the Journal of Clinical Oncology, dissemination by MASCC and ISOO as well as our endorsees, the American Head and Neck Society, the American Society for Radiation Oncology, and the American Academy of Oral Medicine will also be key in broadening the impact and hopefully the utilization of the guideline. And members of these organizations may very well be involved in the management of these patients as well.

And then finally, the guideline is also designed to stimulate future research based on current gaps of the knowledge and we touched on some of those gaps, for example, with HBO for which new high quality research is needed.

Brittany Harvey: Absolutely. It’s great to have so many partners in this guideline and we hope that this guideline will have a large impact for patients with head and neck cancer to improve their quality of life.

So then your final comment leads nicely into my last question and that we’ve already talked a little bit about some of the future research opportunities that this guideline highlights. So, to wrap us up, Dr. Peterson, what are the outstanding questions regarding osteoradionecrosis of the jaw secondary to head and neck radiation therapy in patients with cancer?

Dr. Douglas Peterson: There are several key areas that the panel identified as we went through a rigorous review of the highest quality literature. Some of the key areas to address moving forward include: prospective studies are needed to evaluate the clinical presentation, trajectory, and response to treatment of ORN-related symptoms and function impairment, in other words, the adverse event side of the story. In addition, social determinants of health, quality of life, and psychosocial impact of ORN warrant further investigation in head and neck cancer survivors as well. In addition, new research including randomized controlled trials and prospective multicenter trials regarding the systemic and surgical treatment of ORN is also warranted, and we touched on, for example, hyperbaric oxygen. Hyperbaric oxygen has been a long standing management strategy of ORN. However, the trials to date are of limited quality in relation to supporting its use. So high quality new research related to the role of HBO in these patients is needed.

And the expert panel also encourages creation of predictive tools, a priori tools, directed to development, grading, and staging of ORN. These could include, for example, bone turnover markers and genetic markers to name two. And finally, the research opportunities that are presented in the guidelines such as what I briefly summarized today should ideally be addressed in large prospective multicenter observational studies of risk, outcomes, and financial cost of ORN or the various treatment strategies that are highlighted in the guideline.

Brittany Harvey: Excellent. Well, we’ll look forward to research that addresses those outstanding questions and I want to thank you so much for your all your work on this guideline and for taking the time to share the highlights of this guideline with me today, Dr. Peterson.

Dr. Douglas Peterson: Thank you. My privilege to do so, Brittany.

Brittany Harvey: And thank you to all our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app in the Apple App Store or the Google Play Store. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Raymond Chan and Dr. Larissa Nekhlyudov share the newest standards and practice recommendations from MASCC and ASCO on survivorship care for people with advanced or metastatic cancer. They discuss highlights of the standards across seven domains: person-centered care, coordinated and integrated care, evidence-based and comprehensive care, evaluated and communicated care, accessible and equitable care, sustainable and resourced care, and research and data-driven care. Drs. Nekhlyudov and Chan also comment on the impact of these standards for clinicians and for patients with advanced and metastatic cancer and the goal of providing high-quality evidence-base survivorship care for all patients. Read the standards, “Survivorship Care for People Affected by Advanced or Metastatic Cancer: MASCC-ASCO Standards and Practice Recommendations” at www.asco.org/standards.

TRANSCRIPT

These standards, recommendations, and resources are available at https://asco.org/standards. Read the full text of the standards and review authors’ disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP.23.00716.

My name is Brittany Harvey, and today I'm interviewing Dr. Larissa Nekhlyudov from Brigham and Women's Hospital and Harvard Medical School, and Dr. Raymond Chan from Flinders University, authors on, “Survivorship Care for People Affected by Advanced or Metastatic Cancer: Multinational Association for Supportive Care in Cancer (MASCC) and American Society of Clinical Oncology (ASCO) Standards and Practice Recommendations”. Thank you for being here, Dr. Nekhlyudov and Dr. Chan.

Dr. Raymond Chan: Thank you for having us.

Dr. Larissa Nekhlyudov: Great to be here.

Brittany Harvey: Then, before we discuss these standards, I'd like to note that ASCO takes great care in the development of its guidance products and ensuring that the ASCO conflict of interest policy is followed through each panel. The disclosures of potential conflicts of interest for the expert panel, including the guests on this episode today, are available online with the publication of the standards in the JCO Oncology Practice, which is linked in the show notes.

So then, to dive into the content of the standards and recommendations. First, Dr. Chan, could you provide both an overview of the scope and purpose of these joint MASCC-ASCO standards and practice recommendations?

Dr. Raymond Chan: Thank you, Brittany. First of all, as outlined and introduced by yourself, I would like to acknowledge that this is a great collaboration between the Multinational Association for Supportive Care in Cancer and ASCO. And if you may indulge me for a minute, I would like to give you a little bit of background of how this all started. It was in 2019 when I came across an article written by Ms. Terry Langbaum and Dr. Thomas Smith, who wrote a piece in the New England Journal of Medicine outlining the insufficient work and research done to advance care for people with incurable, long-term, metastatic cancer survivorship. And both Terry and Tom were living with metastatic cancer, and with their lived experience, they provided a new level of meaning to our work. And subsequently, in honor of Terry Langbaum, who is a renowned and esteemed hospital administrator who worked in cancer care, Dr. Thomas Smith and myself created the Terry Langbaum Cancer Survivorship Fellowship and appointed Dr. Nicholas Hart to complete this work.

Within this work, we aim to develop international standards and practice recommendations to guide care for people living with treatable but incurable, metastatic, and advanced cancer. In this work, we conducted an extensive systematic review involving 81 studies, 17 guidelines, and framework documents, gathering the wisdom and consensus from 77 experts from 33 countries around the globe. Together, we reached consensus on 45 recommendations that we hope will be helpful for the clinical care community in improving care, experiences, and outcomes for people living with metastatic cancer.

Brittany Harvey: Excellent. Thank you for providing this essential background information and describing the impetus for this project.

Then, as you discussed, Dr. Chan, these standards and recommendations have over 45 recommendations within them. So I'd like to review each of those key points from each section. This document provides these standards and practice recommendations across seven domains. So to start with that first domain, Dr. Chan, what are the key points you'd like to highlight regarding person-centered care?

Dr. Raymond Chan: Sure, Brittany. Now, without repeating what is in the document because I hope that this podcast can lead you to that document and for you to read it in detail, it is really around a comprehensive set of principles that experts felt were important to ensure that patients themselves participate in the care as much as possible. It is around respecting their agency and making sure that their clinical and psychosocial care needs associated with their metastatic cancer diagnosis are considered and addressed.

Brittany Harvey: Absolutely. Thank you for providing those key points regarding person-centered care. So, moving into that next section, coordinated and integrative care, what points would you like to highlight there?

Dr. Raymond Chan: Thank you, Brittany, for the question. The standards and recommendations within this section are really around articulating the coordination, navigation, and the multidisciplinary care team approach requirements for this population. In particular for people living with metastatic or advanced cancer, it is not a given that they will be able to access survivorship care services or palliative care services. And a lot of the time, we know that care access is around the resource setting. And a lot of the time, palliative care services may not necessarily be able to cover people living with relatively longer prognosis, such as this population, the longer term metastatic and advanced cancer population. Another point is around transition and the shared care arrangement between the oncology team, survivorship care clinicians where available, and the palliative care team. Once again, these recommendations really articulate the importance of a well-coordinated, integrated approach for these patients.

Brittany Harvey: Absolutely. Those points that you just highlighted are important for care for the whole patient.

So then, next, Dr. Nekhlyudov, I'd like to turn to you for the next couple of sections. Could you review what the highlights are for the next section: evidence-based and comprehensive care?

Dr. Larissa Nekhlyudov: Yes. Thank you, Brittany. This standard emphasizes that people affected by advanced or metastatic cancer receive the most up-to-date, evidence-based, comprehensive, multidisciplinary, and interprofessional survivorship care and receive it in programs that continuously evolve their approach as guided by evidence. So as such, it is important that these survivorship programs are informed by ongoing professional development, including educational programs for healthcare professionals, that also includes active contributions by those affected by advanced or metastatic cancer. The other piece is that people affected by advanced and metastatic cancer should receive comprehensive care that encourages and supports informed decision-making in order to promote health, manage disease, and reduce stress.

Brittany Harvey: Definitely, those are very important points regarding care of the patient.

So then, moving into the fourth domain, Dr. Nekhlyudov, what are the key points for evaluated and communicated care?

Dr. Larissa Nekhlyudov: So the famous line is, "What can’t be measured can’t be improved." And so it is important that clinicians routinely and systematically evaluate and monitor supportive care needs and provide appropriate referrals to relevant survivorship care services and healthcare professionals. In order to do that, we need to establish multidirectional communication systems that take into account communication with patients and communication across healthcare professionals involved in their care. Effective communication, of course, needs to be timely, it needs to be clear, effective, respectful, and appropriate. We all know that communication is challenging across cancer care, but it may be particularly so in this specific patient population. For example, in communicating with patients, cancer care clinicians may be comfortable communicating with those with early-stage cancers or patients with early- stage cancers. And may also have had training to communicate with those patients nearing the end of life. But as we already mentioned, those affected by advanced or metastatic cancer may have different needs and as such, it is important that there is additional training for clinicians to address survivorship care needs among these individuals and their caregivers.

And then, in addition to patient-clinician communication, to enable timely communication and collaboration between multiple healthcare providers who may be involved in caring for these patients, enhanced and secure communication strategies are needed. And as with everything else, it's important that healthcare settings engage in service evaluations and quality improvement activities to continue to examine what works, what does not, and make changes that are needed.

Brittany Harvey: It is important that these patients with metastatic or advanced cancer have their unique needs met by providing care and appropriate communication to them.

So then, into the next section. Dr. Nekhlyudov, I believe Dr. Chan mentioned this briefly already in talking about being able to access care as part of integrative care. But what is recommended regarding accessible and equitable care?

Dr. Larissa Nekhlyudov: Right. Absolutely. I mean, as with any healthcare or cancer care, the standard emphasizes that cancer survivorship care for all people affected by advanced or metastatic cancer is not only comprehensive but also accessible. So affordable, acceptable, available, appropriate, and equitable. And the key is that it does not vary based on someone's personal, cultural, or religious factors. It is important that health workforce diversity and cultural awareness training with the development and provision of culturally and linguistically appropriate resources, that these can help healthcare professionals better understand and cater to the unique needs of the cancer survivor and the caregiver populations. We also need to develop metrics to assess the evaluation and improvement and make sure that supportive care options are innovative, inclusive, and targeted towards eliminating disparities.

Some of the work that Dr. Chan has otherwise led is looking at provision of telehealth and virtual care for cancer survivors. So particularly for this patient population, it is important to examine the potential benefits of virtual healthcare so that these patients who may have a lot of different needs, physical challenges, mental health challenges, caregivers, that we don’t necessarily bring them to the healthcare setting and can potentially provide them the care that they need. And the last thing that I would like to point out with respect to this is that people affected by advanced or metastatic cancer may face additional challenges particularly returning to work in some capacity and should be supported by advocacy groups, or consumer groups as they are often called internationally, that advocate for accessible and equitable care and then work with specific personnel to access employment, financial and legal assistance that they may need.

Brittany Harvey: Those are important for providing both inclusive and individualized care to every patient who a clinician may see.

So then following those points, what is recommended and what are the key points you’d like to highlight regarding sustainable and resourced care?

Dr. Larissa Nekhlyudov: Thanks, Brittany. This is a really important point, and not to take away from any of the other standards, but in order for us to provide ongoing high quality cancer survivorship care for people affected by advanced and metastatic cancer, we need to have a sustainable and adequately resourced approach to do so. So, these standards acknowledge that not all countries or healthcare systems have access to sufficient resources. As such, supportive care may need to utilize a step-care or resource stratified approach that offers the least resource-intensive care that aligns with the needs of the patient, but then also takes into account resources that are available, but really the care should not stop there.

Survivorship care interventions and models of care should be cost-effective yet clinically relevant and meaningful and need to have the adequate financial investment by the healthcare systems. So healthcare settings providing survivorship care for those affected by advanced and metastatic cancer have to be properly resourced in order to provide high quality ongoing care. And this includes intentional planning for support services, and where healthcare settings provide these programs with adequate level of human resources, equipment, facilities, and leadership who value support, facilitate, and appropriately invest in such care. And as we mentioned before, it’s always important to continue to evaluate what is being provided, what is being offered, sort of what are the return on investment metrics in order to continue to evolve the programs to serve the needs of the population.

Brittany Harvey: Understood. I appreciate you providing highlights across these past couple of domains.

So then to turn to the last domain, Dr. Chan, what is recommended regarding research and data-driven care?

Dr. Raymond Chan: So the panel actively advocated for cancer registries to enable population-wide surveillance of the incidence and prevalence of people with advanced or metastatic cancer. Knowing the number of people with advanced or metastatic cancer is extremely important for care planning. We also advocated for the active involvement of people affected by advanced or metastatic cancer to participate in the co-design of research so that we can make sure that our research better meets the needs or end-users and enhance the rigor, relevance, reach, and impact of survivorship research.

The last point I would like to highlight is that a number of survivorship trials out there only limit the population or the focus of the trial being on early stage disease, people treated with curative intent. And within this standards and principles, we advocated for research trials to explicitly include people affected by advanced or metastatic cancer in the clinical trials and trying to address also the barriers that impede people from enrolling or participating at all levels.

Brittany Harvey: Thank you both for reviewing these key points, standards, and practice recommendations across these seven domains.

These standards and recommendations cut really across all aspects of care for people impacted by advanced and metastatic cancer. Dr. Nekhlyudov, in your view, what is the importance of these standards and how they will impact clinicians?

Dr. Larissa Nekhlyudov: Thank you for that question, Brittany. The MASCC-ASCO standards were developed, as we already mentioned, to promote the provision of high-quality, evidence-based survivorship care for people with advanced or metastatic cancer emphasizing the need for care that is person-centered, coordinated and integrated, evidence-based and comprehensive, evaluated, and communicated, accessible and equitable, sustainable and resourced, as well as research and data-driven. For clinicians, these standards and practice recommendations provide a critical resource in order to facilitate tailored and effective care for people living with advanced or metastatic cancer across disciplines and settings.

As we know, and much of it is due to the efforts of ASCO, cancer care is always changing resulting in changing prognoses. As such, people diagnosed with cancer in the past that had poor prognosis are now living and are living longer. And so diagnoses that fall into this specific category of patients that we’re discussing here today will continue to evolve. And likewise, advanced cancer is less clearly defined for other cancer such as hematologic or CNS malignancies, but these survivors may face similar issues and challenges.

So overall, applying these standards will help provide survivorship care to these patients. And the important piece is that what we hoped to achieve with these standards is that when we consider survivorship care, we are not only applying it to those who have early stage disease. We’re not applying it only to those whose disease has been “cured.” We’re not applying it to those who have been deemed disease-free or those who have completed treatments. We really need to make sure that clinicians understand the challenges experienced by often disregarded or forgotten population of cancer survivors and yet acknowledge the ever changing landscape of cancer survivors and appropriately apply these survivorship standards for people affected by advanced or metastatic cancer. And I think as Ray would probably say as well, we should focus on including rather than excluding people with cancer, all cancers, from survivorship services and programs.

Brittany Harvey: Definitely. This is an important population with often unrecognized or unmet needs, and the goal of these standards, as you’ve mentioned, is to provide a better quality survivorship care for patients with advanced and metastatic cancer.

So that leads nicely into my final question for you, Dr. Chan. In your view, how do these standards and recommendations impact people affected by advanced or metastatic cancer?

Dr. Raymond Chan: As we continue to promulgate these standards of recommendations, I believe that patients will benefit from these standards in three ways.

First, as clinicians, researchers, and service planners continue to improve care as per outlining the standards, patients are going to indirectly benefit from it. It is meant to lead to better care, better experiences, and better outcomes.

Secondly, it is around the expectations of care. Many of us here would know that if we don’t expect that care, it is unlikely that we would go and try to access it. And so it is extremely important that patients know what to expect. So now that I have been diagnosed with advanced or metastatic cancer, what does good care look like? So in the past, there are a number of pallaiative care standards whereby people are thinking, “Do I need palliative care? What does good palliative care look like?” Their set of standards. And now, these standards would enable patients to develop that expectation around what good care looks like.

Thirdly is around the patients, the family units, and their navigators or their care networks to advocate for themselves, to advocate for the patient, to be able to access that care from the care team. So we hope that as we continue to promulgate these standards, that benefit would be translated into the real world for people affected by advanced or metastatic cancer.

Brittany Harvey: Excellent. We definitely hope that this improves care for all patients impacted by advanced and metastatic cancer.

So, I want to thank you both so much for this important work to develop these recommendations and standards. And thank you for taking the time to speak with me today, Dr. Nekhlyudov and Dr. Chan.

Dr. Larissa Nekhlyudov: Thank you. Great to be here.

Dr. Raymond Chan: Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full standards and practice recommendations, go to www.asco.org/standards. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

View Details

Dr. John Gordan discusses the newest evidence-based guideline update from ASCO on systemic therapy for advanced hepatocellular carcinoma (HCC). He shares the updated recommendations for first-, second-, and third-line therapy for patients with Child-Pugh Class A liver disease, guidance for patients with Child-Pugh Class B liver disease. Dr. Gordan also touches on the importance of this guideline for both clinicians and patients and the outstanding questions regarding treatment options for HCC. Read the full guideline, “Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update” at www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

My name is Brittany Harvey, and today I'm interviewing Dr. John Gordon from the University of California, San Francisco, lead author on "Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update." Thank you for being here, Dr. Gordon.

Dr. John Gordon: Of course, happy to be here.

Brittany Harvey: Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Gordon, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So, to jump into the content of this episode, first, Dr. Gordon, what prompted this update to the Systemic Therapy for Advanced Hepatocellular Carcinoma Guideline, which was last published in 2020?

Dr. John Gordon: So, both the initial guideline in 2020 and then the update now were driven by advances in the standard of care. The original 2020 guideline was actually held for a little bit so that we could incorporate the availability of atezolizumab plus bevacizumab, which just reported back and then received FDA approval during 2020. We were happy to be able to provide what was a very timely update to clinicians about being able to use that new regimen that had really changed the face of therapeutics for advanced HCC. The update was driven again by a shift in therapeutics, specifically it was the presence of much more evidence for the use of combination CTLA-4, PD-1 or PD-L1 immunotherapy strategies. The primary thing was the availability of durvalumab plus tremelimumab, which was studied in the so-called HIMALAYA phase III trial. The key shift in this guideline was being able to incorporate those data as a second first-line option. Furthermore, when the 2020 guideline was released, data were just becoming available about the combination of ipilimumab and nivolumab, and were not covered in any great detail. So we wanted to be able to be sure to incorporate both of those regimens, which we thought were quite significant in the current therapy for advanced HCC.

Brittany Harvey: Appreciate you providing that background on the evidence informing both the original guideline and this update. Next, I'd like to review the key recommendations of this update. So, starting with, what is recommended for first-line therapy?

Dr. John Gordon: The current recommendation in the first-line setting is to offer patients either atezolizumab plus bevacizumab, sometimes called atezo-bev or durvalumab plus tremelimumab. But, at this time, those two regimens we’re not able to distinguish between them based on the primary evidence available. But there are a few distinctions in the studies and the patients that physicians may wish to consider. In particular, because atezo plus bev contains an immune therapy and then an anti vascular agent, for patients who are not eligible for antivascular agents or for whom an antivascular therapy might be of higher risk, for example, people with a history of esophageal varices or people with peripheral arterial disease, we would encourage physicians to preferentially consider durva plus treme.

Similarly, for patients where reactivation of an autoimmune disorder is a particular concern, staying away from the more potent immune combination is also advised. But again, the data themselves support the consideration of both, and it's really up to the provider, their multidisciplinary team, and then communication with the patient to determine what is optimal for that patient.

In addition, in the frontline setting, it is advised that for those patients who are unable to receive atezo plus bev or durva plus treme, sorafenib and lenvatinib, the traditional tyrosine kinase inhibitors that were more commonly used prior to 2020, may also be considered in the frontline setting. Furthermore, for some patients, it's also reasonable to consider the use of durvalumab alone, which is the PD-L1 inhibitor component of the durva-treme combination.

Brittany Harvey: Understood. It’s helpful to understand which regimens are optimal for which patient population and options that are available for shared decision making between patients and their clinicians.

So then, following those recommendations for first-line treatment, what is recommended for second-line therapy?

Dr. John Gordon: One of the things I want to be clear about the second-line recommendations is that these are largely driven by expert opinion rather than primary research studying the use of these agents after either atezo plus bev or durva plus treme. So, if you look at the history of HCC drug development, five or ten years ago, when we were confined to the use of sorafenib in the frontline setting, many studies explicitly studied the second and later-line population. But in the current era, where new frontline therapies have supplanted those agents, it becomes a little bit harder to provide a truly evidence-based answer. As a result, the recommendation is, frankly, to consider all of the options of FDA-approved agents and just as was the case of the frontline setting, to balance what might be patient-specific characteristics, both in terms of comorbidities and also ability to adhere with these regimens, which are not the easiest. All of those things should be considered when opting for a second-line agent.

Just to be slightly more explicit about it, for those patients who've received frontline atezo-bev, the considerations would be either transitioning to a tyrosine kinase inhibitor, most classically sorafenib, lenvatinib, or cabozantinib, or in principle, ramucirumab, the biologic antivascular agent, or a CTLA-4 and PD-1 or PD-L1 combination, such as durva-treme or nivolumab plus ipilimumab. Conversely, for those patients who might have received durva-treme in the frontline setting, it's reasonable to consider either a TKI or atezo plus bev.

Brittany Harvey: Absolutely. Thank you for reviewing both those recommendations and the level of evidence behind those. I think it's important that even in areas where the expert panel didn't have a lot of evidence to go off of, there are still recommendations available for clinicians that are based on expert opinion.

So then, following those second-line therapy options that you just described, what recommendations did the expert panel make for third-line therapy?

Dr. John Gordon: So, regarding the recommendation for third-line therapy, one of the things that we did want to make clear as a panel is that third-line therapy is a reasonable consideration in a subset of HCC patients. Quite often, five or ten years ago, it was very seldom that a patient might be considered for frontline therapy because of the burden of toxicity and/or disease progression during the first two lines. But now, for patients with intact liver function and good performance status, I think it's very reasonable to consider the same list of agents that might have been considered for second line.

And again, I think the general guidance here is if you've already given your patient both atezo-bev and some kind of CTLA-4 and PD-1 combination, it's probably best to use a non-overlapping regimen, something like a TKI. If, in the frontline setting, you followed atezo-bev by TKI or durva-treme by TKI, then it would be reasonable to look at the immune therapy combination that the patient hadn't received yet. Unfortunately, again, at this point, this is all at the level of expert guidance and personal experience. But just thinking about the mechanistic rationale behind these different combinations, and which ones your patient has had the opportunity to benefit from yet, is probably the best guidance that we can give as you move into the later line.

Brittany Harvey: Definitely. Thank you for reviewing that guidance as well.

So then, these recommendations that you've already described refer to patients with Child-Pugh Class A liver disease. What is recommended in the guideline for patients with Child-Pugh Class B advanced hepatocellular carcinoma?

Dr. John Gordon: Thanks. I think that's another important question, and it's a part of the field that's still evolving. So this is in some ways similar to the situation for third line therapy. The level one evidence that we have and the clinical trials that were done were almost exclusively done in the context of Child-Pugh A liver function. But we know well that many patients with hepatocellular carcinoma have some degree of impairment to their liver function, making them Child-Pugh Class B or beyond. Similar to third line therapy, we do believe that it's appropriate to cautiously consider systemic therapy for these patients, particularly a better compensated patient with Child-Pugh Class B liver function may be considered. The same systemic therapy options that are considered for patients with Child-Pugh Class A may be considered here, even to the level of considering atezo-bev or durva plus treme. I will also acknowledge, though, that when considering the liver function, bleeding risk, portal hypertension, and all of the other issues that may be at play, it may end up being safer for clinicians to consider monotherapy with an agent like durvalumab or using a TKI, by simple virtue of the fact that if complications ensue, treatment can be interrupted and the therapeutic will leave the patient's system relatively promptly. The key take home here is please do consider systemic therapy in this population, but also consider it with caution, with an understanding that the underlying hepatic dysfunction also plays a role in considering and affecting the outcome.

Brittany Harvey: Thank you for reviewing those recommendations for patients with Child-Pugh Class B advanced HCC and all of these recommendations, which are based off of expert review of the evidence and consensus of the entire expert panel.

So then, Dr. Gordon, in your view, what is the importance of this guideline update, and how will it impact both clinicians and patients with hepatocellular carcinoma?

Dr. John Gordon: I think the impact of this guideline update was really to open the field and really just make clear that the use of CTLA 4-containing combinations was appropriate for patients with HCC because those data were not available at the time of the last guideline and to try to provide some insight about where and when to incorporate them. We really think that these agents have the potential to significantly impact outcomes for patients with HCC, and so we wanted to be clear that these can be considered therapeutically even after frontline use of a PD-L1 inhibitor like atezolizumab. And so I think the key objective of this guideline is really to be enabling and really to make it clear that within the now somewhat surprisingly broad range of approved agents that we have for HCC, these options are on the table and may be used in succession, depending on patient-specific tolerance and their clinical course.

Brittany Harvey: Absolutely. So then you've specifically mentioned that both the original guideline and the guideline update were developed to provide timely guidance from recently published randomized clinical trials. So what are the outstanding questions still regarding treatment options for advanced hepatocellular carcinoma?

Dr. John Gordon: I think those questions are really reflected in one of the things which is challenging about these guidelines, which is that it's a very kind of open set of guidelines. We provide clinicians with a range of options, but we're really not in a position to provide much evidence-based guidance around treatment selection beyond the sort of careful avoidance of contraindications. I think that there will continue to be drug development for HCC. I think there are more potent immune therapies that are currently in use for other tumors that are being studied here, and I think we do hope to see new agents in future guidelines as well. But I really feel like the key question is going to be starting to stratify patients for who's going to be most likely to benefit from exposure to an antivascular agent, who's going to be more likely to benefit from exposure to a more potent immunotherapy so that we can give our patients the best medicine for them in the first setting, and that we're less in the position of having to sample the available options to see which one might work for our patient. And I think that's going to require significant effort, particularly, honestly, in academic medicine, as these medicines start to get used, to develop the kinds of data that will enable identification of biomarkers and mechanisms of response, as well as identification of efficacy, which has been this sort of key limiting step in HCC therapeutics for the last 10 years. Now that we've got so many effective agents, we would like to see them be more effective, but nevertheless, it's been huge strides forward. Then the question is, who gets what when?

I think the other place of interesting development right now is the integration of locoregional therapies like embolization procedures, either chemoembolization or radioembolization, as well as stereotactic body radiotherapy with systemic therapy. My suspicion is that it's going to take a little bit more time before the use of these is really well understood and how they might fit into the current standards of care. But we're starting to see some large studies tackling this question. I think that we will see impact of the combinations of systemic therapy and local regional therapy in guidelines to come in parallel to a better understanding of which treatment is right for which patient.

Brittany Harvey: We'll look forward to all of the future developments in the care of patients with advanced hepatocellular carcinoma, and look forward to inclusion of all of the things that you just mentioned into guidelines in the future.

So I want to thank you, Dr. Gordon, for all of your work that you've done to update these guidelines and for taking the time to speak with me today.

Dr. John Gordon: Absolutely. And I actually just want to express what a great experience I've had working with the ASCO Guidelines team. I think that this is very challenging work, and I really appreciate the professionalism and commitment that they bring to it. I think it has a huge impact, and I'm glad to be part of it.

Brittany Harvey: Absolutely.

And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Lisa Law and Dr. Randy Taplitz share the latest evidence-based recommendations from ASCO on vaccines in adults with cancer. They discuss recommended routine preventative vaccinations, additional vaccinations and revaccinations for adults undergoing HSCT, CD19 CAR-T treatment, or B cell-depleting therapy, guidance for adults with cancer traveling outside the U.S., and recommendations for vaccination of household and close contacts of adults with cancer. Dr. Law and Dr. Taplitz also share their insights on the guideline, including the importance of this guideline for adults with cancer and their clinicians, future advances in research, and current unmet needs. Read the full guideline, “Vaccination of Adults with Cancer: ASCO Guideline” at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00032

The ASCO Specialty Societies Advancing Adult Immunization (SSAAI) Project is supported by the Centers for Disease Control and Prevention (CDC) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award to the Council of Medical Specialty Societies (CMSS) (with 100 percent funded by CDC/HHS). The contents are those of the authors and do not necessarily represent the official views of nor endorsement, by CDC/HHS or the U.S. Government.

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today, I am interviewing Dr. Lisa Law from Kaiser Permanente and Dr. Randy Taplitz from City of Hope Comprehensive Cancer Center, authors on “Vaccination of Adults with Cancer: ASCO Guideline.”

Thank you for being here, Dr. Law and Dr. Taplitz.

Dr. Lisa Law: Thank you.

Dr. Taplitz: Thank you, Brittany.

Brittany Harvey: Before we discuss this guideline, I'd like to take note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Taplitz and Dr. Law, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content, here first, Dr. Taplitz, can you provide a general overview of both the scope and purpose of this guideline on vaccination of adults with cancer?

Dr. Randy Taplitz: Yes, so people with cancer often experience a compromised immune system due to a variety of factors. This includes chronic inflammation, impaired or decreased function of the hematopoietic system, and treatments that compromise their immune function. Because of this, people with cancer are at a higher risk for infection, including with vaccine-preventable diseases. Also, response to vaccines in patients with cancer may well be affected by this underlying immune status, and their anticancer therapy, as well as the severity of the underlying malignancy. The purpose of vaccination in this group of patients is to prevent infection or to attenuate the severity of the disease when infection cannot be fully prevented.

This ASCO review builds on a 2013 guideline by the Infectious Diseases Society of America, or IDSA, and uses what’s called a systematic literature review of 102 publications between 2013 and 2023. This includes 24 systematic reviews, 14 randomized clinical trials, and 64 non-randomized studies. The largest body of evidence in these studies, not surprisingly, addresses COVID vaccines on the efficacy and safety of vaccines used by adults with cancer or their household contacts. ASCO convened an expert panel to review this evidence and formulate recommendations for vaccinations in this population.

Brittany Harvey: Understood. I appreciate that context, Dr. Taplitz. So then, next, Dr. Law, I'd like to review the key recommendations of this guideline. The guideline addresses four overarching clinical questions. So starting with the first question, what are the recommended routine preventative vaccinations for adults with cancer?

Dr. Lisa Law: Thank you, Brittany. Before I start, I just want to wholeheartedly thank the first author of this paper, Dr. Mini Kamboj, Dr. Elise Kohn from the NCI, as well as the ASCO staff in putting this publication and guideline together. It is a very, very important guideline, and I echo everything Dr. Taplitz just said.

So going back to your question, what are the recommended routine preventative vaccines for adults with cancer? As per this guideline, there are about 7 to 8 based on patient age and risk. Namely, they are: seasonal flu, RSV for those aged 60 or above, COVID-19, Tdap, Hepatitis B, Shingrix, Pneumococcal vaccine, and the HPV vaccine. These vaccines should ideally be given two to four weeks before therapy. However, non-live vaccines can be given anytime during or after chemo, immunotherapy, hormonal treatment, radiation, or surgery.

Brittany Harvey: Excellent. Thank you for reviewing those vaccinations and the timing of them as well. So then, following those recommendations, Dr. Taplitz, what additional vaccinations and revaccinations are recommended for adults undergoing hematopoietic stem cell transplantation, CD19 CAR-T treatment, or B-cell depleting therapy?

Dr. Randy Taplitz: Many studies have shown that stem cell transplant recipients essentially lose immunity from childhood immunizations, and we know that these individuals are very vulnerable to infection, particularly in the first year after transplant. Revaccination is critical to help restore their immunity. The optimal timing of vaccination is based on our understanding of adequate immune reconstitution with B and T-cell recovery so that the individual can mount a response to the vaccine. We know that a lot of factors influence this immune reconstitution, including the age of the stem cell transplant recipient, the source of the donor, the time from transplant, graft-versus-host disease prophylaxis, the treatment and severity of graft-versus-host disease, and the vaccine type and antigens used.

There are a number of bodies throughout the world, IDSA as I mentioned, CDC, American Society for Transplant and Cellular Therapy, European Society for Blood and Marrow Transplant, and European Conference for Infections and Leukemia. All of these bodies have guidelines that approach vaccination in stem cell transplants. However, variation does exist in the use of a variety of things including whether to use immune predictors to help guide vaccination, and there is really not consensus on whether this immune predictor guided vaccination is more likely to produce a protective immune response versus a standardized schedule. In addition, the duration of protection is incompletely understood.

The bottom line in these guidelines is that they recommend complete revaccination starting for most vaccines at 6 to 12 months after stem cell transplant, in order to restore vaccine-induced immunity. And I just want to go through a few of the particulars. For COVID-19, which is a three-dose series in the primary series, influenza - generally high-dose influenza - and pneumococcal vaccine, PCV20 in general, ultimately four doses, can be administered, starting as early as three months after transplant. Although there is really not much data to guide the use of the recombinant zoster vaccine in allogeneic stem cell transplant, the vaccine can be administered after the end of antiviral prophylaxis, which in general is 12 to 18 months after allogeneic and 3 to 12 months after autologous stem cell transplant. Some of the other vaccines, such as hepatitis B, Tdap, meningococcal vaccines, and HPV revaccination in those less than 45 are also recommended.

I want to also spend the moment talking about the two recently licensed RSV vaccines, which were essentially studied in less compromised hosts and really without any immunogenicity data in stem cell transplant, and thus, there is no recommendation in this guideline for the use of these vaccines after transplant. Live vaccines, such as MMR and varicella – varicella would be in varicella-seronegative patients without a prior history of varicella – should be delayed for at least two years and only given in the absence of active graft-versus-host disease or immunosuppression.

Moving briefly to CAR T, which is an immunotherapy that involves adoptive cell therapy, given the available data and after a review by the group, it was recommended that adults with hematopoietic malignancies receiving CAR T therapy directed against B-cell antigens should receive influenza and COVID-19 vaccines either two weeks before lymphodepletion or no sooner than three months after the completion of therapy. Administration of non-live vaccines preferably should occur before CAR T treatment or at least 6 to 12 months after, following the same timing as what we recommend for stem cell transplant. There is really little data to guide the safety and timing of administration of live vaccines after CAR T therapy.

In terms of adults receiving B-cell depleting therapy, they are generally unable for time to mount an effective humoral response but may have at least partially intact cellular immune responses. They are encouraged to be revaccinated for COVID-19 no sooner than six months after completion of B-cell depleting therapy, and they should receive influenza vaccine approximately four weeks from the most recent treatment dose for patients on chronic therapy. For other non-seasonal immunizations, vaccines ideally should be given two to four weeks before commencing anti-CD20 therapy or delayed until 6 to 12 months after completion, except for the recombinant zoster vaccine, which can be given one month after the most recent dose of B-cell depleting therapy.

Brittany Harvey: I appreciate you reviewing each of those vaccinations and when they should be given, and reviewing the available data – albeit, limited data – in these situations.

So beyond these routine preventative vaccinations and revaccinations that you've both just described, Dr. Law, what additional vaccinations does the expert panel recommend for adults with cancer traveling outside the United States?

Dr. Lisa Law: Good question. As per these ASCO guidelines, adults with solid or blood cancer traveling outside of the United States should follow the CDC standard recommendations for their destination. For the 2024 CDC Yellow Book, travel vaccines, in general, should be delayed until three months from the last chemotherapy or, and for those with solid tumors, ideally when the disease is in remission. Of note, hepatitis A, typhoid, inactivated polio, Hep B, rabies, meningococcal vaccine, and Japanese encephalitis vaccines are considered to be safe. In all cases of travel, patients should be counseled by their healthcare provider about the travel timing, with the additional attention to the regional seasonality of infections, for instance, influenza is more common in late summer in Australia, and also with attention to any outbreaks that may be occurring globally at the time of travel.

Brittany Harvey: Absolutely. Those are key points for clinicians to discuss with their patients as they consider upcoming travel.

So then, the final clinical question that the panel addressed, Dr. Taplitz, what vaccinations does the panel recommend for household and close contacts of adults with cancer?

Dr. Randy Taplitz: Thank you. Yes, it is recommended that all household members and close contacts, when possible, be up to date on their vaccinations. And the only further thing I would say is that there are some special considerations for the use of live vaccines in household contacts, particularly in stem cell transplant recipients. Contacts of people who receive stem cell transplants should preferably receive inactivated influenza vaccines. As was mentioned, MMR and varicella vaccines are both safe to administer to close contacts. Vaccine strain transmission to immunocompromised hosts has not been associated with MMR use in family members.

Eleven cases of the varicella vaccine strain transmission are described in the published literature, but none occurred in compromised hosts. Because the vaccine strain can cause severe and fatal varicella in profoundly immunocompromised people, precautions are advised to avoid close contact with a person with a vaccine-induced rash. For household contact travelers, MMR and yellow fever vaccines are considered safe. Oral cholera should be avoided. For smallpox vaccines, the second-generation ACAM2000 has rarely been associated with vaccinia transmission and should be avoided because of this. But the live replication-deficient MVA-based JYNNEOS vaccine is felt to be safe for household contacts of immunocompromised individuals.

Brittany Harvey: I appreciate you reviewing the importance of vaccination for household and close contacts, and some of those precautions that individuals should take. I appreciate you both for reviewing all of these recommendations.

So then in your view, Dr. Law, what is the importance of this guideline, and how will it impact both clinicians and adults with cancer?

Dr. Lisa Law: In my opinion, this is a very important guideline that is long overdue in the oncology community and will have a huge impact on both clinicians and adults with cancer. Over the years, I have often been asked by my colleagues and patients, “Can I have the flu vaccine, and if so, when?” So this guideline really is going to be helpful. More importantly, our cancer patients are living much longer. They may have years of quality of life even with third or fourth line of treatment, especially, for instance, like CAR T for myeloma and lymphoma. However, we know that with additional treatment, that carries a substantial risk of infection complication among these immunocompromised patients. So it is of paramount importance to inform our patients and colleagues to be proactive in advocating preventive therapy ahead of time, meaning trying to get the patients appropriately vaccinated as early as possible to generate immunity.

Another case in point is the Shingrix vaccine. I used to see lots of shingles, but ever since we have the recombinant Shingrix, I have fewer encounters. And this is huge because post-herpetic neuralgia robs a patient’s quality of life. So, again, it is very important to recommend appropriate vaccines for our cancer patients.

Brittany Harvey: Absolutely. It is key to ensure patients receive these preventative vaccines, and we hope that this guideline puts an emphasis on that for clinicians and patients.

So finally, to wrap us up, Dr. Taplitz, what are the current gaps in knowledge regarding the vaccination of people with cancer?

Dr. Randy Taplitz: There are a number of really important gaps in knowledge and really critical unmet needs that require research and other dedicated efforts. Among these are, and I think paramount, are really the participation of people with cancer with varied types of immunocompromise in vaccine trials. Where vaccine trials are only for cancer patients, obviously is ideal, testing vaccines in the appropriate population. But when that's not feasible, pre-existing cancer should not preclude eligibility, and inclusion of cohorts of people receiving anticancer treatment should be incorporated prospectively. So that’s really critical because the quality of our guidelines is based upon the data. We use the data for developing guidelines and gathering more data in the particular patient population is really, really critical.

Secondly, work for creating more immunogenic vaccines and research to understand the immune response to vaccines after immuno-depleting therapies, particularly with newer therapies such as CAR T and newer B cell therapies, bispecific antibodies, etc. is really critical. We need to really understand the immune response and have the most potent vaccines available to these people who may have impaired immune responses.

Switching gears a little bit, we really need mechanisms to promote institutional commitment to integrate and sustain immunization best practices for people with cancer. This will largely be through multidisciplinary, team-based approaches, protocol-based vaccination standing orders, and leveraging data sharing so that we can all be on the same page with giving vaccines to these individuals. We also need education and evidence-based decision-making tools, emphasizing preventive care through immunization, the availability of educational resources to clinicians and patients to address commonly asked questions and also misconceptions about vaccination, that’s absolutely critical.

And finally, I think we need to develop strategies for addressing unique challenges and factors contributing to vaccine hesitancy during cancer therapy. We need to focus on patient and clinician communication, and very importantly, we need to consider health equity considerations in the development and approach to vaccines in these compromised patients.

Brittany Harvey: Definitely, we'll look forward to research and advances in these areas that you've just described to support these guidelines and increase vaccine uptake.

So I want to thank you both so much for your work on this important guideline, and thank you for your time today, Dr. Law and Dr. Taplitz.

Dr. Lisa Law: Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Ilana Braun and Dr. Eric Roeland join us on the ASCO Guidelines podcast to discuss the latest evidence-based recommendations on cannabis and cannabinoids in adults with cancer. They discuss nonjudgmental patient-clinician communication, the relatively narrow cancer-related indications for which there is actionable clinical evidence for cannabis and/or cannabinoids, and key information for adults with cancer and their clinicians. Dr. Braun and Dr. Roeland also review the limited evidence regarding cannabis and cannabinoid use in adults with cancer and the outstanding questions and importance of research in this area. Read the full guideline, “Cannabis and Cannabinoids in Adults with Cancer: ASCO Guideline” at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcast hosts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all of the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today, I’m interviewing Dr. Ilana Braun from Dana-Farber Cancer Institute, and Dr. Eric Roeland from Oregon Health & Science University, co-chairs on “Cannabis and Cannabinoids in Adults with Cancer: ASCO Guideline.”

Thank you both for being here Dr. Braun and Dr. Roeland.

Dr. Ilana Braun: Thanks so much for having us, Brittany.

Dr. Eric Roeland: Thanks, Brittany.

Brittany Harvey: Then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Braun and Dr. Roeland, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

Then to jump into the content of this guideline, first, Dr. Roeland, could you give us an overview of both the scope and purpose of this guideline?

Dr. Eric Roeland: Sure, Brittany. I think it's important for everyone to recognize just how common the issue of cannabis or cannabinoid use is amongst people living with cancer. And I think clinicians in academia as well as through community sites, we are asked about the use of cannabis on a daily basis. And so our target audience is really to focus on clinicians providing care to adults with cancer, but also the health systems in which we work because this is a very complex issue, as well as the people living with cancer and their caregivers, as well as researchers dedicated to this field.

Brittany Harvey: So as you mentioned, this is a complex issue, and I'd like to review the key recommendations of this guideline. This guideline provides recommendations across three clinical questions that the expert panel targeted. So, starting with the first question, what is recommended for patient-clinician communication regarding cannabis or cannabinoids?

Dr. Ilana Braun: Given the high prevalence of medicating with cannabis or cannabinoids that Eric references, somewhere in the neighborhood of 20% to over 40% of adults with cancer consume cannabis products, ASCO's guideline offers the following common-sense, good practice statement: In the clinic, providers should routinely and non-judgmentally inquire about cannabis consumption or consideration of cannabis, and either guide care or direct adults with cancer to appropriate resources. In other words, the guideline works to fully destigmatize this conversation. The guideline goes on to offer suggestions for taking a cannabinoid and cannabis history. This includes the goals of use, how the products are sourced, what formulations are being used (including the ratios of active ingredients like THC and CBD), the inactive ingredients (for instance coconut oil), whether it is herbal or synthetic, and whether the product is pharmaceutical grade or non-pharmaceutical grade. And then other questions like routes of administration, dosing schedules, perceived benefits and risks, and whether the products are being used adjunctively or as a replacement for standard treatments. It is also probably important to query potential contraindications, such as a history of cannabis use disorder or psychosis.

Brittany Harvey: Thank you for reviewing those good practice statements. Those are key for non-judgmental communication and taking an accurate and complete history.

So following those statements, the expert panel next addressed the question: Does use of cannabis and/or cannabinoids by adults improve cancer-directed treatment? What recommendations did the expert panel provide for this section?

Dr. Eric Roeland: When we think about the use of cannabis or cannabinoids in treating the underlying cancer, it's incredibly important to recognize the excitement that patients and clinicians have around the potential promise. Much of this data is generated from preclinical models. However, when we're engaging patients consuming cannabis or cannabinoids to augment their cancer-directed treatment, we could find no evidence to support its use. And so we do not recommend that patients be using it to augment treatment, nor do we recommend that patients should be using it instead of their cancer-directed therapy. And I think this is a major challenge for multiple oncologists, where their patients may be using these with a goal of treating their cancer, and then present with very advanced cancer and/or multiple poorly controlled symptoms.

Dr. Ilana Braun: And I think that there are some areas of particular concern. For instance, there were two oncologic cohort studies that suggest that cannabis, which we know is an immune modulator, may actually worsen immunotherapy outcomes. These outcomes included median time to progression and overall survival. There are obvious limitations of preliminary observational data, and we now need to gather prospective, gold-standard data. But for the time being, the guideline recommends that clinicians should advise against adults receiving immunotherapy from medicating or considering medicating with cannabis and cannabinoids. And then I think there are some additional reasons for concern. First of all, this type of therapy tends to be very expensive and not covered by insurance and there are some risks for drug-drug interactions, in terms of pharmacodynamic ones, Cannabis may exacerbate neuropsychiatric side effects of opioids and even benzodiazepines. In terms of pharmacokinetic drug-drug interactions, it's not a particularly risky substance, but there are three to be wary of in particular: warfarin, buprenorphine, and tacrolimus all have high-risk interactions with cannabinoid products.

Brittany Harvey: I appreciate you both for reviewing these recommendations and evidence regarding the use of cannabis and/or cannabinoids regarding cancer-directed treatment.

So then the last clinical question, Dr. Braun, what is recommended regarding use of cannabis and/or cannabinoids in managing cancer treatment-related toxicities and/or symptoms?

Dr. Ilana Braun: The first thing to make clear is that high-quality clinical evidence evaluating the utility of cannabis and cannabinoids for adults with cancer is limited as Eric has said. The evidence that does exist weakly supports a practice of using cannabis and cannabinoids to address refractory chemotherapy-induced nausea and vomiting when standard treatments have failed. For other potential oncologic indications, like management of cancer-related pain, there is weak, negative, conflicting, or no evidence. But that being said, a 2017 monograph published by the National Academies of Science, Engineering, and Medicine concluded that there is substantial evidence that cannabis is an effective treatment for chronic non-cancer pain, and I’m sad to say, that chronic non-cancer pain happens too in adults with cancer.

Brittany Harvey: Thank you for reviewing those recommendations as well.

So you've both touched on this a little bit in that patients are often asking clinicians for recommendations regarding cannabis and/or cannabinoids, but in your view, what is the importance of this guideline, and what should clinicians know as they discuss these recommendations with their patients?

Dr. Eric Roeland: Probably one of the most important points is for clinicians to ask and to be open and to create a space where our patients are telling us about what they're using. I think we've all had patients that we’ve been surprised that have been using cannabis or cannabinoids in conjunction with other medications that may increase the risk of unwanted side effects or risks, including sedation or falls. I also find it challenging that many patients are receiving recommendations for the use of cannabis or cannabinoids directly from friends or family instead of through their medical providers. Therefore, I think one of the very first things is to just make sure that you’re asking about it and then inquiring what the goal of their use is.

When we talk about the use of cannabis, we also need to recognize the difference between the available data that can guide us in evidence-based recommendations, as well as the enthusiasm and available access that patients have to cannabis that has really outpaced our ability to research it. So it's important to recognize these tensions that we're living with in clinic day-to-day.

Brittany Harvey: Absolutely. Those points are key for clinicians as they discuss this complex issue with their patients.

Following that, how will these guideline recommendations affect adults with cancer?

Dr. Ilana Braun: One really important takeaway from these guidelines is that they clearly state that cannabis and cannabinoids are medicinal, and for a medical community to clearly articulate this point is notable. I suspect they will provide encouragement, legitimacy, confidence, and even a script to oncology clinicians who were previously reticent to inquire, document, and provide clinical recommendations around non-pharmaceutical cannabis and cannabinoids. It may have a similar effect even at the institutional level in terms of supporting these practices. At the same time, I suspect they will encourage those who are recommending oncologic use of cannabinoids and cannabis for myriad cancer-related indications to adopt a more circumscribed approach. The reason I say this is that the cancer-related indications for which there is actionable clinical evidence at this time are quite narrow. So all this to say, I believe these guidelines will lead to greater transparency around cannabis decision-making in the clinic, as Eric mentions, but also lead to a possible narrowing of indications for which cannabis is clinically recommended.

Dr. Eric Roeland: Another major role of the use of these guidelines in clinical care is informing clinicians and patients about cannabis. Cannabis has been used by humans as a plant for thousands of years, and although it's a very complex plant with hundreds of parts, the two parts that researchers have studied most are delta nine-tetrahydrocannabinol, or THC, and cannabidiol, or CBD. In rough terms, THC can cause a high feeling, while CBD typically does not. And there are multiple types of products that have different ratios of THC and CBD. So it's critical for people to understand what those ratios are, how many milligrams of those things there are, as well as what are the programs within your region to measure or quantify what's actually in the products you're consuming.

If a person with cancer medicates with cannabis, most oncologists would prefer that they use it by mouth, such as an edible, rather than inhaling or smoking cannabis given concerns about potential impact on lung function. One challenge when consuming cannabis by mouth is that it can take up to two hours to have its full effect. So patients should be very careful not to take too much or to stack their doses, which can cause sedation, confusion, and even increase the risk of falls. Whereas when patients are consuming cannabis by breathing in a smoke or vapor, they typically feel the effects almost right away, which is why patients sometimes prefer smoking or vaping as their preferred route of administration.

Brittany Harvey: Understood. Definitely. We hope these guidelines provide key information and clarity for both adults with cancer and their clinicians.

So then, finally, you've both mentioned that there is limited evidence regarding cannabis and cannabinoid use in adults with cancer. So what are some of the outstanding questions regarding cannabis and cannabinoids in cancer care?

Dr. Eric Roeland: Thanks, Brittany. I think the questions also align with priorities for future research, and we need to recognize that the lack of evidence aligns with some of the challenges of funding research in this space. However, ongoing future research priorities include what is the nature of healthcare disparities pertaining to medical cannabis use by adults with cancer, and what are effective means to address these disparities? We also wonder, what are the optimal strategies to maximize communication in the oncology clinic regarding medical cannabis and/or cannabinoid use? And when we're thinking about cannabis and/or cannabinoids for cancer treatment specifically, we still need to know do cannabis and/or cannabinoids possess clinically meaningful anticancer activity in humans. We also need to understand what are the drug-drug interactions with our standard-of-care cancer treatments, including cytotoxic chemotherapy, targeted therapy, immunotherapy, radiation, and combinations of all the above. We also are wondering what the effect of cannabis and/or cannabinoids on outcomes in adults with cancer receiving some of our newer therapies, including antibody-drug conjugates and some of our newer vaccine therapies.

Dr. Ilana Braun: I might add that collating the existing research as the guideline did is a very good first step and should serve to highlight where the gaps in knowledge lie. This guideline discusses some of the unique challenges to conducting cannabis and cannabinoid research, including limitations in funding source and study drug, red tape procedures, and issues around legalization. I believe it will take a group of highly determined and creative researchers to move the needle forward in this area, but we must.

Brittany Harvey: Definitely. Thank you both so much for all of your work developing this guideline and creating these evidence-based recommendations. And thank you for taking the time to come on the podcast today and teach us all a little bit more about cannabis and cannabinoids in cancer care. And thank you for your time, Dr. Braun and Dr. Roeland.

Dr. Ilana Braun: Thanks so much, Brittany.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Angela DeMichele, Dr. Lynn Henry, and Dr. Harold Burstein present the latest breast cancer rapid recommendation update impacting two ASCO guidelines. This update focuses on the new option, capivasertib plus fulvestrant, for patients with hormone receptor-positive, HER2-negative metastatic breast cancer with activating PIK3CA or AKT1 mutations or inactivating alterations in PTEN based on data from the recent CAPItello-291 trial. They discuss the updated recommendations on lines of endocrine treatment and selecting between the options for patients with activating PIK3CA mutations. Additionally, we discuss implications for clinicians and patients, and what ongoing research is occurring in the field.

Read the latest update, “Endocrine and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer – Capivasertib-Fulvestrant: ASCO Rapid Guideline Update“ at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

My name is Brittany Harvey, and today I am interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute, Dr. Angela DeMichele from the University of Pennsylvania, and Dr. Lynn Henry from the University of Michigan, co-chairs on “Endocrine and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Capivasertib–Fulvestrant: ASCO Rapid Guideline Update.” Thank you for being here, Dr. Burstein, Dr. DeMichele, and Dr. Henry.

Dr. Harold Burstein: We're happy to be here.

Brittany Harvey: And before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this episode today, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to kick us off, Dr. Burstein, could you first describe what prompted this rapid update, which provides updated recommendations for two ASCO guidelines: the biomarkers for systemic therapy in metastatic breast cancer guideline, and the endocrine treatment and targeted therapy for hormone receptor-positive, HER2-negative metastatic breast cancer guideline?

Dr. Harold Burstein: Thanks, Brittany. Well, this team has been working, as you mentioned, actually, on two guidelines, which are clearly evolving in parallel and kind of converging, actually, when you look at data, as we'll be talking about in the next few minutes. The particular catalyst here was a large randomized clinical trial which looked at a new targeted therapy in the space of estrogen receptor-positive, HER2-negative breast cancer. That drug is capivasertib. And the trial was the so-called CAPItello study. In that trial, patients who were receiving second-line therapy with fulvestrant were randomized to that treatment alone, or that plus capivasertib. So the data from that study were the first strong signal that we needed to update the guideline because they were important clinical data.

The other strong signal was that the drug was tested in a cohort of patients who had a specific set of mutations in their cancers. And that included PIK3CA mutations, a class of mutations for which we already had a targeted drug. But it also included some new potential targets, including mutations in the AKT gene itself, capivasertib is an AKT inhibitor, as well as loss of PTEN protein functionality, which potentially sensitizes tumors to the targeted action of this drug as well. So while we had a couple of guidelines catching up on the endocrine therapy space, which is increasingly looking like a targeted therapy space, it was clear that this major study, which had clinical and diagnostic implications, would sort of push them together and served as the impetus for updating both guidelines at the same time.

Brittany Harvey: Understood. I appreciate that background information.

So then, Dr. DeMichele, based on this updated data that Dr. Burstein just described, what is the updated recommendation from the guideline panel regarding lines of endocrine treatment?

Dr. Angela DeMichele: Well, I think this is where the biomarker evolution that Dr. Burstein just referred to really comes in because now we have the opportunity to perform genomic testing in patients who have ER-positive, HER2-negative metastatic breast cancer, on either the tumor or commonly from the blood. And we can now start to tailor treatment to the specific genomic abnormalities that that patient's tumor contains. So now our guideline really marries both the genomic abnormality with the therapeutic option. First-line treatment remains endocrine therapy plus a CDK 4/6 inhibitor. But things then really start to diverge once we enter second and third-line therapy because at that point, we now have the option to test for several genomic markers: ESR1 mutations, PIK3CA mutations, AKT1 mutations, and PTEN inactivation. And based on whether the tumor has one or any of those mutations, we can then select the therapy based on that.

So in the case of capivasertib, as you just heard, that is a therapy for patients whose tumors have PIK3CA mutations or activating mutations in AKT1 or loss of PTEN. But other patients who don't have one of those mutations may, in the second line, go on to another drug. For example, if they have an ESR1 mutation, they then may be eligible to take elacestrant. Patients who have no targetable mutations still have a targeted option in that they can use everolimus. And in all of these settings, the endocrine therapy partner for this line of therapy is typically fulvestrant. So now we're really starting to tailor therapy in the second- and third-line based on genomic changes.

Brittany Harvey: Excellent. That information is helpful for choosing optimal therapy tailored to the individual patients, as you just described.

So then, Dr. Henry, what guidance does the expert panel provide regarding choosing a PIK3CA targeted option?

Dr. Lynn Henry: Thank you. So for patients whose tumors are found to have an activating mutation in PIK3CA, we now have two drug options: either alpelisib or capivasertib in combination with fulvestrant. And the problem is, these drugs have not been compared head-to-head. We can't say that one is clearly better than the other, either in terms of efficacy or in terms of side effect profile. What we do have is information from two separate trials in which they were each tested against placebo. The efficacy appears to be fairly similar based on the data that we have. It does appear that the side effect profiles may be slightly different. And so, when you have a patient sitting in front of you and you're trying to decide how best to treat her, you really have to think about, what symptoms does my patient already have? What is she more or less likely to tolerate? So what we do know is that it appears that the rates of grade 3 diarrhea and rash were slightly higher with capivasertib. It looks like hyperglycemia was higher with alpelisib, as was treatment discontinuation. So really you have to make an individualized decision when you have a patient sitting in front of you about which drug you'd like to try. Of course, if someone doesn't tolerate one drug, you can always switch to the other one.

Brittany Harvey: I appreciate that analysis and to provide guidance without a head-to-head trial and to specifically provide options based on an individual patient's profile.

So then, Dr. DeMichele, what should clinicians know as they implement these new recommendations?

Dr. Angela DeMichele: Well, first of all, I think most clinicians now are becoming more familiar with the procedures required for doing genomic testing. But this is something that now has become the standard of care. And so, it is incumbent upon all of us who treat these patients to understand what the options for genomic testing are for that patient, which companies offer this testing, how to send a sample, and how to interpret the report that comes back. So, I think this has really added a level of complexity to the therapy for patients. I also think that one can’t simply apply an algorithm to a patient. We have to really treat the whole patient and we have to take into consideration, as Dr. Henry said, the toxicities of these agents and the cost which is also a major issue. So I think that while it is more complex, really that doctor-patient relationship is so important in communicating what these genomic tests mean for a patient and for their options, and also important for the clinician to really understand what the different therapeutic agents might mean for a patient, and really try to pick the agent that’s best for that patient. Using genomic testing is just one of several different features that they’ll consider.

Brittany Harvey: Absolutely. It’s key to obtain the data needed to select appropriate patients and to recognize the complexity.

So then, Dr. Henry, in your view, how will this update impact patients with metastatic breast cancer?

Dr. Lynn Henry: Yes, so as we’ve discussed, I think this is really exciting. Over the last few years, we have had quite a number of new medications that have become available for patients and have been FDA-approved. And so this is yet the latest in a series. For those patients whose tumors have a PIK3CA mutation, as we discussed, there are now two options. So you have a choice depending on which one is better covered by insurance, by which one you may tolerate better. But I think the other thing is now, although it’s a smaller subset of patients, there are patients out there whose tumors have mutations in AKT1 or alterations in PTEN, and so there’s an entirely new endocrine therapy-based option available for them that wasn’t available before. So I think that thinking about the new data that are out there, the new drugs that are out there, really is exciting because there are new options available and hopefully there are more to come as well.

Brittany Harvey: Absolutely. It's great to have these new options.

So, finally, Dr. Burstein, Dr. Henry just mentioned what's to come. Could you touch on what some of the outstanding questions are regarding endocrine therapy for patients with metastatic breast cancer?

Dr. Harold Burstein: A couple of things to say. First, ER-positive metastatic breast cancer is the most common kind of metastatic breast cancer, roughly three quarters of metastatic cases of breast cancer will be hormone receptor-positive cancers. So this is a very big public health issue around the world, actually, breast cancer being the number one most commonly diagnosed cancer of women around the world. So minor or major improvements in treatment for advanced ER-positive breast cancer really have a tremendous impact.

The second thing is it’s been remarkable to see the progress in the past decade. We’ve gone from simply targeting the hormonal access itself with medicines like tamoxifen or aromatase inhibitors or an injectable selective estrogen receptor degrader like fulvestrant to incorporating targeted therapies at the same time. And this whole class of drugs called CDK4/6 inhibitors has emerged which we use in either first- or in second-line therapy. Those drugs have transformed our standard of care, improved survival for patients with advanced ER-positive disease, now with median survival nearly 50% longer than what we had seen in the past. And if you’ve heard, we have a wealth of opportunities. We can target PIK3CA, we can target ESR1 mutations. Other drugs emerging in the space include PROTACs which is another way of degrading the estrogen receptor. And so there’s going to be more progress in the years to come.

So one of the biggest challenges has been to try and understand, is there really an optimal way to use these drugs, or can we be smarter about the particular sequence of all these particular things that are happening. So one example of this was a recent study that is on a drug, not as yet FDA-approved, called inavolisib, which is a PIK3CA targeted drug used in first line in combination with a CDK4/6 inhibitor and endocrine therapy. And that study, for a high-risk group of women with ER-positive metastatic disease, actually showed a dramatic improvement in overall survival, asking the question if combining some of these targeted therapies together might yet further improve outcomes.

And as you’ve heard from the diagnostic space, one of the other interesting things is that tumors evolve over time. And so acquisition of the estrogen receptor mutations, ESR1 mutations, which are typically not found early in the course of advanced breast cancer but otherwise later, now have targeted treatments. So there’s a whole bunch of stuff going on all at the same time, including multiple ways of targeting things, serial testing to look for acquisition of ESR1 mutations and new pathways to explore. It’s an embarrassment of riches in some respects because it has meant it’s actually really hard to write a guideline as you’ve heard, which says, “Do this first, do this second, and do this third.” I suppose that’s a good problem to have under the circumstances, but it’s going to require really thoughtful clinical trials and careful analysis to help guide specific lines of treatment recommendations like that.

Brittany Harvey: Excellent. We’ll look forward to these exciting, continuing developments for patients with metastatic breast cancer. And I want to thank you all so much for your work to develop this rapid recommendation update for these two guidelines. And thank you for taking the time on this podcast today.

Dr. Harold Burstein: Thanks.

Dr. Lynn Henry: Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Natash Leighl and Dr. Jyoti Patel are back on the podcast to discuss the update to the living guideline on stage IV NSCLC with driver alterations. This guideline includes recommendations for first-, second-, and subsequent-line therapy for patients with driver alterations including: EGFR, ALK, ROS1, BRAFV600E, MET exon skipping mutation, RET rearrangement, NTRK rearrangement, HER2, and KRAS G12C. They highlight the key changes to the recommendations, addition of recent trials, the importance of biomarker testing, and the impact of this guideline for clinicians and patients living with advanced NSCLC. Stay tuned for future updates to this continuously updated guideline. Read the full update, “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3” at www.asco.org/living-guidelines.

TRANSCRIPT

My name is Brittany Harvey, and today I am interviewing Dr. Jyoti Patel and Dr. Natasha Leighl, co-chairs on “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3.” Thank you for being here, Dr. Patel and Dr. Leighl.

And before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel and Dr. Leighl, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So, to start us off on this living clinical practice guideline, Dr. Leighl, this guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being routinely updated. What new data was reviewed in this full update to the living guideline?

Dr. Natasha Leighl: Thanks so much, Brittany. So, we looked through the literature for publications between February and the end of October 2023, and also any novel agents that were approved, in particular by the United States FDA, to really incorporate this update in the current guidelines. In particular, we had updates in EGFR-driven tumors, BRAF and RET-driven tumors. And we also worked very hard to make this more digestible. In particular, it was turning into a bit of a laundry list of all of the things that we had ever recommended. So we really wanted to shorten things, pare them down, and really make them helpful and very, very current for the treatment of people with lung cancer in 2023 and 2024.

Brittany Harvey: Excellent. Thank you for providing that overview of the evidence reviewed and the key updates that we will address in this guideline. So then I would like to talk about some of those key updated recommendations from the expert panel. You mentioned both EGFR, BRAF, and RET. So starting with patients with stage IV non-small cell lung cancer with EGFR alterations, Dr. Leighl, what are the key changes to those recommendations?

Dr. Natasha Leighl: So, as I said, we really started to get quite a long list of things we recommended, including drugs that, to be honest, we no longer think are what we should lead with first-line. So we updated the recommendation to recommend first-line osimertinib in patients with sensitizing mutations. We were also able to capture in this update for patients with EGFR exon 20 insertion mutant lung cancer, the data from the randomized PAPILLON trial, recommending amivantamab plus chemotherapy for progression-free survival benefit. Not yet an overall survival benefit, but we will see how these data mature.

The other thing that we did was we moved all of the- I don't want to call them "legacy agents" because, in many countries, these are still very important. But older agents such as gefitinib, approaches such as gefitinib plus chemotherapy, and drugs like dacomitinib and other agents where we truly believe as an international panel that we would prefer a third-generation kinase inhibitor like osimertinib. We moved all of those to our discussion, just to recognize that, around the world, not everybody may have access. And we also specified that things are different in different countries. So, for example, in China, there are other third-generation kinase inhibitors with randomized data to support their use. And those are approved and used in China. And also, for example, in Korea, there are other agents that are used. So, we have really tried to be both inclusive and yet keep things simple at the same time. And hopefully, we have succeeded.

One of the challenges was that, with all of the updates that we made, we did not have all of the publications out yet at the end of October to make recommendations about moving beyond osimertinib in the first-line setting. So, please stay tuned for the next guideline update, where we’re going to tackle whether we should give osimertinib alone or combination therapy.

Brittany Harvey: Excellent. Thank you for providing those updates and clarifications for those patients with non-small cell lung cancer and an EGFR alteration. And we will look forward to the guideline panel's review of that evidence and future updates as well.

So then, Dr. Leighl, you had previously mentioned that additional recommendations were updated, such as those for patients with BRAF alterations and RET alterations. So, Dr. Patel, what are the other key updated recommendations from the expert panel?

Dr. Jyoti Patel: Thanks so much, Brittany. So certainly, I think we have seen many of these trials mature over time, which has been fantastic. I think one remarkable achievement was the reporting of a phase III selpercatinib trial. This was a trial in the front-line setting, in which patients who were RET-positive were randomized to selpercatinib versus carboplatin-based chemotherapy. And the selpercatinib significantly outperformed platinum-based chemotherapy, and I think really demonstrated a significant improvement in progression-free survival. So, based on that phase III trial, the recommendation for selpercatinib was elevated. Many of these agents that are used in clinical practice are approved initially on smaller phase I or phase II trials. And so, seeing the maturity of these phase III trials gives clinicians and patients greater certainty that these agents are really effective. And so, the evidence was increased for that, and that's now a preferred agent over another TKI, pralsetinib, in which there is only phase II data. So, certainly, those kinds of real things that we can explain to patients are important in these guidelines.

Another thing that we were able to update was another doublet for BRAF V600E non-small cell lung cancer. So, the combination of the two TKIs, encorafenib and binimetinib, was also included in the guidelines.

One thing that we tried to help was really identifying the best therapy post-progression on these first-generation TKIs. And again, there is a paucity of data, but often we went back to carboplatin-based doublets, and there is some data regarding whether or not patients with driver alterations should get immunotherapy in the second-line setting. And so, certainly, I think we have a number of randomized studies for patients with classical EGFR mutations, and our recommendation is generally avoidance of immunotherapy for these patients and treating many of these patients with carboplatin and pemetrexed when appropriate. I do not think we have the data for a lot of other subsets of patients. So, again, stay tuned as these data evolve.

Brittany Harvey: Thank you for reviewing those updated recommendations and the supporting evidence. I think it's helpful for our listeners to understand the level of evidence behind these recommendations as well.

So then, Dr. Leighl, what should clinicians know as they implement these new and updated recommendations?

Dr. Natasha Leighl: It's really important, first of all, to make sure that you have the information that you need to get your patients to these great new treatments as part of the shared decision-making process. So your patients need biomarker testing. You need to get that as quickly as you can. As Dr. Patel has highlighted, you really want to get that before they start their first-line therapy, if at all possible. We also really tried to bring out in this guideline that when things are delayed, I mean, this is the real world that we live in, just to be very cautious of immunotherapy with chemotherapy for that first cycle. That obviously, again, is a discussion with your patient, but this concept that the approach of a cycle of chemotherapy while you wait for the next-generation sequencing testing. And then if the patient does not have a driver alteration, adding any other therapy as appropriate is okay. It's something that people do. We believe it's important as we talk about the balance between benefits and harms. And so I think that's in there for clinicians, and I hope that they and patients can really benefit from that to avoid toxicity and also to really improve the ability to get molecular testing results first line.

Also, I think it's really important that when people read the wording of the guidelines, that this really follows GRADE, which is a type of system that we use to develop our recommendations. And so things like "may" do not mean that you shouldn't do it. So sometimes we'll hear back from clinicians and say, "Well, you said that they may use alectinib or lorlatinib, for example, with ALK, and I can only get coverage for one or the other." And so I think it's really important that clinicians and patients recognize that all of the things that we do recommend, even if we do use the word "may" or the recommendation is more conditional, we do think that these agents should be available for patients and clinicians, and that they go through this shared decision-making process together.

And so I think that's something that clinicians, we hope, can help take forward as they advocate for their patients to get access to these different and new and emerging treatments that have clearly shown benefit. Even when we say patients and clinicians may use this or that, there may be excellent reasons for using something newer, that’s emerged, perhaps for toxicity benefits or benefits in terms of efficacy, even though we can't compare directly. And so we really want clinicians and patients to be empowered to access these new compounds and these new exciting agents that are in our guidelines.

Brittany Harvey: Absolutely. Thank you for reviewing those key points. And, yes, that's a great comment that the level of obligation in the recommendations may be based on the evidence quality, but that doesn't mean that clinicians and patients shouldn't have access to all of the recommended treatment options to offer patients based off their individual patient and clinical characteristics.

So then, Dr. Patel, in your view, how will these changes affect patients with non-small cell lung cancer, with driver alterations?

Dr. Jyoti Patel: A lot of this echoes the points made by Dr. Leighl. I think there are opportunities for patients to assess toxicity or what it means for intensification of therapy. So, particularly for EGFR patients, for example, we have data that chemotherapy with osimertinib can improve progression-free survival, or the incorporation of a bispecific antibody, amivantamab, can improve progression-free survival over the TKI alone. It certainly comes with increased toxicity. And so how we weigh this in the absence of a known survival benefit at this juncture is one that, again, really gives patients the opportunity to prioritize what's important for them. And so I think this guideline affects patients and that we have multiple options, we help with the weight of the evidence so they may be able to better discern what treatment makes sense for them.

Brittany Harvey: Understood. Yes, this guideline provides lots of options for different patients based off their driver alterations. So it's helpful to have that information for shared decision-making with their clinicians.

So then finally, to wrap us up, Dr. Leighl, what current research is the living guideline expert panel monitoring for updates to the guideline recommendations?

Dr. Natasha Leighl: This process of the living guidelines has really been to help us stay on top of the amazing and incredibly rapid progress that we're making in lung cancer and other cancers. And even with this process, where we're trying to stay up-to-the-minute, there have already been some changes in the literature between the start of November and now. And so we're already working on some additional commentary and options for the first-line treatment of patients with EGFR-mutant lung cancer. Also, the subsequent treatment of patients with EGFR-mutant lung cancer, depending on what they've had before. Also, a great new study in patients with ROS1 fusion-driven lung cancer. And so these are some of the things that we're looking at.

Also, a bit more discussion about the importance of molecular testing. In our companion article, the Journal of Oncology Practice, along with Dr. Patel, we're going to be talking a bit more about new ways to genotype, for example, using both liquid biopsy and tumor tissue at the same time, and some of the support for that and how it gets us with our patients to the answers that they need faster.

Brittany Harvey: Absolutely. The pace of research in non-small cell lung cancer has moved quite quickly. So we definitely appreciate the panel's efforts to review all of this evidence on a continuous basis and take the time to develop these guideline recommendations for both clinicians and patients with non-small cell lung cancer.

So I want to thank you so much for your work to update these guidelines, and thank you for your time today, Dr. Patel and Dr. Leighl.

Dr. Natasha Leighl: Thanks so much. It's a real pleasure to be here.

Dr. Jyoti Patel: Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Jyoti Patel and Dr. Natasha Leighl discuss the latest full update to the stage IV NSCLC without driver alterations living guideline. This guideline addresses first-, second-, and subsequent-line therapy for patients according to their histology (squamous cell and nonsquamous cell carcinomas) and PD-L1 expression. They discuss the streamlined recommendations, incorporation of recent evidence, and the highlights for implementation of these recommendations in the treatment of advanced non-small lung cancer. Dr. Patel and Dr. Leighl also point out ongoing trials that will inform this continuously updated guideline as we look ahead. Read the full update, “Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.3” at www.asco.org/living-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all of our shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Jyoti Patel and Dr. Natasha Leighl, co-chairs on “Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.3.” Thank you for being here, Dr. Patel and Dr. Leighl.

Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel and Dr. Leighl, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So, to start us off on the content of this episode, Dr. Patel, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is being updated on a regular basis. Could you provide some background information on the process for these living guidelines?

Dr. Jyoti Patel: The ASCO Living Guideline offers continually updated recommendations based on review of systemic randomized controlled trials. We bring a panel of experts together that includes representatives from Ontario Health as well as ASCO patient representatives. We review phase III studies and other published studies between the times from July 2022 and October 2023 for this most updated guideline. We think about the size of the populations that are being tested, what kind of interventions we have, the outcomes. We certainly look at PFS, as well as OS, but also toxicity, and overall response rates. We prioritize randomized trials and really look for studies that have large sample sizes. We exclude studies that were only meeting abstracts and really look at those that are published in peer-reviewed journals.

When we weigh the evidence, we really think about a number of factors. So what is the strength of the evidence, what’s the sample size, and how we can make recommendations for our patients based on the totality of the data. Certainly, because this is such a rapidly evolving field, one of the things we are looking at is how to update in real-time these guidelines. So for this coming year, for example, these guidelines are published and we look forward to quarterly updates and, again, incorporate the latest evidence.

Brittany Harvey: Great. Thank you for that explanation on the background and how these living guidelines are developed.

So, Dr. Leighl, could you describe what the key changes are from the expert panel?

Dr. Natasha Leighl: So what we try to do in the guidelines for this latest publication, was really try and streamline the way we set up a format to make it much easier for people to use. In terms of new recommendations, we made sure to include more recent studies of additional PD-1 or PD-L1 inhibitors, for example, cemiplimab in combination with chemotherapy, or the combination of durvalumab and tremelimumab with chemotherapy, both of these in unselected patients, so with any PD-L1 expression, of course, this continues with pembrolizumab with or without chemotherapy, atezolizumab with chemotherapy combinations, and, of course, nivolumab and ipilimumab with and without chemotherapy. And so it really is just an update on all of the potential options. In the discussion, we’ve really tried to go through some of the nuances in the trials just to help when you’re discussing with patients or discussing with your oncologists, how to figure out which of these is best for you.

Brittany Harvey: Excellent. It's helpful to have all of the recommendations listed out together so that clinicians and patients know all of the available options available to them.

So then, Dr. Patel, what should clinicians know as they implement these changes into their clinical practice?

Dr. Jyoti Patel: I think it's important to stress that our decision-making in the treatment of advanced non-small cell lung cancer is really reliant on adequate biomarker testing. And so the way we approach this is our assumption that all appropriate patients undergo molecular testing and have PD-L1 testing to help us get the best therapies. And the other assumption is that patients and physicians are engaging in a dialogue to better assess patient preferences to have a better understanding of performance status, for example, as we think about allocating therapy. One thing that we’ve been able to do is to take the evidence and break it up by histology as well as PD-L1 expression for patients who don’t have driver alterations. Based upon that, think about the toxicity data with, for example, dual immunotherapy versus chemo-immunotherapy for subsets of patients, and so hopefully get some guidance to clinicians as they are going through this process.

The other part of the guideline was to, once again, look at second-line and subsequent therapies. So, again, for patients who get immunotherapy alone, the recommendation is that patients get a carboplatin-based doublet in the second-line setting. We still do not know if patients should get immunotherapy after that initial exposure, that is the subject of ongoing randomized studies. We also have stronger evidence than ever that docetaxel is an appropriate second-line agent, but there are other options there, so docetaxel and ramucirumab, as well as other single-agent chemotherapies.

Brittany Harvey: Understood. Those are key points for informed and shared decision-making and are helpful for clinicians to know.

So then, Dr. Leighl, in your view, how will these guideline recommendations impact patients with non-small cell lung cancer without driver alterations?

Dr. Natasha Leighl: Thanks. So, we’re really hoping that with all of the focus in the first-line setting, that more patients will receive immunotherapy with or without chemotherapy in the first-line setting to really bring it forward and really make sure that patients can start benefiting as soon as possible. As Dr. Patel said, one of the challenges, of course, is to understand who might benefit most with a chemotherapy-free approach and have treatments in sequence versus who really needs everything together. And so, we’ve really tried in the discussion to try and help with that discussion both from a provider and patient perspective. So, we want more people to get immunotherapy to help improve their outcomes and also to potentially get it earlier.

I think the other thing, and Dr. Patel has brought this up, but when we looked at what happens after first-line therapy, we really have very limited recommendations. And so it’s our real hope that this will spur the community on to do even more studies to help us figure out what’s next and how do we really improve outcomes for our patients after all of these great first-line options have stopped working.

Brittany Harvey: Absolutely. I appreciate you touching on those key points for improved outcomes for patients with non-small cell lung cancer.

Finally, Dr. Patel, you have mentioned some ongoing randomized clinical trials and so has Dr. Leighl. So, what are the ongoing developments that the living guideline expert panel is monitoring for future updates?

Dr. Jyoti Patel: We will continue to update guidelines based on available literature, but certainly, there are a number of trials that we should be reading out in the next year or so, looking at combinations of immunotherapy in the second-line setting. Certainly comparing novel agents to docetaxel in the second-line settings, and things like antibody-drug conjugates. So certaintly that’s evidence that we hope to incorporate this evidence within the guideline with the idea that we can really help clinicians and patients recognize or at least identify the best options for treatment for them.

Brittany Harvey: Definitely. Well, we’ll look forward to the expert panel's review and interpretation of this evidence as those trials read out. And appreciate all of your work on this guideline update and we’ll hear more as these guidelines are continuously updated. Thank you so much for your time today, Dr. Patel and Dr. Leighl.

Dr. Jyoti Patel: Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Banu Arun and Dr. Sana Al Sukhun share recommendations from the newest ASCO resource-stratified guideline on systemic treatment for patients with metastatic breast cancer. They describe the importance of this new guideline, the four-tier resource setting approach, key recommendations, and implementation considerations. Recommendations are discussed for systemic therapy for HER2-positive, triple-negative, and hormone receptor-positive metastatic breast cancer, across Basic, Limited, and Enhanced resource settings. Drs. Arun and Al Sukhun highlight the importance of this guideline for clinicians and patients in regions with limited resources to optimize cancer care.

Read the full guideline “Systemic Treatment of Patients with Metastatic Breast Cancer: ASCO Resource-Stratified Guideline” at www.asco.org/resource-stratified-guidelines."

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/resource-stratified-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the JCO Global Oncology, https://ascopubs.org/doi/10.1200/GO.23.00285

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Banu Arun from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Sana Al Sukhun from Al Hayat Oncology Practice in Amman, Jordan, co-chairs on “Systemic Treatment of Patients with Metastatic Breast Cancer: ASCO Resource-Stratified Guideline.”

Thank you for being here, Dr. Arun and Dr. Al Sukhun.

Dr. Banu Arun: Thank you for having us.

Dr. Sana Al Sukhun: Thank you. Pleasure to join you.

Brittany Harvey: And before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including the guests who have joined us today on this episode, are available online with the publication of the guideline in the JCO Global Oncology, which is linked in the show notes.

Then, to jump into the content of this guideline, Dr. Al Sukhun, can you first provide an overview of the scope and the purpose of this guideline?

Dr. Sana Al Sukhun: Sure. And again, thank you, Brittany. Pleasure to join you. This guideline is really interesting and very important. It addresses the care and treatment of the most common cancer worldwide, particularly metastatic breast cancer, taking into consideration different availability of resources, particularly in countries with limited resources. As you know, most of us are aware of the importance of clinical practice guidelines improving outcomes for patients in medicine, not only in oncology, but most of those guidelines are developed in countries that are highly resourced. So their applicability in countries of limited resources that lack infrastructure and resources is definitely limited because they cannot really adopt and adapt to those guidelines, which makes resource adapted or resource stratified guidelines quite important and helpful. First, to clinicians caring for patients so that they can properly allocate resources, prioritize how to use therapy for patients, but also even policymakers to allocate resources and plan graduated implementation of science to improve outcomes for their patients according to the progressive availability of resources.

So we're talking about breast cancer, the most common cancer worldwide. And not only is it the most common cancer worldwide, but also more than two-thirds of new cases are diagnosed in countries of limited resources. Unfortunately, they also carry the burden of more than 70% of the mortality attributed to breast cancer. Another challenge is that the median age for the patients affected with breast cancer in countries of limited resources is indeed at least a decade younger than Western societies, which adds to the burden, not only the social, but also the economic burden of cancer. And unfortunately, presentation in these countries is mostly locally advanced, metastatic breast cancer, therefore comes the focus on helping our colleagues in countries of limited resources to care for patients according to the resources available, not only in countries of limited resources, even colleagues practicing in less fortunate areas within countries that are highly resourced.

Brittany Harvey: Excellent. Thank you for providing that background information for this guideline.

So then you've just described how many countries and areas have different resources. So, Dr. Arun, could you describe the four-tier resource setting approach that this expert panel used?

Dr. Banu Arun: Yeah, Brittany, that's a good question. I think it's important to know where we started and what infrastructure we used. So for developing resource stratified guidelines, ASCO has adopted its framework from the four-tier resource setting approach, which was actually developed by the Breast Health Global Initiative, and we employed modifications to that framework based on the disease control priorities. What this framework emphasizes is also that variations can be present not only between countries, but actually within countries with disparities, for example, differences between rural and urban areas within one country.

So the four settings are obviously basic, limited, enhanced, and maximal settings. The basic setting includes core resources or fundamental services that are really absolutely necessary for any public health, primary health care system to function at all. These include services that are typically applied in a single clinical interaction. For example, vaccination is feasible for highest need populations.

The next tier would be the limited setting. That includes countries or settings with second-tier resources or services that are intended to produce major improvements in outcomes, such as incidences and cost effectiveness. Unlike the basic setting, it can involve single or multiple interactions with providers or healthcare services.

Then the third tier is the enhanced setting, where the services are optional but important, and these services should ideally produce further improvements in outcome and increase the number of quality of options and also individual choices, maybe countries having the ability to track patients and links to registries.

And then the last one is of course, the maximal setting that includes high-level, state-of-art resources and services that are available in some high-resource countries.

Brittany Harvey: Thank you for describing that framework and the approach that the panel used.

So then I'd like to move on and talk about the key high-level recommendations of this guideline for systemic therapy for metastatic breast cancer across those three lower tiered resource settings - the basic, limited, and enhanced resource settings. So, Dr. Al Sukhun, could you start with the recommendations across these settings focusing on HER2-positive breast cancer?

Dr. Sana Al Sukhun: Sure. You know, HER2-positive metastatic breast cancer is one of the most aggressive subtypes of breast cancer. However, its outcome has been transformed with the introduction of HER2-targeted therapy. So, apart from patients who suffer from congestive heart failure or limited compromised ejection fraction, which can be evaluated on a case-by-case basis, patients are candidates for HER2 targeted therapy. When we made the recommendations according to the availability of resources, we started in a gradual approach. So, in a maximal setting, you treat patients with HER2-positive metastatic breast cancer in the frontline setting using the combination of trastuzumab, pertuzumab, and taxanes or endocrine therapy if patients have limited disease burden, or if they have the recurrence after a long disease-free interval. Usually, the combination of trastuzumab and pertuzumab with taxane is used. But then again, clinicians can use navelbine, considering good data from the HERNATA trial about its efficacy as compared to taxanes and even also, we recommended platinum therapy according to availability.

However, if pertuzumab is not available, you go to the next level where we recommend offering, again, chemotherapy, be it taxane, navelbine, platinum, with trastuzumab, or even without trastuzumab if trastuzumab is not available. So, something to keep in mind, chemotherapy is not without efficacy in this aggressive subtype. It is not as good as when you use the combination with HER2-targeted therapy, but it still works. Patients and clinicians in this era of biologic therapy immunotherapy tend to think only pricey medications are the ones that can be used for treatment and improving outcome. However, definitely adding help with targeted therapy is great whenever it's available. But if it's not available, chemotherapy still could be used in a sequential manner. We listed all possible chemotherapeutic options starting with taxanes, navelbine, platinums, even CMF, capecitabine.

When it comes to second-line therapy, including those patients who relapse within 12 months of adjuvant therapy, the optimal line of treatment would be trastuzumab deruxtecan. However, if it's not available, we recommend to be offered with successive or progressive preference, if it's not available, T-DM1 could be used. If it's not available, capecitabine and lapatinib could be used. If it's not available, trastuzumab with chemotherapy could be used. If it's not available, we go back to the sequential use of chemotherapy, including adriamycin, taxanes, platinums, capecitabine, or even CMF.

Brittany Harvey: I appreciate you reviewing those recommendations for HER2-positive breast cancer.

So then, moving along, Dr. Arun, what are the recommendations for patients with metastatic triple-negative breast cancer?

Dr. Banu Arun: Thank you, Brittany. Triple-negative breast cancer, of course, is one of the serious subgroups of breast cancer. About 10 to 15% of patients have triple-negative breast cancer. What I will do is I will divide it into the three-tier settings as well as first-, second-, and third-line therapies.

For patients with triple-negative PD-L-negative metastatic breast cancer in the limited settings and even enhanced settings, single-agent chemotherapy rather than combination chemotherapy should be recommended as the first-line. However, if patients are symptomatic or have immediate life-threatening disease, combination chemotherapy can be offered.

For patients with triple-negative breast cancer that are PD-L1 positive, they may be offered in addition to chemotherapy, an immune checkpoint inhibitor, as first-line therapy, most probably in enhanced settings and in basic and limited, of course, chemotherapy. When you move on to the second-line for metastatic breast cancer in patients with or without previous PD-L1 checkpoint inhibitors, clinicians can offer palliative or best supportive care in the basic setting. In the limited setting, chemotherapy with anthracyclines, taxanes, platinums are options. And in the enhanced setting if sacituzumab govitecan is not available, chemotherapy would be an option.

Now, when we move on to the third-line setting for triple-negative breast cancer, clinicians can actually offer chemotherapy and/or palliative care, depending really on the status of the patient.

Brittany Harvey: Excellent. Thank you for providing those recommendations for triple-negative breast cancer. As you mentioned, it's one of the rarer forms of breast cancer. So then, Dr. Al Sukhun, I'd like to move into the last section of patients, actually the most common, but hormone receptor-positive breast cancer. What are those recommendations?

Dr. Sana Al Sukhun: Thank you, Brittany. As you mentioned, it's the most common subtype worldwide. The rule of the thumb is sequential hormonal therapy, depending on availability. So, whatever you have hormonal therapy, sequential hormonal therapy unless pending visceral crisis or symptomatic disease, it's recommended that you offer sequential single-agent chemotherapy, unless it's a real visceral crisis, where we recommend combination chemotherapy. That's a classic in all our guidelines.

When considering frontline hormonal therapy, again, I will start from the maximal level and gradually recommend according to availability. So in enhanced levels in many countries now, we have generic CDK4/6 inhibitors, which increase their availability. So we do recommend hormonal therapy with CDK4/6 inhibitors. Upon progression or when they are not available, on progression, you move to the second line of hormonal therapy. If you have liquid biopsy, check for PIK3CA mutation. Sometimes you do have the liquid biopsy, but you do not have alpelisib to offer to your patients with hormonal therapy, then it's okay, you still can move to second-line fulvestrant with everolimus. Sequentially, you can move forward to fulvestrant by itself if you do not have everolimus. And even you can sequence tamoxifen until your patient stops responding to hormonal therapy then you can offer sequential single-agent chemotherapy.

Brittany Harvey: Thank you, Dr. Al Sukhun for providing those recommendations.

So then, Dr. Arun, what should clinicians do when we do not have access to receptor assessment? What is recommended for best practices for management of those patients?

Dr. Banu Arun: So, Brittany, that's an important question. There are some basic settings where unfortunately, immunohistochemistry for ER/PR HER2neu determination is not available. Our group really recommends in these cases that clinicians may presume hormonal receptor positivity and offer tamoxifen in most cases. It is expected that IHC would be available in limited and, of course, enhanced settings.

Brittany Harvey: Great. Thank you for providing that information.

So further, what else should clinicians know as they implement these recommendations, Dr. Arun?

Dr. Banu Arun: It's very important that we, all healthcare provider clinicians, really know the data. I think reading the guidelines or knowing about first and second line therapies is obviously important, but the devil is in the details. And I think knowing the publications and subgroup analyses, if needed, because every patient is different and sometimes the recommendations cannot go by the books. You really need to do an assessment of the patient and see in which setting you are and then make the most of the guidelines that are recommended. It's to guide. The name is guidelines. It's to guide. And ultimately, it's the clinician's responsibility to find the best available therapy for the patient. And sometimes that includes no treatment and supportive care.

Dr. Sana Al Sukhun: Totally agree with Dr. Arun. They are there to support the clinician decision. After all, the clinician is the one who sees the patient, who can evaluate the patient from all aspects — social aspect, physical aspect, the tumor aspect. So it's not just about the tumor, it's about the patient and the environment where the clinician is treating the patient. However, I believe there is support to the clinician not only in treating the patient, but also on addressing priorities for research to improve outcomes for patients in different resource settings. There is also support for the clinicians to help them advocate for improving care for patients in a strategic way, where they prioritize resource allocation. So they are there to support the clinician at all levels, not only when treating patients, but when advocating for patients, when helping patients to make decisions, when they're discussing with their health officials and policymakers.

Brittany Harvey: Absolutely. Those are excellent points that you both made about individualizing patient care for the specific person in front of you. So then, finally, Dr. Al Sukhun, how will these guideline recommendations impact patients with metastatic breast cancer globally?

Dr. Sana Al Sukhun: The ultimate goal for anything we do, including guidelines, is to improve outcomes for patients worldwide. They are there to support clinician decisions, empower clinicians to optimize care for their patients, to advocate for improving outcomes for patients by strategically allocating resources according to the most impactful strategy. They help clinicians to identify areas for research that are needed according to the resources available to them. They are there to guide policymakers, again, also implementing strategies to implement science that could improve outcomes in an efficient way for their societies. So hopefully, all these, with our research, with our advocacy, with our health policy, with our treatment decisions, hopefully all these will improve outcomes for breast cancer patients and ultimately reduce mortality, particularly in less fortunate, limited resource settings for patients everywhere.

Brittany Harvey: Absolutely. We hope that these guidelines improve outcomes and quality of life for patients worldwide.

So I want to thank you both so much for your work to develop this guideline. There's certainly a large amount of recommendations, so I encourage our listeners to read the full guideline, which is linked in the show notes. And I want to thank you so much for your time today, Dr. Al Sukhun and Dr. Arun.

Dr. Sana Al Sukhun: Thank you for having us.

Dr. Banu Arun: Thank you, Brittany.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/resource-stratified-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Isabelle Bedrosian and Dr. Mark Robson discuss the new guideline from ASCO and SSO on germline testing in patients with breast cancer. They discuss the framework for which patients should be offered BRCA1/2 testing, and what additional moderate- and high-penetrance genes may be considered for inclusion in germline testing. They highlight key aspects of personal and family history, recommendations surrounding counseling for genetic testing, and the impact for patients and their families. They close the conversation with a discussion of gaps in the research. Read the full guideline, Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02225

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Isabelle Bedrosian from the University of Texas MD Anderson and Dr. Mark Robson from Memorial Sloan Kettering Cancer Center, co-chairs on “Germline Testing in Patients with Breast Cancer: American Society of Clinical Oncology – Society of Surgical Oncology Guideline.”

Thank you for being here, Dr. Bedrosian and Dr. Robson.

Dr. Mark Robson: My pleasure.

Dr. Isabelle Bedrosian: Thank you, Brittany.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bedrosian and Dr. Robson, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to jump into the content of this particular guideline, Dr. Bedrosian, could you give us a general overview of both the scope and the purpose of this guideline?

Dr. Isabelle Bedrosian: Yeah, sure. So, in the last decade or so, the whole area of clinical cancer genetics has become incredibly complicated, driven, I think, predominantly by the development of extended gene testing. And in the midst of this complexity, our goal here was to try to give providers a framework through which they can think about the application of germline testing within their patient population. And really, this framework was to help them think through how testing can best be applied to patients that were both newly diagnosed with breast cancer or had a history of breast cancer, and also to help them think through the scope of that testing as well, be it BRCA testing or testing in a more extended fashion that may help inform longer-term decisions such as risk management.

Brittany Harvey: Absolutely. We appreciate your efforts to provide recommendations in this framework in this complicated space.

So then, I'd like to review the key recommendations of this guideline developed by the expert panel. So first, Dr. Robson, who should be offered BRCA1/2 testing?

Dr. Mark Robson: Thank you. I think this is perhaps one of the most important things that comes out of the guideline is that we, and the group, are now recommending that anyone who is either newly diagnosed with breast cancer at or before the age of 65, or if they're over 65 and have suggestive personal or family history criteria, or alternatively, if they are eligible for PARP inhibitor therapy, that they all be offered BRCA1 or BRCA2 testing. And the same would hold for women who had a personal history of breast cancer but were not currently under active treatment if their diagnosis had been made at or before 65 or older than that, with certain criteria then they should be offered testing. This is a much simpler way to look at things than the rather complicated existing criteria, which are perhaps a bit both difficult to remember and unfortunately inadequately sensitive in a setting where there is such critical, both therapeutic and risk management implications to the identification of a BRCA mutation.

Dr. Isabelle Bedrosian: Yeah, I would just also add there's one other, albeit a much smaller group of women for whom BRCA testing could be considered, and those are women who develop a second primary breast cancer. That's another group that I think we can think about offering BRCA1/2 testing to.

Brittany Harvey: Understood. I appreciate you both reviewing those recommendations for BRCA1/2 testing.

So, Dr. Bedrosian, which additional genes does the panel recommend including in germline testing?

Dr. Isabelle Bedrosian: Yeah. So, in this area, outside of BRCA genes, Brittany, I think the panel didn't make any definitive recommendations or any specific genes that should be tested for. I think the panel felt that the decision to test for additional high penetrance genes and also for some moderate penetrance genes should be guided by the specifics of the individual case, whether the identification of germline mutations makes sense in the context of the patient's personal history and family history. So, in other words, is there a worrisome pattern in the family that might warrant more in-depth testing beyond BRCA, and also considerations around the implications of those test results. Would it change the management for the patient themselves? Either in the treatment of the index malignancy, which, in the case of most of these non-BRCA genes, there really is not changes to the management of the breast cancer that would be offered based on the finding of non-BRCA germline mutations. But potentially, the finding of a non-BRCA germline mutation in a breast cancer patient might help better understand risks of second malignancies that would then be addressed. And certainly for families as well of the patients, identifying those that are carriers could offer opportunities for risk assessment, risk mitigation.

Dr. Mark Robson: I totally agree with Dr. Bedrosian. One thing I think it's important to understand is that most commercial testing done in the United States now does involve panels of genes. And the group certainly did not intend to suggest that that practice not continue. So, I think if somebody has a history of breast cancer, I think the panel felt that it would at least be reasonable to test for breast cancer susceptibility genes. However, this issue of do you test for all of the high penetrance genes when the family history doesn't suggest it, was certainly something we left open and we did not want to imply that it was obligatory to test for a large number or large panel of genes that weren't related to the patient's personal and family history. So, in other words, didn't want to imply that it was obligatory to do an extremely large panel just as a target of opportunity, if you will.

Dr. Isabelle Bedrosian: I think really a key part of these guidelines was that we wanted to afford the oncologist flexibility. It's very difficult beyond BRCA to be prescriptive. There are so many considerations about testing, and those considerations will be applied differently in every patient context. So, we really wanted to let providers know that while they have to think about these other genes, and oftentimes there'll be good reason to do these other genes as part of the overall germline testing, again, that it's not obligatory to do so. It's not a fixed set that needs to be tested for. And really, the understanding of the patient's personal history, family history, therapeutic goals, and risk assessment goals should be used to determine kind of the ultimate scope of the testing.

Brittany Harvey: It sounds like these decisions will be individualized, based on patient characteristics and with working between both patients and their clinicians. So that leads into my next question. But, Dr. Robson, how should patients with breast cancer considering genetic testing be counseled?

Dr. Mark Robson: With this recognition and emphasis on the therapeutic implications for patients with breast cancer, both surgical and potentially systemic using PARP inhibitors, the approach has gradually moved away from the concept of testing for personal utility, in other words, just wanting to know, and more towards the idea of this being a clinically useful test that's to some extent necessary for the appropriate management of a fair number of patients. And so the counseling is usually- the pre-test counseling is perhaps more educational than we have used in the past, rather than this extensive discussion of whether or not somebody wants to know. Obviously, it's always the patient's ultimate decision whether or not to be tested, and we have to give them the same elements of education that we would have given back in the day. But it can be delivered in a more didactic type of context rather than necessarily the back and forth that takes place with formal genetic counseling.

Now, for patients who have complicated or extensive family histories or who have histories that may suggest predispositions other than those for breast cancer, the type of thing that Dr. Bedrosian was talking about earlier, they could certainly benefit, again, from a more formal evaluation by a provider experienced in cancer genetics to help select what the scope of the testing should be, for instance, and also to help interpret those results. And certainly anybody who had a pathogenic variant or a likely pathogenic variant identified should be considered for meeting with somebody who's experienced in clinical cancer genetics both to interpret and also to help with family expansion when appropriate.

Brittany Harvey: Excellent. Thank you for reviewing those recommendations from the expert panel. So, Dr. Robson just touched on this a little bit, but Dr. Bedrosian, how will these guideline recommendations affect patients with breast cancer and their families?

Dr. Isabelle Bedrosian: Yeah, so from a patient perspective, I think there are two ways that these recommendations can impact care. For those women that are identified as germline carriers, specifically with BRCA, it will open the door for receipt of PARP inhibitors, which are currently recommended for patients that are high-risk primary cancer or those with metastatic disease. The other ways that patients will be affected by a germline testing is really in this idea of second cancer risks. Some of these germline mutations are well established to carry risks of either second primary breast cancer or non-breast malignancies. And understanding those risks will allow the patients and their providers to create management strategies, be they surgical or with more intensified screening that will help them mitigate the effects of that germline-driven risk.

And I think similarly for the families of patients, the ones the proband has identified, I think that family now has a very real opportunity to better understand their cancer risks and again be able to more effectively manage those risks through either surgical or non-surgical means. And it would really underscore the family component of this. I think oftentimes oncologists are very much focused on the patient and admittedly so that is the person that has the most immediate needs. But I think there's a real opportunity to extend efforts at prevention and early detection by identifying the at-risk family members and allowing them the opportunity to access care that mitigates their cancer risks and hopefully will improve survival outcomes in so doing. So, I think the opportunities for families here to understand risks of germline testing is a really important one to underscore from these recommendations.

Dr. Mark Robson: Just to expand a little bit on what Dr. Bedrosian was saying, I think this is a very important place for collaboration between the oncology community and the clinical cancer genetics providers because the oncologist is pretty occupied taking care of all of their cancer patients, and the approach to people who are unaffected is a little bit different. People who are unaffected perhaps do need a little bit more pretest counseling to understand the pros and cons of choosing to be tested for the familial mutation. And certainly that idea of family expansion is something that's well known to clinical cancer genetics providers and that's really very much something that they can help the primary oncologists do.

Brittany Harvey: Absolutely, these recommendations have impacts beyond just the individual patient, but also for their families as well.

So then, finally, Dr. Robson, what are the outstanding questions regarding germline testing in breast cancer?

Dr. Mark Robson: Oh, there are so many. Where should I start? I think over the years we've become, as a community, pretty comfortable managing individuals who have BRCA1 or BRCA2 mutations. There are certainly some questions left, but there's a lot of familiarity with that. I think the challenges expand into these what we call moderate penetrance genes and how to guide people with alterations in those genes. Because except for PALB2, which is relatively uncommon, many of the other genes don't really have the same implications for therapy because it's not clear that they confer PARP sensitivity. It's not at all clear that they have high risks of contralateral breast cancer. And even in the unaffected setting, we know that there's a wide distribution of risk for people who carry these alterations. And some individuals with these alterations probably are not at increased risk at all because they have protective factors. So the management of breast cancer susceptibility genes beyond BRCA1 and BRCA2 is still very much in evolution. They can't be handled exactly the same way as a woman with a BRCA carrier.

And then, of course, this issue of how much should we test and what do we do with some of the alterations that we find, if you will, out of context, what are the implications for that and what's the most appropriate management? Those still remain very much open questions. So I think there's still plenty of work to do.

Dr. Isabelle Bedrosian: Yeah, I agree. I think one of the enormous challenges has been the disconnect between how rapidly our technology has advanced and can sequence alterations, and our ability to really understand the biologic and clinical implications, which really is a time-dependent issue. We need to see over time how patients do for us to understand the implications of some of these germline findings. So that disconnect is a very difficult one to bridge, particularly, I think, for surgical oncologists because they are oftentimes referred patients who don't have a cancer history, necessarily, or have a distant history, and really the concern is “I'm at risk and I would like to reduce my risk.” And it becomes very difficult to counsel patients as to the benefits of risk reduction when we don't have such a great handle on the degree to which they are actually at risk. So that really is a significant gap, I think, for surgeons in particular to have to contend with.

Brittany Harvey: Definitely. We'll look forward to answering some of those questions as we learn more and get more data to address those gaps.

So I want to thank you both so much for your work to develop this framework for genetic testing in breast cancer, and thank you so much for your time today, Dr. Robson and Dr. Bedrosian.

Dr. Isabelle Bedrosian: Thank you, Brittany.

Dr. Mark Robson: Thank you for having us.

Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Rohan Garje reviews the latest rapid recommendation update for the ASCO guideline on systemic therapy in men with metastatic castration-resistant prostate cancer (mCRPC). He reviews what prompted the guideline update and the latest recommendation from the expert panel. Dr. Garje also discusses future updates to the guideline that are currently underway, and outstanding questions regarding systemic therapy for mCRPC. Read the latest update, “Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Rohan Garje from Miami Cancer Institute Baptist Health South Florida, lead author on “Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Rapid Recommendation Update.

Thank you for being here today, Dr. Garje.

Dr. Rohan Garje: Thank you so much for having me, Brittany.

Brittany Harvey: And then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Garje, who has joined us on this episode today, are available online with the publication of the update in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content of this rapid update, first, Dr. Garje, what prompted this rapid update to the guideline on Systemic Therapy for Metastatic Castration Resistant Prostate Cancer?

Dr. Rohan Garje: So, last year, when we did a rapid update on ASCO prostate cancer guidelines, we recommended the addition of 177Lutetium-PSMA-617, also called as PLUVICTO, as a treatment choice for patients who have PSMA-positive metastatic castrate-resistant prostate cancer. After that approval, the primary imaging modality at the time of this initial drug approval was based on gallium-68, which was used in that clinical trial, which was VISION. Since then, we have access to a couple of new radiotracers, one of them being piflufolastat, also called as PYLARIFY, and the newer one called flotuflastat F-18, which is also called as POSLUMA, as additional imaging agents to detect PSMA-positive lesions. So, our expert panel group, along with my co-chairs, we thought to add these additional choices for patient selection because this provides the treating physicians additional options because there really are nuances involved in these imaging agents. So this helps broaden the access to 177Lutetium-PSMA-617 for patients.

Brittany Harvey: Excellent. I appreciate you providing that background that the panel was reviewing.

So then, based on this updated information, what is the updated recommendation from the expert panel?

Dr. Rohan Garje: So, for the new recommendation, the guideline expert panel recommends use of one of these three radio tracers, that is Ga-68PSMA-11, or piflufolastat F-18, or flotufolastat F-18 as one of the radiotracer choices to screen for PSMA-positive lesions on a PSMA scan, and potentially select the patients for PSMA 177lutetium. This way, we can use one of these three agents rather than previously recommended, as per FDA approval of gallium 68. Now, the reason behind these additional agents, as I was just alluding in my initial comment, is each institution may have access to one of these agents. For example, if a patient had a testing done by piflofolastat or flotufolastat, if they are PSMA-positive, it has shown PSMA-positive lesions as per VISION criteria, we do not suggest the patients to undergo gallium-68 assisted imaging again to have selection for PSMA lutetium therapy. This is unnecessary imaging. We have evidence now, based on the studies which were done with PYLARIFY, which is the piflofolastat, or the flotufolastat, which is POSLUMA, that they are equally good in detecting PSMA-positive lesions. This way we can avoid additional imagings for patients who are being screened for lutetium therapy.

Brittany Harvey: Understood. Thank you for reviewing the expansion of this recommendation to avoid additional or unnecessary screening.

So then, Dr. Garje, the article mentions complete updates to the metastatic castration-resistant prostate cancer guideline are underway. At a high level, could you review what new evidence the panel will look at to update their evidence-based recommendations?

Dr. Rohan Garje: There have been a lot of developments in the last year, at least, in the treatment strategies for patients with metastatic castration-resistant prostate cancer. Earlier this year, we have seen three big updates about the first-line metastatic CRPC setting, where the combination of PARP inhibitors and androgen receptor pathway inhibitors were tested. For example, in the TALAPRO-2 study talazoparib and enzalutamide, and in the MAGNITUDE study, it was niraparib along with abiraterone. And in the PROpel study, the combination of olaparib and abiraterone was studied. Now, all these combinations have recently received FDA approval with specific nuances with regards to folks who have biomarker positive disease, specifically BRCA1 and BRCA2 mutations. So it is very important to refine this information so that it is utilized by practicing oncologists so that it is widely adapted in their day to day practice.

Now, in addition, we also are focusing on addressing the need for utilizing biomarkers. The biggest thing for us to offer a biomarker driven therapy is to do biomarker testing. So we are focusing on making sure patients with advanced prostate cancer get biomarker testing so that we can identify who are the patients who get selected. So this particular guideline update is addressing those needs.

And then most recently at the recent ESMO meeting, we also noted the positive data from a study called PSMAfore, which evaluated PSMA 177lutetium prior to chemotherapy. This study showed positive data based on progression free survival benefit. So we will review additional data from that and see if a guideline update can be done based on this. So it is very exciting. Now, obviously, we are also waiting on survival data on all the studies. So we are closely monitoring all the updates on these studies so that we can provide more rational guidance based on not only progression-free survival benefit in a specific cohort and also to see if it helps with overall survival improvement.

Brittany Harvey: Absolutely. We'll look forward to the panel's review of this evidence and then future updates to this full guideline.

So then, finally, Dr. Garje, you've alluded to awaiting some data. So could you expand on what are some of the outstanding questions regarding systemic therapy for metastatic castration-resistant prostate cancer?

Dr. Rohan Garje: I would put that in two boxes. Number one, sequencing. So we are excited that we have a broad spectrum of options; androgen receptor pathway inhibitors, chemotherapy options, radium-223. We have lutetium based options and then biomarker selected patients with PARP inhibitor combinations and select patients with benefit for checkpoint inhibitors. Now, the biggest question we need to answer is how to sequence them, which drug or which combination strategy is ideal for one particular patient. Now, obviously, when we do not have clinical trials which have addressed sequencing, we as an expert panel would want to come up with some mechanism of consensus to identify what treatment sequence would work best for patients. So that is an important question this guideline panel wants to address where we can give some generic information as a consensus, based on the experience of the panel to give guidance for practicing physicians the best sequencing.

Now, second thing, very equally important, is biomarkers. This particular guideline update is also focusing on making sure biomarker testing is universal. There has been a lot of evidence that biomarker testing happens very late in the course of the disease, which precludes a lot of patients from these combination strategies. So this particular guideline also is focusing on what biomarkers to be tested and at what time frame, so that they can be optimally utilized for the patient treatment so that the patients will have the best cancer outcomes.

Brittany Harvey: Definitely, those are important questions for personalized care for people with prostate cancer.

I want to thank you so much for your work on this rapid update and your ongoing work on the updates to the full guideline, Dr. Garje, and thank you for your time today.

Dr. Rohan Garje: Sure, thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Greg Kalemkerian joins us on the ASCO Guideline Podcast to discuss the newest ASCO – Ontario Health (Cancer Care Ontario) Guideline on systemic therapy for small-cell lung cancer (SCLC). He reviews the evidence-based recommendations from the panel, including guidance on systemic therapy options for resected, limited-stage, extensive-stage, and relapsed SCLC, and NSCLC with an EGFR mutation that has transformed to SCLC, recommendations for older adults with poor performance status, the role of biomarkers, and the use of myeloid supportive agents. Dr. Kalemkerian also highlights future research for systemic therapy options for SCLC, and the impact of guidelines on both clinicians and patients with SCLC. Read the full guideline, “Systemic Therapy for SCLC: ASCO-OH (CCO) Guideline” at www.asco.org/thoracic-cancer-guidelines."

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01435

My name is Brittany Harvey, and today I'm interviewing Dr. Greg Kalemkerian from the University of Michigan, co-chair on “Systemic Therapy for SCLC: American Society of Clinical Oncology – Ontario Health Guideline.” Thank you for being here, Dr. Kalemkerian.

Dr. Greg Kalemkerian: Thank you.

Brittany Harvey: Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kalemkerian, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to move into what we're here today to discuss, Dr. Kalemkerian, can you provide an overview of both the scope and the purpose of this guideline?

Dr. Greg Kalemkerian: So, the guideline is meant to update the systemic treatment for small-cell lung cancer. There have been several changes in the last couple of years. For the first time in quite a few decades, we actually have some newer drugs that have demonstrated benefits in this disease. So we're really focusing on the systemic therapy. And ASCO does endorse the ASTRO guidelines for the radiotherapy involved in patients with small-cell lung cancer.

Brittany Harvey: Great. That's great to hear that there's new systemic therapy options for patients with small-cell lung cancer.

So then I'd like to review the key recommendations of this guideline. This guideline reviews eight clinical questions in total, so we can go through the key points of the recommendations for each question. So let's start with what is recommended for adjuvant systemic therapy in patients with resected small-cell lung cancer?

Dr. Greg Kalemkerian: So, to start with, only fewer than 5% of people have what would be considered resectable small-cell lung cancer, and that's stage I small-cell lung cancer. So tumors less than 5 cm in size without any lymph node involvement, either hilar or mediastinal lymph node involvement. So purely the very early stages, which are rare in small-cell. And if patients undergo surgical resection for such tumors, the recommendation afterward is to provide adjuvant chemotherapy with four cycles of either cis-or carboplatin plus etoposide in order to try and improve longer-term survival for those patients.

The other part of the recommendation is we do recommend that treatment be started within eight weeks of surgery. There is little data on timing in small-cell lung cancer, but that's derived from extrapolating from non-small cell lung cancer as well.

Brittany Harvey: Understood. I appreciate you reviewing those recommendations for resectable small-cell lung cancer.

So then, moving along, what does the panel recommend for patients with limited-stage small-cell lung cancer?

Dr. Greg Kalemkerian: So, the treatment with limited-stage small cell lung cancer unfortunately has not changed in quite some time. We recommend that patients receive four cycles of either cisplatinum or carboplatin and etoposide concurrently with radiotherapy. Preferably the radiotherapy should be given early and concurrently with the chemotherapy, though we do not recommend that people wait for the radiation to get started in order to start the chemotherapy. So we do recommend that the chemotherapy get started as soon as possible and then the radiation can be added in on the second cycle of chemotherapy.

Brittany Harvey: Then to follow that up, what is recommended for patients with extensive stage small-cell lung cancer?

Dr. Greg Kalemkerian: So, extensive stage small-cell lung cancer now is probably the most straightforward of the portions of this. Based on the data from two trials thus far, the IMpower 133 trial and the CASPIAN trial, we now recommend chemotherapy with immunotherapy. The chemotherapy should be cisplatinor carboplatin plus etoposide along with concurrently either atezolizumab or durvalumab as the immunotherapy for four cycles of the combined chemo-immunotherapy followed by maintenance with the immunotherapy drug of choice. With regard to the choice of either cisplatin or carboplatin, meta-analysis has demonstrated that there is no significant difference between the two and our belief is that carboplatin is likely the more reasonable drug in the palliative treatment situation based on its better non-hematologic toxicities.

Brittany Harvey: Appreciate you sharing those recommendations and some of the rationale behind those.

So then moving along, what options are available for patients with relapsed small-cell lung cancer?

Dr. Greg Kalemkerian: So relapsed small-cell lung cancer gets a little more potentially complicated. One of the main drivers of outcome in patients with relapsed small cell lung cancer is the time since they completed their initial chemotherapy. Patients who have had a longer time since chemotherapy do better and have better responses to subsequent therapy. For patients who relapse with a short interval within 90 days or three months of completion of prior chemotherapy, our recommendation is that they be treated with single-agent chemotherapy. There are two drugs that are currently FDA approved for use in relapsed small cell lung cancer, topotecan and lurbinectedin, and either one of those is the preferred agent as a single-agent treatment in this scenario.

For people with a longer chemotherapy-free interval, so beyond the 90 days or three months, one could either use combination chemotherapy, so reinitiation or re-induction with the regimen such as carboplatin and etoposide, or one could use single-agent chemotherapy with the preferred agents being topotecan or lurbinectedin again. The use of combination chemotherapy has been shown to improve response rates in this situation over topotecan alone. However, we have not been able to demonstrate that there is a significant improvement in overall survival. So one has to look at the individual patient and make some judgment on whether you think that the added potential toxicity of combination chemotherapy is beneficial for that individual.

For people who have progression of disease while they are on maintenance therapy with immunotherapy for extensive stage small-cell lung cancer, we do not recommend continuation of the immunotherapy. So if people progress while they're on the immunotherapy, even if they're nine months out on that, then treatment with second-line chemotherapy, either with the combination agent or with single agents, would be what we would recommend, and not continuing the immunotherapy. If patients had previously been treated for limited-stage small-cell lung cancer where immunotherapy is not part of the initial treatment at this time, and they relapse, say, six months or nine months out from their initial chemotherapy and radiation therapy treatment, then it would be reasonable to perhaps initiate carboplatin etoposide and one of the immunotherapy agents as appropriate treatment, because that patient is immunotherapy naive.

However, the single-agent immunotherapy does not have a role in the treatment of patients with relapsed small-cell lung cancer.

Brittany Harvey: Understood. It sounds like some of the treatment options are individualized to the specific patient then.

So the next question also addresses specific groups of patients. So what did the panel recommend for older adults with small cell lung cancer or for those with poor performance status?

Dr. Greg Kalemkerian: Approximately half of people who have small-cell lung cancer are over the age of 70 years old, so it is a disease of older smokers. Many of these people have comorbidities that can limit our ability to use standard treatments. Many of these individuals also have poor performance status because the disease is an aggressive disease that causes a lot of problems for people. So the issue of older individuals and people of poor performance status is something that we run into on a regular basis in treating people with small-cell lung cancer.

For patients with limited-stage small-cell lung cancer who are older and have a performance status of 0 to 2, it is very reasonable to utilize standard treatment with standard chemo and radiotherapy with curative intent. For people with limited-stage small-cell lung cancer who have a performance status of 3 or 4, and this would include people who might be in an ICU with an obstructive airway, then it is reasonable to initiate chemotherapy in order to try and shrink the cancer down and improve their situation.

Small-cell lung cancer is a disease that is very sensitive to chemotherapy initial treatment, so many of these people will have shrinkage of tumor and improvement of their symptoms. If the poor performance status is due to the small-cell lung cancer, it has potential to get better. So we do recommend for people at limited-stage small-cell lung cancer and a poor performance status that is felt to be due to the disease, the cancer, then it is reasonable to initiate treatment with chemotherapy. And depending on the person’s response and recovery and improvement in their performance status, then one could add radiotherapy later on or do it sequentially with the definitive radiotherapy for the limited-stage small-cell lung cancer.

For older individuals with extensive stage small cell lung cancer who have a performance status of 0-2, it is very reasonable to utilize the standard chemotherapy and immunotherapy as we outlined previously in treating that. For individuals who have a poorer performance status, so performance status 3 or 4, one really needs to individualize the situation. If the poor performance status is due to the cancer, then again, it would be reasonable to attempt chemotherapy in an effort to try and shrink the cancer. There is no data on the use of chemo plus immunotherapy in this patient population. But the use of standard chemotherapy, obviously, in the older individuals preferring carboplatin over cisplatinum with etoposide would be a reasonable option, taking into account abnormalities in organ function that may require dose adjustments or reductions.

Because small-cell lung cancer is a disease that is quite sensitive and responds well to chemotherapy, then one can individualize in those situations for patients with poor performance status to see if they can improve their overall situation and have some period of time of optimized quality of life. Clearly, it is a very individualized decision-making whether or not to treat these patients. That requires clearly the patient’s input as well, as a primary driver of what is done.

Brittany Harvey: Absolutely. That nuance is helpful for patient-clinician shared decision-making, depending on the factors that you mentioned.

So then, switching to the next topic that the expert panel addressed, what does the panel recommend for patients with non-small cell lung cancer with an EGFR mutation that has then transformed to small-cell lung cancer?

Dr. Greg Kalemkerian: The EGFR mutant non-small cell lung cancer transformation to small-cell lung cancer is relatively rare. I think in the real world, this probably is occurring in 2%-3% of people with EGFR mutant non-small cell lung cancer, but we do see it. Now, these patients are initially being treated with EGFR inhibitor therapy for their mutant non-small cell lung cancer and then they develop a more aggressive progression of disease. It is important to note that when people progress in that situation, it is important to get a biopsy in order to see whether or not transformation has occurred and whether or not there are any other new driver mutations that might be targetable. If the patient has a small cell lung cancer transformation, then the recommendation is to treat them as we treat patients with small cell lung cancer with chemotherapy consisting of platinum and etoposide for four to six cycles, as we usually do.

It does not appear that there is a role for immunotherapy in this situation, though we clearly have a paucity of data on these patients. So we do not yet have any trials that have looked at the management of this population. We do have several series that have presented these individuals and what their outcomes are with treatment. And their outcomes are very similar to people with de novo small-cell lung cancer. So not a very good situation, but we do recommend that they be treated with standard chemotherapy, platinum plus etoposide.

Another question that arises is do you continue with the targeted therapy with the EGFR inhibitor. And the honest answer is we don't know. We don't have data on that. We do know from case reports, the series, and from personal experiences, that some people, in fact, I think many people, if not most of these individuals, have a mix of both EGFR mutant adenocarcinoma and small-cell lung cancer at the time that they transform. So not every tumor in their body is transforming, so that EGFR mutant tumor is still present in their body. So even though the small-cell lung cancer component, because it's progressing, is clearly not responsive to the EGFR inhibitor any longer, the adenocarcinoma component most likely is still sensitive to the EGFR inhibitor. So it is not unreasonable to continue with the EGFR-targeted therapy along with the small cell lung cancer-directed chemotherapy. Even though we don't have any strong data supporting one way or the other.

Brittany Harvey: I appreciate that guidance, even with the dearth of data in this relatively rare scenario.

So then we've talked a bit about individualized treatment, and often in that conversation, biomarkers come up. So what does the guideline say regarding the role of biomarkers for patients with small-cell lung cancer?

Dr. Greg Kalemkerian: This is pretty straightforward. Thus far, in people with de novo small-cell lung cancer - so we're not talking about the transformed patients from EGFR mutant, we're talking about people who present with small-cell lung cancer - we have no evidence that molecular diagnostic testing would help guide treatment or improve patient outcomes at this time. So we do not support obtaining molecular diagnostic testing for the routine care of patients with de novo small-cell lung cancer. I would love to talk for the next half hour about what's coming down the pipeline in small-cell lung cancer with regard to identifying subsets of patients and trying to identify the vulnerabilities within those subsets of patients that may lead to better-targeted therapy based on molecular diagnostics, but in the current environment, there is no role for molecular diagnostics.

Brittany Harvey: Understood. We'll look for that in future guideline updates instead, then.

So then the last clinical question that the guideline addressed - what myeloid supportive options may be offered for patients with small cell lung cancer?

Dr. Greg Kalemkerian: So this has to be couched initially with whether or not one thinks that myeloid suppressive agents are necessary in the treatment of patients with small-cell lung cancer. So in extensive-stage disease with the use of chemotherapy, say, carboplatin and etoposide, the majority of patients likely don't require myeloid supportive agents. However, if one believes that the patient, because of their own individual characteristics, or in a patient who has already developed myelosuppressive problems, then one could either utilize trilaciclib, which was FDA-approved a couple of years ago and was shown to improve the blood counts in people with small cell lung cancer treatment, or one could utilize G-CSF. So either trilaciclib or G-CSF could be utilized to support the patient's bone marrow.

In patients who have limited-stage disease, for many years, we have recommended against using G-CSF in combination with chemotherapy and radiotherapy due to concerns for increasing toxicities, including thrombocytopenia. Recent data suggests that this may not necessarily be a hard and fast rule and that if one feels that the patient requires or would benefit from some myeloid support, then G-CSF may be offered to patients undergoing chemotherapy and radiotherapy. I do not think that the standard patient that we see who is starting on treatment requires such support, but some subsets of patients or patients who have already proven that they're getting into trouble with their counts, G-CSF could be utilized in this situation.

So with regard to this recommendation, overall, it's that for patients with extensive stage disease, trilaciclib or G-CSF could be used if one feels they're necessary. And for limited-stage small cell lung cancer, G-CSF could be utilized if you feel it's necessary.

Brittany Harvey: Thank you for reviewing those options and all of these recommendations. The panel was certainly hard at work reviewing the evidence and developing these recommendations.

In your view, Dr. Kalemkerian, what is the importance of this guideline for both clinicians and for patients with small-cell lung cancer?

Dr. Greg Kalemkerian: Well, I think it's not just small-cell lung cancer, but when you look at guidelines overall, I think they are very important to have evidence-based guidelines as well as expert consensus-based guidelines because, quite honestly, the field is moving very quickly, the field of oncology. Now, small-cell lung cancer hasn't moved as quickly as we would like compared to other aspects of oncology, but it's very hard for the clinician who is trying to care for patients with lots of different tumor types to keep up with all of the flood of literature, the flood of new FDA approvals that are coming out every week. So I do think that utilizing the guidelines is important in order to see what the standard approach might be.

Now, I also have to couch that with saying that guidelines are never enough. We have to look at the individual sitting across the exam table from us. We have to personalize the treatment to that individual. I will say that in my own practice, there are very few people who walk in the door who are the optimal patient, who are the person who has outstanding physical function. And in lung cancer, that's even more true because patients tend to be older smokers, and they have a lot of comorbidities and other things that you have to personalize therapy towards in them. So the guidelines are a very good starting point in order to know what the optimal treatment might be and then to adjust that accordingly to the person sitting in the room with you.

Brittany Harvey: Definitely, we hope guidelines are a place that clinicians can turn to for evidence-based recommendations and succinct recommendations, but individualized patient and clinician decision-making is paramount to each of our guidelines.

So then, Dr. Kalemkerian, we've already talked about this a little bit when you mentioned molecular testing advances down the road. So maybe I'll ask what are the most pressing, unanswered questions about systemic therapy for small-cell lung cancer?

Dr. Greg Kalemkerian: Yeah, so one of them I'll come back to limited-stage small-cell lung cancer. So, obviously, in the extensive stage, we've now incorporated immunotherapy. And yet I didn't talk about immunotherapy in the limited-stage setting, and neither do the guidelines because thus far we don't have any data on the use of immunotherapy in limited-stage small-cell lung cancer. We are expecting data to be coming down the line within the next year hopefully, definitely, within the next two years, because a number of trials that are either ongoing or have recently been completed looking at incorporating immune checkpoint inhibitors into the treatment of limited-stage small-cell either concurrently with chemoradiation or as consolidation after chemoradiotherapy. So that data is anxiously anticipated. And we're hoping that that might move the needle a little bit further in limited-stage small-cell lung cancer and hopefully improve that long-term survival or cure rate that we see in that disease.

Other avenues coming down the line – many of us have made a career of doing negative trials in small-cell lung cancer, myself included, and a lot of that has had to do with trying to target therapies to specific molecular abnormalities, and none of those have really panned out thus far. But coming down the line, as we start to molecularly subtype lung cancers, and the best molecular subtyping that we have thus far is not based on mutational analysis, but more based on expression, gene expression analysis, expression of particular transcriptional factors within different subsets of small cell lung cancer, we're now starting to see some vulnerabilities. So one of these subsets in the small cell lung cancer array has a high expression of DLL3, which is part of the Notch pathway, and we can target that. We haven't figured out how to target it as far as its activity goes, but we can target it as a homing device in order to get either drugs delivered by use of antibody-drug conjugates, or to use a BiTE—a T-cell engaging type molecule—that targets both DLL3and T cells in order to try and amplify that immune response in small cell lung cancers. So recently a compound called tarlatamab had data presented at ASCO and also published in JCO that shows some response, about 20-25% response, in people with relapse small cell lung cancer. These were heavily pretreated patients. So that's moving the needle a bit in favor of a specific targeted therapy. And we're hoping that will lead to further avenues to look at the vulnerabilities of different subsets and be able to develop newer targeted treatments for these diseases, trying to amplify that immunotherapy response as well.

Small cell lung cancer is a little bit of an outlier in that it does not respond well to immunotherapy compared to other tumors. Not what we expected based on the high tumor mutational burden and the aggressiveness of the disease. But we know that it does not express a lot of PD-L1. We know that it doesn't have MHC class I molecules. So there are a number of reasons why it doesn't respond, and there is work going on to try and amplify that immune response as well. So I think those three things: the use of immunotherapy in limited-stage, the development of targeted therapies based on subsets, and trying to amplify that immune response are the things that I look forward to in the next few years.

Brittany Harvey: That's great to hear. We'll await the data to provide answers to those outstanding questions.

So I want to thank you so much for your work to develop these evidence-based guidelines, and thank you for sharing your perspective with me today, Dr. Kalemkerian.

Dr. Greg Kalemkerian: Thank you, Brittany. And thanks to ASCO for getting these guidelines together and getting the outstanding group of people we had to work on it and getting them out in a timely manner so they can help our patients.

Brittany Harvey: And also, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Eric Singer highlights the recent rapid recommendation update from ASCO on the management of metastatic renal cell cancer (ccRCC), based on the review of evidence from the phase III COSMIC 313 trial. Dr. Singer reviews the discussion from the Expert Panel and emphasizes clinicians should continue to follow the previously issued recommendations for the management of metastatic ccRCC. He also mentions future directions, ongoing clinical trials, and outstanding questions for these evidence-based guidelines. Read the latest update, “Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Eric Singer from the Ohio State University Comprehensive Cancer Center, lead author on the “Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update.”

Thank you for being here, Dr. Singer.

Dr. Eric Singer: Brittany, great to be with you. Thank you for the invite.

Brittany Harvey: Great. Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Singer, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, Dr. Singer, to dive into this rapid update, can you tell me a little bit about what prompted this rapid update to the Management of Metastatic Renal Clear Cell Cancer Guideline, which was previously published in 2022?

Dr. Eric Singer: Sure. One of the big motivators for this was the fantastic work done by Toni Choueiri and colleagues in publishing the COSMIC-313 trial, which looked at triplet therapy for the management of metastatic kidney cancer: a combination of ipilimumab, nivolumab, and cabozantinib versus patients with placebo plus ipi and nivo. And this was a much-awaited trial, and these results came out. And certainly, there was a lot of interest amongst providers as well as patients to help understand the results of this important study and whether or not we should be changing our practice. So, the guideline group who wrote the initial guideline in 2022 felt that this was a significant enough study to warrant a rapid update.

Brittany Harvey: Understood. So then, based on this new data from COSMIC-313, what is the updated recommendation from the Guideline Expert Panel?

Dr. Eric Singer: So, the recommendations largely do not change. Unfortunately, while there was some fantastic information gleaned from COSMIC-313, the survival outcomes that were seen at this point, in context with the toxicity signals that were seen at this point, led the Guideline Committee to recommend against adopting triplet therapy as a standard option. However, the Guideline Committee did encourage patients and providers to continue to refer to and accrue to clinical trials that will be again asking similar questions about the combinations that we should be using to treat metastatic kidney cancer going forward. So essentially, we felt that the survival benefit was not adequate to recommend first-line treatment adoption of this triplet regimen in context with the toxicities that were seen in the triplet regimen.

Brittany Harvey: Understood. That's helpful to know.

So then, what should clinicians know as they implement this guidance into practice?

Dr. Eric Singer: I would recommend that we continue to follow the original guideline as published. There are multiple doublet agents or doublet therapeutic combinations that are available, which we found to have strong survival outcomes and more manageable toxicity profiles than the triplet regimen studied in COSMIC-313.

Brittany Harvey: Great. Additionally, what does this update mean for patients with metastatic renal clear cell cancer?

Dr. Eric Singer: Yeah, as we all think about how best to manage patients with metastatic kidney cancer, a lot of the things that we're thinking about are, will this treatment make people live longer, and will this treatment make patients live better, balancing both efficacy and also looking at toxicity. And I think in this case, there wasn't the survival endpoints or the survival benefit we were hoping for, again, sort of a surprisingly low number of complete responses seen in this study compared to prior pivotal trials, and quite a bit of toxicity because we're combining three different drugs. And when we do combine medications, we're always hoping for synergy in terms of the efficacy so the combination working better than what we'd expect just by adding those outcomes together. But unfortunately, we also got quite a bit of additive toxicity in the combination as well. So, I think that we still have many excellent options to choose from and that, unfortunately, at this time, there didn't seem to be the survival benefits in light of the toxicity to warrant a change.

Brittany Harvey: Absolutely. That balance of benefit and harms is crucial.

So then, finally, you mentioned that this guideline encourages enrollment in clinical trials, but I want to also ask you, what are the outstanding questions that we're looking forward to regarding the management of metastatic renal cell cancer?

Dr. Eric Singer: Brittany, I think there's a lot of important questions for us to work on answering. Like we were sort of alluding to in a study like this, we want to know not only which patients are likely to benefit from a combination of therapies, but we also want to begin to learn more about which patients are at an especially high risk of toxicity from combined treatments. So, not only can I counsel a patient about what we think this will do for disease control, but also to identify potential risk factors for adverse events because that can help us choose between the multiple different options we have available. We also have a lot of options at our disposal now in terms of combining different types of therapy: How should we integrate surgery, radiation, systemic therapy? What order should we do them in? What is the best combination to use at each of these steps, so that we can continue to help patients live longer and live better on their kidney cancer journey?

Brittany Harvey: Absolutely. Well, I want to thank you so much for your work to update this guideline very rapidly, and thank you for sharing your insights with me today, Dr. Singer.

Dr. Eric Singer: Brittany, my pleasure. And again, I really appreciate the work of everyone who's been on the metastatic kidney cancer panel, such fantastic professionals in terms of their clinical expertise, and then also the fantastic ASCO staff, where we really wouldn't be able to do this work without the amazing dedication and hard work of our ASCO team members.

Brittany Harvey: Definitely a big thank you to the entire expert panel.

And also thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Jaydira Del Rivero and Dr. Kimberly Perez discuss the latest ASCO guideline featuring evidence-based recommendations on systemic therapy for well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). They discuss the recommendations, insights from the guideline expert panel, impact for clinicians and patients, and outstanding questions in the field. Read the full guideline update, "Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01529

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today I am interviewing Dr. Jaydira Del Rivero and Dr. Kimberly Perez, co-chairs on “Systemic Therapy for Tumor Control in Metastatic Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.”

Thank you for being here, Dr. Del Rivero and Dr. Perez.

Dr. Jaydira Del Rivero: Thank you.

Dr. Kimberly Perez: Thank you, Brittany.

Brittany Harvey: Then before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Del Rivero and Dr. Perez, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology which is linked in the show notes.

Now, to start us off on the content of this guideline, Dr. Del Rivero, can you provide an overview of both the scope and the purpose of this guideline?

Dr. Jaydira Del Rivero: Thank you so much, Brittany for the introduction. I would also like to thank ASCO as well for giving us the opportunity, me and Dr. Perez, to discuss briefly the guidelines for gastroenteropancreatic neuroendocrine tumors.

In terms of your question of providing an overview of the scope and purpose of this guideline, we wanted to make recommendations about the various systemic therapies and the management of advanced, unresectable, metastatic gastroenteropancreatic neuroendocrine tumors from grade 1 to grade 3. I’m fortunate to be the co-chair with Dr. Perez, but among the different experts and panelists on this guideline, it is important to establish a guide on how to manage patients with gastroenteropancreatic neuroendocrine tumors. And one of the reasons is because there really is not sequencing enough therapy, and there have been a lot of discussions even among the neuroendocrine tumor experts for at the same time provide information and guide to oncologists in the community to understand more about the management of these neuroendocrine tumors as well as provide in a more standardized manner about how a neuroendocrine tumor expert sees or manages a patient with neuroendocrine tumor.

Brittany Harvey: Great. Thank you for providing that overview.

So, you just mentioned that this guideline covers grade 1 to grade 3 gastroenteropancreatic neuroendocrine tumors. So, Dr. Perez, what are the general recommendations that the panel made for grade 1 to grade 3 gastroenteropancreatic neuroendocrine tumors?

Dr. Kimberly Perez: Thank you, Brittany. I think the biggest take home for treatment for this group of tumors is based on the heterogeneity of the disease. We can classify this very broad group of tumors into grade 1 to 3 based on histologic features, and we use that to guide treatment. But we also take use the functionality of the tumors to direct treatment, and that can be assessed clinically as well as by functional imaging or nuclear medicine-based imaging. And that’s really how our intention is in trying to provide recommendations for the treatment of these various tumor types. So, we, as a group in our discussions, it really came down to approaching the patient's situation, determining whether or not the patient had functional symptoms as a result of hormone excess, and then determining what their radiographic features were, specifically whether or not somatostatin receptor presence was noted and then the grade of the tumor and lastly, the bulk of disease and the rate of growth. And it’s really those features that drive the different treatment options.

Brittany Harvey: Excellent. Thank you for reviewing those general recommendations to identify those features that lead to specific treatment options.

So, Dr. Del Rivero, what systemic therapy options are recommended for first, second, and later line therapies for grade 1 to grade 3 gastroenteropancreatic neuroendocrine tumors?

Dr. Jaydira Del Rivero: As Dr. Perez mentioned earlier, neuroendocrine tumors are quite heterogeneous, and it's not a one-size-fits-all in terms of how we manage patients with neuroendocrine tumors. As Dr. Perez also mentioned, too, in terms of how we manage these neuroendocrine tumors, we need to consider the extension of the disease, whether it's low burden tumors versus high burden tumors. What is the pace of growth? Whether it's stable or rapidly progressive, and whether it's widely metastatic as well or if it's only localized in one area, liver-dominant disease. We also need to understand the primary site, and that's why these guidelines, we also divided it in terms of how we see it in terms of first and second line therapies between pancreas and small bowel neuroendocrine tumors. And as Dr. Perez said, the grade differentiation is also important. That's the reason why, when discussing and developing these guidelines, it was important to differentiate between grade 1, grade 2, as well as the grade 3. And also, as Dr. Perez mentioned, whether they are functional tumors, meaning they produce hormones or not and the symptoms related to that.

And I just would also like to mention that we are currently working on the symptom management of neuroendocrine tumors, taking into consideration the hormone status of the tumors. That is something that we’ll follow up in these guidelines as well. And as Dr. Perez mentioned whether they express somatostatin receptors or not. So based on that, the expert panelists as well in developing these guidelines, we divided them into grade 1 and grade 2 GI (or gastrointestinal) neuroendocrine tumors or pancreas neuroendocrine tumors. And that is based on the proliferation index as well. If the proliferation index of the Ki-67 is greater than 20%, we know that this is a grade 3 gastroenteropancreatic neuroendocrine tumor, which that, in itself is a different category in terms of management.

Now, for gastrointestinal grade 1 and grade 2 neuroendocrine tumors, the first line of therapy, one of the things that we need to establish is whether the tumor expresses a somatostatin receptor or not, and that we confirm this via 68Ga-DOTA-peptides or 64Cu-DOTATATE scan. If they expressed the receptors, then I would initiate first line therapy or what is recommended in these guidelines is to start with a somatostatin agonist, either octreotide or lanreotide. One thing to mention here is that either octreotide or lanreotide is considered equivalent in terms of efficacy, we don’t have any head-to-head comparison to determine which one may be better. We think it's equivalent, the two of them. And because of that, whichever is available is what we recommend.

Now if there is evidence of disease progression after the use of a somatostatin agonist, we need to determine whether they still express somatostatin receptors. And as a second line therapy, we can consider patients as candidates for 177Lu-Dotatate or PRRT with 177Lu-Dotatate. Usually, our recommendations are, if the patient has a functional tumor, if it’s producing hormones and symptoms related to hormone excess, we still continue the somatostatin agonist. But if the tumor is a non-functional tumor after disease progression on a somatostatin agonist, we don’t necessarily need to continue with either lanreotide or long-acting octreotide.

Now, sometimes, some of the discussions that were done as well when developing these guidelines is a concern about hematologic toxicity. And if there is any concern of hematologic toxicity, the patient may not be a candidate for 177Lu-Dotatate. In these situations, everolimus can be considered as a second or later line therapy in patients with G1 or G2 gastrointestinal neuroendocrine tumors. If the patient is somatostatin receptor negative, we can consider everolimus as well. As you can see, with GI neuroendocrine tumors, we really need to take into consideration what we discussed earlier today, and also discussed with Dr. Perez.

Now, in terms of the grade 1 or grade 2 pancreatic neuroendocrine tumors, similar to what we discussed on the small bowel or gastrointestinal neuroendocrine tumors, we first need to determine whether the tumor is somatostatin receptor positive through scans such as 68Ga-DOTA-peptides or 64Cu-DOTATATE scan. Based on that, the first line is also considered, a somatostatin agonist, either octreotide or lanreotide. If there is disease progression on that, then we can consider other lines of therapy, such as Peptide Receptor Radionuclide Therapy or PRRT with 177Lu-Dotatate or chemotherapy with capecitabine and temozolomide, or everolimus, or sunitinib. Now, one thing to keep in mind whenever we make these recommendations is for those pancreas neuroendocrine tumors that, in addition to being somatostatin receptor positive, are the ones that have a lower volume of disease or without significant symptoms related to tumor burden.

Now we have pancreas neuroendocrine tumors with a higher volume of disease and symptoms related to tumor burden, regardless of somatostatin receptor expression, then usually what the panelists have considered as a first line therapy is chemotherapy with capecitabine and temozolomide. And if there is any disease progression after that, then we also need to establish as well whether they still retain somatostatin receptors avidity if it’s positive. Other options to consider will be 177Lu-Dotatate, everolimus, or sunitinib. Those are the FDA-approved agents for the management of neuroendocrine tumors. And if they are somatostatin receptor negative, it will be everolimus or sunitinib.

Now, in terms of grade 3 gastroenteropancreatic neuroendocrine tumors, when the Ki-67 is greater than 20%, there are various options as well. And a lot of the treatments that have been recommended for grade 1 to grade 2 neuroendocrine tumors can also be recommended for grade 3 neuroendocrine tumors. But that said, as we discussed earlier, we also need to understand the growth of disease or the aggressiveness of the disease, as well as the symptoms related to that as well as the tumor burden. But based on that, there may be other treatments available for grade 3 neuroendocrine tumors, such as various types of chemotherapy as discussed in the guidelines. There are also ongoing clinical trials that will help us better understand and have more evidence-based therapy for the treatment decisions of patients with gastroenteropancreatic neuroendocrine tumors.

Brittany Harvey: Dr. Del Rivero, I appreciate you reviewing those recommendations and the nuance from the panel's discussion.

Dr. Perez, is there anything you'd like to add about those recommendations?

Dr. Kimberly Perez: Dr. Del Rivero covered everything that we intended to impart to the community about treatment of gastroenteropancreatic neuroendocrine tumors. I think the only highlight I would make and was intentional on our part was separating gastrointestinal and pancreatic neuroendocrine tumors; because there have been clinical trials demonstrating the different efficacy of treatments based on the primary site of disease.

Brittany Harvey: Absolutely, that makes a lot of sense. So then, Dr. Perez, in your view, what is the importance of this guideline and how does it impact both clinicians and patients with gastroenteropancreatic neuroendocrine tumors?

Dr. Kimberly Perez: I think the importance of the guidelines, I found, was the common theme in our discussions with the other panelists on the group was because of the rarity of the disease and the clinical trials that we are drawing our experience from, there’s a lot of different ways to interpret the data that’s available. And we all spent a lot of time discussing how we've interpreted the data and how we implement it in our practice and how it’s influenced the development of current clinical trials and the ideas supporting future clinical trials. So I think that our intention was to provide community oncologists or general oncologists, who don't see patients with this disease very often, with an algorithm or review of what is available and how you can try to put your patients into the algorithm in a way that would result in best results or best outcomes.

Brittany Harvey: Absolutely. We hope this is a resource for community oncologists to help improve outcomes for their patients.

You also just mentioned future clinical trials, so I'll turn back to Dr. Del Rivero. What are the outstanding questions regarding systemic therapy for metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors?

Dr. Jaydira Del Rivero: Great, thank you for that question. I would like to mention that in the development of these guidelines, there were a few discussions about when to implement observation. Because we know that patients with neuroendocrine tumors, in terms of the biology, they may be very slow-growing tumors. One of the discussions was: when is observation recommended? Usually, what the discussion was based on the consensus from all the panelists is that observation could be considered in patients with low volume or very slow-growing disease in the absence of any symptoms, meaning from either tumor burden or functional tumors. I think this could still be considered in a subset of patients. It's not necessarily for everyone. I think we agree that a lot of the patients with neuroendocrine tumors, when they present to us, they already had metastatic disease and that's when they are sick. The recommendations of medical oncologists is to determine the next line of therapy.

One of the other discussions I would like to mention was about the deficiency of MGMT, and that was based on the data report by Dr. Pamela Kunz. This was also presented at the ASCO meeting and recently published in the Journal of Clinical Oncology, the validity of MGMT deficiency in patients with pancreas neuroendocrine tumors and how that correlates with response. That said, I think the consensus was that even though we can consider that as a predictive biomarker, it's still not something that is a primetime to use, but it was something that was recommended, was discussed during the discussion of the development of these consensus statements. Dr. Perez, we would also like to note that, also Dr. Perez, and what other important aspects were discussed during the development of the guidelines. With that said, a lot of the questions will be answered in ongoing critical trials as well from metastatic neuroendocrine tumors.

I think we’re in a very exciting time where we have not seen a lot of more clinical trials for neuroendocrine tumors and a lot of treatment options than where it was more than 10 years ago. I think one of the questions about sequencing, too, and that's something where there's insufficient evidence in terms of what to recommend, a particular sequence of therapy. With that said, there have been ongoing studies presented at the ESMO Meeting as well, and that in terms of some of the trial results in patients with gastroenteropancreatic well-differentiated neuroendocrine tumors. But I say still, that’s an ongoing question too. And ongoing trials are also currently active, not only for pancreatic neuroendocrine tumors, but as well for gastroenteropancreatic neuroendocrine tumors. And that’s an exciting time to also learn more about these studies and looking forward to also learn about the results of these studies.

And Dr. Perez, what are your thoughts?

Dr. Kimberly Perez: I agree with all of your sentiments. I think some additional topics of discussion that came up were in regards to: how to define the burden of disease? So we use that as one of the characteristics for determining what treatment option we want to consider. We found that the data really only addressed this when trialists were looking at liver burden of disease. I think that is something as a scientific and clinical community, we need to define a bit better in our future clinical trial efforts.

I think the second is this question of Ki-67 and rate of growth. In Jennifer Ead's study, looking at CAPTEM versus platinum and etoposide and the grade 3 group, the delineation made was a Ki-67 of around 55%. As her trials and other trials looking at the therapeutic options in this grade 3 category mature, we will be able to better characterize that, and I think it will be important to provide guidance to patients and providers on how to really define the Ki-67 that requires a certain type of treatment.

And then I think the last question I recall was in regards to using somatostatin receptor-based therapy when you don’t yet have somatostatin-based imaging or when you have somewhat of a mixed uptake in somatostatin imaging. I think that too, as the new radiopharmaceuticals are developed and technology improves, this question will be answered.

Brittany Harvey: Definitely, those are important questions to determine therapeutic options for patients. We'll look forward to those future developments ahead.

Thank you both so much for your work to develop this guideline and these recommendations, and I want to thank you so much for joining me here on the podcast today, Dr. Perez and Dr. Del Rivero.

Dr. Jaydira Del Rivero: Thank you, Brittany.

Dr. Kimberly Perez: Thank you so much for having us.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experiences, and conclusions. These do not necessarily reflect the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Julia Rowland shares the newest evidence-based recommendations from SIO and ASCO on integrative therapies for managing anxiety and depression symptoms in adults with cancer. Listen in to hear recommended options, such as acupuncture, aromatherapy, hypnosis, mindfulness, music therapy, relaxation, reflexology, Tai Chi and/or Qigong, and yoga. Dr. Rowland also discusses therapies the panel investigated but found insufficient evidence to support a recommendation for use in treating anxiety and depression. We also review how this guideline complements the recent ASCO guideline on conventional therapies for managing anxiety and depression, and the impact for patients and clinicians.
Read the full guideline, "Integrative Oncology Care of Symptoms of Anxiety and Depression in Adults with Cancer: SIO-ASCO Guideline" at www.asco.org/survivorship-guidelines

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the update and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00857

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Julia Rowland from the Smith Center for Healing in the Arts, Co-chair on “Integrative Oncology Care of Anxiety and Depressive Symptoms in Adult Patients with Cancer: Society for Integrative Oncology – American Society of Clinical Oncology Guideline.”

Thank you for being here, Dr. Rowland.

Dr. Julia Rowland: Lovely to be here, Brittany. Thanks for this opportunity.

Brittany Harvey: We're glad to have you on.

Then before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including the guest on this episode, are available in line with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then I'd like to jump into the content of this guideline. So Dr. Rowland, what is the purpose of this joint SIO and ASCO guideline?

Dr. Julia Rowland: The purpose of the joint guideline, Brittany, published in the Journal of Clinical Oncology is to provide evidence-based recommendations to healthcare providers on integrative approaches to managing anxiety and depression symptoms in their adult cancer patients. By integrative approaches, we mean such interventions as yoga, relaxation, hypnosis, mindfulness, acupuncture, music therapy in treating anxiety and depression. Many of these therapies are already being used by people with cancer both during and after their treatment, with rates increasing over time. While use of integrative interventions can serve to improve quality of life, reduce stress, and provide individuals with a sense of control over their health, and they're often reported by patients as doing just that, it's important to note that for the purpose of this guideline, we examine specifically the ability of these interventions to significantly reduce symptoms of anxiety and depression.

Brittany Harvey: Great. And then, as you just mentioned, this guideline covers both anxiety and depression. So then I'd like to review the recommendations made by the expert panel and we'll go in order of those. So starting with those recommendations for anxiety, what integrative therapies are recommended for managing symptoms of anxiety experienced after diagnosis or during active treatment?

Dr. Julia Rowland: The strongest recommendations in the guideline are for the use of mindfulness-based interventions, which include mindfulness-based stress reduction, meditation, and mindful movement. These interventions were recommended across the board to treat both anxiety and depression symptoms in patients in active treatment, and those post-treatment due to the strong evidence to show their benefits to patients. Yoga was also recommended for patients with breast cancer to treat both anxiety and depression symptoms, although the strength of the evidence was moderate. Data was less compelling for its use during or after treatment in other cancers, likely due to the lack of small numbers of non-breast cancer survivors included in study samples. There was also evidence for the use of relaxation, music therapy, and reflexology for treating anxiety symptoms during active treatment, and that the use of hypnosis and aromatherapy using inhalation were of modest to some benefit during diagnostic or treatment procedures.

Brittany Harvey: Understood. Thank you for reviewing those recommendations. And you already mentioned a few items that are helpful and recommended for adults with cancer experiencing anxiety post-treatment, but which additional integrative therapies are recommended for this patient population?

Dr. Julia Rowland: In addition to mindfulness-based interventions and yoga, acupuncture, Tai Chi, and/or Qigong, and reflexology are recommended for treating anxiety symptoms post-treatment.

Brittany Harvey: Excellent. Thank you for that summary of recommendations. So then, moving into the recommendations on depression, what does the expert panel recommend for adults with cancer experiencing symptoms of depression?

Dr. Julia Rowland: For depression symptoms during treatment, the panel recommended mindfulness-based interventions, yoga, music therapy, relaxation, and reflexology, while post-treatment mindfulness-based interventions, yoga, and Tai Chi or Qigong were recommended.

Brittany Harvey: Excellent. Thank you for reviewing all the recommendations that the panel put forward. So this guideline reviewed a large breadth of integrative therapies. Are there any therapies that the panel reviewed but couldn't make a recommendation for, for this particular guideline?

Dr. Julia Rowland: Thank you for asking that question because as people listen to this podcast, they may realize that there are some therapies that may be widely used by their population or in their center or clinic, including such things as natural products and supplements, melatonin, healing touch, massage, light therapy, to name a few. Where the panel found in its review of the literature of over 110 studies or systematic reviews, there was insufficient evidence for the vast majority of these to make any conclusive recommendation. It just means we have a lot more work to do in assessing the efficacy of these, especially in treating anxiety and depression.

One intervention stands out in particular that's widely used and that's expressive writing. While this may be very helpful for improving quality of life or making sense of the cancer experience and providing an outlet for self-expression, the data does not support its use for treating anxiety and depression. It may be because it's too brief an intervention for conditions that have more depth and permanence. It doesn't mean you can't use it for other purposes, but the panel did not recommend its use for treating anxiety and depression.

Brittany Harvey: Understood. That makes sense that there are some integrative therapies that work across different parts of the treatment spectrum and that there are some areas in which we just don't have the evidence yet. So, thank you for reviewing all of those recommendations.

So then, how does this guideline complement the recently published ASCO Guideline on the Management of Anxiety and Depression in Adult Survivors of Cancer?

Dr. Julia Rowland: That's a terrific question. The recently published ASCO Guideline on Management of Anxiety and Depression in Adult Cancer Survivors represents an update of our original 2014 guideline. The ASCO guideline provided recommendations regarding the use of conventional therapies, psychological, behavioral, and psychopharmacologic interventions for managing anxiety and depression. The current SIO and ASCO guidelines sought to expand upon and essentially complement these recommendations by identifying those integrative therapies that might also be effective in the management of anxiety and depression in adults treated for cancer. Further, the SIO and ASCO guidelines attempted to determine when, in the course of care, during diagnosis and active treatment and/or post-treatment, these interventions worked best. Both sets of recommendations strongly endorse the benefits of mind-body interventions in addressing both anxiety and depression, specifically mindfulness-based interventions in this SIO and ASCO guideline and cognitive, behavioral, behavioral activation, and mindfulness-based stress management programs in the ASCO guideline.

Brittany Harvey: It's great to have these complementary guidelines available at the same time for a complete approach to managing anxiety and depression during treatment and post-treatment. So then, in your view, Dr. Rowland, what is the importance of this guideline and how will it impact clinicians and patients with symptoms of anxiety and/or depression?

Dr. Julia Rowland: Brittany, cancer takes a significant psychological toll on affected individuals. Research has shown that cancer survivors have a significantly elevated risk of developing mental health disorders compared with the general population. Despite this, their psychological symptoms are often under-recognized and undertreated. As the number of cancer survivors continues to grow, so does the challenge to healthcare providers of meeting their mental health needs. Anxiety and depression symptoms have long been associated with lower quality of life and higher mortality in people with cancer. Treating symptoms of anxiety and depression using evidence-based, integrative therapies has the potential to not only improve patients' quality of life and help them better manage their care but may also improve length of life.

With the publication of this guideline, we now know which therapies could have the biggest impact. An added benefit of incorporating, or at least considering, integrative therapies to manage anxiety and depression are that they have few, if any, side effects, can be readily modified to accommodate individuals with multiple comorbidities, are well received by the majority of patients, and can be received in a variety of settings, including at home and online.

Brittany Harvey: Those are key points that you just made. These recommendations are key for improving quality of life for patients, and it's great to have options for patients, including, as you mentioned, at home.

So then finally, what are the outstanding questions for the use of integrative approaches in managing anxiety and depression in patients with cancer?

Dr. Julia Rowland: As I look at these new guidelines, both the SIO and ASCO, as well as the renewed ASCO guidelines, perhaps the biggest question raised is how to increase the use of recommended care. And I think there are three parts to this challenge. One critical first part is raising awareness about these guidelines, which it's hoped this podcast will help us achieve. A second, equally critical step, however, is identifying available treatment resources. While most treatment clinics and centers have access to mental health resources in a number of settings, this may be quite limited. Further, it's not clear how many such programs include integrative programs and services.

In addition to the questions about availability, lack of familiarity with some of these therapeutic modalities may leave clinicians reluctant to refer their patients for such care and raise questions for them about how to assess the training and qualifications of integrative care providers and the rigor of the therapy they provide. An important recommendation made by both ASCO and the SIO and ASCO Anxiety and Depression Management Guideline panels is that oncology clinicians should conduct a landscape analysis of who is and what types of programs are available to provide the recommended therapies to their patients. Arguably, not knowing where to refer a patient suffering from anxiety and depression is the most significant area to that patient's receipt of optimal care. The landscape review should include in-house or affiliated mental health providers, integrative program leads if present, local professionals, and organizations offering this care, as well as access to community-wide and national groups providing integrative care remotely via online and telephone. Asking patients themselves who they have seen and found helpful in improving their emotional well-being can also broaden resource lists generated.

A third challenge is how best to identify and refer those patients most in need. Recommendations regarding screening and assessment of anxiety and depression were not within the scope of the SIO and ASCO guidelines. However, in the two published ASCO Guidelines on use of conventional interventions for managing anxiety and depression, both the 2014 original and the updated 2023 revised, the expert panels emphasize the critical need to routinely screen for both anxiety and depression using standardized measures such as the GAD-7 and the PHQ-9.

ASCO's QOPI or Quality Oncology Practice Initiative already includes screening for emotional distress early in the course of care as a key practice standard. Other appropriate times for screening include changes in disease or treatment status, transition to palliative and end-of-life care, and when clinically indicated. Screening is the critical and necessary first step to identification and referral for appropriate and timely care of cancer patients and survivors suffering from anxiety and depression. Figuring out how to do this well and systematically should be a priority for reducing the burden of cancer nationally.

Brittany Harvey: Absolutely. As you mentioned, screening is critical for identifying patients experiencing anxiety and depression, and I appreciate you reviewing those implementation barriers and how clinicians and practices can work to reduce these barriers and increase the uptake of these recommendations. We'll have some of those resources linked in the guideline also on the ASCO website and in the show notes of this episode.

So I want to thank you so much for your insights on this guideline and for your time today, Dr. Rowland.

Dr. Julia Rowland: My pleasure, Brittany. I hope the word gets out and we'll see more uptake of these affected therapies and in broader use. Thank you.

Brittany Harvey: Definitely. That's the goal of all of these guidelines.

I also want to thank all of our listeners for tuning into the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of medical conditions.

View Details

Dr. Michael Atkins and Dr. Vernon Sondak highlight the latest updates to the systemic therapy for melanoma recommendations in this newest guideline. The discussion covers neoadjuvant and adjuvant therapy for resected cutaneous melanoma, options for unresectable and/or metastatic cutaneous melanoma, and therapies for noncutaneous melanoma. They review the importance of this guideline and the most pressing outstanding questions to help inform better treatment strategies for patients with melanoma.
Read the full guideline update, "Systemic Therapy for Melanoma: ASCO Guideline Update" at www.asco.org/melanoma-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/melanoma-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO. 23.01136

My name is Brittany Harvey, and today I'm interviewing Dr. Michael Atkins from Georgetown Lombardi Comprehensive Cancer Center, and Dr. Vernon Sondak from H. Lee Moffitt Cancer Center and Research Institute, authors on “Systemic Therapy for Melanoma: ASCO Guideline Update.”

Thank you for being here today, Dr. Atkins and Dr. Sondak.

Dr. Vernon Sondak: Happy to be here.

Dr. Michael Atkins: Yeah, it's a pleasure.

Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Sondak and Dr. Atkins, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content here, Dr. Sondak, what prompted this full update to the Systemic Therapy for Melanoma Guideline, which was initially published in 2018?

Dr. Vernon Sondak: Well, the last 10 years or so have seen enormous advances in the management of metastatic melanoma and localized melanoma with systemic therapy, and the last few years haven't slowed up at all. So since 2018, we've seen new approvals, we've seen key pivotal trials that have shown some amazing results that we'll talk about, and all of these things together weighed into the decision to update the systemic therapy guidelines.

Brittany Harvey: Great. Thank you for that background on what prompted the update. So then, this guideline provides updated recommendations across four clinical questions. I'd like to review the key updated recommendations for our listeners. So first, Dr. Sondak, what has changed in the updated recommendations regarding neoadjuvant therapy for adults with resectable cutaneous melanoma?

Dr. Vernon Sondak: Neoadjuvant therapy is one of the most rapidly evolving and exciting parts of the management of melanoma with systemic therapy. The updated guidelines now include neoadjuvant pembrolizumab as a new recommendation for patients with resectable stage IIIB to IV cutaneous melanoma. This is based on the SWOG S1801 clinical trial, which was a very simple and yet incredibly influential clinical trial. It took patients with resectable metastatic melanoma, either metastatic to the lymph nodes or beyond, as long as it could be removed surgically, and randomized all of the patients to either get surgery, followed by a year of adjuvant pembrolizumab, which is very standard, or the same exact surgery and the same total amount of pembrolizumab, but with three of the doses given before surgery. So that simplicity, that ability to just compare the effect of neoadjuvant or preoperative pembrolizumab to entirely postoperative adjuvant pembrolizumab, made this trial a really pure assessment of the value of neoadjuvant pembrolizumab.

Impressively, this study showed a significant improvement in event-free survival for patients who got those three doses of pembrolizumab upfront. What's event-free survival? That includes relapse-free survival, but also the kinds of events that you can see happening with neoadjuvant therapy, such as progression of the disease prior to surgery that makes the patient unresectable. And the bottom line is that there was really the same number of issues with neoadjuvant pembrolizumab as with surgery, followed by adjuvant therapy, but there were many fewer recurrences among the patients who got neoadjuvant pembrolizumab. So that's why this was put into the guidelines.

Brittany Harvey: Excellent. I appreciate you reviewing the evidence behind those recommendations and what's new for neoadjuvant therapy.

So then, Dr. Atkins, moving into adjuvant therapy, for patients with resected cutaneous melanoma, what is new in the recommendations regarding adjuvant systemic therapy options?

Dr. Michael Atkins: Sure. In the prior version, adjuvant therapy was recommended for patients with stage IIIB, IIIC, and for some patients with stage IV resected to NED. And those were based on studies with adjuvant pembrolizumab, adjuvant ipilimumab, and adjuvant nivolumab compared to ipilimumab. But what's happened since then is some really important adjuvant studies have been carried out in patients with stage IIB, IIC, and IIIA disease who are at slightly lower risk of recurrence, but still have substantial risk of recurrence, and make up a large percentage of the patients who eventually develop stage IV disease.

And in these studies, one with pembrolizumab compared to placebo, there was about a 40% to 50% reduction in relapse-free survival observed, leading to the FDA approval of pembrolizumab in that setting. And then recently we saw the results of a similar study involving nivolumab that showed maybe even a slightly better reduction in the risk of relapse in that same patient population. Ultimately, this will lead to FDA approval as well. And we felt it was important to put in the guidelines the results of these studies so that people can have informed discussions with their patients about whether they want to receive this therapy going forward. It's important to point out that we don't have good data yet on overall survival. We just have data on relapse-free survival. So we don't, for sure, know that treating patients early, rather than waiting until a subset of them relapse and treating those late leads to an improved overall survival. That's an important discussion to have with patients to provide them with this option.

In addition, we saw the results of the IMMUNED trial, which looked at nivo-ipi or nivo monotherapy versus placebo or observation in patients with stage IV disease that had been completely resected. And we saw dramatic improvement for the nivo-ipi combination compared to nivo or observation in those patients with stage IV NED. And we felt that, therefore, this was also an important patient population where we should offer guidance

Brittany Harvey: Absolutely. That shared patient-clinician decision-making is paramount. And then you've both reviewed the options for resected cutaneous melanoma. But Dr. Atkins, what is new regarding systemic therapy options for patients with unresectable and/or metastatic cutaneous melanoma?

Dr. Michael Atkins: Yes. For patients with unresectable metastatic cutaneous melanoma, there was a new drug combination that was approved combining nivolumab with relatlimab, which is an anti-lag-3 antibody that showed benefit compared to nivolumab monotherapy across almost all subgroups. In particular, the benefit was similar regardless of BRAF mutation status, regardless of elevated LDH, and regardless of patient stage. That led to FDA approval, and this is now an available treatment option, which is associated with less toxicity and similar efficacy to the standard of care nivo-ipi.

In addition, although nivolumab-ipilimumab had been approved and was in our last recommendation for patients with BRAF-mutated melanoma, we didn't really know whether they should receive BRAF/MEK inhibitors, which were also approved, versus nivolumab-ipilimumab as their initial therapy. And so in the past few years, we saw the results of the DREAMseq trial, which randomized patients with BRAF-mutant melanoma to either nivolumab-ipilimumab, followed by BRAF-MEK inhibitor progression, versus the converse sequence. And we saw that at two years, the starting with a nivolumab-ipilimumab had a 20% improvement in two-year overall survival. This prompted the NCCN to change their guidelines to list nivolumab-ipilimumab or other immunotherapies as a preferred frontline therapy. And we thought that this data was important enough and somewhat validated by a randomized phase II trial, the SECOMBIT, which had a lot smaller numbers to encourage us to change the guidelines.

Other minor things that we did were to take T-VEC and no longer recommend that as an option for patients with BRAF-wild type disease who had progressed on anti-PD-1 therapy and that ipilimumab and ipilimumab-containing regimens were no longer recommended for patients with BRAF-mutated disease after progression on other immunotherapy. We felt that those patients probably are best served to get BRAF/MEK inhibitors.

Brittany Harvey: It's good to have clarity on some of those sequencing options for patients and also on which treatments are working better for patients in these subpopulations.

So then, Dr. Sondak, the last set of recommendations. What has changed regarding options available for patients with noncutaneous melanoma?

Dr. Vernon Sondak: There's no question that our patients with noncutaneous melanomas, such as uveal melanoma or mucosal melanoma, have many fewer options and haven't benefited as much from the revolution in treatment that we've seen with our cutaneous melanoma patients, but there have been definite improvements and progress. The full update incorporates new recommendations for uveal melanoma that were published in 2022 as a rapid recommendation update, specifically a new drug called tebentafusp, which is restricted to HLA-A02:01-positive patients. It's HLA-type restricted, but it is active in patients with metastatic uveal melanoma. And so the new guideline is that previously untreated patients with metastatic uveal melanoma who are HLA-A02:01-positive should be offered tebentafusp as a treatment option. So that means all our patients with metastatic uveal melanoma should get HLA typed, so they know if they're a person who is eligible for this treatment and it should be considered early on in the treatment paradigm.

Brittany Harvey: Well, thank you both for reviewing the updates to these evidence-based recommendations. There's a lot that's new in this field.

So then, Dr. Atkins, what is the importance of this guideline? And in your view, how will it impact clinicians, and also how will these guideline recommendations affect patients?

Dr. Michael Atkins: Sure. Well, we have new treatments such as relatlimab and tebentafusp that are available and should be offered to appropriate patients, and new data on how to optimally apply previously approved treatments such as nivolumab-ipilimumab in patients with BRAF-mutated or resected stage IV melanoma, pembrolizumab use in the neoadjuvant setting, and nivo and pembro in earlier stage disease. And with this new information out there and included in the guidelines, hopefully, this will allow practitioners to give the best possible treatments to their patients, and patients to receive treatments which will improve their outcomes.

Brittany Harvey: Absolutely. It's great to have new data to better inform treatment options for patients with melanoma.

So then, finally, Dr. Sondak, what are some of the most pressing outstanding questions regarding systemic therapy for patients with melanoma that may need to be addressed in a future guideline update?

Dr. Vernon Sondak: Every advance brings up new questions. In neoadjuvant therapy, we have single-agent pembrolizumab with strong data from the randomized trial I spoke about. We anticipate more data about combination immunotherapy, specifically low-dose ipilimumab and nivolumab in the setting of neoadjuvant therapy. There are some trials going on with that. The best neoadjuvant treatment, the best sequence, how long should we treat, and even should we change the surgery based on the results of neoadjuvant therapy, not just the surgery, but the postoperative adjuvant therapy? Those are all questions that are key in the neoadjuvant side.

In the adjuvant therapy side, we have much more clarity now about BRAF versus immunotherapy in unresectable disease, but we still don't know always what's the best adjuvant therapy for our BRAF-mutated patients. That's an area we hope will eventually get more clarity, but I think it's going to take a while for that.

And finally, we'll learn more about the optimum sequencing of patients with metastatic disease, but especially for the patients who've already failed adjuvant or neoadjuvant therapy. So much of the data that Dr. Atkins and I talked about in metastatic disease, whether cutaneous or noncutaneous, involved previously untreated patients. But so many of our metastatic disease patients today have come to us already with some form of treatment in the adjuvant or neoadjuvant setting. We still have a lot of work to do to define the best treatment strategies for those patients.

Brittany Harvey: Definitely. Well, we'll look forward to learning more as new data comes out and as some of that research comes to fruition. So I want to thank you so much for your work to update this guideline and thank you for your time today, Dr. Sondak and Dr. Atkins.

Dr. Vernon Sondak: Thank you.

Dr. Michael Atkins: You're very welcome. Thanks a lot.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/melanoma-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Navneet Singh joins us again, this time to discuss the rapid recommendation update for stage III non-small cell lung cancer, incorporating updated data presented at the 2023 ASCO Annual Meeting. He discusses the new trials that prompted the guideline update and updated recommendations on adjuvant osimertinib for patients with EGFR exon 19 deletion or exon 21 L858R mutation, and the option of neoadjuvant chemoimmunotherapy for patients with stage III NSCLC.

Read the update, "Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/thoracic-cancer-guidelines

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01261

My name is Brittany Harvey, and today I'm interviewing Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, Co-chair on “Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update.”

Thank you for being here, Dr. Singh.

Dr. Navneet Singh: Thank you for having me.

Brittany Harvey: Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Singh, who is joining us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content of this guideline, first, Dr. Singh, what prompted this rapid update to the ASCO management of stage III non-small cell lung cancer, which was initially published in 2021?

Dr. Navneet Singh: There have been a number of studies that have involved patients with stage III non-small cell lung cancer since the publication of the stage III NSCLC management guidelines. Of note, three trials deserve special recognition and have actually formed the basis for this rapid update. These include the ADAURA trial for use of osimertinib as adjuvant treatment for completely resected stages Ib to IIIa NSCLC and harboring a sensitizing EGFR mutation. The other two trials have explored the use of PD-1 immune checkpoint inhibitor therapy in combination with chemotherapy as neoadjuvant treatment of potentially resectable stages I to III NSCLC. And these are the CheckMate 816 trial with nivolumab and the KEYNOTE-671 trial with pembrolizumab.

Brittany Harvey: Great, thank you for that background. So then, based off these three new trials that you just mentioned, what are the updated recommendations issued in this rapid recommendation update?

Dr. Navneet Singh: The first updated recommendation is based on the overall survival benefit observed in the ADAURA trial. And this recommendation is that patients with dissected stage III NSCLC and harboring an EGFR exon 19 deletion or an exon 21 L858R mutation should be offered adjuvant osimertinib after platinum-based chemotherapy. The second important update is that in the absence of contraindications, patients with stage III non-small cell lung cancer who are planned for surgical resection should receive a neoadjuvant combination of a platinum doublet chemotherapy, and immunotherapy. Now, both of these are based on high-quality evidence and have a strong strength of recommendation.

Brittany Harvey: Understood. I appreciate you reviewing both the level of evidence and the strength of the recommendation for those as well. So then, what should clinicians know as these new recommendations are implemented?

Dr. Navneet Singh: Now, it's very important for clinicians involved in the management of lung cancer to realize the importance of biomarker testing, something that was initially believed to have relevance only for metastatic disease. But now, with the availability of data indicating the benefit of immunotherapy and targeted therapy not just in metastatic disease but also in early-stage as well as locally advanced disease, clinicians need to ensure that biomarker testing, especially EGFR mutation and PD-L1 expression by approved and validated methods is performed in all patients with stages I to III non-small cell lung cancer. This is important to decide and select patients for the appropriate biological therapy, which is either targeted therapy or immunotherapy that can be used in conjunction with or following chemotherapy. I need to clarify here that the spectrum of biomarker testing that is recommended for metastatic disease is much larger than what is currently being advocated for early or locally advanced NSCLC.

Brittany Harvey: Great, and I appreciate that clarification. So then you've just described what this guideline means for clinicians, but how does this rapid update impact patients diagnosed with stage III non-small cell lung cancer?

Dr. Navneet Singh: Well, for patients with stage III non-small cell lung cancer, all the three trials that form the basis for this rapid update indicate very encouraging developments. The neoadjuvant chemo-immunotherapy approach is now the standard of care for potentially resectable stage III disease, as this combination has been shown to be superior to chemotherapy alone in terms of higher probability of achieving a complete or major pathological tumor response, as well as improving recurrence or event-free survival following surgical resection. Similarly, adjuvant osimertinib for resected stage III NSCLC patients having a sensitizing EGFR mutation has been shown to significantly improve overall survival compared to placebo. It is important to highlight here that osimertinib treatment in stage III NSCLC should be initiated following the completion of adjuvant chemotherapy.

Brittany Harvey: Understood. So then this panel works to rapidly update this guideline, turning it around after the ASCO Annual Meeting. But what are the ongoing research developments that the panel is monitoring for future guideline updates?

Dr. Navneet Singh: Well, the expert panel is eagerly awaiting overall survival data from the neoadjuvant chemo-immunotherapy trials. We have several unanswered questions which ongoing research will attempt to answer. And some of these questions include number one, whether adjuvant immunotherapy is beneficial for patients who have already received neoadjuvant chemo-immunotherapy, and if so, what is the optimal duration for the same? Second, is the three-year adjuvant osimertinib duration appropriate? Can lesser duration of treatment suffice for a subgroup of patients? And if so, it would lead to a reduction in both treatment costs as well as a reduction in potential treatment-related adverse effects. On the other hand, other patients in whom stopping at three years may not be warranted, and should patients with exon 19 deletion be treated differently from those with exon 21 L858R mutation? Third, does a similar adjuvant targeted therapy approach be warranted for ALK-rearranged NSCLC that has been surgically resected? And fourth, are there specific subgroups of patients undergoing neoadjuvant treatment in whom immunotherapy as a neoadjuvant treatment may not be effective? Examples are those with EGFR mutations or ALK rearrangements, or even those with no PD-L1 expression.

Brittany Harvey: Absolutely. We'll look forward to finding the answer to those questions for future guideline updates. So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Singh.

Dr. Navneet Singh: Pleasure.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Surpiya Mohile, Dr. William Dale, and Dr. Heidi Klepin discuss the updated guideline on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy. They highlight recent evidence that prompted the guideline update, and share the updated evidence-based recommendations from the panel, focusing on geriatric assessment-guided management. Dr. Mohile also reviews what the expert panel recommends should be included within a geriatric assessment, and Dr. Dale highlights the Practical Geriatric Assessment tool, aimed at helping clinicians implement a geriatric assessment. Dr. Klepin comments on the impact for both older adults with cancer and their clinicians, and reviews outstanding questions and challenges in the field.
Read the full guideline, "Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update" at www.asco.org/supportive-care-guidelines

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the update and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00933. See also the Practical Geriatric Assessment tool and associated videos (How to do a Geriatric Assessment, What to do with the Results of a Geriatric Assessment) mentioned in the podcast episode.

My name is Brittany Harvey, and today I'm interviewing Dr. William Dale from City of Hope National Medical Center, Dr. Heidi Klepin from Wake Forest Baptist Comprehensive Cancer Center, and Dr. Supriya Mohile from University of Rochester Medical Center—co-chairs on “Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update.”

Thank you for being here, Dr. Dale, Dr. Klepin, and Dr. Mohile.

Dr. William Dale: Nice to see you. Thanks for having us.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests joining us on this podcast episode today, are available online with the publication of the guideline in the Journal of Clinical Oncology linked in the show notes.

Diving into the content of this guideline first, Dr. Dale and Dr. Mohile, can you speak to what prompted an update of this ASCO guideline on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy, which was previously published in 2018?

Dr. William Dale: Sure. Yes. In 2018, that was the very first guideline for older adults that ASCO had created, and that was based on work that had been done up to that time, focused on chemotherapy toxicities. And to summarize what was put out at that time, the evidence was thought to be strong enough for doing geriatric assessments. And these are specialized assessments across a number of domains, including functional impairments, cognitive losses, social impairments, etc. But to do these kinds of geriatric assessments with validated tools; that a certain selection of these domains to cover everything that was relevant; to conduct non-cancer prognostication so that for decision-making purposes, if someone were to have their cancer cured, what would be their prognosis, and help make decisions about giving chemotherapy and what doses; and then to enact geriatric assessment-guided target interventions was the fourth recommendation. And so that's where we were in 2018.

In 2020 at ASCO, there was an oral session that had four randomized controlled trials that enrolled older adults. And in that was kind of the signal that there was more coming. And in 2021, two big trials that are practice-changing were published. One led by Dr. Mohile in Lancet that we call the GAP70+ study, and another one was published in JAMA Oncology. And they essentially showed the same thing, which was that GA-guided interventions could change the primary outcome, which was to reduce chemotherapy toxicity up to 20%, and also to affect a number of other outcomes.

That, along with a number of other trials that have since come out and are included in the upcoming guidelines, and made it a high priority to update these guidelines. So that's where we got from there to here. And I think it's worth saying a few words about these new trials, particularly the GAP and GAIN studies.

So the GAIN study included patients who were 65 and older who were starting systemic chemotherapy and looked at the likelihood of having chemotherapy toxicity as described and looked at a number of other outcomes. Most importantly, it showed that chemotherapy toxicity could be reduced with these interventions based on the geriatric assessment from about 60% to about 50%. It also showed that the likelihood of completing advanced directives would go up by around 25%. And importantly, there was no impact after all of the use of the geriatric assessments on mortality. So patients were living just as long, but they were having less toxicity and they were having more goal-concordant care. And at almost the same time, the GAP study came out, which I would hand over to Dr. Mohile to describe.

Dr. Supriya Mohile: Thank you, Dr. Dale. I agree that it was time for an update, and I'm glad ASCO partnered with us to do this. I'll also just mention that Dr. Dale, Dr. Klepin, and I lead the Cancer and Aging Research Group, and many of the original predictive models that showed that geriatric assessment could help us identify patients at highest risk for toxicity were designed by Cancer and Aging Research Group investigators. And that's what informed the first guideline. I'll mention Dr. Arti Hurria, who unfortunately passed away a few years ago, and she led some of the first large studies that developed these predictive models. We built on that data in both GAP and GAIN studies to show that the geriatric assessment—when you assess and provide management—can reduce chemotherapy toxicity.

Like GAIN, GAP70+ implemented a geriatric assessment intervention that both assessed and provided management to older adults. There were some key differences. In GAP70+, the patients had advanced cancer, whereas, in the GAIN study, it was a more generalizable population of patients with both curative intent and advanced cancer. And in the GAP70+ study, we enrolled patients who already had geriatric assessment domain impairments, meaning that these patients were more vulnerable because of those aging-related conditions. We were trying to enroll patients who are traditionally excluded from therapeutic clinical trials. The GAP70+ study was done in oncology offices by Community Oncology practices.

So this was what I think was really interesting, in that geriatricians were not involved in implementing the geriatric assessment in this study. Oncologists received the assessment information from their team, and they're the ones that implemented the recommendations. We found in GAP70+ that not only chemotherapy toxicity was reduced, that we were able to reduce the prevalence of falls and reduce the incidence of polypharmacy, which are important geriatric outcomes for older adults. We included patients who were receiving chemotherapy, but also patients who are receiving high-risk targeted agents in GAP70+, which also leads us to believe that these interventions are important for patients who are receiving treatments other than chemotherapy.

So we believe these two trials, plus others, really inspired the ASCO guidelines.

Brittany Harvey: Absolutely. I appreciate you both for providing that context and background and some of the new evidence that's informed this latest update. So then I'd like to move into some of the updated recommendations of the guideline. So, Dr. Mohile, what is the updated recommendation from the panel regarding the role of geriatric assessment in older adults with cancer?

Dr. Supriya Mohile: So the first guideline really focused on the assessment piece, what should be assessed, and why, which we still incorporate in this new guideline. This guideline extends now because of the randomized controlled trials into management. And when we think about geriatric assessment, we think about two pillars of management. One is how geriatric assessment influences cancer decisions, that includes what treatments to provide, what dose to provide. And then the second is how geriatric assessment can influence management recommendations that are supportive care based that address some of the geriatric assessment domain impairments.

I’ll just give you an example of both. So when we see patients with advanced cancer who have geriatric assessment domain impairments who are presenting for treatment, often the doses of chemotherapy may be overtreatment because those doses were developed in therapeutic clinical trials in younger, more fit patients. And in our geriatrics world, we often think about going slow and starting low, and we may do a first cycle that’s dose reduced a touch, to kind of see how the patient does physiologically with that first cycle. There are therapeutic clinical trials like FOCUS2 in patients with metastatic colon cancer that show the benefits of being careful with dosing in the first cycle.

So, in GAP70+, the oncologists who received information from the assessment were more likely to reduce the dose of the treatment in the first cycle which led to less toxicity but did not lead to a difference in survival, so do not compromise survival. And I think this is because we don’t know the right doses for patients who have significant aging-related impairments. So that’s one example of decision-making.

As examples for geriatric management recommendations that are supportive care, this can be done in almost like an algorithmic approach. So, if a patient has an impairment on a physical function test, then through the geriatrics literature we know of management recommendations that can improve outcomes like physical therapy, home safety evaluations, balance, training, fall prevention information. And if we implement those supportive care recommendations through that patient who’s at risk for falls, we may prevent falls and we were able to show that in addition in GAP70+ as well as other trials showed benefits in some of those outcomes.

And so those are the two pieces that I think are newer with this guideline than with the previous guideline. We know more about how those management recommendations can improve outcomes.

Brittany Harvey: Understood. Yes. It's helpful to understand those examples of how integrating this geriatric assessment can help improve the management of care for these patients. So then you've mentioned some of the geriatric assessment domain impairments. So, Dr. Mohile, what does the guideline recommend should be included within a geriatric assessment?

Dr. Supriya Mohile: This was a really great question for us to rise and think about, as part of this guideline and as a panel, we went back and forth with all of the authors to try to think about what is the most streamlined number of domains that should be assessed? What are the highest priority domains that, if you could only do a few things in a busy oncology clinic, which are the ones that oncologists should have to do because without doing them, they won't have relevant information to inform treatment decisions or to improve the outcomes of their patients?

And so when we think about geriatric assessment, there has been literature to show that almost all of the domains we do are important in identifying patients who are at risk of poor outcomes. These include physical function, cognitive function, emotional health, comorbidities, polypharmacy, nutritional status, and social support. That sounds like a lot, but we do many of those assessments sort of naturally in oncology clinics. There are just a few that are not done as standard. For example, it is not standard for oncologists to assess cognition using a validated screening test for cognition. And we know that recognizing patients who may have cognitive impairment is really important in identifying vulnerabilities and providing support systems in place so patients who are receiving treatment can go through treatment safely.

Other things, like just doing a formalized nutritional assessment, really bringing in the caregiver, are done not in a standard way. And so what the geriatric assessment allows is for us to assess each of those domains in a standard way. When we're communicating to our colleagues and tumor boards, we can describe vulnerabilities in a standard way. And we're moving now past the eyeball test, which is different for different clinicians, and having more objective ways of describing health status to be able to have a common language across studies and in clinical care.

Brittany Harvey: That's helpful to understand moving past the less formal approach to geriatric assessment and making it more standardized.

So then, Dr. Dale, this guideline offers a specific tool, the Practical Geriatric Assessment, as an option for clinicians conducting a geriatric assessment. What is this tool and where can clinicians access it?

Dr. William Dale: Very good question. Just to set the context a bit, after hearing about all the evidence that we've just described. We did do some work as a task force through ASCO and through some work that Dr. Klepin and her colleague have done to understand now that the guidelines in 2018 had come out, they weren't really being used. So when we asked, about 25% of people would say they were using them very much, even though we saw in these large studies that we did, that those who were using the guidelines were changing their practice significantly in the ways that Dr. Mohile mentioned. And this was among a large group of community oncologists.

So we have been breaking down the geriatric assessment into the most concise, most straightforward, and easiest-to-use version of the geriatric assessment, maintaining its validity and maintaining the number of domains. We really tried to make it simple. So the Practical Geriatric Assessment is not the only tool, but it is a tool that accomplishes this practical charge to make it accessible to community oncologists while also being valid. So those domains that Dr. Mohile mentioned physical function, functional status, nutrition, social support, psychological considerations, comorbidities are all in the Practical Geriatric Assessment.

But what we've done is boil it down to here's a very specific tool that we think is valid but easily applied. Here are the very specific thresholds that tell you when a deficit has been identified and then gives recommended actions to be taken, whether it's in decision-making or in other interventions like a referral to somebody, perhaps physical therapy, or a cognitive specialist, all of which come from the GAP. So this tool is designed to be very straightforward and practical, but still cover all the relevant domains. And it will be made available through both the ASCO website and through the Cancer and Aging Research Group website so that people can access it easily.

Brittany Harvey: That sounds like a real challenge that the ASCO working group took on to create a comprehensive yet practical tool for clinicians to use. We'll also provide some links for people to access this in the show notes of this podcast episode.

So then I want to move on. Dr. Klepin, in your view, how will this guideline update impact both clinicians and older adults with cancer?

Dr. Heidi Klepin: Yes. Thank you. As was mentioned, for clinicians, the guidelines provide an overview of new evidence and concrete recommendations to address the challenge experienced every day in practice, that of providing personalized care in the context of age-related conditions to maximize benefits and minimize the risk for older adults with cancer. The evidence summary will educate clinicians on key outcomes that can be positively impacted by use of geriatric assessment, including decreasing treatment toxicity, enhancing decision-making, and improving communication and patient-caregiver satisfaction.

And this information on outcomes is really critical to informing the use of geriatric assessment in practice. We hope that the evidence-based recommendations with the provision of the practical geriatric assessment and the associated trigger table to guide management strategies will empower clinicians to incorporate geriatric assessment into their workflow by helping them overcome some of those known barriers that Dr. Dale mentioned, such as lack of time and uncertainty about which measures to use and what to do with the information once you have it. So, we anticipate that providing clear recommendations and accompanying readily available materials to support the implementation that clinicians in both community and academic practices will be able to use the geriatric assessment and incorporate it into routine care.

For patients, we anticipate that the guideline recommendations would translate into increased use and access to this type of assessment as part of their routine oncology care. So, we hope that our patients will actually be able to access this regardless of whether they're receiving care at a specialized academic center versus a community oncology clinic. So, by doing this, we would extend the proven benefits of geriatric assessment, including lower rates of side effects, experiencing fewer hospitalizations, and improving satisfaction to older adults regardless of where they receive treatment.

And we feel like this is critically important, since currently, most older adults receive cancer care in community oncology clinics without access, as was mentioned, to any geriatric specialty care. So, as more older adults have the opportunity to participate in this type of assessment as part of routine care in their oncology clinics, they'll be able to discuss the results of the assessment with their healthcare providers, which can help them make better-informed decisions and engage, I think, more completely in what we would consider patient-centered decision making. And ultimately, we would hope that the guidelines would provide an evidence-based and practical strategy for improving the quality of care received by older adults with cancer.

Dr. Dale, would you be interested in commenting a little bit more on the patient perspective informed by our patient partners on the guideline panel?

Dr. William Dale: Yeah. Thank you, Dr. Klepin. Very well said. Yeah, our guideline panel, just to fill out the picture of that, included our patient partners, along with a wide diversity of perspectives. We had experts in geriatric oncology, but we had community oncologists who take care of cancer patients. We have people from across the country. We had different backgrounds and different levels of experience. But to focus on the patients for a group that we've worked with for some time called SCOREboard, and they were some of the strongest voices on this.

Whenever people said, “Well, do we really need to require this?” The patient partners were insistent that this be included as a requirement as much as possible for what happens. I think one of the most important roles they've played is as advocates for this. If I can, when the community oncologists are having some concerns about how hard this would be or how difficult it might be, the patient partners have been the first to say, we need to find a way to do it and insist that we empower the patients to ask for it. So, one of the hopes for all of these guidelines is also that it get disseminated to patients who can self-advocate as they go forward and have tools that will be made available for them to use in this self-advocacy.

Brittany Harvey: Definitely, that self-advocacy is important and the geriatric assessment is critical for optimal care for older adults.

So, then we've talked a lot about the new evidence regarding geriatric assessment and also making it easier for clinicians to implement the geriatric assessment, but Dr. Klepin, what are the outstanding questions and challenges regarding geriatric assessment in older adults with cancer?

Dr. Heidi Klepin: Thanks. So, while there's strong evidence and clear rationale to incorporate geriatric assessment into routine clinical care, there are outstanding questions and challenges that we have to consider. First and foremost, still remains a challenge of implementation. As mentioned, we hope that the Practical Geriatric Assessment, the detailed recommendations, and the associated educational materials on what to do with the geriatric assessment information will help overcome implementation barriers for many. But we recognize that more work needs to be done to both train providers to facilitate behavior change as well as to tackle clinic and healthcare system barriers to routine use.

And along these lines, we also recognize that it's important to educate patients and caregivers about the role of geriatric assessment and its value in order to optimize uptake in community clinics. We want all of our patients to be as enthused and recognize the importance of the geriatric assessment, as our colleagues on the recommendation panel did. Another consideration is the challenge of tailoring use of geriatric assessment to specific disease and treatment settings. And more research is underway testing geriatric assessment and management strategies in varied disease settings, as well as with varied treatment types and intensities.

And finally, I would suggest that another challenge is the lack of routine incorporation of geriatric assessment measures into cancer clinical trials. And this will really be necessary to interpret clinical trial data for older adults optimally and to reinforce the value of routine geriatric assessment in clinical care.

Brittany Harvey: Absolutely. These are key points for moving forward and looking forward to additional research in this area and maybe future guideline updates down the line.

So, I want to thank you all so much for your work on updating this guideline and for your time today. Dr. Dale, Dr. Klepin, and Dr. Mohile.

Dr. Heidi Klepin: Thank you for having us.

Dr. William Dale: Yeah, thanks for having us here. We're delighted to be talking about this.

Dr. Supriya Mohile: Thank you.

And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Charles Loprinzi shares the latest update to the management of cancer cachexia guideline. Dr. Loprinzi discusses the evidence that prompted the rapid update to the guideline and reviews the new evidence-based recommendations, including the addition of low-dose olanzapine as a treatment option for patients with advanced cancer to improve weight gain and appetite. Dr. Loprinzi reviews the limitations of the update, and outstanding research questions in the domain of cancer-associated cachexia.

Read the latest update, "Cancer Cachexia: ASCO Guideline Rapid Recommendation Update" at www.asco.org/supportive-care-guidelines

TRANSCRIPTThis guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01280

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Charles Loprinzi from Mayo Clinic, Co-Chair on “Cancer Cachexia: ASCO Guideline Rapid Recommendation Update.” Thank you for being here today, Dr. Loprinzi.

Dr. Charles Loprinzi: It's a pleasure to participate.

Brittany Harvey: Then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Loprinzi who has joined us here today, are available in line with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

Then, to get into the content of this rapid recommendation update, first, Dr. Loprinzi, what prompted this rapid update to the ASCO management of cancer cachexia guideline, which was previously published in 2020?

Dr. Charles Loprinzi: The impetus for the updated guideline was a recent JCO publication regarding the results of a randomized controlled trial looking at olanzapine. This prompted the expert panel to revisit this topic. The trial, conducted in India, involved 124 patients with stomach, hepatopancreatobiliary, or lung cancers as they initiated chemotherapy. Weight gain greater than 5% occurred in 60% of patients in the olanzapine arm versus 9% of the patients in the placebo arm with a p-value of 0.001 or less. Substantially improved appetite was seen in 43% versus 13%, with placebo also a p-value of less than 0.001. Grade 3 or greater chemotherapy toxicity was less common with olanzapine 12% versus 37%, with placebo with a p-value of 0.002. No substantial olanzapine-associated toxicity was apparent. There was one evidence of this with olanzapine versus two for placebo. So that was the reason for going ahead with this update.

Brittany Harvey: I appreciate that background information. So then, based on this updated study on olanzapine, what are the updated recommendations from the expert panel for treating cancer cachexia?

Dr. Charles Loprinzi: So, let me start to address this question by reviewing what the 2020 ASCO guidelines published said regarding the management of cancer cachexia in adults with advanced cancer. It concluded that evidence was insufficient to strongly endorse any pharmacologic agent for established anorexia/cachexia. Nonetheless, the guideline recommendation supported that clinicians could offer a short-term trial of a progesterone analog such as megestrol acetate or a corticosteroid such as dexamethasone to patients experiencing weight loss and/or appetite stimulation. These drugs stimulated appetite and caused weight gain, but they did not improve quality of life, they did not improve survival, and there was toxicity associated with these agents and therefore it was not strongly recommended.

The expert panel thoroughly discussed a potential role for olanzapine because of a couple of trials suggesting it was beneficial but concluded that the evidence was insufficient for a recommendation. Now, there was evidence from two randomized trials that supported olanzapine was an effective alternative for treating cancer-associated anorexia/cachexia. Thus, olanzapine was considered promising, but the data were not conclusive enough to support a guideline treatment recommendation. The new JCO publication was the impetus for making this guideline change.

Brittany Harvey: Understood. So then, based off this new change to the recommendations, what is the breadth of these recommendations and what do these options mean for patients with advanced cancer?

Dr. Charles Loprinzi: The updated guidelines recommended that for adults with advanced cancer, clinicians could offer low-dose olanzapine once daily to improve appetite and cause weight gain. It was noted that the majority of the evidence for this recommendation came from patients with lung or GI cancers, and the largest study enrolled patients who were receiving cytotoxic chemotherapy concurrently. Having said this, there's evidence from the other two randomized trials noted above that olanzapine is helpful in patients with a wide variety of cancers and regardless of whether patients were receiving concomitant chemotherapy.

Of note, extensive data support that olanzapine leads to significant appetite stimulation and weight gain in patients without cancer who were taking olanzapine for psychiatric reasons. This was known from a long time ago in patients in that situation, who don't necessarily want to gain weight, would gain 10-20-30-40 pounds, get prediabetes, and get diabetic sort of troubles. The guideline update continues to support that clinicians may offer a short-term trial of a progesterone analog or a corticosteroid to those experiencing weight loss and/or appetite when there's a good reason for not using olanzapine.

Brittany Harvey: Understood. I appreciate you reviewing those two updated recommendations from the guideline panel.

So then you've talked about this a little bit already in describing the study details, but what is exciting about olanzapine in this setting and what should clinicians know as they implement these updated recommendations?

Dr. Charles Loprinzi: It's exciting that olanzapine is now the best-studied established treatment available for patients suffering from cancer-associated anorexia/cachexia in different oncologic situations, for prevention and/or for treatment of cancer-associated or cancer treatment-associated nausea and/or vomiting, and for treatment of cancer-associated anorexia/cachexia. Varying daily doses of olanzapine have been used, ranging from 2.5 to 10 milligrams per day. Data support that it is quite appropriate to use the 2.5-milligram per day dose for the initial treatment of cancer-associated appetite and/or weight loss. For patients who do not appear to benefit and have no apparent olanzapine toxicity, it seems reasonable to me to try a higher dose. Another thing to note is that olanzapine is a generic drug which is relatively inexpensive. While this drug has been noted to cause sedation, such sedation is usually short-lived despite drug continuation.

Brittany Harvey: So then, it's great to hear that recent data have caused an update to these guidelines. But in your perspective, Dr. Loprinzi, what are the most pressing outstanding questions regarding the management of cancer cachexia?

Dr. Charles Loprinzi: My goodness, you're putting pressure on me. I've been involved with a large number of cancer anorexia/cachexia trials for the better part of four decades, which did not support as strong an ASCO guideline recommendation as we now have with olanzapine. Noting that I was involved with one of the trials that supported that olanzapine was helpful for treating cancer-associated anorexia/cachexia. This is one of the trials. It was a short trial. We were mainly looking at nausea and vomiting treatment for advanced cancer, but we saw a marked increase in appetite in over just a day or two of using olanzapine. Having said this, there's always room for improvement, and a number of drugs are under development for treatment of cancer-associated anorexia/cachexia.

Recent discussions regarding the topic of olanzapine for treating cancer-associated anorexia/cachexia noted that the primary endpoint of the current trial was weight gain and that this was felt to be a more objective endpoint than appetite would be. As noted in the earlier part of the discussion, substantial improvement was seen both in weight gain and appetite, both with p-values of less than 0.001. My own opinion is that appetite improvement is as important, if not more important than is weight gain in the study population. Given that the trial was double-blinded and placebo-controlled, appropriate questionnaires regarding appetite should be able to be considered as an objective evaluation of a subjective symptom in the same way that appropriate questionnaires regarding a patient's pain can be considered an objective evaluation of a subjective symptom. For some of these subjective symptoms, you just don't have other good ways we can figure these things out by a blood test or something like this. So it's what the patient says which is most important.

Brittany Harvey: Absolutely. Incorporating how the patient feels is key to achieving better outcomes for patients.

So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Loprinzi.

Dr. Charles Loprinzi: You're welcome. Pleasure to participate.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Navneet Singh highlights the latest evidence-based recommendation updates from the ASCO living guideline on stage IV non-small cell lung cancer with driver alterations. This update focuses on new second-line options for patients with advanced NSCLC and an EGFR exon 20 insertion, including amivantamab and mobocertinib. Dr. Singh also discusses updated results from CodeBreaK 200 and the option of second-line therapy with sotorasib for patients with advanced NSCLC and a KRAS-G12C mutation.

Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.2” and view all recommendations at www.asco.org/living-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01055

My name is Brittany Harvey, and today I am joined by Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2023.2.”

Thank you for being here, Dr. Singh.

Dr. Navneet Singh: Thank you for having me, Brittany.

Brittany Harvey: Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the Guideline panel, including Dr. Singh, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into this living clinical practice guideline, Dr. Singh, this living guideline for systemic therapy for stage IV non-small cell lung cancer with driver alterations is being routinely updated. What new studies were reviewed by the panel to prompt an update to the recommendations in this version?

Dr. Navneet Singh: So for this 2023 version 2 update, three trials were included. These include two studies which involved patients with exon 20 insertion mutations, who had received prior platinum-based chemotherapy and subsequently were treated with either amivantamab in the CHRYSALIS trial or with mobocertinib in the EXCLAIM trial. The third trial which formed the basis for this update was one which involved patients with KRAS G12C mutation who had previously received systemic therapy and subsequently were treated with sotorasib. And this was the CodeBreaK 200 trial.

Brittany Harvey: Understood. So then, based on these three new trials that you've just mentioned, what are the updated recommendations from the expert panel for patients with advanced non-small cell lung cancer?

Dr. Navneet Singh: For patients with advanced NSCLC with an EGFR exon 20 insertion mutation and an ECOG performance status of 0 to 2 who have received prior platinum-based chemotherapy, clinicians may offer amivantamab or mobocertinib as monotherapy. It is important to mention here that in the absence of head-to-head comparison of amivantamab or mobocertinib with each other or with other standard second-line therapies, no recommendation for sequencing can be made and therefore treatment should be individualized. Now, use of either of the two drugs is based on low-quality evidence and has a weak strength of recommendation. And the updates for treating KRAS G12C-mutated NSCLC is largely similar; that patients who have received prior systemic therapy may be offered sotorasib.

Brittany Harvey: Thank you for reviewing those updated recommendations. So what should clinicians know as they implement these new recommendations and how do they interface with the existing recommendations?

Dr. Navneet Singh: It is important for clinicians involved in the management of EGFR mutant lung cancer to realize that exon 20 insertions are the third most common group of EGFR mutations and comprise approximately 5% of all EGFR mutations. Now, historically, the EGFR targeted drugs which have been the first, second, or third generation tyrosine kinase inhibitors have largely shown efficacy for the two common types of EGFR mutations, namely the exon 19 deletions and the exon 21 L858R point mutation.

Exon 20 insertion mutations thus did not have any effective targeted therapy so far. But now, both of these drugs, amivantamab and mobocertinib, have shown very promising results for pretreated patients with this molecular aberration and therefore may be used in view of standard second line therapy. Similarly, in the case of KRAS G12C mutation, before this, there was no effective targeted therapy, but now sotorasib, based on the CodeBreaK 200 trial, appears to be a very valid option in view of standard second-line therapy.

Brittany Harvey: Excellent. So then, what do these new treatment options mean for patients with stage IV non-small cell lung cancer and an exon 20 insertion or a KRAS G12C mutation?

Dr. Navneet Singh: For patients with stage IV NSCLC and harboring an EGFR exon 20 insertion, the availability of two specific targeted drugs will improve the treatment options available following standard first-line therapy. Furthermore, ongoing trials for these agents in the treatment-naive setting may eventually lead to a scenario wherein such patients may be treated upfront with targeted therapy rather than chemotherapy or chemoimmunotherapy, analogous to how patients with the common EGFR mutations are treated. The ultimate aim of precision medicine is to offer the most effective treatment based on biomarker expression and targeted therapies in comparison to chemotherapy because these lead to better treatment outcomes and lesser side effects.

Brittany Harvey: Absolutely. The goal of better outcomes with less side effects is what we're looking to achieve here. So then, finally, as this is a living guideline, what emerging therapies or targets is the panel monitoring for future guideline updates?

Dr. Navneet Singh: As was already said, the expert panel eagerly awaits data from ongoing trials which are assessing the efficacy of drugs targeting the EGFR exon 20 insertion mutations, namely amivantamab and mobocertinib as first-line therapy, as also the drugs which target the KRAS G12C mutations which is sotorasib and adagrasib in the treatment-naïve setting. Ultimately, the optimal sequencing of therapies needs to be established in advanced and metastatic non-small cell lung cancer for several of the oncogenic driver alterations other than classical EGFR mutations and ALK and ROS-1 rearrangements. These include the EGFR exon 20 insertions and other uncommon EGFR mutations, the BRAF V600E, KRAS G12C, the HER2, and the MET exon 14 skipping mutations as well as the RET and NTRK fusions.

Brittany Harvey: It sounds like the living guideline expert panel will be busy moving forward then. So I want to thank you so much for your work to update this living guideline and thank you for your time today, Dr. Singh.

Dr. Navneet Singh: Thank you so much, it was a pleasure being here.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Antonio Wolff and Dr. Kim Allison discuss the latest ASCO-CAP guideline update on HER2 testing in breast cancer. This guideline update affirms previous recommendations, and provides commentary based on data from the DESTINY-Breast04 trial. Dr. Wolff and Dr. Allison review the questions from the oncology and pathology community raised by these results, and provide commentary on patients with HER2 IHC 1+ and 2+ and ISH-negative metastatic breast cancer.
Read the guideline update, "Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update" at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.22.02864

My name is Brittany Harvey, and today I am interviewing Dr. Antonio Wolff from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Dr. Kim Allison from Stanford University School of Medicine, co-chairs on ‘Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update’. Thank you for being here, Dr. Wolff and Dr. Allison.

Dr. Antonio Wolff: Thank you.

Dr. Kim Allison: Thanks for having us.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in developing its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the full guideline panel, including our guests on this episode today, are available online with the publication of the guideline and the Journal of Clinical Oncology, linked in the show notes.

So now jumping into the content, to start us off, Dr. Wolff, what prompted the update expert panel to revisit the 2018 ASCO-CAP recommendations on HER2 testing and breast cancer, and what is the scope of this update?

Dr. Antonio Wolff: Thank you, Brittany. We appreciate the opportunity of being with you today, and it's great to be here with my colleague, Dr. Kim Allison, as well.

What triggered this informatory update was the release from data in trial DESTINY-Breast04, which tested the antibody-drug conjugate trastuzumab deruxtecan in patients who in the past would have been considered to have HER2-negative disease. This ADC, trastuzumab deruxtecan, has a topoisomerase inhibitor payload that is linked to the antibody trastuzumab. And in the past, from all the previous data we had, trastuzumab alone, or in combination with chemotherapy, or as part of another antibody-drug conjugate T-DM1 was essentially active in patients with HER2-positive disease, which is traditionally defined as having overexpression of the HER2 protein, which almost by default is a result of gene amplification of the HER2 gene.

And what data from initial studies appear to suggest is that patients who would not be traditionally considered HER2-overexpressed or HER2-amplified were potentially benefiting or having evidence of clinical activity against this disease in the study of metastatic disease. And this was a randomized clinical trial for patients with metastatic breast cancer whose tumors were centrally determined to have IHC 1+ or IHC 2+ expression and would not have been called HER2-positive, would not have been called HER2-overexpressed. And for the tumors that were HER2 2+, they also had to have absence of gene amplification by an in-situ hybridization assay.

And what was very interesting is that there was a meaningful, clinically significant improvement in survival for that patient population. And that has some clinicians to begin asking whether there is a different subset of patients who would have in the past been called as having HER2-negative disease that now could potentially be a candidate for this drug. And is there a difference between these patients and patients who, in the past, would have been called as HER2-negative on the basis of IHC 0? And so what complicated things for us a little bit is that patients with IHC 0 were not eligible for this trial. And what is left unanswered by this clinical trial is whether all patients who don't have HER2 protein overexpression or HER2 gene amplification would potentially have benefited from this drug. Kim?

Dr. Kim Allison: Yeah, agree. I think the main impetus for the update was the exciting results from the DESTINY-Breast04 trial and the questions then that the pathology community and the oncology community had about whether this should change HER2 testing guidelines.

Brittany Harvey: I appreciate that background on what prompted the panel to revisit this guideline. So then, Dr. Allison, how did the panel come to the conclusion that the previous recommendations are current and valid?

Dr. Kim Allison: Right. So, as Antonio mentioned, the whole reason HER2 testing was first initiated was HER2-targeted therapies that showed response in the overexpressed or amplified tested population. And so guidelines have really been fine-tuned and crafted around distinguishing the HER2-positive for over-expression and amplification from negative. And this trial really questioned that in that maybe we can target lower levels of the HER2 protein, but this assay really wasn't designed for that. So we looked at the data from the trial and some of the limited other data that's out there and really came to the conclusion that, look, everyone in DESTINY-Breast04 benefited. The whole population benefited, whether you were 1+ or 2+. And because 0s were excluded from the trial, we don't know if they benefited.

So we thought it was premature to create a new category, a new result category, and change our current reporting to a HER2-low category, mainly because we don't know that there's a new predictive threshold for response to treatment. So essentially, what we've got is a trial that showed great benefit but didn't create a new biomarker that is predictive or prognostic. Instead, it repurposed this older test as a trial entry criteria. And so now we're kind of stuck with 1+ or 2+ ISH negative as their trial entry criteria that gives you eligibility for trastuzumab deruxtecan. So essentially, we reaffirmed our prior recommendations with acknowledgment that what these categories: positive, equivocal, and negative, refer to is for protein overexpression or gene amplification and that we should continue to use the same scoring criteria, 1+, 2+, 0, and interpretation as were used in DESTINY-Breast04 for their clinical trial criteria. But awareness is important.

Dr. Antonio Wolff: Yeah, the other thing that I would add, Brittany, I think we need to go back to what was the purpose of HER2 testing back in 1998 when we identified the survival benefit from trastuzumab in metastatic disease. And then, in 2005, when we had evidence of adjuvant benefit in improving disease-free and then overall survival for patients with early-stage disease. And the immunochemistry assays at that time were developed to differentiate between patients who had HER2 overexpressing disease or HER2 gene amplified disease versus not. At that moment, it was clearly identified that patients were considered as having HER2-positive disease that defined a biological entity, a tumor subtype, a group of patients who had worse prognoses in the absence of therapy. But then when they were treated with, for instance, chemotherapy with anthracyclines at that time, but then with HER2 targeted therapies with antibodies, these patients that otherwise would have a poor prognosis now were having an improved outcome.

HER2 was a marker of poor prognosis but also a marker of a good chance of deriving clinical benefit, so there was a predictive benefit. And everything else, IHC 0, 1 or 2+, ISH-negative, there has been no evidence that targeting the HER2 pathway was clinically important. Or even more meaningful, there was no evidence that these patients have– within the subset of patients that don't have HER2 positive or overexpressing disease - there has been no evidence that those patients have a different outcome based on low levels of expression of HER2.

A couple of years ago, in terms of trastuzumab, the NSABP reported findings in the data from NSABP B-47 where the antibody trastuzumab was added to chemotherapy to patients who were considered to have low levels of IHC expression, and in that case, was IHC 1+ or IHC 2+ gene non-amplified. And that settled the issue for sure, that there was absolutely no benefit in the adjuvant setting from the addition of trastuzumab. So we know that there's something different going on here. We know that if you now combine trastuzumab with a specific payload, in this case, the drug deruxtecan, which is a topoisomerase inhibitor, we are potentially targeting the HER2 protein. But these are tumors that are not considered HER2 addicted. These are not tumors whose biology is dependent on the HER2 pathway, so this is simply a better drug delivery.

And in this sense, data and evidence from Michael Press, a pathologist at USC that has done some seminal work with HER2 and HER2 testing, he once proposed that the vast majority of breast cancers have some level of HER2 present. And a lot of what is considered IHC 0 is an artifact related to suppression of the detection of the HER2 protein. So there's a chance that the tumors that are truly HER2 negative or HER2 0 are going to be a very small proportion. And IHC assays were never optimized to measure very low levels of HER2. They just don't have the dynamic range for that. And then, from a clinical standpoint, there is no evidence that different levels of HER2 when, in the absence of overexpression, identify groups of patients that have disease that have a different biologic behavior.

And I think, as Dr. Allison just mentioned, we don't have any evidence from the DESTINY-Breast04 trial that there is a differential benefit between IHC 1+ versus IHC 2+, ISH-negative. Those patients appear to equally benefit from therapy.

Brittany Harvey: Understood. That context is helpful in understanding this updated guideline.

So then you've both mentioned the category of patients who are HER2 IHC 1+ and 2+, and ISH-negative. So, Dr. Allison, this article includes a special commentary on those patients, those with HER2 IHC 1+ or 2+, and ISH-negative metastatic breast cancer. What are the essential points of this commentary?

Dr. Kim Allison: Yeah. So some of them we've brought up already that this test for HER2 IHC wasn't really designed to detect the low levels of protein expression that may be present in some breast cancers, including the all-important issue that the IHC 0s may not be truly null for HER2, that we may just not be sensitive enough to detect it, or there may be fixation and ischemia, time issues that are very subtle and create a false negative result, essentially by IHC that, and that in addition to not being necessarily predictive or prognostic, the 0 versus 1+ threshold, which really is a threshold that hasn't been tested yet.

But since eligibility for trastuzumab deruxtecan essentially now hinges around that 0 versus 1+ threshold, since these were clinical trial entry criteria, what can pathologists do to make best practice efforts to distinguish 0 from 1+? Because we felt like we should make some helpful recommendations, at least since this does appear to be a current status point that pathologists are going to be struggling with in practice. So the points we come up with in that commentary are to follow best practices, like making sure you're using the standardized ASCO-CAP Guidelines criteria. Making sure you pay attention to pre-analytic conditions of the tissue sample and that you're using controls with a range of protein expression, including 1+, to help ensure you've got an assay that's really looking at the right limit of detection since that has shifted somewhat in this instance.

And then for interpretation side, for pathologists to be sure to look on high power, so discriminating at 40x when you're trying to score a 0 versus 1+ stain since that's now relevant, you're going to need to go on high power and really distinguish from those two. And then, consider a second pathologist review in borderline or challenging cases or perhaps using additional tools. There's some additional tools online. There are learning sets that are out there to help with that distinction.

Dr. Antonio Wolff: What I would add to that is that I think, and Kim, I'm thinking of the pathologist now getting phone calls from oncologists saying, “Hey, Doctor Pathologist, you report this cancer as being IHC 0, and are you sure that this is truly IHC 0?” And I think we need to be careful not to put pathologists in an unfair situation. And I think we also need to be careful based on our behavior as oncologists that we could almost cause the extinction of the diagnosis of IHC 0 if pathologists feel somehow compelled to “try to help the oncologists” and potentially call a tumor that they would otherwise have called IHC 0, that they call that tumor IHC 1+.

And I think the reason for being cautious, as Kim mentioned, is these assays were not optimized for the ability to truly distinguish between IHC 0 and 1+. And we do not know if tumors that are IHC 0 clinically behave differently from tumors IHC 1+. Right now, that does not appear to be the case. And I think to a degree, we are being forced, based on the decision by the study sponsors to launch a study that excluded patients of IHC 0. We are left, I often say, twisting ourselves into pretzels, trying to come up with a way to discriminate between IHC 0 and 1+ simply because of the eligibility of the clinical trial and now the resulting FDA label for the study.

Because it is plausible that what if patients who had tumors that were IHC 0 had been included in this clinical trial? And what if we had determined that those patients also benefited from this new exciting antibody-drug conjugate? In that case, we would not be talking about creating new categories of HER2 low versus HER2 “ultra-low” and HER2 0, HER2 null. Because essentially, we would have identified a new clinical use for this exciting antibody-drug conjugate for patients who have tumors that are HER2 not overexpressed and HER2 not amplified. So, in fact, it is entirely plausible that the population of patients that could benefit from this antibody may go well above the original intent of DESTINY-Breast04. We just don't have the evidence at this point to say that those patients who would be called IHC 0 don't benefit. It's just that they were not included in the clinical trial.

Brittany Harvey: Well, your points there from both of you lead nicely into my next question, in that you've talked a little bit about how this impacts both oncologists and pathologists. So, Dr. Wolff, what does this guideline and commentary mean for both clinicians and patients with breast cancer?

Dr. Antonio Wolff: So I think what I would try to reassure oncologists, pathologists, and also patients and their caregivers and loved ones, over the last 20 years, I think we have seen a meaningful improvement in the quality of HER2 testing. And I think pathologists and oncologists recognize that breast cancer biomarkers, in general, in the past, were used purely for prognostic reasons or to complement anatomic pathology from a diagnostic standpoint. But now, many of these assays, especially ER and HER2, are used as the sole determinant of therapy selection in a binary fashion. If you are positive for ER, you can be a candidate for ER-targeted therapy. If you're positive for HER2, you may be a candidate for HER2-targeted therapy. And I think even though the current generation of IHCs were not equipped to make a differentiation between very low levels of HER2 expression from potentially no levels of HER2 expression, with all the limitations we just said, I think pathologists are today doing a very good job. They understand the importance of the work they do in helping us clinicians take care of patients in the clinic. As I often joke, pathologists are wearing the stethoscope with us. So I think we need to be kind to pathologists and not put them under the microscope, if you will, pun intended, or putting a lot of pressure on them. And I think I tend to trust the quality of the work they do.

I think there are two things that I would like to see happening. Number one, I would love to see the study sponsor allowing investigators to use a new generation of assays that are more quantitative to be able to back on DESTINY-Breast04 and test specimens of the patients that were triggered on the trial and see if there is a differential benefit in the observed outcomes of patients treated with trastuzumab deruxtecan according to levels of HER2, but that can be measured using a truly quantitative assay. And there are a lot of new assays out there. And I think the sponsors, they do have an obligation to all the patients who are participating in the trial to allow those things to happen. And the second piece is obviously to develop assays that are more quantitative than a traditional IHC.

And Kim, along these lines, a question that often comes up is what to do with patients who may have had a previous test that was IHC 0. And what should we, I guess, recommend to clinicians that they do with this situation?

Dr. Kim Allison: Yeah, I think this is a common question, and because of the unreliability of a 0 versus 1+ result, and we do see them change when you look at metastatic, or core versus primary surgical excision, 0 versus 1+ results shift around much more so than you'd expect if this was a true biologic difference. So I would look at a spectrum of samples across the metastatic progression. So if any of them are not 0, I think that's a result worth looking at. And considering that either there's heterogeneity there potentially or the 0s were false negatives and not consistent over time, so I would test the metastatic sample again. If you have a new sample, if that's 0, I would still consider treating based on a prior 1+ result or a different sample that's metastatic.

Dr. Antonio Wolff: Yeah, the one thing that I haven't done yet is actually for patients who have had– Let's say, that I have a primary term that was IHC 0, and then, they had, unfortunately, metastatic disease, and the diagnostic tissue that confirmed that they had metastatic disease also tested IHC 0. And now they are– unfortunately, disease has progressed after first or second-line therapy, be it anti-estrogen if they had ER-positive disease or chemotherapy if they had ER-negative disease. What I have not done is to request a new biopsy exclusively for the purpose of doing another HER2 test because in case the tumor had changed expression from 0 to 1+. Because what we don't know because of the variability, etc., Dr. Allison was just describing whether that change is real or not.

Again, it's really unfortunate that patients who were IHC 0 were not allowed for this study. There are other studies taking place right now looking at tumors that are more than IHC 0 and less than IHC 1+; that’s DESTINY-Breast06. And those patients are being called by the study sponsor as “ultra-low”. Although I am not a pathologist, but I have no idea how a pathologist can truly try using immunohistochemistry today; really reliably differentiate between it's not 0, it's not 1+, it’s in between. I am just concerned that I think we may be asking or putting pathologists in a hard spot, asking them to do something with an assay that was not designed to perform that way.

Dr. Kim Allison: Even if we could get the interpretation perfect, to have digital tools to help us with interpretation, I think at that low level, IHC is just really sensitive to pre-analytics and analytic factors that are subtle. Even having a slide that's been sitting unstained for a week or so might change a 1+ to a 0 result. So it really is sensitive, maybe too sensitive, to those kinds of factors.

Brittany Harvey: Absolutely. Well, thank you both for those insights on what's facing clinicians and patients and the commonly asked questions today.

So then we've spent a lot of time talking about what's happened recently in this field. But, Dr. Allison, what are the ongoing developments and outstanding questions you're all facing regarding HER2 testing and breast cancer?

Dr. Kim Allison: Yeah. I mean, I think we've covered some of those. Is IHC 0 truly 0? Would it be responsive to T-DXd or other antibody-drug conjugates targeting HER2? And so if that is relevant, then there's a lot of work looking at maybe more sensitive or quantitative assays that are really designed to detect those lower levels of expression, unlike the current assays. And then digital image analysis to standardize interpretation if they are leading to differences. And then new standards to help us calibrate.

Brittany Harvey: Great. Well, I want to thank you both so much for all of your work to review and update this guideline on HER2 testing in breast cancer. And thank you for your time today, Dr. Wolff and Dr. Allison.

Dr. Kim Allison: Thanks for having us.

Dr. Antonio Wolff: Our pleasure. It’s fun. Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Angie DeMichele and Dr. Lynn Henry present the latest rapid recommendation impacting two ASCO guidelines. This update focuses on testing for ESR1 mutations in patients with hormone receptor-positive, HER2-negative metastatic breast cancer, and presents treatment recommendations for patients with a detectable ESR1 mutation. Dr. DeMichele and Dr. Henry review the recent data from the EMERALD trial, discuss it's implications for practice, and ongoing developments they're monitoring for more effective therapeutic options. Read the latest update, "Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the update and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.2300638

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Angie DeMichele from University of Pennsylvania, and Dr. Lynn Henry from the University of Michigan, authors on ‘Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update’.

Thank you for being here, Dr. DeMichele and Dr. Henry.

Dr. Angie DeMichele: It's a pleasure.

Dr. Lynn Henry: Thank you.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this podcast episode today, are available online with a publication of the rapid recommendation update in the Journal of Clinical Oncology, which is linked in the show notes.

So then, getting into the content of this rapid recommendation first, Dr. Henry, what prompted this rapid update, which provides updated recommendations for two ASCO guidelines? First, the ‘Biomarkers for Systemic Therapy and Metastatic Breast Cancer Guideline’, last published in 2022, and the ‘Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer Guideline’, which was last updated in 2021.

Dr. Lynn Henry: Thank you, Brittany. There's been a lot of exciting news for the treatment of metastatic breast cancer in the last few years. This particular update reflects the results of the phase III EMERALD trial. This trial compared the new oral selective estrogen receptor degrader, elacestrant, to standard-of-care endocrine therapy with either fulvestrant or an aromatase inhibitor in patients with hormone receptor-positive, HER2-negative metastatic breast cancer that had previously progressed during treatment with a CDK4/6 inhibitor in combination with endocrine therapy. Compared to standard-of-care, in this trial, they showed improved progression-free survival in both the overall study population as well as specifically in the patients who had a detectable ESR1 mutation in their circulating tumor DNA. These findings were published in the Journal of Clinical Oncology in 2022, and the drug was subsequently approved by the US Food and Drug Administration in January 2023. Therefore, we felt that it was important to update the guidelines to reflect the results of this trial and the new drug approval.

Brittany Harvey: Excellent. Thank you for describing the results of that trial and the new approval.

So then, based on this data, Dr. DeMichele, what is the updated recommendation from the guideline expert panel for testing for ESR1 mutations?

Dr. Angie DeMichele: So, the guideline panel has now recommended that ESR1 mutation testing occur for any patient who develops a recurrence or progression on endocrine therapy. And this is specifically in reference to the development of ESR1 mutations that can occur after a patient has been exposed to aromatase inhibitors. The guideline itself recommends that this testing be done on either tumor or blood, but blood is preferable because there is increased sensitivity using ctDNA testing over tumor testing. So this was an important component of the change in the recommendation because it's linked to the approval of elacestrant as a therapy. Patients are only eligible to receive elacestrant if they harbor an ESR1 mutation.

Brittany Harvey: Understood. I appreciate that explanation.

So then, Dr. Henry, following that recommendation for testing, what is the new recommendation for treatment for patients with a detectable ESR1 mutation?

Dr. Lynn Henry: Yes. So patients who have a detectable ESR1 mutation and who have previously received treatment with endocrine therapy in combination with the CDK4/6 inhibitor for advanced breast cancer now have multiple treatment options. The newest option is this new drug, elacestrant, which is given 345 milligrams orally daily. There are still the other options that we already knew about, which include a different endocrine therapy alone, such as fulvestrant or an aromatase inhibitor, or possibly an endocrine therapy in combination with a targeted agent, such as alpelisib or everolimus. And those decisions really need to be based on what other mutations are present in the patient's cancer.

Importantly, at this time, there are no safety or efficacy data to support using elacestrant in combination with targeted agents. Therefore, to date, it has only been approved to be used as monotherapy. But really, this is an exciting new potential option for treatment for patients whose tumors have a detectable ESR1 mutation.

Brittany Harvey: Yes, this is an exciting option, and I appreciate you describing how this fits in with the existing treatment paradigm for these patients.

So then, Dr. DeMichele, as these new recommendations are implemented, what should clinicians know?

Dr. Angie DeMichele: I think this is a really important new step in breast cancer in testing for ESR1 mutations. We've not previously had a medication that required the existence of an ESR1 mutation for patients to be eligible for therapy. So obtaining ESR1 mutation testing may be new for some clinicians. As I stated earlier, this can be done either on a tumor biopsy or on blood testing using the Guardant360 ctDNA test, which is the test that was used in the clinical trial. And it was stated that the ctDNA test is more sensitive than the tumor test. But what's really important here is that the testing occur at the time that the clinician is considering switching therapies, because it's important to find that ESR1 mutation prior to starting the next therapy. ESR1 mutations don't typically exist in a tumor at the time it's diagnosed. They only emerge over time after patients have been exposed to different endocrine therapies, particularly aromatase inhibitors. It's also possible that at the time of a recurrence after aromatase inhibitor therapy or progression on an aromatase inhibitor, there will not be any detectable ESR1 mutation. However, with subsequent therapy, an ESR1 mutation can occur. So a patient may need serial testing over time to determine whether an ESR1 mutation has developed.

Brittany Harvey: Understood. Those are important clinical implications.

So then, Dr. Henry, Dr. DeMichele just described some of the testing implications for patients. But in your view, how does this rapid update impact patients with hormone receptor-positive, HER2-negative metastatic breast cancer?

Dr. Lynn Henry: So as Dr. DeMichele mentioned, this update specifically highlights approval of a new drug, oral SERD elacestrant. This is an exciting new option for treatment of patients whose tumors have an ESR1 mutation. So previous data have demonstrated that cancers with ESR1 mutations do not respond as well to previously available standard-of-care treatments such as aromatase inhibitors. It's nice to have a drug that may be a better option than some of the previously existing treatments for hormone receptor-positive, HER2-negative metastatic breast cancer.

Brittany Harvey: Definitely. That's great to hear.

So then, finally, Dr. DeMichele, are there ongoing research developments that the panel is monitoring for future updates to these guidelines?

Dr. Angie DeMichele: We certainly are monitoring additional research developments, Brittany. Specifically, there are numerous other selective estrogen receptor degraders that are being tested, and these also may ultimately require ESR1 mutation testing and detection for therapies. So we'll be monitoring the results of those clinical trials. We'll also be watching for additional trials that help us understand how to best utilize elacestrant and whether it can be combined with other therapies. And then, finally, I think we have to think about how to place this in the context of other types of molecular changes that we may detect in metastatic breast cancer, such as PIK3CA mutations and others. And as we move forward, I anticipate that we will have additional therapies that are specifically targeted to molecular changes in the tumor. And I think this is a really exciting development because this is a major step forward toward precision medicine, where we're really tailoring the therapy to the specific biology of the patient's tumor and actually responding to the ways in which the tumor is evolving over time and in response to treatment. So as tumors become increasingly resistant to therapies, we can actually take advantage of those resistance mechanisms to develop therapies that will be more effective.

Brittany Harvey: Yes, we'll look forward to those new therapies and research developments and then updated guidelines in the future.

So I want to thank you both so much for your work on this rapid recommendation update and for your time today, Dr. DeMichele and Dr. Henry.

Dr. Angie DeMichele: Thank you.

Dr. Lynn Henry: Thank you very much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guidelines, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this Podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Nigel Key and Dr. Anna Falanga join us for a conversation on the updated ASCO VTE prophylaxis and treatment in patients with cancer guideline. They discuss recent evidence assessing apixaban for VTE treatment in patients with cancer and evaluating direct factor Xa inhibitors for extended postoperative prophylaxis. Based on this new evidence, they present updated evidence-based recommendations from the guideline expert panel. Dr. Key and Dr. Falanga also discuss outstanding questions regarding VTE prophylaxis and treatment in patients with cancer. Read the full guideline update, “Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update” at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00294.

My name is Brittany Harvey, and today I'm interviewing Dr. Nigel Key from University of North Carolina, and Dr. Anna Falanga from University of Milan Bicocca, co-chairs on ‘Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update’.

Thank you for being here, Dr. Key, and Dr. Falanga.

Dr. Nigel Key: Thank you.

Dr. Falanga: Thank you.

Brittany Harvey: Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology, linked in the show notes.

So then, jumping into this guideline update, Dr. Key, what prompted an update to the ‘ASCO VTE Guideline’, which was last updated in 2019?

Dr. Nigel Key: Okay, well, thank you, Brittany, for that question. Well, first of all, ASCO has been providing this guideline since 2007 with iterations and full reviews of the data, the last complete one being in 2019. This update was really triggered by ASCO's signals approach, which relies on experts in the field suggesting an update to the guidelines based on recent publications that may be practice-changing. So, in this case, the signals were really a randomized control trial assessing apixaban for VTE treatment, venous thromboembolism treatment, in patients with cancer called the CARAVAGGIO trial, and we'll discuss that a little bit later. There were also a couple of randomized control trials which evaluated direct factor Xa inhibitors for extended postoperative prophylaxis, and these were new areas subsequent to the 2019 guidelines. So, a systematic review was carried out in the relevant topics for randomized control trials published between November 1, 2018, and June 6, 2022. And what you'll hear today is the result of that process.

Brittany Harvey: Great. And then you just described that guideline recommendations were updated both for prophylaxis and for treatment. So then, Dr. Falanga, what is the updated recommendation for perioperative VTE prophylaxis?

Dr. Falanga: Thank you for this question. For this update, actually, there were two randomized trials addressing the extended thromboprophylaxis in cancer patients. This is an important question, and direct oral anticoagulants had never been included in the previous guidelines. So this new data indicating safety and in some way efficacy of these drugs were important to be in some way included. Actually, the two trials, one tested laparoscopic surgery in patients with colorectal cancer, so major surgery in colorectal cancer and tested the drug rivaroxaban against the placebo after one week of low molecular weight heparin. And the other trial tested in a different type of cancer, gynecological cancer surgery, apixaban versus a placebo after a short course with low molecular weight heparin.

So the two trials are very different, and the recommendation, after all, is weak. But the panel felt it was important to split the previous recommendation 3.5 into three recommendations. The 3.6 specifies which are the cancer patients that really need extended prophylaxis, or the recommendation addresses this population in particular at high risk, which means patients with laparoscopic or laparotomic abdominal pelvic surgery for cancer who have high risk characteristics, including restricted mobility, obesity, previous history of thrombosis, and other additional risk factors. So the recommendation is limited to this population. As I said, there is a weak recommendation because the two trials differ in the type of surgery, the type of the number of patients, the timing of prophylaxis, and one tested rivaroxaban and one tested apixaban.

But in any case, the recommendation now reads that prophylaxis with these two direct oral anticoagulants may be offered in addition to the previous recommendation with the low molecular weight heparin for this indication, although the low molecular weight heparin indication remains a strong recommendation where these other two drugs are added. But still other research is needed to strengthen this recommendation.

Brittany Harvey: Understood. Thank you for describing where there is evidence and where future research is needed to strengthen those recommendations and the qualifying statements for who is appropriate to receive this VTE prophylaxis.

So then, Dr. Key, what did the expert panel update regarding treatment of patients with cancer with established VTE to prevent recurrence?

Dr. Nigel Key: Yes. First of all, I want to make it very clear that this particular recommendation deals, as you say, with patients with established venous thromboembolism. This is quite distinct from recommendations regarding primary prophylaxis in ambulatory patients, which is dealt with in a separate recommendation. That's number two in the 2019 guideline, and those have not been updated. But in terms of treatment of established venous thrombosis, there were three randomized control trials considered. They essentially all addressed the possible role of apixaban, which had not been included in the 2019 guideline. In this revised recommendation, the data looked at both the initial treatment of patients presenting with venous thrombosis as well as extended treatment, which what we know at present, really extends out to six months in terms of using non-vitamin K antagonists, preferably for extended prophylaxis.

So, in 4.1, the CARAVAGGIO trial that I mentioned earlier was a very large trial involving almost 1200 patients with cancer who had symptomatic or incidental acute proximal DVT or pulmonary embolism. And these patients were randomized to six months of treatment with either apixaban or dalteparin. And, in a nutshell, apixaban was non-inferior to dalteparin for the primary outcome of a recurrent VTE during the six month trial period. There was also a similar rate of major bleeding, 3.8 versus 4% in the two arms. So this was strong evidence that initial treatment could include apixaban in addition to what was already in the recommendations. And for those choosing to treat with heparin for initial five to ten days, as before, the recommendation is for low molecular heparin over unfractionated heparin.

So, the second part of this took into account the CARAVAGGIO trial, which I've already mentioned the result of, as well as two smaller trials. They had a VTE trial which had almost 300 patients, and again compared apixaban to dalteparin. And then there was a third smaller study comparing apixaban to lovenox in about 100 patients. But, essentially, the net outcome of the systematic review was that the recommendations 4.1 and 4.2 for, respectively, initial and extended treatment of established VTE, gave high quality evidence with a strong recommendation to include apixaban both for initial treatment and for extended treatment.

Brittany Harvey: Understood. So then you've both discussed this a bit by describing the randomized trials supporting these recommendations. But Dr. Falanga, what should clinicians know as they implement these updated recommendations?

Dr. Anna Falanga: Well, clinicians should know that there are more options to offer to their patients for long-term treatment of VTE, as Dr. Key said, up to six months. This is an important expansion of the spectrum of choices for a more personalized treatment on the basis of the patient's characteristics and the drug characteristics. So this is very important to know. Also, for the postoperative prophylaxis, this update is relevant because of the recommendation. Although we are open to the perspective of using new drugs based on oral intake as an alternative to low molecular weight heparin, and knowing this drug appears to be safe in the specific setting where they were tested in the trial is important.

Brittany Harvey: Definitely, it's great to have more options for patients.

So then in your view, Dr. Key, how will these guideline recommendations impact patients with cancer?

Dr. Nigel Key: Well, I think that with more information that Dr. Falanga just presented, essentially we're looking at two different situations here, both the extended thrombosis prophylaxis after surgery and the choice of agent does need to be individualized with a discussion with a physician. There are still remaining concerns about increased bleeding with direct Xa inhibitors in patients with GI and GU malignancy, for example. So this needs to be taken into account, patients' creatinine values and so on, and what other drugs there are in terms of interactions with direct Xa inhibitors. So I think what you're looking at though is the ability to be confident for that patient that oral agents are, for the most part, as safe and effective as low molecular weight heparins. And hopefully, this will be something that is seen as a positive and maybe somewhat liberating effect for patients.

Brittany Harvey: That's great to hear.

So then finally, Dr. Falanga, you've already mentioned a few areas in which more research would be helpful to strengthen the recommendations. But are there other outstanding questions regarding VTE prophylaxis and treatment in patients with cancer?

Dr. Anna Falanga: Yes, there is a lot of work to be done ahead for prophylaxis. As we already mentioned, it's important to improve the evidence for direct oral anticoagulant safety and efficacy for extended, postoperative prophylaxis. In the medical setting, we have open questions about how to improve the management of patients with VTE beyond six months; we don't know for the treatment of VTE beyond six months, and identify better what are the best drugs and the best strategies to be utilized in this interval.

Then I think that we need to understand, in collaboration with cardiologists and neurologists, whether arterial thrombosis associated with the cancer may need a different treatment compared to subjects without cancer, and understand how to manage anticoagulant together with antiplatelet drugs in these patients who are often thrombocytopenic.

Finally, it is, of course, important to test new drugs for VTE treatment with potentially reduced bleeding risk, such as the new inhibitors of factor XI and factor XII. I think these are the major points that we need to address in the near future possibly.

Brittany Harvey: Absolutely. Well, we'll look forward to future updates of this ASCO guideline to discuss that research as it comes along.

So I want to thank you both so much for your work to update this guideline and thank you for your time today, Dr. Falanga and Dr. Key.

Dr. Anna Falanga: Thanks a lot. Bye bye.

Dr. Nigel Key: Thank you. You’re very welcome. Bye bye.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

Dr. Barbara Andersen delves into the newly updated guideline for management of anxiety and depression in adult survivors of cancer in this ASCO Guidelines podcast episode. This guideline affirms prior guidance regarding screening and assessment of anxiety and depression, and updates evidence-based recommendations for management of both anxiety and depression. Dr. Andersen reviews the principles of the recommended stepped-care model, along with recommended treatments, including options such as cognitive behavior therapy, cognitive therapy, behavioral activation, structured physical activity and exercise, and mindfulness-based stress reduction. Challenges regarding managing anxiety and depression in adult survivors of cancer are also discussed. Read the full guideline update, “Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update” at www.asco.org/survivorship-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00293.

My name is Brittany Harvey, and today I'm interviewing Dr. Barbara Andersen from the Ohio State University, lead author on “Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update.”

Thank you for being here, Dr. Andersen.

Dr. Barbara Andersen: Thank you. Thank you for the invitation.

Brittany Harvey: And then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Andersen on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to jump into the content of this guideline, Dr. Andersen, what prompted an update to this guideline, and what is the scope of this updated version of the guideline?

Dr. Barbara Andersen: Well, as your listeners probably know, guidelines are routinely updated, primarily due to new accumulated evidence that suggests a change in diagnostic or treatment procedures. The first guideline from ASCO was in 2014. They made this important first step, which alone made that an important advance. The prior scope was on assessment, that is, which measures at what time points were important for assessing patients' depressive or anxiety symptoms. We then provided treatment pathways thereafter, noting currently available evidence for treatment. But a systematic review of the literature wasn't done at that time. So what this guide does is first affirm the prior recommendations regarding the measures to use for assessment, the PHQ-9 and the GAD-7. But the departure for these guidelines is based on a systematic review of the intervention and treatment literature, and from that review, we recommend particular treatments.

Brittany Harvey: Understood. So, focusing on that intervention and treatment aspect of this updated guideline, I'd like to review the key recommendations starting with, what are the key general management principles for people with cancer and anxiety and/or depression?

Dr. Barbara Andersen: Well, one key principle is that of education. Your listeners probably are familiar with the fact that many hospitals or centers provide patient-tailored cancer treatment-related information, treatment information on surgery, chemotherapy, immunotherapy, and other topics. But we recommend that general first-level materials on coping with stress, anxiety about treatment, and depression be routinely provided as well. What that does is for individuals with elevated symptoms, it validates what they're experiencing and normalizes the patient experience. So we hope that all patients with cancer and any patient-identified caregiver, family member should be offered the information. We have so many ways we can give information to patients these days. Verbally, material, whatever mode is easy for you and the patient, but please choose one to give information to patients.

Another characteristic of the guideline is our recommendation that treatment follow the principle of stepped care. So what this means is you match the assessment of the severity, level of depression or anxiety, and you match that data to the selection of treatment contexts. This is most clearly seen in the recommendation that group treatment formats be used for those with moderate severity of symptoms versus individual or face-to-face therapy for those with severe symptoms. And this is the case for both anxiety and depressive disorders. This is a principle that's cost-effective and tailors the treatment recommendations. Another principle that we offer is when making a referral of a patient for further evaluation or psychological care; we plead with you to make every effort to reduce the barriers and facilitate patient follow-through. We say it's essential because low motivation, for example, is a symptom of depression. And that low motivation and low mood can conspire to reduce the likelihood that patients will pursue treatment. So just keep that in mind when referring patients.

Brittany Harvey: Absolutely. Those are key points for general management across anxiety and depression symptoms. So, moving beyond those principles, what are the recommendations from the expert panel for treatment and care options for patients with depressive symptoms?

Dr. Barbara Andersen: For depressive symptoms, we recommend cognitive behavior therapy or cognitive therapy, behavioral activation, psychosocial interventions using empirically supported components, and moderate structured physical activity and exercise. All of those are efficacious, empirically supported treatments for moderate depressive symptoms. And it might be easiest to offer group therapy for individuals with these problems.

Brittany Harvey: Great. Thank you for reviewing those recommendations for patients with depressive symptoms.

So, in addition, what does the expert panel recommend for treatment and care options for patients with anxiety symptoms?

Dr. Barbara Andersen: Many of the same treatments are used. Cognitive therapy, cognitive behavior therapy are the most efficacious treatments out there for cancer patients or individuals without cancer coping with anxiety symptoms or depressive symptoms. Again, behavioral activation would be useful. Mindfulness-based stress reduction has garnered significant support in the recent years, as well as interpersonal therapy.

Brittany Harvey: Understood. So thank you so much for going through each of those recommendations.

But in your view, Dr. Andersen, what is the importance of this guideline, and how will it impact both clinicians and patients with cancer and symptoms of anxiety and/or depression?

Dr. Barbara Andersen: An important element to this guideline is it names the specific empirically supported standard therapies for treatment of anxiety and depression. There's a departure, though, from our prior guideline, and in this one, pharmacotherapy is not recommended as a first-line treatment, neither alone nor in combination. It's simply not supported by the evidence. However, clinicians might consider pharmacotherapy when there's low or no availability of mental health resources. Perhaps a patient might have responded well to pharmacotherapy in the past, and patients with severe neurovegetative, or agitated symptoms of depression, those patients, as well as patients with psychotic or catatonic features, would be ones for which pharmacotherapy might be appropriate.

Brittany Harvey: Understood. And then you've just mentioned that sometimes there is no or low availability of mental health resources, so that leads to my next question. But what are the both outstanding research questions and challenges regarding managing anxiety and depression in adult survivors of cancer?

Dr. Barbara Andersen: The largest challenge is that we're in the midst of a mental healthcare crisis, and COVID has made that abundantly clear. There are problems with access to psychological care due in part to workforce problems, maybe organizational ones, but there is a shortage of mental health professionals, and that, in turn, limits referral networks from managing depression and anxiety. So that's one significant issue that is in place right now.

Since the 2014 guideline, screening is a care aim that has been disseminated, but the principles and procedures remain to be fully implemented. I was just looking at a 2022 article in the Journal of Oncology Practice. It was a study examining screening for lung and ovarian cancer patients, two very important groups because the frequency of depressive and anxiety symptoms is perhaps highest of any other groups. So they looked at more than 20 CoC-accredited facilities that studied the electronic records to see if there was screening for the patients. And the troubling finding, from my perspective, was that there was no screening for 45% of the patients in this study. So we know that there are disparities in the use of screening and its management. Those disparities exist across race, ethnicity, cancer type, stage, and facilities. And so, that remains a challenge for many sites, including CoC hospitals, to achieve a rigorous screening program.

Having said that, I want to say what some might disagree with, but from my standpoint, it's a myth that screening takes a long time. The measures that we recommend probably would take a patient maybe five, maybe ten minutes to complete. But what's time-consuming or what's troublesome in many places is the infrastructure is not in place to do the screening and interpret it in an efficient manner. The other perspective on screening is that it is the effort thereafter, which is, in fact, time and resource intense - that is, finding referral sources, making referrals. But that's the most important step because when that's not done, when patients continue with symptoms, it really incurs the greatest cost for the patients.

Brittany Harvey: Absolutely. Screening and then further management of anxiety and depressive symptoms is key for maintaining quality of life.

So I want to thank you so much, Dr. Andersen, for coming on today and sharing your insights and also for all your work you did to update this guideline.

Dr. Barbara Andersen: Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast.

To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Dwight Owen is back on the ASCO Guidelines podcast, discussing the latest updates to the ASCO living guidelines for stage IV NSCLC. In Part 2, Dr. Owen presents the update for stage IV NSCLC with driver alterations. He reviews new evidence from KRYSTAL-1, and reviews a new recommended option for patients with stage IV NSCLC with a KRAS G12C mutation, adagrasib.

Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.1” and view all recommendations at www.asco.org/living-guidelines.

Listen to Part 1 for recommendations for patients with stage IV NSCLC without driver alterations.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00281

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast, one of ASCO’s podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey, and in our last episode, we addressed the living guideline updates for therapy for stage IV non-small-cell lung cancer without driver alterations. Dr. Dwight Owen from Ohio State University in Columbus, Ohio, has joined us again to discuss the updates for therapy for stage IV non-small-cell lung cancer with driver alterations, as a co-chair on ‘Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.1’.

Thank you for joining us again, Dr. Owen.

Dr. Dwight Owen: Thanks for having me, Brittany.

Brittany Harvey: Then, before we discuss this update, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Owen, who's joined us on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology linked in the show notes.

So then, jumping into the content here, this living clinical practice guideline for systemic therapy for stage IV non-small-cell lung cancer with driver alterations is being routinely updated. What new studies were reviewed by the panel to prompt an update to the recommendations?

Dr. Dwight Owen: Yeah. Thank you, Brittany. For this update, the panel and committee felt that it was important to review the KRYSTAL-1 trial. This was a phase I/II open-label study of adagrasib in patients with KRAS G12C mutation-positive solid tumors, which included multiple expansion cohorts, including a cohort of patients with non-small cell lung cancer. Importantly, the data that was presented in this recent publication included only patients treated at the phase II dose of 600 milligrams twice daily. The study included 160 patients with a primary endpoint of a response rate, which was evaluated in 112 of those patients. The confirmed response rate was 43%, including one complete response, with the remaining being partial responses. The median progression-free survival was six and a half months, and the median overall survival for this pretreated patient population was approaching one year.

One thing of note is we saw similar toxicities as we have seen with other KRAS G12C inhibitors, which included predominantly GI side effects such as diarrhea, nausea, vomiting, but also hepatic side effects including transaminitis, some renal dysfunction as well. Dose interruption was common in over 60% of patients, and dose reduction was required in over half of patients. Overall, given the efficacy seen in this cohort, again, even though it was a phase I/II trial, it was a substantial number of patients, and we felt that it met the criteria for us to be able to include this as an additional recommendation in our guidelines.

Brittany Harvey: I appreciate you reviewing that data. So then, based off this data from KRYSTAL-1, you just mentioned that there's a new recommendation from the panel. So what is this new recommendation for patients with advanced non-small cell lung cancer with a KRAS G12C mutation?

Dr. Dwight Owen: For patients with stage IV non-small cell lung cancer with KRAS G12C who have received prior treatment with a chemotherapy and/or immunotherapy with a PD-1 therapy, we have added that clinicians and oncologists may consider treatment with adagrasib to our current recommendations for these patients.

Brittany Harvey: Great. And then you just mentioned this is an addition onto current recommendations. So what should clinicians know as they implement this updated recommendation, and how does it fit in with those previous recommendations for patients with previously treated non-small cell lung cancer with a KRAS mutation?

Dr. Dwight Owen: That's a really important point, is this is now our second option for these patients, including sotorasib, which many of us have been familiar with so far. Of course, we don't have a head-to-head trial comparing these two, but looking at the efficacy and toxicity data, they do seem quite similar. We have some more data for sotorasib from the CodeBreaK 200 study, which we'll be reviewing in a future update. However, at this point, looking at the monotherapy studies that have been done, the toxicity profiles seem fairly similar, the efficacy profiles seem fairly similar, so we don't yet have a clear differentiator that we can see, again, in the absence of a head study.

The other thing I would note is that the inclusion criteria for these studies, for the most part, excluded patients with active brain metastases, which, unfortunately, is something that we see quite commonly in patients with lung cancer. And although we have seen some case reports and some anecdotal data for CNS activity with these compounds, we're still waiting for defined cohorts, which there were defined cohorts in these studies that included patients with asymptomatic but untreated brain metastases. And I think that will be something that we are actively looking for and looking forward to. Because I think having a better understanding of potential CNS activity of either or both of these compounds would really alleviate a lot of concerns that we have that those patients who really are the patients that we see in clinic were just not represented in the studies that we reviewed to date.

Brittany Harvey: Understood. I appreciate that additional context around these recommendations.

So what does this new therapeutic option mean for patients with stage IV non-small cell lung cancer with a KRAS G12C mutation?

Dr. Dwight Owen: The end result is that we have more treatment options for patients. Again, both of these compounds seem active. There are clearly patients who benefit and, in some cases, for a substantial period of time because of these options, which were not available as of just recently and until the very recent past, KRAS was, of course, considered an undruggable target. So it's really incredible that we have these treatment options and that they're coming to clinic so quickly. I think there are some areas that we still don't understand yet in terms of the sequencing of treatment. Right now, these treatments are only approved as a subsequent treatment. In most of the studies, the vast majority of patients had received both chemotherapy and immunotherapy. We don't really know how that sequence might affect the tolerability or efficacy of the KRAS inhibitors. We do know that toxicity is an issue, and with both agents, dose reductions are frequently utilized to try to assist with tolerability. There is a slight difference in terms of how these are administered, whether it's daily with a higher pill burden versus twice daily.

And so there are some nuances that clinicians can discuss with patients. But again, absent a

head-to-head study, it's really important to have a discussion with your patient about what the toxicity profiles of these agents are and what the likelihood of benefit is. And we look forward to seeing more data as these get combined with other therapies and potentially have more insight into the optimal sequence of therapies for patients with KRAS G12C non-small cell lung cancer.

Brittany Harvey: Absolutely. It's great to have additional treatment options for patients, and those are key points for discussions about personalized therapeutic regimens. So then, finally, are there emerging therapies or targets that the panel is considering for future living guideline updates?

Dr. Dwight Owen: As I mentioned in the last podcast, the data coming out is happening so quickly that we are working to make sure that the guidelines are as up-to-date as possible based on the most recent published literature where we can actually take time to delve into the data and be transparent about the evidence based from our recommendations. We are very interested in the subsequent studies in the KRAS G12C pathway. I mentioned the CodeBreaK 200 study that we’d be including in a future publication, as well as in some of the emerging data in KRAS non G12C non-small cell lung cancer.

As of now, it's very important to keep in mind that the only inhibitors we have are dependent on the G12C on the cysteine, and therefore those are the only patients that are currently able to benefit from these treatments. But in the future, we hope that that patient cohort becomes expanded, and we continue looking for new therapies for patients with other alterations, including subsequent therapies for EGFR non-small cell lung cancer and, of course, other actionable alterations as well.

Brittany Harvey: That's great to hear. We'll look forward to that future research and the review of that evidence by the panel and future guideline updates.

So thank you so much for your work on these updates and thank you for your time today, Dr. Owen.

Dr. Dwight Owen: Thanks very much, Brittany.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/living-guidelines. There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer without driver alterations available there and in the JCO. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Dwight Owen is back on the ASCO Guidelines podcast, discussing the latest updates to the ASCO living guidelines for stage IV NSCLC. In Part 1, Dr. Owen presents the update for stage IV NSCLC without driver alterations. He reviews new evidence from EMPOWER-Lung3 and POSEIDON and discusses new recommended options for patients with squamous cell carcinoma and non-squamous cell carcinoma, and PD-L1 tumor proportion score 0-49%. Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.1” and view all recommendations at www.asco.org/living-guidelines.

Listen to Part 2 for recommendations for patients with stage IV NSCLC with driver alterations.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00282

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO’s podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and I'd like to welcome back Dr. Dwight Owen from Ohio State University in Columbus, Ohio, co-chair on ‘Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline Version 2023.1’.

Thank you for being here, Dr. Owen.

Dr. Dwight Owen: Thanks for having me, Brittany.

Brittany Harvey: Then, before we discuss this update, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Owen on this episode, are available online, with a publication of the guideline in the Journal of Clinical Oncology linked in the show notes.

So then, diving into this update, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is being updated on a regular basis. What was the new evidence identified by the expert panel through routine literature searches to prompt an update to the recommendations?

Dr. Dwight Owen: Yeah. Thanks, Brittany. I think it's really important to point out that these living guidelines are evidence-based. And so, we are constantly reviewing the literature to find new data to support recommendations for treatment options for clinicians to choose for their patients with metastatic non-small cell lung cancer. Clinicians these days, and physicians and oncologists are faced with so much information coming from abstracts to press releases to publications of new clinical trial results that it can be sometimes overwhelming to keep track of all the latest breakthroughs and nuances in the literature for non-small cell lung cancer.

So for this specific update, the panel and the committee reviewed two papers, including the

EMPOWER Lung-3 Study and the POSEIDON Study. The EMPOWER Lung-3 study was a double-blind, placebo-controlled phase III study investigating cemiplimab plus platinum doublet chemotherapy as the first treatment for patients with either locally advanced stage III or stage IV non-small cell lung cancer without either an EGFR, ALK, or ROS1 alteration. And this is a mode of treatment that we've seen before, which is a PD-1 plus chemotherapy or PD-L1 plus chemotherapy compared to a chemotherapy control. And indeed, we did see an improvement in median overall survival in this study with the addition of cemiplimab to chemotherapy of almost 22 months versus 13 months with the placebo. This was accompanied by a higher rate of grade 3 or higher toxicities. But overall, these data were consistent with what we have seen with other studies of checkpoint inhibitor therapy plus chemotherapy in the first-line setting, which is now the current standard of care.

The second study we reviewed was the POSEIDON Study, and this was an open-label phase III study of combination checkpoint inhibitors. So this was PD-L1 plus CTLA-4, durvalumab + tremelimumab with chemotherapy versus chemotherapy alone, and these patients were metastatic non-small cell lung cancer without EGFR or ALK alterations. The interesting thing about this study is there was a cohort of patients treated with durvalumab plus chemotherapy alone. But it was really the cohort of patients treated with tremelimumab, durvalumab, and chemotherapy who had a significant improvement in median survival of 14 months versus 11.7 months with chemotherapy alone, with a hazard ratio of 0.77. In this study, the tremelimumab was only given for a total of five cycles, so it was not continued during the maintenance phase with durvalumab, which is a slight difference from other combination checkpoint inhibitor therapies, which are approved based on CheckMate 227 and CheckMate 9LA, which is nivolumab + ipilimumab.

So, overall, neither of these two studies present a new paradigm of treatment. But they present new treatment options for patients as a first-line treatment for non-small cell lung cancer in the form of either PD1/L1 plus chemotherapy or combined checkpoint inhibitor with a PD-L1 plus CTLA-4 plus chemotherapy, again showing improved survival compared to chemotherapy alone.

Brittany Harvey: I appreciate you reviewing the details of those two trials. So then, based off this new data from the trials that you mentioned, EMPOWER Lung-3 and POSEIDON, what are the updated recommendations from the expert panel?

Dr. Dwight Owen: So we felt it was important to update our prior recommendations for patients, especially with low to intermediate PD-L1 expression from 0% to 49%, that patients may offer cemiplimab plus chemotherapy as an additional treatment option in addition to the recommendations that have already been in place, regardless of histology. And then, based on the POSEIDON data, we felt that this was also a treatment option for those similar patients, especially with PD-L1 negative or up to 49%.

We do feel that the patients with PD-L1 TPS scores of 50% or higher still seem to benefit the most from checkpoint inhibitor monotherapy and multiple studies that have been done there. And so we did not make any changes to the recommendations for those patients with PD-L1 high non-small cell lung cancer.

Brittany Harvey: Understood. And then you just mentioned that neither of these therapies represent a paradigm change for treatment options. So what should clinicians know as they consider these new options in addition to previously recommended therapies?

Dr. Dwight Owen: Yes. So I think when clinicians are looking at these studies, things to keep in mind are the size of the study, the cohorts included, the endpoints. The comparison arm, for now, remains chemotherapy alone, which again is no longer the standard of care. So we are sort of looking backwards at a historical standard of care that we no longer really confront other than for patients who have some contraindication to immunotherapy.

The other thing to keep in mind is, of course, when you add more treatments together, you expect more toxicities. And that is certainly the case when we see the dual combined checkpoint inhibitor therapies plus chemotherapy. Regardless of whether it's nivolumab + ipilimumab and chemotherapy or whether it's durvalumab + tremelimumab plus chemotherapy, we do expect a higher rate of toxicities when we do add the CTLA-4 to the PD1/L1 backbone.

And so this is a conversation that's really important to have with your patients. We don't have a head-to-head trial, so we are inferring differences in terms of response and benefit using the same comparison of chemotherapy but from different studies and also different populations. So that is probably one of the more important lessons to take from all of these studies is that we know that the toxicity rate does change depending on how you add therapies for these patients. And we also know that there are patients who may not need that additional therapy. So patient selection is key.

And I think one of the most unmet needs right now is for patients with PD-L1 negative tumors who don't seem to benefit from checkpoint inhibitor monotherapy or even in long term data when checkpoint inhibitor therapy is given just combined with chemotherapy, these patients seem to be the ones who don't benefit as much. And so I think that would be the patient population that really warrants that extra discussion where you may consider a more aggressive treatment depending on a patient's preference in terms of susceptibility, in terms of toxicity.

Brittany Harvey: Absolutely. Considerations of the toxicity profiles of these agents is key for patient quality of life. That leads nicely into my next question, but what do these new recommended therapies mean for patients with stage IV non small cell lung cancer without driver alterations?

Dr. Dwight Owen: Well, I think, of course, it is beneficial to have more treatment options, but when we have more treatment options, the decision can actually become more challenging because how do you select from any of the treatment options that we have? And in the absence of direct head-to-head trials for now, we really need to look at the toxicity data, look at the outcome data, and see how the patient in front of you fits into the studies that have been done in order to make an inference and to have that informed discussion with the patient about what to expect from a specific treatment.

And I think the higher rates of immune toxicities that we see when we use combination checkpoint therapy needs to be a discussion with patients, and also the type of chemotherapy backbone and how long that chemotherapy will be continued. Whether it's two cycles like Checkmate 9LA, whether it's four cycles like POSEIDON, whether we have a non-chemotherapy option to offer patients, these are all nuances that right now lead to a really robust conversation with our patients up front. And really trying to guide patients through these discussions because the information can be so overwhelming when it's given at one time. So, really trying to have that meaningful conversation in a way that the patient can help advocate for themselves in the clinical decision-making.

Brittany Harvey: Definitely, those nuances are important for those individual discussions. So then, finally, you've mentioned that the panel is reviewing literature on an ongoing basis. So, what ongoing developments is this panel monitoring for future updates?

Dr. Dwight Owen: So, I think all of us are very excited about the announcements that we have been hearing, both in terms of press releases, in terms of abstracts at the upcoming ACR meeting, and of course, ASCO later this year, where we expect to have a wealth of new data for patients with non-small cell lung cancer, both in the metastatic setting but also in the early stage setting. And I think one of the challenges for us in this committee and for practicing oncologists every day is the speed at which this information is coming out and making sure that we have time to really review each study and give each study the time needed to understand how it can impact our treatment selection based on what's already an accepted practice and what maybe is something that we should reconsider.

And so I think it's very rewarding work to work with the committee members and the panel and ASCO. But it is also something that we take very seriously, just because data can come out so quickly at varying levels of detail. And we really want to make sure that when we make a guideline recommendation, that we are very clear that it is evidence-based and what that evidence is.

Brittany Harvey: Absolutely, we appreciate the panel's evidence-based approach to developing these recommendations.

So, I want to thank you for your time working on this update and for coming on the podcast to speak with me today, Dr. Owen.

Dr. Dwight Owen: Thanks very much, Brittany.

Brittany Harvey: And thank you to all of our listeners for tuning into ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/living-guidelines. There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer with driver alterations available there and in the JCO. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Katherine Virgo discusses the latest evidence-based guideline recommendation updates regarding initial management of metastatic prostate cancer based on the new clinical trial results comparing triplet therapies (the addition of darolutamide, abiraterone, or enzalutamide to docetaxel plus androgen deprivation therapy) to standard of care. Dr. Virgo also discusses cost of treatment options and ongoing research questions in this field.

Read the full guideline, “‘Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update” at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00155.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today I am interviewing Dr. Katherine Virgo from Emory University, lead author on the ‘Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update’.

Thank you for being here, Dr. Virgo.

Dr. Katherine Virgo: Thank you.

Brittany Harvey: Before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Virgo, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes.

So then, getting into the content of this update first, Dr. Virgo, what prompted this update to the initial management of noncastrate advanced, recurrent or metastatic prostate cancer guideline?

Dr. Katherine Virgo: The update is primarily driven by new clinical trial results comparing triplet therapies to standard of care. Triplet therapy here refers to the addition of darolutamide, abiraterone, or enzalutamide to docetaxel plus androgen deprivation therapy for patients with de novo metastatic noncastrate prostate cancer.

Brittany Harvey: Great. And then, based on this, what are the new and updated recommendations from the guideline panel?

Dr. Katherine Virgo: The first updated recommendation adds darolutamide to the list of treatment options as follows: docetaxel, abiraterone, enzalutamide, apalutamide or darolutamide, each when administered with androgen deprivation therapy, represent five separate standards of care for noncastrate metastatic prostate cancer, with the exception of the triplet therapies of docetaxel plus abiraterone plus ADT and docetaxel plus darolutamide plus ADT. The use of any of these agents in any other particular combination or in any particular series cannot yet be recommended.

The second updated recommendation states: for patients with metastatic noncastrate prostate cancer with high volume disease as defined per CHAARTED, who are candidates for treatment with chemotherapy but are unwilling or unable to receive triplet therapy, for example, due to insurance constraints, docetaxel plus ADT should be offered. We add some practical information here. Patients should be made aware that doublet therapy, docetaxel plus ADT, has inferior overall survival compared to triplet therapy, such as abiraterone and prednisone plus docetaxel plus ADT.

Then, I have a few recommendations here with respect to triplet therapy, and these are new. For patients with de novo metastatic noncastrate prostate cancer with high volume disease as defined per CHAARTED who are being offered ADT plus docetaxel chemotherapy, triplet therapy, abiraterone and prednisone plus ADT and docetaxel should be offered per the PEACE-1 trial. Abiraterone and prednisone plus ADT and docetaxel demonstrated significant overall survival and radiographic progression-free survival benefits compared to ADT and docetaxel alone for patients with high volume disease.

Again, we add some practical information. Overall survival data for patients with low volume de novo metastatic noncastrate prostate cancer from the PEACE-1 trial are still too immature to justify recommending abiraterone-based triplet therapy, in other words, abiraterone and prednisone plus ADT and docetaxel, for patients with low volume de novo metastatic noncastrate disease.

A second new recommendation, as opposed to a revised recommendation with respect to triplet therapy, is: for patients with de novo metastatic noncastrate prostate cancer who are being offered ADT plus docetaxel chemotherapy, triplet therapy, darolutamide plus ADT and docetaxel should be offered per the ARASENS trial. Compared to placebo plus ADT and docetaxel, darolutamide plus ADT and docetaxel demonstrated significant overall survival benefits, in addition to significantly longer times to castration-resistant prostate cancer, pain progression, first skeletal event, and initiation of subsequent systemic antineoplastic therapy.

The practical information offered here is that discussion with patients should include the cost of darolutamide treatment compared with other options, such as abiraterone. There was no change to the 2021 recommendation for enzalutamide other than to report long term results from the ENZAMET and ARCHES trials that was not available in 2021. We added similar practical information here with respect to discussing costs of enzalutamide treatment. Discussion with patients should include the cost of enzalutamide treatment compared with other options, such as abiraterone.

Brittany Harvey: Excellent. I appreciate you reviewing those new and updated recommendations from the expert panel along with that practical information.

So then, Dr. Virgo, what should clinicians know as they implement these updated recommendations? And also, in your view, how will these guideline recommendations affect patients with noncastrate metastatic prostate cancer?

Dr. Katherine Virgo: That's a good question. Clearly, cost is a factor for patients, and we felt it was important to emphasize this in the guideline update. In the data supplement to the guideline update, we included a table listing all the agents discussed in the update, as well as the associated pivotal trials, main outcomes, the control group, the cost per cycle of treatment, and the cost for the full treatment course. This should be particularly helpful to clinicians as they discuss treatment options with patients. We also thought it would be helpful to have a visual guide to treatment options that reflects the clinician's decision-making process more directly. So figure one is the result of a group effort to achieve that aim.

Brittany Harvey: Excellent. And there have been a lot of changes in this field that prompted this update, but what are the outstanding questions regarding triplet therapy in the treatment of patients with metastatic noncastrate prostate cancer?

Dr. Katherine Virgo: Well, the burning question is whether docetaxel is really still necessary in the treatment of patients with metastatic noncastrate prostate cancer. No phase III clinical trials have yet compared, for example, androgen deprivation therapy plus darolutamide or androgen deprivation therapy plus abiraterone versus androgen deprivation therapy plus docetaxel. Also improved overall survival for patients undergoing triplet therapy is largely confined at present to those with high volume disease. So for patients with low-volume disease, clinical trials as yet show no significant benefit of triplet therapy.

Brittany Harvey: Great. Well, then I guess we'll look forward to future trials to determine if that's still appropriate and look for future updates of this guideline.

So I want to thank you so much for your time developing and updating this guideline. And thank you for joining me today, Dr. Virgo.

Dr. Katherine Virgo: Thank you. I appreciate it.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Scott Tagawa and Dr. Oscar Brouwer come on the ASCO Guidelines podcast to discuss the new EAU-ASCO Collaborative Guidelines on Penile Cancer. These comprehensive guidelines cover pathological assessment of tumour specimens, diagnosis and staging, local treatment of penile carcinoma, radical inguinal lymph node dissection, prophylactic pelvic lymph node dissection, surgical management, neoadjuvant and adjuvant chemotherapy, radiotherapy, systemic and palliative therapies for advanced penile cancer, follow-up, and quality of life. They highlight key recommendations, and describe the importance of a patient-focused and multidisciplinary approach to management of penile cancer.

Find more information about the guidelines at www.asco.org/genitourinary-cancer-guidelines

The full text of the guideline is available at https://uroweb.org/guidelines/penile-cancer

Conflict of interest disclosures:

Guideline Working Group

Dr. Scott Tagawa

Dr. Oscar Brouwer

TRANSCRIPT

My name is Brittany Harvey, and today I'm interviewing Dr. Oscar Brouwer from the Netherlands Cancer Institute in Amsterdam, and Dr. Scott Tagawa from Weill Cornell Medical College in New York, co-chairs on the ‘ASCO-EAU Collaborative Guidelines on Penile Cancer’.

Thank you for being here, Dr. Brouwer and Dr. Tagawa.

Dr. Scott Tagawa: Thanks very much.

Dr. Oscar Brouwer: Yeah, thanks for having us.

Brittany Harvey: Before we discuss this guideline, I'd just like to note that the guideline was led by the European Association of Urology, and the conflict of interest disclosures of the Guideline Working Group are publicly accessible through the European Association of Urology website linked in the show notes. Additionally, Dr. Brouwer's and Dr. Tagawa's individual disclosures are provided in the show notes of this episode.

So, to jump into the content of this guideline, first, Dr. Tagawa, could you give us a general overview of the purpose and the scope of this collaborative EAU-ASCO Guideline?

Dr. Scott Tagawa: So, I think the key word there is collaborative. This was truly a collaborative effort, and I say that in a number of ways. So, the two key organizations, the EAU and ASCO, came together with a Memorandum of Understanding and got together from the very beginning in terms of developing the scope and then throughout the methodology for the guidelines. And then, on a practical basis, I'd say even more importantly, a collaboration between multiple physicians of different disciplines from across the world. Whether we're talking about surgeons, radiation oncologists, medical oncologists, pathologists, we had panel members from all over the world as well as patient representatives from all over the world. And patient representatives really played a key role in the development of this guideline.

By way of background, penile cancer in most places is considered a rare disease. For example, in the United States, we expect around 2000 cases per year. In the genitourinary world, the next rare cancer is going to be testis cancer, which is going to be four or five times higher than that per year and nowhere near prostate cancer, for instance. So, just kind of put that into perspective. But, importantly, a disease that is a worldwide issue in a number of different ways. That includes the kind of general stigma of being diagnosed with that, the physical and emotional consequences of the diagnosis, as well as treatment. And then, because in part of its rarity, the lack of prospective randomized trials to really guide clinicians and that, I would say, that total package underscores the importance of coming together with a guideline.

Brittany Harvey: Great. Thank you for providing that background and perspective.

So then, next, Dr. Brouwer, I'd like to review the key recommendations of this comprehensive guideline. Starting with what are the key recommendations regarding diagnosis and staging of penile cancer?

Dr. Oscar Brouwer: First of all, I guess just to underline what my colleague, Dr. Tagawa, just said, it's a worldwide guideline, international, multi-continental. I think that's quite a special thing. But it also poses a few challenges, of course, because cultural differences and treatments may differ, opinions as well, distances that patients have to travel, lots of factors there, and also economy, et cetera, et cetera. So, to find a consensus there has been one of the challenges. I think we did a good job there to really make it accessible to all patients and physicians, of course, in the world.

When talking about diagnosis, I think comparing our new guidelines to old guidelines really emphasizes the new 2022 WHO classification in which distinction between HPV-positive and HPV-negative disease is highlighted. We increasingly have some knowledge on the difference between the HPV-related and the non-HPV-related penile cancers. I'd say it's about 50-50, the distinction. So, 50% is HPV-related, and 50% not HPV-related. But what we know from other cancers, for instance, that HPV-positive disease is associated with better prognosis than HPV-negative. This distinction is not so clear in penile cancer yet. And one of the reasons is just the lack of data, a lack of perspective for large studies, so to say. So, what we're really highlighting and underlining in the new guideline is the importance of doing HPV testing in all patients that have penile cancer, and that tissue is taken from. We chose to go for the cheapest and easiest but reliable methods to do so. So, immunohistochemistry of p16, to be exact. This is one of the important, I think, recommendations, or maybe even more than a recommendation; obligations we set to all physicians treating penile cancer.

So, just in terms of diagnosis and in terms of staging, we all know that lymph node status is the most important factor determining survival. So, finding those lymph nodes, if they are involved with cancer, yes or no. So, if they are metastatic, yes or no, is of crucial importance. This has always been the case, but I think it cannot be emphasized enough. And in this new guideline, we again emphasize the importance of doing surgical lymph node staging in high-risk patients. And what's a little bit new is that we are more or less going to the direction of preferring central node biopsy as the best method to do so. You could also, of course, remove all the lymph nodes, what we call radical lymph node dissection. It's still possible inside our new recommendations, depending on availability of all the techniques or availability of expert centers in proximity. But I think we can all see that in terms of complication rates, central node biopsy is probably superior. So this is also one of the new things in terms of staging.

Brittany Harvey: Absolutely. Thank you for those highlights of diagnosis and staging in the guideline.

So, following those recommendations, Dr. Tagawa, and I know this is a large section, but what does the expert panel recommend for disease management of penile cancer?

Dr. Scott Tagawa: A single-sentence summary would say a multi-disciplinary approach in an expert center when possible. Re-emphasizing one of the statements that Dr. Brouwer made about sentinel lymph nodes; it appears to be better, but clearly is not available everywhere. And if I just make this US-centric for a minute, just within this country, where there are centers that are able to do it and have that expertise, there are centers that are not so far away that may not be able to do that. So regional differences within a single country that’s what happens. So, anyway, multi-disciplinary input, I think, is important for many diseases, including penile cancer.

A little bit of a segue, but one part of this guideline of which most of us are proud is that, front and center really, the introductory paragraph of the guidelines, where it really states that we need to really have this disease and the management patient-focused and that includes addressing some of the emotional aspects of the disease. Those are included in the management. But to kind of go through very quickly on a very high level, in the early stages management is mostly in the hands of the urologist. But sometimes there’s dermatologists and others, so when there is superficial disease, we talk about superficial therapy and I’m just going to leave it at that, many of them don’t have level 1 evidence, but there is, for instance, topical chemotherapy that can be helpful.

And then, as the disease becomes more invasive, so does the treatment. So there’s sections on organ or penile sparing that is a reasonable option that needs to be done in a good multi-disciplinary system. That is a good and sometimes a preferred option when there is adequate staging for earlier stage disease. And then the more invasive the disease becomes is when the management needs to become more multi-disciplinary both in terms of workup as well as treatment. Where there is a consideration for, in certain situations, particularly in very locally advanced where it becomes unresectable at least in some eyes, where we say, “Okay, we’re actually going to recommend starting off with chemotherapy,” the intent is for surgery with an alternative of chemotherapy and radiation. And currently, there are no head-to-head trials, but those are both reasonable approaches for the most locally advanced disease setting.

Taking a step back, if someone starts off with a little bit less locally advanced, so we’d say the alias, gross resectable, we would at least discuss in a multi-disciplinary setting what are the risk benefits of then post-operative therapy, whether that is radiation or chemotherapy, or both. I think all patients at least deserve the opportunity to have that discussion, and then that would be on an individual basis whether we decide to do that or not. Coming from the medical oncology-centric viewpoint where we really deal with systemic therapy, we don’t really have any randomized trials to say that one approach is preferred to another, so they’re kind of generic. But it does look like platinum chemotherapy, taxane chemotherapy are the most active current drugs. So when we’re looking at multi-agent therapy when the setting is a goal of cure, we’re generally saying platinum plus taxane combinations without being specific about doublets or triplets. Triplets when they can handle them, but not everyone can handle them.

And then for metastatic disease whether it’s current or at presentation metastatic disease, the old guidelines actually said ‘don’t even bother’, but now that we have some effective drugs, we would say that for palliative purposes to come in with systemic chemotherapy, the same drugs that we talked about before. And then, there may be additional therapeutic agents. So we’re now in the genomic era where there has been at least an initial look at what are the genomics of HPV related, non-HPV related, and there may be some targets, we just are a little bit too early to say that there are absolutely some targets, but there definitely are recommendations for participating in clinical trials. There are some trials that are specific to penile cancer. There are other ones that are non-specific or basket trials. Let’s say any disease that has EGFR positivity, a patient with penile cancer may be able to get into that clinical trial or maybe meet a therapy-based trial, so considerations for the trials, I think, are important.

Brittany Harvey: It sounds like multidisciplinary care is a key tenet of this guideline. You mentioned patient-focused care is also key in this guideline. So that leads nicely into my next question. But Dr. Brouwer, what are the key recommendations both for follow-up and quality of life?

Dr. Oscar Brouwer Yeah so we have, like Dr. Tagawa already said, we have quite an elaborate section, not only in the introduction of the guideline but also a separate chapter at the end, really, to acknowledge the psychosocial, sexual impact this disease can have on patients. And again, I think it's more or less a plea for a form of centralized care for such a rare disease. We have a set of recommendations that we give in terms of follow-up and quality of life, and mainly several points that should really be discussed with patients, and support should be offered. So things like psychological sexual help, but also lymphedema therapist, physiotherapy in terms of complication management. And this mainly goes for patients that undergo lymph node surgery or treatment. And in our experience, if you don't see the disease often enough, you don't have all these things in place in your hospital to offer dedicated people that can do this. So I think that's something to consider in the future for healthcare in general when treating rare diseases such as these. But, yeah, like Dr. Tagawa said, our patient representatives have had a big role in this, and we're happy with that. So I recommend everyone to read it.

Brittany Harvey: Absolutely. You've both mentioned that this is a rare disease. So, in your view, Dr. Tagawa, what is the importance of this guideline, and how will it impact clinicians?

Dr. Scott Tagawa: There are certain centers that have high volume and certain countries that will have a high volume. For instance, areas in Brazil have a high volume. Whether there's a high volume or a low volume, like an average center in the United States, there haven't been any recent guidelines out there from any organization. So, the EAU has had an old guideline that was really out of date - updating that, number one. And number two, having the backing of two major organizations in the EAU and ASCO, I think is quite important to get this out there on a true international basis. Because not just in this disease, but in most diseases, when there is standardization of care, there's overall better outcomes, whether it's at the center that sees a lot or the centers that rarely see any. I think this document provides guidance, and, actually, take a step back for those that are interested, on the EAU website will be the entire very comprehensive guideline. So, someone that wants to get a lot of details, it's there, very comprehensive and honestly long, but it's, I think, an excellent reference document. And then, published in European Urology will be the summary guideline that has all the key points of the guidelines and summary in the text that will refer to the overall guideline for someone that wants to get through it on a quicker basis. That will also be published on the ASCO website just to kind of get that out there. A little bit of the side in terms of answering your question is that this is a rare tumor. We want everyone to have access to the best care possible, and if nothing else, it provides guidance in a setting where most clinicians don't have a lot of expertise.

Brittany Harvey: Definitely. And thank you for highlighting both the summary and full text of the comprehensive guideline. We'll provide those links in the show notes, too, for easy access for any listeners.

And then, finally, you've both mentioned the impact this has for patients. But Dr. Brouwer, in your view, how will these guideline recommendations affect patients with penile cancer?

Dr. Oscar Brouwer: Well, of course, it's our hope that it will be very beneficial for patients around the world. I think it cannot be emphasized enough that this initiative, in which ASCO, in this case United States group, has collaborated with the European one to make an international multi continental guideline, is quite rare, in urological cancers is the first one. I'm not even sure if there are many others like these. I do really believe it makes sense for rare diseases to not have several guidelines. It's confusing which guideline to choose, especially if there are contradictions. So I guess this initiative is the first step towards having more comprehensive, literal guidelines for such a rare disease. And I really do hope that it will help clinicians, especially when they don't have experience treating this disease, to really look at this guideline first. And in turn, of course, I hope that will benefit patients because they'll have, hopefully, access to better quality care that way. And especially, like we already touched upon, also the importance of early access to support and to palliative care throughout the whole disease process. I really hope that is something that will be offered to patients worldwide more frequently now because it is not only about treating the disease itself but also about the consequences, of course. And I really do think that people will benefit from that in terms of quality of life.

Brittany Harvey: Absolutely. I want to thank you both so much for your work on this comprehensive EAU-ASCO Guideline and for talking with me today and sharing your insights, Dr. Brouwer and Dr. Tagawa.

Dr. Scott Tagawa: Thank you very much. It was a pleasure.

Dr. Oscar Brouwer: You're welcome. I would just like to add also a short opportunity, maybe just to thank all the panel members because it has been a huge effort. Not only an update, it has been actually rewritten from the ground up. So a lot of panel members, not only from the United States and Europe but also Canada, South America, patient representatives, all the associates that have helped. So it has been a big effort, and I congratulate and thank everyone. And thank you, Brittany, for the interview.

Brittany Harvey: Definitely, it was a large group and multidisciplinary effort. So thank you to them as well.

And also, thank you to all our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. I also encourage you to check out the companion episode on this guideline from EAU podcasts, which you can find on Apple Podcasts, Google Podcasts, and Spotify. You can also find additional ASCO guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Beverly Moy is back on the ASCO Guidelines Podcast to discuss the latest guideline rapid recommendation update regarding sacituzumab govitecan for patients with hormone receptor-positive HER2-negative metastatic breast cancer based on recent evidence published in TROPiCS-02. Dr. Moy reviews how this update intersects with the previous rapid recommendation update on trastuzumab deruxtecan and future areas of research that may impact further updates to this evidence-based guideline.

Read the latest update, "Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor–Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/breast-cancer-guidelines.

View Details

Dr. Praveen Vikas, Dr. Tyler Johnson, and Dr. Russell Broaddus present the ASCO endorsement of the Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer. They discuss key evidence-based recommendations, focusing on the appropriate modality of testing (immunohistochemistry, polymerase chain reaction, or next generation sequencing) across multiple cancer types. Additionally, they cover the ASCO endorsement process, points of emphasis raised by the ASCO expert panel, and implications for clinicians and patients.

Read the full guideline endorsement, Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline at www.asco.org/molecular-testing-and-biomarkers-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome, to the ASCO Guidelines podcast; one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today, I'm interviewing Dr. Praveen Vikas from the University of Iowa, Dr. Tyler Johnson from Stanford University, and Dr. Russell Broaddus from the University of North Carolina; authors on, 'Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline'.

Thank you for being here, Dr. Vikas, Dr. Johnson, and Dr. Broaddus.

Dr. Praveen Vikas: Sure.

Dr. Tyler Johnson: Thanks for having us.

Dr. Russell Broaddus: Thank you.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline product. The full conflict of interest information for this guideline endorsement panel is available online with the publication of the guideline endorsement in the Journal of Clinical Oncology.

To start, Dr. Vikas, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Praveen Vikas: I don't.

Brittany Harvey: And Dr. Johnson, do you have any relevant disclosures that are directly related to this guideline?

Dr. Tyler Johnson: I do not.

Brittany Harvey: And finally, Dr. Broaddus, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Russell Broaddus: I do not.

Brittany Harvey: Great. Thank you all for providing that information.

So, starting us off on the content of this endorsement, Dr. Vikas, what is the scope of this guideline endorsement?

Dr. Praveen Vikas: So, as you can see from the topic and headline, the guideline endorsement was focused on mismatch repair and microsatellite instability testing for immune checkpoint inhibitor therapy, and this is basically an endorsement by ASCO, of a guideline that was developed jointly by CAP, and others.

Brittany Harvey: Great. And then you just mentioned that this is an endorsement of the guideline developed by CAP and other organizations. Can you provide us an overview of how this guideline endorsement process works?

Dr. Praveen Vikas: ASCO definitely takes great pride in endorsing some of the guidelines that are relevant to our cancer community, and of course, mismatch repair and microsatellite instability testing has been one of those areas where there is a lack of clear guidance. So, when we were approached from CAP about endorsing this guideline, we definitely realized that there's not much published from most of our oncology community, so we were very excited about looking into this guideline and endorsing it. So, this was very much for a topic that we thought is very useful and very timely.

Brittany Harvey: And that's great to hear. So then, Dr. Broaddus, as an author both on the guideline endorsement and as a member of the original guideline panel, what are the key recommendations of the CAP guideline?

Dr. Russell Broaddus: So, there are six key recommendations from the College of American Pathologists guideline that ASCO recently endorsed. I like to think of the first four as being bundled together because they're interrelated - we dealt with these by cancer type for the first four. So, for colorectal cancer, there's by far the most published evidence on this type of testing, and the evidence-based guideline found that really did not matter so much whether you used immunohistochemistry, or PCR-based microsatellite instability analysis, or next-generation sequencing-based analysis to detect mismatch repair or microsatellite instability. The three different techniques are almost interchangeable in their metrics.

Similarly, for gastroesophageal adenocarcinoma and small intestinal adenocarcinoma, immunohistochemistry and PCR-based MSI are very, very similar. There's not quite enough published evidence to equate next-generation sequencing. There were one or two very, very good papers with limited number of patients. The guideline committee felt like if there was maybe one or two more published papers in this space, that for gastroesophageal adenocarcinoma and small bowel adenocarcinoma, it would be similar to colorectal adenocarcinoma, whereas the three techniques were nearly interchangeable. After that, unfortunately, the published evidence really drops off in both quantity and quality for almost all other cancer types.

So, endometrial cancer, there's quite a bit of literature. Most of it really points to the immunohistochemistry outperforms PCR-based MSI analysis and PCR-based next-generation sequencing analysis. Most likely, that's because these PCR-based approaches nearly always are optimized to detect mismatch repair defects in colorectal cancer, or other GI types of cancer. And there's actually very good published evidence that this detection of mismatch repair can be cancer-type specific. So, the recommendation is to use immunohistochemistry for endometrial cancer.

Fourth recommendation for all other cancer types not encompassed by those first three recommendations, the committee recommends to choose a laboratory-based approach to detect mismatch repair or microsatellite instability defects, but there is no good published evidence to suggest which is the best approach. And again, like with endometrial cancer, there's evidence that the PCR-based approaches, which are usually optimized for colorectal cancer and GI-type cancers, may not be sufficient to work well with cancer types outside of the GI tract. So, almost by default, the recommendation is to choose immunohistochemistry.

Fifth recommendation: Many people tend to equate microsatellite instability and high tumor mutation burden. For sure, in colorectal cancer and other GI tract cancers, these two entities, there is substantial overlap. But for cancer types outside of the GI tract, you can easily have a tumor that has a mismatch repair defect, or high levels of microsatellite instability and not have high tumor mutation burdens. So, the recommendation is to not equate those two entities.

And finally, last recommendation is that for all of us to remember that these defects in DNA mismatch repair or microsatellite instability, are also hallmarks of hereditary cancer syndrome - Lynch syndrome, and that if you identify unexpectedly that a patient with an advanced cancer has one of these defects and DNA mismatch repair, to consider the possibility of Lynch syndrome, and to alert the appropriate care team, for those patients’ family members can be screened as well.

Brittany Harvey: Understood. Thank you for reviewing those evidence-based recommendations made by the CAP panel, and then endorsed by the ASCO panel.

So, were there any additional points of discussion or emphasis raised by the ASCO endorsement panel?

Dr. Russell Broaddus: Yes. And very appropriately, I believe. One-- and this is purely because of the issue of scope, and not to minimize the importance of these issues. One issue that the CAP guideline did not address was the important issue of pre-analytic variables and how they can impact diagnostic testing. A second issue, again, not considered by the CAP evidence-based guideline group, because of just tremendous scope problems, is how do these tests - immunohistochemistry, PCR-based MSI analysis, PCR-based next-generation sequencing analysis - how do we incorporate their use with PD-L1 immunohistochemistry, for example? Liquid biopsies, as a second example. Should we have a staged approach in assessing tumors with all these different testing modalities? And frankly, the answer is, we don't know right now. I think this represents an excellent area where oncologists and pathologists can actually work to provide the evidence in some specific cancer types on whether multiple modalities provide benefit compared to just one modality.

Brittany Harvey: Definitely, those are key points perhaps for future research, and I appreciate you explaining what was in and out of scope of this guideline.

So then following that, Dr. Johnson, in your view, what is the importance of this guideline endorsement, and how will it affect ASCO members?

Dr. Tyler Johnson: I think to understand the importance of this particular endorsement, it's helpful to zoom the lens out to 30,000 feet for a minute. Pretty much, all oncologists, I think remember 10 or 12 years ago, the types of drugs that we now commonly use for immunotherapy, burst onto the scene with the treatment of melanoma. And those trials were quite remarkable because previous to that, not only did we not have a cure for metastatic melanoma, we hardly had a treatment for metastatic melanoma. We had really almost nothing to offer those patients. And then there was this, initially a small and then a larger, and then a much larger series of patients, who we now know with 10 or 12 years of follow up, that many patients who were treated with immunotherapy, who had metastatic melanoma were actually cured. Not just treated but cured.

So, in the decade or so since then, there has been this understandable and appropriate stampede of trying to figure out, "Okay, how do we use similar drugs in all of the other many metastatic tumor types?" And I think to generalize a lot, and to make overly simple a very complicated picture, what has emerged from that is that unfortunately for many metastatic solid tumors, immunotherapy just doesn't do much. It's essentially inert, as best we can tell clinically. But there is a small percentage of patients, exactly what percentage depends on the tumor type and the genetic analysis as we're talking about here, but there's a small percentage, maybe 10-20% of patients, who derive this unbelievable benefit from immunotherapy in metastatic solid tumors, to the point that some of those patients, including in other solid tumors, not just melanoma, appear to be functionally cured by the administration of immunotherapy.

And so, the question of course that has resulted from that, is if eight or nine patients are going to get no benefit and maybe even harm from administration of immunotherapy, but one or two patients out of 10 is going to get this really remarkable benefit, it would be so great if we could be much more specific in knowing which patients are going to derive benefit, and which patients are not going to derive any benefit and may even be harmed. And I think that that's the context within which we have to understand this guideline endorsement, is that this is getting us one step further to knowing which patients are likely to get benefit from immunotherapy in metastatic solid tumors.

And the really nice thing, as Russell pointed out, is that one kind of shorthand takeaway from this is that it is almost never wrong to look at the question with immunohistochemistry. And that's a great answer, because it is also almost always the most readily available test. And so, if you have a patient who has a metastatic solid tumor and you order immunohistochemistry to look for microsatellite instability, that's almost regardless of the tumor type, it's probably going to give you a reliable answer. And if it shows that they're microsatellite unstable, then that means that that patient, regardless of the tumor type, really probably should get immunotherapy upfront or very close to upfront. And then there are more nuances sort of beyond that. But I think that's really the take home message, that this gives us one powerful tool for discerning who is likely to get benefit from these therapies.

Brittany Harvey: Absolutely. That's a key thought that you just mentioned, that this is about delivering personalized medicine to individual patients.

So then, you've already touched on this a bit in your last answer, but finally, to wrap us up, how will these recommendations impact patients with cancer being considered for immune checkpoint inhibitor therapy?

Dr. Tyler Johnson: I think that many clinical oncologists have the experience that when you sit down to talk to a patient who has newly diagnosed metastatic cancer, what their treatment is going to be, almost all of them have heard about immunotherapy somewhere; in the newspaper, or from friends, or in a cancer support group or whatever. So, most of them want to know what part, if any, immunotherapy is going to play in the care of their cancer right upfront. And I think this gets us one step closer to being able to answer that question. Now, the one thing that-- and Russell touched on this a little bit, but I think it's just important to highlight, this gives us an important way to predict people who are going to respond, but that does not necessarily mean that people who this does not identify as likely responders are therefore not going to respond. And that gets into a much more complicated question that depending on the tumor type, you may have to look at PD-L1 expression, or other things. So, it's just to say that this is not a comprehensive, definitive answer, but it is one important part of the answer.

I don't know if Russell or Praveen wants to add any more thoughts about that, but that's kind of how I would contextualize this.

Dr. Russell Broaddus: I think where there's a lot of opportunity here for us to start developing the evidence on the utility or not, of such staged approaches that if-- say like, immunohistochemistry does not reveal a mismatch repair defect, should we, for some of these cancer types where we don't routinely assess PD-L1, should we next do PD-L1 immunohistochemistry? And if that doesn't show overexpression, should we next try next-generation sequencing approach? Because sometimes those don't overlap with immunohistochemistry. So, I think there's a lot of room for us to provide this evidence.

Dr. Praveen Vikas: Yeah. And one point I would like to add, we had a lot of discussion among our ASCO endorsement panel, was that by recommending IHC or PCR over NGS in certain cancer, there would be scenarios where NGS will be needed, because NGS would tell us a lot more, like HER2 amplifications, and that was our point of discussion. We wanted to make sure that we send that message that even in cases where IHC and PCR is being done, that we may still have additional need for NGS testing.

Dr. Tyler Johnson: Yeah. Thank you, Praveen, for that. I should qualify, just to make sure that it's clear, that when I said that IHC is a good go-to, I only meant in terms of testing for this specific thing.

Part of the problem with next gen sequencing is that it often takes 4-6 weeks, and so I think the practical approach is, you should send the next-generation sequencing, but in the meantime, you can do the IHC to have an answer to that particular question, and usually in one or two days, depending on the lab, and then the next gen sequencing can come back whenever it comes back, and then you can use that for directing later lines of therapy.

Brittany Harvey: Excellent. Well, I've really enjoyed this discussion today, and I want to thank you all for your work on this guideline endorsement, and thank you for your time today, Dr. Vikas, Dr. Johnson and Dr. Broaddus.

Dr. Praveen Vikas: Thanks so much, Brittany.

Dr. Russell Broaddus: Thank you.

Dr. Tyler Johnson: Appreciate the time.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast.

To read the full guideline, go to: www.asco.org/molecular-testing-and-biomarkers-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App store or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy, should not be construed as an ASCO endorsement.

View Details

Dr. Manish Shah discusses the first ASCO guideline for advanced gastroesophageal cancer. He addresses biomarker testing to help guide therapy - including HER2 testing, mismatch repair testing, and assessment of PD-L1 expression. Dr. Shah then reviews the evidence-based recommendations from the ASCO Expert Panel, including first-line therapies for esophageal, gastroesophageal junction (GEJ), and gastric adenocarcinoma, along with esophageal squamous cell carcinoma, based on these biomarker results, as well as evidence in the second-line setting – and beyond – and how to provide optimal care for these patients.

Read the full guideline, "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline" at www.asco.org/gastrointestinal-cancer-guidelines

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today, I'm interviewing Dr. Manish Shah, from Weill Cornell Medicine, in New York, New York, lead author on 'Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline’.

Thank you for being here, Dr. Shah.

Dr. Manish Shah: Thank you for having me. It's great to be here, and I'm looking forward to our interview.

Brittany Harvey: Great. And first, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online, with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Shah, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Manish Shah: Yeah. So, I've received research funding from Merck, as well as from Bristol Myers Squibb, as well as from Oncolys Pharma. These are all companies that have worked for immunotherapy and upper GI cancers.

Brittany Harvey: Okay, thank you for those disclosures.

Then diving into the content here, what is the scope and purpose of this first ASCO guideline for advanced gastroesophageal cancer?

Dr. Manish Shah: Thank you. As you point out in the question, this is the first guideline for advanced gastroesophageal cancer, and really it is a very timely guideline because the landscape for the management of upper GI cancers has evolved and changed dramatically in the last several years. For a long time, we were really focused on chemotherapy for esophagus and gastric cancer. We, in fact, treated squamous cell cancer of the esophagus very similar to adenocarcinoma of the esophagus. And even though we knew of the different disease subtypes for gastric cancer, they didn't really play a role in differentiating management.

About 10 years ago, trastuzumab was approved for the treatment of HER2-positive gastric cancer, but since then, we've had really a run of significant positive studies that have informed practice, and we felt that this was really a timely guideline to help us with regard to our patients with upper GI cancer, particularly, with metastatic disease who need first-line, and beyond therapy.

Brittany Harvey: Excellent. Then you've just mentioned that the management of these upper GI cancers has evolved, so I'd like to review the key recommendations of this guideline that you just gave an overview of. So, starting with first-line therapy - is immunotherapy, or targeted therapy in combination with chemotherapy, recommended as first-line treatment for advanced gastroesophageal adenocarcinoma or squamous cell carcinoma? And what are these recommendations by the subgroups of patients by HER2 status or PD-L1 protein expression?

Dr. Manish Shah: The answer to that is that, in fact, it is now recommended for most patients, but I think I might start a little bit one step behind. So, with a newly diagnosed patient with an upper GI cancer, I think the first step in the management is to test for the biomarkers that will help guide therapy. So, for esophageal adenocarcinoma gastroesophageal junction, and gastric cancer, which is almost always adenocarcinoma, we recommend that everybody undergo HER2 testing immunohistochemistry, as well as a mismatch repair testing or MSI-high; either way you get it is fine, as well as an assessment of the PD-L1 expression, which is scored according to the Combined Positive Score or CPS.

So, that panel of biomarkers will help guide the management for the adenocarcinomas. And so, if you are HER2-positive, then we've known for a long time that the standard of practice would be chemotherapy with trastuzumab; typically, it's a platinum and 5-FU-based treatment with trastuzumab. Most recently, and this is in the guideline and the second part of your question, if you're HER2-positive, and you actually now are recommended to do chemotherapy with trastuzumab and pembrolizumab, which is a PD-1 inhibitor. Then that's based on the KEYNOTE-811 study, that we have the first analysis, which is a response rate analysis, and the response rate improves significantly with the addition of the immunotherapy.

But for the majority of patients who are HER2-negative, we do look at the PD-L1 status by CPS, then here it's a little bit trickier. The FDA guidance is to recommend immunotherapy with chemotherapy for all patients in the first-line setting. However, we also recognize that the higher the PD-L1 expression, the more likely the benefit from immunotherapy. And several studies have demonstrated that, and we've shown that in the guideline as well.

And there seems to be a very reasonable cutoff of a CPS score of five or higher, and above that, there really is clear benefit of the addition of immunotherapy, specifically, nivolumab to chemotherapy for gastroesophageal cancer, that's based on CheckMate 649. And then for esophageal adenocarcinoma, the additional recommendation is the addition of chemotherapy with pembrolizumab for a CPS of 10 or higher. And I think for CPS zero, most of us really felt pretty strongly that there was really no role for the use of immunotherapy because remember, these drugs do have some side effects, that although rare, can be really debilitating.

And then, there's an intermediate category of CPS, 1-4, and here, I think you have to use a little bit of a judgment call. We didn't recommend it in general but did suggest that that would be more of an individual-use basis. And the judgment call is that if the CPS is four, if you showed the slides to another pathologist, it's very possible it could have been a five. So, that kind of heterogeneity is something that we might consider to go ahead and use the immunotherapy.

But if the CPS is lower, the context is also questionable. We talked a little bit about the side effects of immunotherapy. If someone really has bad rheumatoid arthritis, we've all actually had patients given immunotherapy, they come in debilitated. So there, we really would want to be sure that the CPS is high, so that way, the patient is deriving the benefit, and we then adjust the rheumatoid arthritis medicines accordingly.

So, I think the other theme through our guideline is that with more options, we are able to actually provide more personalized care to our patients, giving them the best opportunity to receive the care with minimizing toxicity and maximizing benefit. So, that was a long-winded answer to the question that we do recommend immunotherapy in the first-line setting, in the right context, and for HER2-positive tumors, we recommend trastuzumab plus immunotherapy in the first-line setting, in the right context.

And then, the final thing was the mismatch repair status. So, unlike colon cancer where there's level one evidence comparing immunotherapy to first-line chemotherapy, we don't have that in upper GI cancers. So, we do recommend it, but as for the guidance, it would be in the second-line setting, or later.

Brittany Harvey: Great. Those are key clinical considerations that you just reviewed, and I appreciate you talking through both the evidence, and then the discussions that the panel had on the benefits of therapy, and also the adverse effects that can affect patients.

So, then, beyond first-line therapy for later-line therapies, is immunotherapy or targeted therapy recommended as second-line or third-line treatment for advanced gastroesophageal adenocarcinoma?

Dr. Manish Shah: Yeah. This is a great question, and I think it can be a point of confusion. So, for a long time, immunotherapy, specifically pembrolizumab, was approved and indicated in the third-line setting for CPS 1 or higher patients. The FDA actually removed that approval, and so it's no longer indicated in that setting. And most patients will have gotten immunotherapy in the first-line setting, and as of now, there's no data that suggests that continuing immunotherapy or rechallenging with immunotherapy would be of any benefit.

So, in general, the answer is that we would not use immunotherapy beyond first line. I guess the one caveat is if your CPS is low and you didn't receive immunotherapy in the first-line setting, but you happen to be MSI-high, then certainly, that would be an indication to use immunotherapy in that setting. But I think that would be a pretty rare event. So, if you use immunotherapy in the first-line setting, then there's really no role for continuing or re-challenging with immunotherapy in the second or later-line settings. But that's an active area of drug development, and we think that there will be an opportunity in the next few years for combination strategies to salvage people who had immunotherapy in the first-line setting.

So, in terms of second line and beyond, the other area that we should talk about is in squamous cell cancer. So, squamous cell cancer is a little bit unique, of the esophagus. It is more sensitive to immunotherapy than adenocarcinoma, and in fact, the guidance is to use immunotherapy, either with chemotherapy or as a doublet nivolumab and ipilimumab, in the first-line setting for most patients with squamous cell cancer. If, however, immunotherapy wasn't used in the first-line setting for squamous cell cancer, it is indicated in the second-line setting as nivolumab monotherapy. So, that would be one distinction between the squamous esophageal cancer and adenocarcinoma of the upper GI tract.

Brittany Harvey: Great. I appreciate you reviewing those considerations for later-line therapies, and we'll look forward to more research in this area in the future, as you just described.

Thank you for reviewing all of those recommendations. In your view, what is the importance of this guideline, and how will it impact clinical practice?

Dr. Manish Shah: So, this is an important guideline, because as we've talked earlier, there are lots and lots of options for patients, and we think that the guideline will help frame the discussion on how to best manage our patients in the first line, second line, and beyond.

I think it also frames where there are holes in our knowledge. These knowledge gaps are opportunities for research, for us to continue to develop therapies in gastroesophageal cancers.

Brittany Harvey: So, that's excellent. And you just mentioned that there's more options for patients with advanced upper GI cancers. So, finally, Dr. Shah, how will these guideline recommendations affect patients with advanced gastroesophageal cancer?

Dr. Manish Shah: Yeah. I hope that it will give patients and their physicians a strategy for how to treat patients in the first-line and beyond setting. Gastroesophageal cancer treatment has evolved significantly. Not too long ago, there was a debate of whether or not chemotherapy had a benefit in the first-line setting, or in the second-line setting, and there are randomized studies that demonstrate that for sure. Now, we're in an era where people should get chemotherapy, and then in the right context, get additional targeted agents, like immunotherapy or HER2-targeted therapy.

And if we can treat patients along the continuum of their care, thinking about first line, second line, third line, much as we do for colon cancer, we think that more patients will be able to get access to more of the drugs that are available, and in the long run, that will ultimately help more patients, and give patients better outcomes. I hope this guideline will achieve that goal for our community.

Brittany Harvey: Absolutely. And I appreciate you providing the details and the context for this new guideline. Thank you so much, for all of your work to develop these evidence-based recommendations. And thank you for your time today, Dr. Shah.

Dr. Manish Shah: Oh, absolutely. Thanks so much for having me, and I'm happy to come back anytime.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series.

To read the full guideline, go to: www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC with driver alterations. He identifies the latest trials that informed this update, and the updated evidence-based options for second- or later-line therapies for patients with advanced non-small cell lung cancer and an activating HER2 mutation or a KRAS-G12C mutation. Additionally, he provides important context on the reported toxicities associated with these therapeutics.

Read the update, “Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2“ and view all recommendations at www.asco.org/living-guidelines. Listen to Part 1 for recommendations for patients with stage IV NSCLC without driver alterations.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and in our last episode, we addressed the living guideline updates for ‘Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations.' Today, Dr. Dwight Owen from Ohio State University in Columbus, Ohio, is joining us again to discuss the updates for therapy for stage IV non-small cell lung cancer with driver alterations, as the lead author on, 'Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, version 2022.2.'

Thank you for being here, Dr. Owen.

Dr. Dwight Owen: Thanks for having me.

Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Owen, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Dwight Owen: Yeah, thanks for asking that really important question. My institution has received research funding for me to conduct clinical trials from Merck, BMS, Pfizer, and Genentech and Palobiofarma. I have no employment, stocks, stock options, or other disclosures to declare.

Brittany Harvey: Thank you for those disclosures. Then getting into the content of this update, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small-cell lung cancer with driver alterations. What new studies were reviewed by the panel to prompt an update to this guideline?

Dr. Dwight Owen: Thanks for that question. This is a particularly exciting update because as we were preparing for this update, reviewing two manuscripts that we think offer new options for our patients with driver alterations, there were actually updated presentations at a recent meeting that showed us even more data for these targets. So, it's really an ongoing and dynamic place. So, we really focused on two updates; one was for KRAS-G12C alterations, and then one was for HER2 alteration-positive non-small cell lung cancer.

So, I'll take them one at a time; for KRAS-G12C, we included an updated recommendation based on the CodeBreak 100 study - this was a multi-center, single group, open-label, phase II study of sotorasib, which is a KRAS-G12C inhibitor, in patients with non-small cell lung cancer positive for KRAS-G12C, who had received prior systemic therapy that could either be with chemotherapy or immune therapy, and the majority of patients had received both. 124 patients were evaluable for response, and the objective response rate was 37%, with the impressive median overall survival of over 12 months, of 12.5 months, specifically.

Now, there were some notable toxicities. There's GI toxicities such as diarrhea and nausea, as well as some elevations in LFTs. We also heard recently at ESMO about CodeBreak 200, which was a randomized study of sotorasib compared to docetaxel in previously treated patients with KRAS-G12C non-small cell lung cancer. And that study did meet its primary endpoint of improvement in PFS for sotorasib-treated patients compared to docetaxel, and we are very much looking forward to seeing that final publication.

For HER2 alteration-positive non-small cell lung cancer, we really focused our efforts on DESTINY-Lung01. Now, this was a multi-center, multinational, open-label, phase II study evaluating trastuzumab deruxtecan in patients with previously treated HER2-positive non-small cell lung cancer. In this study, 91 patients were evaluable for response, and 50, which was 55%, had a confirmed objective response, and the median survival was presented at 17.8 months.

A pretty unique toxicity was observed here. So, drug-related interstitial lung disease or pneumonitis occurred in just over a quarter of patients, and there were two deaths related to this. So, this needs to certainly be monitored for. Also at ESMO, we heard results for DESTINY-Lung02, which was a multi-center, multi cohort, randomized blinded study, which was also a dose optimization study. And this study eventually led to the accelerated approval of the 5.4 milligrams per kilogram dose that seemed to be just as effective as other doses, but perhaps with less toxicity. Again, we're currently awaiting the final publication of DESTINY-Lung02. However, these results are particularly impressive and especially leading to the FDA accelerated approval for a new treatment option for our patients with HER2 alteration positive non-small cell lung cancer.

Brittany Harvey: I appreciate you reviewing that data and the new updates for both of these drugs and targets in this population.

So then, I'd like to review the recommendations that the panel updated for our listeners. First, what is the new recommendation for patients with advanced non-small cell lung cancer and in activating HER2 mutation?

Dr. Dwight Owen: So currently, these patients should continue to receive standard first-line treatment as we do not have head-to-head trials for HER2-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a HER2-activating mutation, trastuzumab deruxtecan certainly should be offered to these patients.

Brittany Harvey: Understood. And then the second category of patients that you identified, what does the expert panel recommend for patients with advanced non-small cell lung cancer and a KRAS-G12C mutation?

Dr. Dwight Owen: So, similarly, these patients should continue to receive standard first-line treatment, as we do not have head-to-head trials for KRAS-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a KRAS-G12C mutation, sotorasib can be offered as a subsequent therapy. Keep in mind that this is only approved in patients with the KRAS-G12C mutation, and not other KRAS alterations.

Brittany Harvey: Thank you for reviewing those two recommendations for second or later-line therapies. What should clinicians know as they implement these updated recommendations?

Dr. Dwight Owen: So, I think what we're really excited about is that both of these agents offer new treatment options for patients who historically did not have a personalized targeted treatment option. We are awaiting publication of additional studies to help interpret these data, but for now, clinicians should discuss these treatment options with their patients, and also keep in mind the pattern of toxicities that seem to be unique to each treatment.

Brittany Harvey: Great. And then, you've just addressed some of this in your last response, but what does this change mean for patients with stage IV non-small lung cancer with a HER2 or KRAS-G12C mutation?

Dr. Dwight Owen: I think the bottom line is that our patients for whom their cancer does not respond, or where it progresses after first-line treatment, will now have additional effective and approved treatment options that are really tailored to the unique characteristics of their tumor and cancer cells.

Brittany Harvey: Absolutely. It's great to have new options for patients in this field.

So then finally, are there future research developments that the panel is considering for future living guideline updates?

Dr. Dwight Owen: So, we're particularly looking forward to the final publication of the studies that were recently presented, including the CodeBreak 200, and DESTINY-Lung02 trials. There are multiple ongoing studies for additional targets, including in the targets that we talked about; so, KRAS-G12C as well as HER2, as well as a number of other targeted options that may benefit subsets of our patients with metastatic non-small cell lung cancer.

Brittany Harvey: Great. Well, I appreciate you reviewing all this data and the updated recommendations, and thank you for your time today, Dr. Owen.

Dr. Dwight Owen: Thanks for having me.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines. There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer without driver alterations, available there and in the JCO.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes, or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC without driver alterations. He reviews the new evidence identified by the panel along with the updated recommendation regarding the role of bevacizumab in pemetrexed maintenance therapy. Dr. Owen also discusses exciting trials the panel is looking forward to seeing results of to drive future updates to the living guidelines.

Read the update, “Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2“ and view all recommendations at www.asco.org/living-guidelines. Listen to Part 2 for recommendations for patients with stage IV NSCLC with driver alterations.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Dwight Owen, from Ohio State University in Columbus, Ohio, lead author on, 'Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, version 2022.2.'

Thank you for being here, Dr. Owen.

Dr. Dwight Owen: Thanks very much, Brittany, for having me.

Dr. Owen, do you have any relevant disclosures that are directly related to the guideline topic?

Dr. Dwight Owen: I have research funding to my institution to conduct clinical trials from several companies, including Merck, Pfizer, Genentech, BMS, and Palobiofarma, but no ownership, no stock, and no employment history.

Brittany Harvey: Okay, Thank you for those disclosures.

Then let's get into the content of this living guideline update. So, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations. What new evidence was identified by the routine literature searches to prompt an update to the guideline?

Dr. Dwight Owen: Yeah, so this is a really exciting time for patients with stage IV non-small cell lung cancer. We are anxiously awaiting the results of some ongoing immunotherapy combination studies. However, for this update, we focused on a specific paper and study that evaluated a treatment that is not our first option anymore, but maybe the first option for a subset of patients.

So, before the standard introduction of immunotherapy for patients with stage IV non-small cell lung cancer, we often offered platinum-based doublet chemotherapy, and for years, we studied ways to make that better. So, we might introduce maintenance therapy where we continue a treatment after the first line of induction chemotherapy. We did either continuation maintenance, which is where you continue a treatment that seemed to be effective, or switch maintenance, where you were introduced to new therapy.

For many folks with non-squamous non-small cell lung cancer, the standard treatment options included carboplatin or cisplatin with pemetrexed, which is an antifolate chemotherapy, or carboplatin and paclitaxel with or without a VEGF inhibitor, such as bevacizumab. One of the big questions was whether there was a benefit for continuing maintenance therapy with something besides pemetrexed, in this case, bevacizumab, and if bevacizumab was given in combination with pemetrexed, whether continuing that as a maintenance would offer benefit.

Now, it's important to point out that the current FDA approval, at least in the United States, is for bevacizumab to be given with carboplatin and paclitaxel. However, several studies looked at the combination with pemetrexed and there were several issues with those studies. So, in one study they used a different agent, so ramucirumab instead of bevacizumab, both VEGF, but slightly different. In one study, the combination that was compared of pemetrexed plus bevacizumab was only compared to bevacizumab maintenance. And so, we really had a sort of hodgepodge of different trials that never answered the question of whether bevacizumab or VEGF therapy, given as maintenance offered any benefit to our patients.

What Dr. Garon and co-authors did in a study that we evaluated was conduct a meta-analysis of four of those randomized trials, focusing on the question of comparing pemetrexed maintenance therapy alone versus in combination with bevacizumab. And what they found is that there was no significant difference in overall survival with the addition of bevacizumab compared to pemetrexed by itself, and there were higher rates of toxicity in those patients, including serious and higher-grade toxicities.

So, I felt that it was really important to point out that the addition of bevacizumab or other VEGF therapies does not seem to add to a survival benefit when given as maintenance. And even though this is a subset of patients who perhaps could not get immunotherapy as a first-line treatment, maybe because of a pre-existing autoimmune disorder, but for those patients, it doesn't seem that the addition of VEGF as maintenance offers what we were hoping for.

Brittany Harvey: Understood, and I appreciate you laying out the landscape of the data in this area. So then, based off this new data and the meta-analysis that you just described, what is the updated recommendation from the expert panel?

Dr. Dwight Owen: So, the updated recommendation is a tweak to the established recommendation, which is essentially that for patients who are not candidates for immunotherapy for any reason, that platinum doublet chemotherapy is really the mainstay, and that if maintenance is offered, that it should not include VEGF therapy in combination with pemetrexed as compared to pemetrexed by itself.

Brittany Harvey: Understood. And then, what should clinicians know as they implement this updated recommendation?

Dr. Dwight Owen: I think, again, this should be a relatively uncommon scenario. Most of our patients are candidates for immune therapy. Many patients are offered platinum pemetrexed by itself. But when thinking about continuing maintenance therapy, we would recommend that most clinicians avoid the addition of therapies that haven't seemed to offer a survival benefit and incur higher rates of toxicity.

Brittany Harvey: Great. That's helpful to know. And then you've just mentioned that this doesn't apply to a lot of patients, but what does this change mean for patients with stage IV non-small cell lung cancer without driver alterations?

Dr. Dwight Owen: I think, hopefully, for the subset of patients where we're really thinking about here that we can at least avoid additional toxicity if there isn't a trade-off in terms of benefit, in terms of survival.

Brittany Harvey: Great. Definitely, that's helpful. And then finally, what ongoing research is the panel keeping an eye on for future living guideline updates?

Dr. Dwight Owen: So, there are a lot of exciting trials that are ongoing, and hopefully, we'll be able to read out soon, that would offer us updates for really how to manage these patients in the frontline setting with stage IV non-small cell lung cancer. We have multiple options now. This discussion that we've had today really focuses on the pre-immunotherapy era, but of course, bevacizumab is utilized in a regimen along with carboplatin, paclitaxel, and atezolizumab, compared to monotherapy with checkpoint inhibitors compared to chemoimmunotherapy and dual checkpoint inhibitors.

And we don't really have any head-to-head trials yet, or strategies on how to identify which patients need more aggressive combination therapies versus which patients could potentially do without chemotherapy, or with single-agent checkpoint inhibitor by itself. So, while we wait for those studies like the ECOG and Cigna study, we're really looking forward to having those to be able to help decide and tailor our treatment options for our patients.

Brittany Harvey: Great. Well, we'll look forward to the ongoing review of the literature by the panel and any future guideline updates to recommendations in the meantime.

So, thank you so much for your work on this update and thank you for your time today, Dr. Owen.

Dr. Dwight Owen: Thanks for having me.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series.

To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines. There's also a companion living guideline update on Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations, available there and in the JCO.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes, or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Emrullah Yilmaz reviews the latest evidence and recommendations for health care providers on biomarker testing and immunotherapy for head and neck cancers. He discusses the ASCO Expert Panel’s recommendations for biomarkers for the selection of patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy. Additionally, he reviews recommended treatment options, including first-line treatment based on PD-L1 status, therapies for platinum-refractory disease, options for patients with nasopharyngeal cancer, the role of radiation therapy for oligometastatic head and neck cancer, and immunotherapy for rare head and neck cancers. Dr. Yilmaz also explores future areas of research for therapeutic options for patients with head and neck squamous cell carcinoma.

Read the full guideline, “Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline” at www.asco.org/head-neck-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Emrullah Yilmaz, from Cleveland Clinic in Cleveland, Ohio, lead author on, 'Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline’.

Thank you for being here today, Dr. Yilmaz.

Dr. Emrullah Yilmaz: Thank you so much.

Brittany Harvey: Then first, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Yilmaz, do you have any relevant disclosures that are directed related to this guideline topic?

Dr. Emrullah Yilmaz: No, I don't have a relevant disclosure.

Brittany Harvey: Thank you. Then let's dive right into this guideline.

So, generally, what is the purpose and the scope of this guideline?

Dr. Emrullah Yilmaz: Immunotherapy with anti-PD-1 immune checkpoint inhibitors has become one of the most important treatment options for patients with recurrent metastatic head and neck cancers. And in the last few years, there has been new studies leading to new indications such as combinations with chemotherapy, or single-agent immunotherapy in the first-line treatment. And moreover, several studies also shown the effectiveness of immunotherapy for patients with nasopharyngeal carcinoma. All these advances in this complex disease group made it necessary to have an evidence-based guideline. So, that was the basis of building this guideline.

Brittany Harvey: Understood. And then this evidence-based guideline addresses six clinical questions. So, I'd like to review the key recommendations for each of those questions for our listeners. So, let's start with the first question. What did the expert panel recommend regarding biomarkers for selecting patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy?

Dr. Emrullah Yilmaz: Biomarkers are key for selection of treatment for immunotherapies, especially for the first-line treatment for head and neck cancer patients. PD-L1 is measured by immunohistochemistry and reported as Combined Positive Score, CPS, or Tumor Proportion Score, TPS. CPS is slightly different than TPS, and it includes lymphocyte and macrophage PD-L1 expression, in addition to tumor cells. Head and neck cancer studies have shown that CPS is a better marker for predicting response to immune checkpoint inhibitors, and key head and neck trials started to use CPS for reporting PD-L1 status. Therefore, we recommend CPS for recurrent metastatic head and neck cancers for PD-L1 reporting. This also makes it important for the oncologists to have a communication with the pathologists to make sure the right PD-L1 scoring is reported for head and neck cancer patients. Tissue tumor mutation burden is another emerging biomarker when CPS is not available, or for rare head and neck tumors, tumor mutation burden can be used as a biomarker as well.

Brittany Harvey: Great. And then based on that PD-L1 status that you just mentioned, what is the optimal first-line treatment regimen for patients with recurrent or metastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: If PD-L1 is positive, which is CPS more than one, there are two different options. Both pembrolizumab, single agent or pembrolizumab plus chemotherapy with platinum and 5-Fluorouracil can be offered. KEYNOTE-048 study showed an overall survival benefit with pembrolizumab alone for patients with CPS more than one, which was greater for the patients with CPS 20 or more. However, the pembrolizumab plus chemotherapy has showed benefit for the patients regardless of the PD-L1 status. So, if an early response is needed for a patient with high disease burden, pembrolizumab with chemotherapy could be an option, even if the PD-L1 is positive. For patients with negative PD-L1, which is CPS less than one, we recommend pembrolizumab and chemotherapy.

There was a recent subgroup analysis of KEYNOTE-048 for CPS-low patients. Patients with CPS less than one subgroup did not have significant survival difference with pembrolizumab plus chemotherapy when compared to cetuximab plus chemotherapy. This included a small number of patients, and this study was not powered to look at this subgroup, but cetuximab and chemotherapy can also be considered in the PD-L1 negative patient.

Brittany Harvey: Understood. It's important to recognize which patients benefit from these treatments more than others in different subgroups. So, following that, what is the effect of immunotherapy compared to other systemic treatments in platinum-refractory recurrent, or metastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: Platinum-refractory disease is defined as recurrence within six months of platinum-based chemotherapy. And effectiveness of immunotherapy was actually proven in this disease group first, several years ago. The effectiveness of immunotherapy as a single agent was proven in two similarly designed phase III trials in this setting. CheckMate 141 trial compared nivolumab to standard-of-care methotrexate, cetuximab, or docetaxel, and KEYNOTE-040 trial compared pembrolizumab to similar standard-of-care agents. And both studies showed overall survival benefit when compared to standard-of-care systemic agents, and the responses were independent from the PD-L1 expressions. So, nivolumab or pembrolizumab, are options as single-agent immunotherapy treatments for the patients with platinum-refractory head and neck squamous cell carcinoma, regardless of their PD-L1 expression.

Brittany Harvey: Understood, and thank you for getting into those options for those patients. Getting into the specifics for nasopharyngeal carcinoma, what did the panel recommend regarding the role of immunotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma?

Dr. Emrullah Yilmaz: So, the combination of immunotherapy with cisplatin and gemcitabine was shown to be effective in first-line treatment of recurrent metastatic nasopharyngeal carcinoma, in several phase III studies from Asia in the last few years. JUPITER-02 study used toripalimab, CAPTAIN-1 study used camrelizumab, and RATIONALE-309 study used tislelizumab in combination with cisplatin and gemcitabine in the first-line treatment, and all these studies showed progression-free survival benefit with addition of immunotherapy to chemotherapy.

Since these agents are not available in the United States as of now, our panel members recommend that pembrolizumab or nivolumab may be offered in combination with chemotherapy for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma. But the role of immunotherapy in the platinum-refractory nasopharyngeal carcinoma without the prior immunotherapy use is not well established yet. There are phase II studies that have shown that responses to immunotherapy are comparable to chemotherapy with a better safety profile. So, single-agent immunotherapy could be considered in a platinum-refractory setting if a PD-1 inhibitor was not used before.

Brittany Harvey: Those are excellent points that you just made. So, following that, the next question that the panel considered is, what is recommended regarding the use of radiation therapy in combination with immunotherapy versus immunotherapy alone, for the treatment of locoregionally recurrent or oligometastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: This is a great question, and radiation therapy is used a lot in head and neck cancers for different purposes. And immunotherapy and SBRT combinations were not shown to increase efficacy for abscopal effect for the treatment of oligometastatic disease in head and neck cancers. So, radiation therapy should not be given to increase the effectiveness of immunotherapy in recurrent metastatic head and neck cancers. However, there are several ongoing studies to evaluate the efficacy of radiation such as SBRT with immunotherapy for locoregional recurrence. So, although radiation therapy is safe to give the patients with recurrent and metastatic cancers, with immunotherapy, it should be considered for palliation or local control until the results of these trials are available.

Brittany Harvey: Great. And yes, we'll look forward to the results of those trials to find some more definitive results for these patients. So, then, the last clinical question that the panel addressed, what is recommended for the role of immunotherapy for rare head and neck cancers?

Dr. Emrullah Yilmaz: The role of the immunotherapy for rare head and neck cancers depends on the biomarkers. KEYNOTE-158 study has shown the effectiveness of pembrolizumab in advanced cancer patients, which included different types of cancers with high tissue TMB defined as more than 10 mutations per megabase. And looking at the results from that study for the patients with advanced rare head and neck cancers with limited treatment options, such as, salivary gland cancers or sinonasal cancers, if high TMB, which is Tumor Mutational Burden, is identified, then pembrolizumab may be considered for those patients. And pembrolizumab was also shown to have activity in salivary gland cancer patients expressing more than 1% PD-L1. So, that makes it an option for these patients as well.

Brittany Harvey: It sounds like understanding the biomarker status of these patients with rare head and neck cancers is essential for determining their therapy options. I want to thank you so much for reviewing all of those recommendations.

So, in your view, Dr. Yilmaz, what is the importance of this guideline, and how will it impact clinicians and patients with head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: This guideline was written by panel members, experts in their field, including medical oncologists, radiation oncologists, head and neck surgeons, pathologists, and radiologists. It is really important for oncologists to communicate the treatment options to their patients clearly while planning treatment of head and neck cancers. So, this guideline can help the clinicians to provide evidence-based resource when to use the immunotherapy for their head and neck cancer patients. So, that can be really helpful to the clinicians.

Brittany Harvey: Excellent. Yes, it's important to have a multidisciplinary group working on these guidelines to help clinicians in all capacities.

Finally, what outstanding questions or ongoing research are you interested in for future therapeutic options in head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: Our guideline focuses on recurrent metastatic head and neck cancers since it is the only area where the immunotherapy is approved as of now. We've had a few studies in the curative intent setting, which has not shown the benefit of addition of immunotherapy to radiation therapy, or chemoradiation. There's still several studies ongoing to investigate the effectiveness of immunotherapy in the curative intent setting, and the neoadjuvant setting, or adjuvant setting, or different combinations with the radiation therapy, with the immunotherapy, with the different sequences. So, it will be interesting to see the results of those studies in the future. So, that might be another area that the field might be moving in the future.

There are also studies ongoing to improve effectiveness of the immunotherapy in the recurrent and metastatic disease. Chemoimmunotherapy seems to be among the strongest systemic treatment options right now that we have, but there are several other combination strategies that are being developed combined with the PD-1 inhibitors, including combinations with EGFR inhibitors, angiogenesis inhibitors, intratumoral injections, vaccine developments, and there are a lot of different novel checkpoint inhibitors being developed. So, the field is advancing in that area as well. So, those are the areas that research are ongoing at this point.

Brittany Harvey: Definitely. We'll look forward to the results of those ongoing trials to inform future updates and future guidelines in this area.

So, I want to thank you so much for all of your work that you put into developing these evidence-based guidelines and thank you for your time today, Dr. Yilmaz.

Dr. Emrullah Yilmaz: Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning to the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/head-neck-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

Dr. Judith Paice and Dr. Eduardo Bruera discuss the latest evidence-based recommendations from ASCO on the use of opioids in managing cancer-related pain. They review the safe and effective use of opioids, including when clinicians should offer opioids, which opioids should be offered, how opioids should be initiated and titrated, management of opioid-related adverse events, modifying opioid use for patients with specific comorbidities, management of breakthrough pain, and how opioids should be switched. Additionally, they address barriers to care, considerations of health disparities, cost, and patient-clinician communication in achieving optimal pain management.

Read the full guideline, “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline” at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today, I'm interviewing Dr. Judith Paice from Northwestern University Feinberg School of Medicine in Chicago, Illinois and Dr. Eduardo Bruera from the University of Texas MD Anderson Cancer Center in Houston, Texas, co-chairs on “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline.”

Thank you for being here, Dr. Paice and Dr. Bruera.

Dr. Judith Paice: Thank you.

Dr. Eduardo Bruera: Thank you for having us.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Paice, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Judith Paice: I have no relevant disclosures.

Brittany Harvey: Thank you. And then Dr. Bruera, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Eduardo Bruera: Regrettably, I don't.

Brittany Harvey: Great. Then getting into the content of this guideline, to start us off, Dr. Paice, can you provide an overview of the purpose and the scope of this guideline?

Dr. Judith Paice: The use of opioids has become so complicated, so controversial, and just so associated with so much stigma that we wanted to provide oncology clinicians some guidance about safe and effective use of opioids.

We wanted to help people be aware of the current literature, and so we conducted a systematic review and identified randomized controlled clinical trials and other systematic reviews. And we found that there were 31 systematic reviews in 16 RCTs.

We carefully reviewed all of these literature and all of these studies, and our expert panel met via the web and via numerous conference calls and emails, and we came to consensus regarding these recommendations related to the use of opioids for people with cancer.

Brittany Harvey: Great. Sounds like there was a lot of effort that went into developing this and to tackle an important topic.

So, then Dr. Bruera, I'd like to review the key recommendations of this guideline for our listeners. This guideline addresses seven different clinical questions. So, let's review these questions starting with; in what circumstances should opioids be offered?

Dr. Eduardo Bruera: That's a very important point because the reality is that although opioids have been around for more than 300 years in different modalities, they continue to be the mainstay of care of patients with severe pain.

So, it's very important to try to figure out in the clinical practice why the patient has a pain syndrome. But in the great majority of patients who have pain that is due to the presence of the primary cancer or metastatic disease.

And also, in the vast majority of patients who develop severe complications from treatment such as mucositis from radiation and chemotherapy, an opioid will be needed. And the oncologist and the oncology clinician is in perfect conditions to safely prescribe that opioid so the patient can achieve fast relief of their pain.

Brittany Harvey: Great. Thank you for that explanation. So, then the next clinical question that the panel addressed, Dr. Paice, which opioids does the panel recommend clinicians should offer?

Dr. Judith Paice: Yeah, thank you. This is a really important question, one that gets asked all of the time, and yet, the data are insufficient to really suggest that there is one preferred opioid over another.

So, a patient with moderate to severe cancer-related pain is a candidate for any of the approved medications either approved by the FDA or because our audience also includes international experts, other regulatory agencies for pain treatment. We did call out a couple agents for which there is some concern or for issues where they are less than desirable in some settings.

So, one of those drugs is tramadol. And our rationale for identifying tramadol as a potential agent of concern is that it's a prodrug. It has a threshold, a ceiling unlike most of the other opioids, and that threshold is pretty low for neurotoxicity, which is of particular concern in the person with cancer. And it also, has a significant amount of drug-drug interactions.

So, we were concerned about tramadol, even though it is an agent that many, many people are using, in part, because it is a lower schedule on the controlled substance scheduling system, and there's a perception that it is less potent, and it is less potent.

The other drug that we call out is codeine. And our rationale for identifying it as an agent that may be of difficulty in certain populations of patients, is that it is also a prodrug and it is metabolized through the cytochrome P450 system, particularly through the isoenzyme CYP2D6. And that's what allows codeine to be metabolized to morphine, which allows it to be analgesic.

The challenge is there are some individuals who are poor metabolizers, and so they will not receive an analgesic effect. And then there are others who are ultra-rapid metabolizers, and they may actually experience a greater prevalence of adverse effects. So, for those reasons, we call out tramadol and codeine.

Now, we don't call out methadone as an agent that we're concerned about in terms of not being desirable. It is an agent that has a role in cancer pain management. However, we do caution clinicians that it is a complex drug to use.

And so, as result, people should obtain some guidance either from their palliative care program, their supportive care program, pain experts, or pharmacists, whomever can assist them in the dosing associated with this really important, but somewhat complicated drug to use.

Brittany Harvey: Understood. And I appreciate you reviewing where there's a lack of evidence and where there is evidence in identifying those potential agents of concern or where clinicians need to seek other expertise in this area.

So, then following those recommendations, after identifying patients who should be offered opioids, Dr. Bruera, how should opioids be initiated and titrated?

Dr. Eduardo Bruera: One possible way to do this is to give the patient an immediate release opioid. That could be a combination of hydrocodone with acetaminophen, a combination of other opioids or a straight strong opioid in a low concentration.

And ideally, we suggest that you use it as needed for the first few days and see if the patient needs to take it frequently. And there is a magic number around 30 milligrams of morphine equivalent per day.

Once the patient needs to take that opioid on a more frequent basis and gets through that threshold of needing about five, six tablets a day of immediate release opioid, then it might be necessary to start a regular opioid that is to stay on top of the pain.

And the way we do that are two ways; if the patient can afford it and insurance covers it, an extended release opioid is a wonderful option, because then, the patient can take the opioid a couple of times a day or put a patch for three days and they're going to be comfortable.

But if that is not an option, taking the immediate release opioid around the clock, not anymore as needed. But now, around the clock, will maintain that blood level and allow the patient to have less episodes of breakthrough pain.

An important thing to remember is that whether we decide to go with the extended release opioid or immediate release, it's nice to tell the patient that there might be moments in which the pain might break through. And so, giving that extra prescription and advice might help if there are moments in which the patient might break through.

Brittany Harvey: Understood. And then the next clinical question that the guideline panel addressed, Dr. Paice, how should opioid-related adverse events be prevented or managed?

Dr. Judith Paice: So, Brittany, I'm glad you asked me that question because I am called the pain and the poop nurse in the clinic, and it is so important whenever we can to prevent the adverse effects of opioids, and constipation is one where we can implement some preventive measures, and then treat unfortunately if your measures have not been totally effective.

But we wanted to address the gamut of potential adverse effects. So, we included not only constipation, but delirium, endocrinopathies, sedation, nausea, vomiting, itching, and urinary retention.

And we've included a table with very specific suggestions about how to prevent in some cases, and how to manage these adverse effects. Again, we wanted to make this document of the most use for all oncology clinicians who might be prescribing opioids for people with cancer.

Brittany Harvey: Absolutely. And that's key to maintaining quality of life for patients. So, then Dr. Bruera, what does the panel recommend regarding modifying opioid use in patients with either renal or hepatic impairment?

Dr. Eduardo Bruera: That's a great question, Brittany, and I think we have some evidence that some opioids are particularly desirable when the patient has renal dysfunction.

One of the ones that comes to mind is methadone because it has almost no major renal elimination, and therefore, that might be a wonderful option. One of the challenges is that changing from one opioid to another sometimes is a little bit more complex than maintaining the opioid that is being used.

And so, in absence of a major and fast deterioration, one option is to carefully titrate the dose of the opioid we’re using to reduce the risk of accumulation in a given patient.

There are some opioids that have traditionally been associated with a little bit more accumulation in cases of renal failure and traditionally, morphine is included, but there are other opioid agonists that also produce metabolites that are massively eliminated by urine that might be a little bit less desirable in patients with renal failure.

With regards to liver failure, it's very hard to find a complete consensus about the opioids that are less desirable or potentially more desirable. And we could say that careful titration is important.

But the one that was so good for renal failure might be the one you might not want to use for liver failure, and that would be methadone, because a vast majority of its metabolism happens in liver.

So, I think cautious individualized titration might be a nice recommendation to our patients. And perhaps, the most important thing is that there might be a little bit of renal failure or liver failure, but it's very, very important that we maintain the opioid therapy, that we don't give up on the opioids.

Brittany Harvey: Yes, those are important clinical considerations for individualized patient care. So, then Dr. Paice, Dr. Bruera touched on this a little bit earlier, but what are the recommendations regarding management of breakthrough pain?

Dr. Judith Paice: So, breakthrough pain is very common in the person with cancer. We see this when the individual has bony metastases and they place pressure on that limb or joint. And the patient who's normally well-controlled with either a regularly scheduled immediate release agent or a long-acting agent, now experiences what we call breakthrough.

And that's probably the most common type of breakthrough pain. There are also other breakthrough pains where the short-acting agent that's given regularly doesn't provide the relief that lasts four hours or six hours. Or similarly, if a long-acting agent is given every 12 hours, we may see that the pain breaks through prior to the next dose.

But for that patient who requires breakthrough medication, unfortunately, the literature does not reveal that one agent is superior to another. So, any immediate release opioid that's appropriate for that patient can be used for breakthrough-related pain.

Now, a common clinical conundrum is - which dose? What's the correct dose for the breakthrough medication? And again, the literature has a wide range of appropriate doses, and our committee established a range of 5 to 20% of the daily regular oral morphine equivalent daily dose.

And our rationale for that was that you really cannot come up with one figure. Every patient is different. So, on average it's somewhere around 10%, but the range is five to 20% of the daily regular morphine equivalency.

And so, what you need to do as you're examining the patient and exploring their needs is to look at the patient's frailty, the patient's pain, of course, their function when these breakthrough episodes occur. What about the comorbid kinds of organ dysfunction that Eduardo just spoke about?

So, all of those other factors need to be considered when selecting the appropriate opioid for the breakthrough as well as the appropriate starting dose.

Brittany Harvey: Definitely, it's important to consider all of those factors that you just mentioned. So, then the last clinical question that the panel addressed, Dr. Bruera, when and how should opioids be switched or rotated?

Dr. Eduardo Bruera: Thank you, Brittany. This is a hugely important issue because for many, many years, we believe that since opioids stimulated an opioid Mu receptor, and they all had a similar effect, there will be limited rationale for changing.

The answer to increasing pain was what we call opioid dose escalation. Just give more of the same. And we realized that that had serious limitations. And one of them is the development of side effects. And a lot of those side effects are neurotoxic side effects.

Patients get unduly sedated, get hyperalgesia, paradoxical increase in pain due to active metabolites and changes in their receptors, and they also get sometimes myoclonus, hallucinations, confusion.

And so, there are moments in which the side effects require us to say, okay, this opioid has done a good job for a while, but now, we have to change. And so, changing can be done due to side effects.

But also, sometimes, since we're all different and there's a lot of interpersonal variation in response — as some patients may just not be controlled, their pain syndrome might not be controlled well-enough with one type of opioid because we know there are multiple sub-Mu receptors, and they might really benefit from another.

So, the two main reasons are the development of toxicity to the opioid that so far was working reasonably well. And the second is failure, inability to control the pain, and in that case, going cautiously respecting the fact that there is limited cross-tolerance so that the dose of one opioid is not always exactly equivalent to the dose of the other opioid that you find in the actual tables that are published around is necessary to understand that that's a general guideline.

But the most important thing is to go progressively and monitor your patient frequently when you change from one opioid agonist to another opioid agonist.

There is limited understanding in the literature about the exact equianalgesic dosing. And because of that, a new guideline is being produced that addresses opioid rotation and deals exactly with trying to find out consensus from all the different existing tables on how to change what is the dose that is most likely to be appropriate when you move from one opioid, for example, morphine to hydromorphone or to fentanyl, or to oxycodone or vice versa.

We dealt with great trepidation to give all our oncology clinicians some kind of a fixed table, but the evidence is unfortunately not there at this point. It is sad because these medications are not that new, but the evidence unfortunately, is not there.

And that's why I think what we can tell you is go through your guidelines, use in a very careful monitoring of your patient to see if the dose you're giving is clearly not enough or it's a little bit too much. And you will learn that very rapidly — in a couple of days, you'll learn if you're doing okay or if you're doing too much or not enough.

And stay tuned because hopefully, very soon, ASCO, together with MASCC and a couple of other organizations will provide you with a little bit more evidence around this.

Brittany Harvey: Definitely, we'll look forward to that future guideline on opioid conversion tables as it is a confusing and complicated area, but it sounds like a lot of these recommendations are about providing individualized care for your patients.

So, I want to thank you both for reviewing all of those recommendations that the panel came up with.

So, then Dr. Paice, what does this guideline mean for both clinicians and for patients with pain from cancer or their cancer treatment?

Dr. Judith Paice: Well, speaking on behalf of the panel, our wish is that this will improve the management of cancer-related pain, that people will feel more comfortable in safe and effective use of these agents, and they'll be used more effectively.

There are other barriers that we've addressed, in addition to all of these recommendations. We talk about the care of people who have multiple chronic conditions. We address the disparities that we see in cancer pain management, and we talk about cost as another consideration, as one is developing a treatment plan for patients.

We also address the patient-clinician communication that is so essential. This is definitely a team effort, and we guide our clinicians and offer for patients the need to have clear communication, open dialogue throughout the development of a treatment plan, and then throughout the course of treatment while we reassess whether the plan has been effective.

Brittany Harvey: Absolutely. And it's really key what you just said about the safe and effective use of opioids for patients.

So, then finally, Dr. Bruera, you've both mentioned this throughout our conversation today, where the literature is either inconclusive or evidence is insufficient. So, what are the outstanding questions about the use of opioids for pain from cancer or cancer therapies?

Dr. Eduardo Bruera: I think there are questions that relate to the relative lack of specificity of the opioids for the different receptor pathways, and there are very likely considerable differences because they're chemically quite different, but they're considerable differences.

But we have not done an awful lot of the head on comparisons that would be so wonderful to do. And I think we need more studies comparing the different existing medications, and more importantly, we need a lot of translational work to get to specific areas.

Wouldn't it be fantastic if we were able to stimulate the Mu receptor all along the nociceptive pathway to reduce nociceptive input, but avoid completely the limbic system and avoid those Mu receptors in the area where reward is going to happen, an anti-reward and the possibility of developing non-medical use and eventually, opioid use disorder.

That would be, to me, the corollary, the ability to dissociate those receptors along the nociceptive pathway from those receptors in the areas where we would like our opioids to not go, but we cannot avoid it because they're a bit dummy drugs. And so, hopefully, getting smarter opioids would be wonderful.

Brittany Harvey: Absolutely. Well, I want to thank you both so much for your work developing this guideline, addressing these important questions for optimal pain management in patients with cancer. And thank you for your time today, Dr. Paice and Dr. Bruera.

Dr. Judith Paice: Thank you.

Dr. Eduardo Bruera:Thank you so much.

Brittany Harvey:And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/supportive-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

Voiceover: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

An interview with Dr. Van Morris from The University of Texas MD Anderson Cancer Center in Houston, TX and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, TN, co-chairs on "Treatment of Metastatic Colorectal Cancer: ASCO Guideline." Dr. Morris and Dr. Eng review the evidence-based recommendations from the guideline, focusing on areas of uncertainty in the treatment of metastatic colorectal cancer, and highlighting the importance of multidisciplinary collaboration and shared decision-making between patients and clinicians. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Van Morris, from The University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee - co-chairs on, 'Treatment of Metastatic Colorectal Cancer, ASCO Guideline.'

Thank you for being here, Dr. Morris, and Dr. Eng.

Dr. Cathy Eng: Thank you.

Dr. Van Morris: Thank you.

Brittany Harvey: First. I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Morris, do you have any relevant disclosures that are directly related to the guideline topic?

Dr. Van Morris: Not personally, but I do have research support to my institution from Pfizer and Bristol Myers Squibb who have products that I'll be discussing on this podcast.

Brittany Harvey: Thank you, Dr. Morris. And Dr. Eng, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Cathy Eng: Also, not personally associated with any honorarium specific to this topic.

Brittany Harvey: Great. Thank you both. So then, let's talk about the content of this guideline. So first, Dr. Morris, can you provide an overview of the scope of this guideline?

Dr. Van Morris: Sure. So colorectal cancer is the second-leading cause of cancer-related death in the United States. And especially in the time of the recent COVID-19 pandemic with people less likely to go for screening colonoscopies, there's great concern that more and more patients will be presenting at the time of their initial diagnosis with later-stage, more advanced colorectal cancer. So with that said, research is moving very quickly for the benefit of patients with colorectal cancer, and we were interested in assembling a multidisciplinary team that consisted of medical oncologists, surgical oncologists, radiation oncologists, pathologists, and radiologists as well, to help us make guidelines that really summarize the most relevant up-to-date practices, based on rigorous literature review for treatment recommendations for advanced metastatic colorectal cancer.

Brittany Harvey: Great. And then as you just mentioned, this guideline provides recommendations, and a lot of those focus on areas of uncertainty in the treatment of metastatic colorectal cancer. And I'd like to review those key recommendations that you mentioned for our listeners.

So, Dr. Eng, starting with - for patients with previously untreated, initially unresectable metastatic colorectal cancer, who are candidates for chemotherapy plus bevacizumab, is doublet or triplet cytotoxic chemotherapy recommended?

Dr. Cathy Eng: For treatment-naive patients, bevacizumab has been approved, and we do agree that it's a very reasonable treatment option with doublet or triplet therapy for our patient population. Obviously, these are guidelines, and it's extremely important to keep in mind that as a provider, you need to discuss the potential side effects with the patient. With bevacizumab, you know, standard concerns must be discussed with the patient, especially in regards to wound healing, if they've had recent surgery or any potential risk factors for a recent cardiac event from a recent thrombosis. So, those things obviously, would preclude the patient from initiating treatment with bevacizumab. But currently, doublet therapy or triplet therapy could be a potential option for patients.

Brittany Harvey: Great. And yes, as you mentioned, shared decision-making is paramount to these decisions.

So then following that recommendation, Dr. Morris, which patients should be offered pembrolizumab in the first-line setting?

Dr. Van Morris: Yeah. So, I think that this represents really one of the exciting advances in the treatment of metastatic colorectal cancer over the past several years. We have great data now that suggests for patients with microsatellite instability-high metastatic colorectal cancer, especially who have not had any prior treatment, we would recommend use of immune checkpoint blockade therapies, really coming from the seminal KEYNOTE-177 trial. This was a phase III international trial that looked at patients with advanced unresectable or metastatic colorectal cancer. And patients were either randomized to pembrolizumab monotherapy, or cytotoxic chemotherapy with FOLFOX, with or without bevacizumab. And this trial did meet its primary endpoint and showed an improvement in progression-free survival, with use of pembrolizumab as a single agent relative to cytotoxic chemotherapy. And based on this trial and the clear benefit that we see in patients with pembrolizumab, the FDA has approved this as an option for patients with MSI-high untreated metastatic colorectal cancer.

There are other trials which have looked at use of immunotherapy; the CheckMate 142 trial looked at combination PD-1 CTLA-4 therapy as a single-arm study. And, you know, there's another trial, the CheckMate 8HW, which is looking at one versus two immunotherapy agents in this setting as well. But really, as it stands for now, patients with MSI-high untreated metastatic colorectal cancer are the ones who benefit from the use of immunotherapy.

One of the questions that we often get in talking with other clinical oncologists is the FDA approval for pembrolizumab in any cancer type for a TMB, tumor mutation burden, greater than 10. And, we talked about this with our panel in this context, and we don't see that patients with microsatellite-stable metastatic colorectal cancer, who have a tumor mutation burden over 10 benefit from use of immunotherapy. There is one exception to this for patients who harbor pathogenic POLE or POLD1 mutations, these patients oftentimes do experience sustained clinical benefit with immunotherapy. But in general, patients with microsatellite-stable metastatic colorectal cancer, who don't have POLE/POLD1 mutations, we don't favor use of immunotherapy in that context at this point in time.

Brittany Harvey: Great. Thank you for reviewing that recommendation and the data behind who benefits and who doesn't benefit from immunotherapy in this setting.

So then following that, the next question that this guideline addressed is for treatment-naive RAS-wild type metastatic colorectal cancer. So, for these patients, Dr. Eng, is anti-EGFR therapy recommended for patients with right or left sided primary tumors?

Dr. Cathy Eng: That is such an important question, and thank you for asking this. We know based upon pivotal data from CALGB/SWOG 80405, that right-sided tumors treatment-naive, even if they're RAS-wild type, these patients should not receive anti-EGFR therapy. But also, we've learned from 80405, FIRE-3, and PEAK, which was a phase two study, that there appeared to be some benefit versus anti-VEGF therapy for left-sided tumors based upon studies that have been conducted.

So, at this year's ASCO, actually, the PARADIGM trial was specifically a phase III trial, more focused on left-sided tumors. It was amended twice before it decided to focus on the left-sided patient population. And it was a phase III study where patients were randomized to FOLFOX plus panitumumab versus FOLFOX and bevacizumab. And the primary endpoint was overall survival. And we added this data to our guidelines. This data just came out, hot off the presses in June, at this year's ASCO. And the primary endpoint was fulfilled. And basically, it prospectively demonstrated that the data from the other three trials, based upon a pooled analysis, suggested left-sided tumors fare better with anti-EGFR therapy. And in fact, the PARADIGM trial basically validated those findings. Obviously, the PARADIGM trial just recently presented, we have not seen the final publication, we do not know much about the maintenance setting, but specifically, when thinking about anti-EGFR therapy, it is very reasonable to consider it in a left-sided tumor, all RAS-wild type patient population.

I would like to mention though, and we do highlight this also in the guidelines, which is critically important, is that there was another study, which is a phase III trial called, TRIPLETE, that was presented as well, looking at FOLFOXIRI plus panitumumab versus basically, standard treatment. And what it noted is that there is no additional benefit for FOLFOXIRI plus panitumumab in left-sided tumors in regards to response or progression-free survival, there was no additional benefit. So, FOLFOX plus panitumumab seems very reasonable, FOLFOXIRI plus panitumumab is not necessarily needed in left-sided tumors.

Brittany Harvey: Great. Thank you for that explanation, and also for the work of the panel to rapidly include this new information recently presented at ASCO.

So then following those recommendations, Dr. Morris, what recommendation did the panel make for patients with previously-treated metastatic colorectal cancer with a BRAF V600E mutation?

Dr. Van Morris: Yeah. So, this recommendation was made essentially based on one randomized phase III clinical trial, which reported out about three years ago now, the BEACON trial. This is looking at patients with BRAF V600E mutated metastatic colorectal cancer, which we know accounts for probably eight to 10% of all patients with advanced colorectal cancer, and when found, really harbors a poor prognosis relative to BRAF-wild type counterparts.

So, the BEACON trial was a trial that looked at patients with previously-treated metastatic colorectal cancer, who have BRAF mutations, either kind of standard of care cytotoxic chemotherapy, or a BRAF/EGFR combination with encorafenib and cetuximab or alternatively, a BRAF/EGFR/MEK combination. That trial showed that improvement in survival outcomes with a BRAF/EGFR-targeted approach, as well as the BRAF/MEK/EGFR. However, because there was no difference in survival with the addition of the MEK inhibitor, the FDA subsequently approved encorafenib and cetuximab as the recommended treatment for patients with BRAF V600E previously-treated metastatic colorectal cancer. Because the MEK combination with binimetinib was not recommended by the FDA, you know, we did not include that analysis in our guidelines for ASCO. But as it stands right now, we do strongly encourage all clinicians to check for their BRAF V600E mutation status in their patients with metastatic colorectal cancer, with the goal of getting them to a targeted therapy approach over their treatment course.

Brittany Harvey: Great. Thank you for providing that information.

So, following that, Dr. Eng, what are the recommendations for patients with colorectal peritoneal metastases?

Dr. Cathy Eng: The current recommendations for colorectal cancer with peritoneal disease, really, there's no strong evidence to support the role of heated intraperitoneal chemotherapy. We now know based upon the literature from one of the largest studies to date, the PRODIGE data, demonstrating that there may be some potential benefit from cytoreductive surgery for the patients in regards to overall survival. But these patients are at high risk for bowel obstruction, potentially for perforation, and obviously, quality of life is an issue. So, these patients should always be discussed in a multidisciplinary tumor board whenever possible, and hopefully, to meet with a surgeon that is more experienced, specifically, in treating peritoneal disease, because these patients do require a lot of multidisciplinary care and discussion. So currently, based upon the existing data, we don't recommend heated intraperitoneal chemotherapy, but there may be a role for cytoreductive surgery.

Brittany Harvey: Thank you, Dr. Eng for going over those recommendations.

So then following that, Dr. Morris, for patients with unresectable liver-limited metastatic colorectal cancer, which liver-directed therapies are recommended?

Dr. Van Morris: So, this is I think a really good question and one that just like the prior question with regards to peritoneal surgery, is one that we felt was a challenging one, but a common one that we wanted to address. And specifically, I think this is an example of where level of evidence comes into the strength of recommendation.

So, for patients with unresectable liver-limited metastatic colorectal cancer, we looked at the questions of, "What is the role of SBRT - stereotactic body radiotherapy, and what is the role of SIRT, which is selective internal radiotherapy?" And for both of these, we felt that the level of evidence was weak, and I think that it's very important to make note of that in assessing the recommendations.

But to start with, for SBRT, we looked at one meta-analysis for patients with oligometastatic colorectal cancer, and also analyzed 18 non-randomized control trials in this setting. Most of the patients in these studies had one to five liver metastases, with the majority having one or two liver metastases. From the meta-analysis, we saw kind of a one-year local control rate of around 67%, a two-year control rate of 59%. So, based on those and recognizing the limitations of non-randomized trials and making recommendations, the panel did feel that it was reasonable to consider use of SBRT for oligometastatic colorectal cancer. The SABR-COMET trial is one that had looked at the role of radiotherapy for treatment of oligometastatic colorectal cancer, and I just want to make the point as well, that we did not include that in our analysis or recommendations at this point in time, because this really didn't include a lot of patients with colorectal cancer that we felt warranted inclusion.

Now, with regards to SIRT, we looked at kind of one meta-analysis and three randomized control trials for patients with mostly liver-limited metastatic colorectal cancer. All patients had liver disease, but there were about 40% of the patients we looked at in the meta-analysis, had extra hepatic disease as well. In the frontline setting, there really was no difference in progression-free survival or overall survival with the use of SIRT. And more recently, we've seen in a second-line trial, it was called the EPOCH trial, reported several years ago, this looked at patients with previously-treated metastatic colorectal cancer in the second-line setting. Patients were randomized to either chemotherapy with, or without transarterial radioembolization with Y90.

While there was an improvement in overall response rate, there was no meaningful improvement in overall survival with the use of SIRT. But there were significant increases in grade 3 or grade 4 toxicities when SIRT was added to chemotherapy. So, kind of given this, we didn't feel at this point in time that SIRT should be recommended for patients with metastatic colorectal cancer. Although, again, I do want to highlight that really these discussions should be happening at high-volume centers, kind of with a multidisciplinary group of clinicians.

Brittany Harvey: Definitely. And thank you for highlighting that multidisciplinary collaboration.

And the last section of recommendations, Dr. Eng, what is recommended for patients with metastatic colorectal cancer, and potentially-curable oligometastatic liver metastases?

Dr. Cathy Eng: So, another controversial topic. And once again, this is why we decided to include this as part of the guidelines, because this is a common scenario where patients are potentially curable, following liver resection for oligometastatic disease. We cannot highlight enough the importance of multidisciplinary discussion. Prior data has not been strong regarding specific guidelines following liver resection. We do recommend that based upon the existing data, there is no level one evidence to say, you should go one way or another following metastatic resection, and whether or not adjuvant therapy is warranted in that setting. But we do recommend multidisciplinary management and engagement and discussion. So, although it's not definitive, it basically suggests that there is a role for resection. It does provide improved five year survival relative to systemic chemotherapy, if the patient is potentially resectable, but does require multidisciplinary discussion. And it is a shared decision-making process.

Brittany Harvey: Great. Thank you. And I appreciate you highlighting the importance of shared decision-making throughout this guideline.

So then, Dr. Morris, what is the importance of this guideline in your opinion, and how will it impact clinical practice?

Dr. Van Morris: Yeah. So, I think that we understand that management of metastatic colorectal cancer is extremely complex given the various molecular annotations and the multimodality therapies which are possible for our patients. So, we tried to limit the guidelines here to include what we feel are the most recent updates, but also kind of the most clinically-relevant multidisciplinary questions that get asked for treatment of metastatic colorectal cancer. We also recognize that things are changing quickly. And for example, we didn't decide to include at this point in time, management of HER2 neu amplified metastatic colorectal cancer, although we are seeing more and more data coming out, suggesting targeted therapies. So, I think it's important for clinicians to realize that these are guidelines which are ever-changing, given the updates with new therapies available for our patients.

And the other thing I think that's very good about these guidelines is that, even though we may be making recommendations about controversial topics in the management of metastatic colorectal cancer - specifically, I think the use of HIPEC with cytoreductive surgery, locally-directed therapies to the liver, and the role of perioperative chemotherapy and metastasectomy - I think it's important for oncologists to realize that these recommendations come with varying strengths of level of evidence and that we as oncologists should be considering the level of evidence that's out there when making recommendations that affect our patients as well. So, we really wanted to support these guidelines and recommendations and empower clinicians to know and understand the quality of evidence that exists in the management of patients with metastatic colorectal cancer.

Brittany Harvey: Excellent. And yes, those are key points on the level of evidence and the strength of recommendations throughout the guideline.

And then finally, Dr. Eng, you've talked a bit about shared decision-making and the importance of this guideline for patients. So, how will these guideline recommendations affect patients with metastatic colorectal cancer?

Dr. Cathy Eng: The reason that we created these guidelines is to help patients, their caregivers, and providers, learn of the most recent developments in colorectal cancer, and the best approach based upon the information that we have personally reviewed with our multidisciplinary team of faculty members that participated in this exercise. We really just want to make sure that patients do get optimal care. And we hope that these guidelines also will help provide a foundation for some of the clinical trials that may be under development, or for other clinical trials that are being considered. So, we really just want to provide the most up-to-date information to all individuals that are interested in colorectal cancer so we can help guide their care better.

Brittany Harvey: So, I want to thank you both so much for your work on these guidelines, and all of the time it's spent developing these recommendations, and thank you for your time today, Dr. Morris, and Dr. Eng.

Dr. Van Morris: Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to: www.asco.org/gastrointestinal-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

An interview with Dr. William Tew from Memorial Sloan Kettering Cancer Center in New York, NY, lead author on "Poly(ADP-Ribose) Polymerase Inhibitors in the Management of Ovarian Cancer: ASCO Guideline Rapid Recommendation Update." Dr. Tew reviews changes to the recommendations for PARPi therapy for patients with epithelial ovarian cancer, and the outstanding questions in the field. For more information, visit www.asco.org/gynecologic-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today, I'm interviewing Dr. William Tew from Memorial Sloan Kettering Cancer Center in New York, New York; lead author on “PARP Inhibitors in the Management of Ovarian Cancer, ASCO Guideline Rapid Recommendation Update.” Thank you for being here, Dr. Tew.

Dr. William Tew: Thank you, Brittany. Glad to be here.

Brittany Harvey: Great. Then first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Tew, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. William Tew: I do not.

Brittany Harvey: Thank you. Then let's get into the content of this rapid update. So, what prompted this rapid update to the ASCO Guideline on PARP inhibitor therapy in the management of ovarian cancer, which was previously published in 2020?

Dr. William Tew: Yeah, there's been rapid change in the use of PARP inhibitors over the last five years. We have seen marked improvements and patient outcomes with the use of PARP inhibitors in the maintenance setting and treatment settings.

And new data has developed specifically in the last three months that we felt it was really important to help our patients and their providers, give them the best and safest treatments with PARP inhibitors.

Brittany Harvey: Understood. So, then based off this new data that you mentioned, what are the updated recommendations from the expert panel?

Dr. William Tew: Well, there's a few. First, at ASCO 2022 in June, there was the ATHENA-MONO phase III randomized control trial that was presented and published looking at rucaparib monotherapy in patients with stage III-IV epithelial ovarian cancer who were in complete or partial response to platinum-based therapy and in remission. And then studies showed a significant improvement in progression-free survival.

And that's what first prompted the update of the guideline. We felt it was an important note that now, there are three PARP inhibitors that are approved and showing significant benefit in patients in the first remission setting. And those are olaparib, niraparib, and rucaparib.

And then as we were working on the guideline, there has been several updates provided primarily through Dear Doctor letters directed through the U.S. FDA, as well as different labeling changes that were made to different PARP inhibitors.

However, the changes that were made are in the settings outside of the first line setting. So, we are talking about patients who had recurrence of their ovarian cancer and where PARPs are being used either as treatment or as a maintenance strategy after completion of another round of platinum-based treatment.

Brittany Harvey: Understood. So, these sound like important updates to the recommendations. So, then what should clinicians know as they implement these updated recommendations?

Dr. William Tew: Well, I think first and foremost, PARP inhibitors are a really critical treatment strategy for our patients. And patients that benefit the most from PARP inhibitors are women with a germline or somatic mutation in the BRCA gene. These are the patients that are going to benefit the most.

And then I think where the confusion lies is how best to use PARP inhibitors in patients that don't have a BRCA mutation. These groups of patients kind of fall into different categories.

One, a group of patients that have what's called homologous repair deficiency, or those patients that don't have a BRCA gene or have a BRCA gene mutation, or have this HRD positive status.

The emerging data that has been presented is really focused on mostly these patients, this non-BRCA patient population. And again, I want to just be cautious here because this is all evolving data and I suspect further data is going to emerge over the coming months and years.

And we wanted to give some flexibility as far as how patients and their providers use PARP inhibitors, but we felt given that this new emerging data specifically with signals affecting survival, was important to outline to our community.

Brittany Harvey: Excellent. And then you've just touched on those who respond best to PARP inhibitor therapy, but how does this rapid update impact patients with epithelial ovarian cancer?

Dr. William Tew: Yeah, I think what we described and outlined in this updated guideline is that, one, as a general rule, PARP inhibitors are not particularly recommended in patients as a treatment.

That is, if patients have recurrence of their ovarian cancer, using PARP inhibitors as a treatment rather than a maintenance strategy does not offer significant benefit and may have some survival decrements. At least, this is the data that we are following.

And so, as a general recommendation, we're expressing caution in the use of PARP inhibitors in patients that have platinum sensitive recurrence as a treatment. And we are continuing to recommend (this was in the initial 2020 guideline) that PARP inhibitor monotherapy is not recommended for patients with platinum-resistant recurrent ovarian cancer or BRCA wild-type.

The other broad category is PARP inhibitor maintenance, and where we've made some adjustments in the guideline is as far as the strength and the overall recommendations of the use of PARP inhibitors after completion of platinum-based therapy in the recurrent setting.

And specifically, we're expressing caution and the use of PARP inhibitors, particularly for those that have BRCA wild-type, meaning they don't have a germline or somatic BRCA mutation, and expressing some caution in patients that are just homologous repair deficient score positive.

Brittany Harvey: Well, I appreciate you reviewing the updated data that the panel reviewed and what those new recommendations that you all made.

So, you just mentioned that further data may emerge over the coming days and years. So, what are the outstanding questions regarding PARPi therapy in the management of ovarian cancer?

Dr. William Tew: Well, I think a few things. One, the way PARP inhibitors have been developed was first in the recurrent setting as a treatment, then in the recurrent setting as a maintenance, and most recently, in the frontline treatment as maintenance therapy.

And what we're seeing as this data evolves is that PARP inhibitor has remain a very important treatment strategy in the first line maintenance group. And patients with BRCA mutations continue to have significant improvements and outcomes.

But what I think the data that we're following closely, is what about those patients that have recurrent ovarian cancer and where PARPs now are being used as treatment and maintenance — we're seeing that as a treatment, there may be harm, although, again, cautioned because of the data that is used. There's faults with how we look at this data.

But really, these subgroups of patients, specifically those patients without a positive HRD score or those patients without a BRCA mutation, is the benefit going to still outweigh the risk in the PARP inhibitor maintenance setting, particularly in the recurrent setting.

Brittany Harvey: Yes, those are important questions and I'm sure the panel will keep their eye on those to update the guideline further as needed.

So, I want to thank you so much for your work on this rapid update, and thank you for your time today, Dr. Tew.

Dr. William Tew: You’re welcome.

Brittany: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

Voiceover: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy, should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Surendra Shastri from the University of Texas MD Anderson Cancer Center in Houston, TX, and Dr. Jose Jeronimo from the National Cancer Institute in Bethesda, MD, co-chairs on "Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline Update." Dr. Shastri and Dr. Jeronimo review the updated recommendations in the guideline, covering screening, triage, management, follow-up, and considerations for special populations. Read the full guideline at www.asco.org/resource-stratified-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Surendra Shastri from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. José Jerónimo from the National Cancer Institute in Bethesda, Maryland; co-chairs on ‘Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline Update’.

Thank you for being here, Dr. Shastri and Dr. Jerónimo.

Dr. José Jerónimo: My pleasure.

Dr. Surendra Shastri: Thank you very much.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with a publication of the guideline in the JCO Global Oncology.

Dr. Shastri, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Surendra Shastri: No, I don't have any disclosures.

Brittany Harvey: Thank you. And Dr. Jerónimo, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. José Jerónimo: No, I don't have any.

Brittany Harvey: Thank you both. So, to start us off, Dr. Jerónimo, what prompted this update to ASCO’s guideline on secondary prevention of cervical cancer, last published in 2016? And what is the scope of this guideline update?

Dr. José Jerónimo: That's a great question. Yes, it's natural for people to start wondering why the guidelines change or are updated so frequently. And I think there are several factors. The main one is that science on cervical cancer and other diseases is evolving very rapidly; there are new publications, there are new technologies, there is new information about different aspects of cervical cancer prevention specifically. The updates of those technologies is so fast that we need to periodically update the guidelines to accommodate these new options.

Now, I have to highlight that the ASCO guidelines in 2016 -- those guidelines were already very ahead of everyone else. What I mean is, in 2016, we were already recommending HPV testing for everyone all over the planet as a preferred option. It's something that other guidelines, other organizations were still wondering about, but we were really very upfront on that recommendation, considering that that’s the best technology we have. I think the updates of the guidelines is important because we need to keep with science, and we need to keep the doctors using the guidelines also updated on what exactly is out there, and what options could be usable for the different settings.

Brittany Harvey: Great, thank you for that background on the guideline update and for describing why the guideline needs to be updated over time. So then, Dr. Shastri, as this is a resource-stratified guideline, can you describe the four-tiered framework of the guideline? Specifically, what are the Basic, Limited, Enhanced and Maximal resource levels?

Dr. Surendra Shastri: Saying one size doesn't fit all would be a cruel example in health situations where it's really unfortunate that there are large disparities across the world, between countries, within countries, and that's the reason why we need resource-stratified guidelines. We can't just sit in ivory towers and preach to people who don't have anything. So that's the reason why we have the resource-stratified guidelines, and we have followed the same resource structure that the Breast Health Global Initiative is following.

So, we basically have four different resource levels. The most Basic one, or the core resources, is where you have just very basic public health services available. It's not services which are looking for outcomes and are just part of the social welfare that the country has to provide. Many times, those are also situations where the health priorities are very different.

For example, health priorities for some countries might still be infectious diseases, as it was amply displayed in the current pandemic. So, considering those situations, the expenditure that the country does or expenditure a local governing body does on a particular disease could be very different. So, at Basic, just available screening services at the lowest level.

Then you have the Limited; the Limited is slightly better than the Basics. They have maybe some of the newer technologies like Dr. Jerónimo just explained, not all of it. Some of those may not be able to provide in the same frequency or to everybody out there. But they are at this point of time looking at outcomes, looking at cost-effectiveness and those kinds of things.

Step up a little bit, and you have Enhanced level. That's the third tier of the resource level that we are talking about. In the Enhanced level, we have much better services available, we have organized services available. And those services have probably a system of tracking and recording clients or people who undergo screening and early detection.

And the final is the Maximal level. In the Maximal level, it is what we see across North America, or what we see in Europe, where you have the latest technologies, you have established systems, and you have systems to track and follow people. Again, I will caution here, even if I say North America or Europe, it's not across North America and across Europe. There are several places in North America, there are several places in Europe, which do not have the same resources. And that's why in this guideline, we're not talking about country guidelines, we're talking about resource-limited guidelines.

Brittany Harvey: Understood. I appreciate that description of the stepwise approach and how it isn't necessarily applicable just to one country, but there are differences in resource levels across countries and within countries.

So then, the guideline panel made recommendations across these four resource levels. Next, I'd like to review the key recommendations of this guideline update across those resource levels. So, Dr. Jerónimo, what are the recommended methods for cervical cancer screening?

Dr. José Jerónimo: That's a challenging situation on what to use in the different settings. Dr. Shastri already described very clearly the different scenarios we are facing; places with extremely limited resources where basically you have only maybe an evaluation table there, and places in the other extreme with all the resources and all the technologies available.

But even though we have very different areas with very different resources, the most recommended test for a screening for cervical cancer in all of them is HPV testing; the testing for the Human papillomavirus that is directly related to cervical cancer. The question could be, "Okay, why are you recommending that test for places where maybe now they are not going to be able to do it?" I think it's important to put that technology as a target, even though the sites are not prepared right now to do it, but they have to go towards that goal of implementing HPV testing.

Meanwhile, the guidelines also highlight that there are other options that could be used in the meantime to do some screening, one is visual inspection with acetic acid that is being already implemented in many places. And the reason why we are recommending HPV testing even in those places with extremely limited resources is because there are some advantages. First, with HPV testing, it's very highly sensitive, extremely highly sensitive. That means that you have a sensitivity over 90% with good validated tests. Second, because it's highly sensitive, you have the option to have a smaller number of screenings in the lifetime. Instead of -- some people remember, some years ago, the screening for cervical cancer with Pap smear was done every year.

But now we know that it's changing. With HPV testing, we are now recommending every five years or in these guidelines, depending on the resources, could be every 10 years, or could be once or two times in the lifetime of the woman. And with that, we are going to have a huge impact.

The other great advantage of HPV testing is that it can be self-collected by women. That means that basically, a woman takes the small brush, goes to a private place and introduce that in their vagina and collect the sample herself, without the need of specula, without the need of trained personnel, without the need of having all the infrastructure that is required for a pelvic evaluation.

And that's big because in that way, we can reach populations that are hard to reach. And also, we are dealing with some issues like cultural resistance to have a pelvic evaluation. I mean, that's the biggest advantage for HPV testing. And we have now examples showing that this is very well accepted in many, many studies around the world with different populations around the world showing that self-collection is very accepted. That means that the preferred test for cervical cancer prevention is HPV testing right now. There are options displayed in the guidelines for cities where it's not possible to do it now, but that’s the role.

Brittany Harvey: Understood. Thank you for explaining what testing is recommended; HPV testing, and then also the timing and collection strategies across settings. So, then following that, Dr. Shastri, what is recommended regarding triage for patients who have positive results or other abnormal results?

Dr. Surendra Shastri: So, let me briefly explain what triage is; right up following the primary screening when the woman has a positive result, a second technique or technology is used to determine whether this person needs to be treated, or this person needs to be tracked and followed up in a particular way. So, our recommendations for triage in the updated guidelines is that for the Basic settings, just like Dr. Jerónimo mentioned, if we have used HPV screening in the basic settings; that's the molecular test, and if that is positive, then we use another strategy which is known as, visual assessment for treatment. And this strategy is used to determine whether a woman should be treated with thermal ablation, or with LEEP, or she just needs to be followed. Whereas all the other three settings, HPV genotyping along with cytology, or cytology alone should be used for triage.

Brittany Harvey: Great. Thank you for explaining those triage recommendations. So then following triage, Dr. Jerónimo, what is recommended regarding management and follow-up strategies for patients with precursors of cervical cancer?

Dr. José Jerónimo: I think treatment also has evolved significantly in the last 20 or more years. And specifically, in the last five years or 10 years, there are new options that are becoming more popular because there is more evidence supporting the effectiveness of this technology, and ablation of that tissue is really one of the best options in most of the places.

I always try to compare the pre-cancer lesion like the paint on your wall, in your house. If one of the kids come with something and you start to scratch something in there, you don't need to turn the wall down in order to fix that problem. Basically, you just have to remove that area and put some new paint, and that's going to be corrected. In the same way, when you have a pre-cancer of the cervix, it's very, very superficial. It's not cancer, it's pre-cancer. You don't need to remove the whole cervix or the whole uterus to treat that. With ablation, basically what we are doing is destroying that tissue that is in the very surface, and new cells, healthy cells are going to come and are going to cover that area. That's the idea. The technologies that are more usable for areas with limited resources could be the thermal ablation or could be cryotherapy.

The other advantage of those technologies is basically there is no major complication; no bleeding, no major problems. Of course, as Dr. Shastri explained, there are more resources in other places. In other places, you have more resources, you can do a LEEP; that is, basically using an electrical device, removing part of the cervix and sending that to the pathologist. That's also one option that is acceptable and recommended in the guidelines. I think the main idea is, we need to remove that area with disease, with pre-cancer. We can remove it using ablation; just destroying the cells, or we can remove it using some excisional procedure. That all depends on the resources you have.

But how effective those technologies are, I could say there is very high cure rates using thermal ablation, for example, or LEEP. Very important to consider, doing the procedure, you can do it anywhere. Doing a LEEP, in theory, you can do it anywhere where you have electricity and you have the equipment. But remember, you have to be prepared not only for the treatment, you have to be prepared for the complication. If you have a LEEP, a very portable device and you have electricity, but if you are far from the next health facility, if you have a complication like you are bleeding in that setting, it's going to take hours, hours and hours just to evacuate that patient to the health facility. That's why you need to be very careful not only on the treatment, but also managing the complication.

Brittany Harvey: Understood. I appreciate you reviewing those technologies. So then, following those notes that Dr. Jerónimo just made, Dr. Shastri, are there any changes to the recommendations for special populations or highlights that you'd like to note that are identified in the guideline?

Dr. Surendra Shastri: This is a speciality of the ASCO guidelines really also to take a look and make recommendations for special populations. And by special populations here I mean the ones that we have looked at and recommended cervical cancer screening for are; women who are HIV positive or immunocompromised, immunosuppressed due to any other disease, or any other reasons, maybe because of medication, or cancer or other disease conditions which requires immunosuppressives.

For such women, we would say you start screening for cervical cancer as soon as the first diagnosis; the diagnosis of the disease which is causing immunosuppression is done. That's the first time. And then, through their lifetime, you screen them twice as frequently as you would do for other women who do not have an immunocompromised situation. So, you do it more frequently. As far as the management post-screening with positive results is concerned, for women with HIV as with all immunosuppressed women, it is the same. The triage is the same and the management will be the same as for all other women.

Then also pregnant women. For pregnant women, we recommend in the very Basic settings, pregnant women should be screened six weeks postpartum. And in all other settings, all other levels, we recommend that they should be screened six months postpartum. The very reason is, in many basic settings, you may not even get those women back for screening. That's the reason why we try to screen as early as possible. But on the safer side, the earliest possible is six weeks postpartum; that is, she is still probably following up for postpartum reasons of the pregnancy or immunization for the kid. That's the time we should go ahead and do it.

And finally, women who have undergone a hysterectomy but still have an intact cervix, need to get screened in the same way as other women. However, they could stop screening over a period of time, if they have more than three negative results.

A very interesting subject that we discussed in our committee, and we have put it up there as a statement to bring it up is that, we now come across several people who are transgender, who have an intact cervix. So, getting such people into screening, and screening them like all others, will be an important priority. We have put out a statement saying that, although we mentioned that this is for women, it is for all persons who have an intact cervix. So these screening guidelines apply to everyone.

Brittany Harvey: Yes, it's important that all persons with a cervix get screened for cervical cancer as it is something that can affect anyone with a cervix. And those are important considerations for clinicians that you noted across several different populations.

So then, in your view, Dr. Jerónimo, what is the importance of this guideline overall, and how does it impact clinicians?

Dr. José Jerónimo: That’s, I think the core of the guidelines is how this is going to affect the practice of clinicians. I think the main message here with the guidelines is: first, clearly acknowledging that the resources are different in different settings, and we need to accommodate to those settings to provide the best service. I think for clinicians, it is presenting options that could be suitable for their setting. As Dr. Shastri mentioned at the beginning, we are not talking specifically about countries. Because in one given country, you can have areas with Maximal resources, you can have areas with Limited resources, and you can have areas with Basic resources. If you try to apply that new, most modern, expensive technologies everywhere, you're going to be just doing the screening in very few places in the country because it's not possible.

With the guidelines, we are giving the option saying, "Okay, if you don't have access to those technologies, you can get started using this. For example, visual inspection. If the technology becomes available, for example, HPV testing, you can start to use HPV testing, because that's the goal. That's what you really need to look for. If you don't have the resources or the conditions to do excision procedure like a LEEP, you can do ablation, and that's okay. And basically presenting, you have different options to accommodate to your place. But the most important part is, do it well. Do it well, reach as many women as possible with your screening, and treat as many positive women as possible." I think that's the best message here. And I think that's the way these guidelines are going to help and impact the world of clinicians.

Brittany Harvey: Yeah, that's the core message of the resource-stratified guidelines; is using the resources you need to help and treat and screen the most people possible. So then finally, Dr. Shastri, how do these guideline recommendations affect patients?

Dr. Surendra Shastri: I will just add one line to the response that Dr. Jerónimo just gave you. We already have an existing country guideline, these are meant to complement those guidelines, and meant for the policymakers in those countries to open their eyes and realize that there are people at different resource levels, who may or may not have an insurance program, who may or may not have a socialized system which provides the same level of health care for everyone. So, use what we recommend because that's the current evidence for use.

Coming to how people are going to benefit, which was your question, these guidelines are going to make cervical cancer screening available and accessible to all women across the globe. We are talking about different options. We are not saying that, "if you don't have X, don't screen." We are saying, "if you don't have X, try Y. If you don't have Y, try Z." So, this opens up doors for all women across the globe to get screening. That is the ultimate goal, because if you want to reach the WHO goal of eradication of cervical cancer, then that's possible only through two means; one, is giving cervical cancer screening, preferably HPV, through whatever means or resources that the country has, and the vaccination, which is of course, being dealt by another committee over here.

So of course, all women across the globe will get benefit of newer technologies, simpler, cost-effective technologies, technologies that don't require them to -- for example, a self-collection, the woman doesn't really have to go anywhere. She doesn't have to go and wait in a clinic for hours to get a screen. She doesn't have to make repeat visits to get a screen. She doesn't have to lose her wages. These are things which are real. She doesn't have to lose her wages for the day, she doesn't have to arrange for child support to look after her children just to go and get herself screened. Those are some of the social determinants of health, which prevent women from going and getting themselves screened. So, by a simple technique like self-collection, we removed that entirely.

Going forward, we are going to see Artificial Intelligence, we are going to have deep machine learning, we are going to change the technology and the strategies, and we will come back with another update to this, maybe very soon, sooner than what we did this time.

Brittany Harvey: Absolutely. Those are excellent points. And we'll look forward to future updates as technologies continue to advance. So, I want to thank you both so much for your work on updating these resource-stratified guidelines for the secondary prevention of cervical cancer. And thank you for your time today, Dr. Shastri and Dr. Jerónimo.

Dr. José Jerónimo: My pleasure.

Dr. Surendra Shastri: Thank you for inviting us.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO guidelines podcast series. To read the full guideline go to: www.asco.org/resource-stratified-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Rohan Garje from Miami Cancer Institute in Miami, FL, lead author on "Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Rapid Recommendation." Dr. Garje reviews the new evidence and the latest recommendation update for the use of 177Lu-PSMA-617, a radioligand therapy in patients with PSMA-positive mCRPC, along with it's implications for clinicians and patients. For more information, visit www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Rohan Garje from Miami Cancer Institute in Miami, Florida, lead author on, ‘Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Rapid Recommendation’.

Thank you for being here, Dr. Garje.

Dr. Rohan Garje: Absolutely. Thank you so much for having me, Brittany.

Brittany Harvey: Great. And first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Garje, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Rohan Garje: Yes. I have received institutional research funding from Pfizer, Amgen, Endocyte, and AAA, who have drugs for the treatment of prostate cancer.

Brittany Harvey: Excellent. Thank you for those disclosures.

Then getting into the content of this guideline update, what prompted this rapid update to the ‘ASCO Guideline on Systemic Therapy in Men with Metastatic Castration-Resistant Prostate Cancer’, which was previously published in 2014?

Dr. Rohan Garje: Since 2014, there are several new drugs that have been approved for prostate cancer management. And most recently in March 2022, FDA has approved 177Lutetium-PSMA-617 for patients with PSMA scan-positive metastatic castration-resistant prostate cancer. This led to the team from ASCO to develop this new rapid recommendation update. Now, this approval actually has been based on the efficacy data published in VISION clinical trials.

To give you a little background about Lutetium, it is a novel β-energy-emitting radioligand therapy. In this particular study, this agent was combined with best standard of care, and compared to best standard care alone, in men with metastatic castration-resistant prostate cancer, who had a positive PSMA scan. Briefly, the study was both clinically and statistically positive, and has shown improvement in both overall survival and radiographic progression-free survival. The median overall survival was about 15.3 months with the combination therapy, compared to 11.3 months with the standard care arm.

Brittany Harvey: Great. And then based off this new evidence and the new approval from the FDA for 177Lutetium-PSMA-617, what are the updated recommendations from the guideline panel?

Dr. Rohan Garje: The panel recommends the use of 177Lutetium-PSMA-617 as a treatment option in patients with PSMA PET/CT positive metastatic castration-resistant prostate cancer, who have been previously treated with at least one line of androgen receptor pathway inhibitor, and at least one line of prior taxane-based chemotherapy.

Brittany Harvey: Great. And then, what should clinicians know as they implement the use of this drug and this new recommendation by the guideline panel?

Dr. Rohan Garje: A very good question. It is important to select patients based on a positive PSMA scan. That is, all the metastatic lesions should be positive on the PSMA scan, and there should not be any large lymph nodes or visceral organ metastatic disease that are PSMA negative. Additionally, physicians can use Gallium 68 PSMA-11, or F-18 piflufolastat as radiotracers for PSMA scan to determine eligibility.

Additionally, there are several other factors that need to be considered, such as: the patient should have baseline good blood counts, as well as renal function to be eligible for this therapy, as this treatment has a potential to cause myelosuppression and impairment of renal function. The most common side effects associated with this drug are fatigue, dry mouth, dry eyes, and nausea. The treatment in general is for four to six cycles. Each cycle is for every six weeks. The fifth and sixth cycles should be considered only if patients are responding well to the therapy and have no significant toxicities.

It is also important for the physicians to note that there are several additional treatment options for patients with metastatic castration-resistant prostate cancer, who had prior anti-androgen docetaxel therapy. They include; cabazitaxel, PARP inhibitors for patients who have mutations in DNA repair, gene mutations such as BRCA1 and BRCA2, and immunotherapy with pembrolizumab for patients with MSI-high status, or tumor mutation burden greater than 10.

Brittany Harvey: Thank you for describing that nuance behind the recommendations. So then, in addition, how does this update impact patients with metastatic castration-resistant prostate cancer?

Dr. Rohan Garje: 177Lutetium-PSMA-617 is the first radioligand therapy approved for the treatment of prostate cancer. Previously, we had Radium-223 as a radiopharmaceutical, but this particular agent is unique in the sense, it is a radioligand therapy where it is chelated to PSMA. So, it is very targeted therapy which works for both bone and visceral organ metastasis. So, this is an exciting treatment option for patients, as it has been shown to have improvement in overall survival. This adds to the current treatment choices of anti-androgens, chemotherapy, as well as targeted therapies for prostate cancer patients.

Brittany Harvey: Great. It's exciting to have a new treatment option for patients.

So then finally, what are the outstanding questions regarding systemic therapy for metastatic castration-resistant prostate cancer?

Dr. Rohan Garje: We are at an exciting stage in the management of prostate cancer. In the last decade, we have seen several new drugs; some are specific targeted agents, some are specific immunotherapy agents. Now, we are entering into this realm of radioligand therapy, which is very exciting. There are several other novel radioligand therapies such as; actinium, thorium, lead, which are being evaluated in the treatment of prostate cancer. So, in the next several years, we will see several new drugs that have been developed.

In addition, there are other agents called T-cell-engaging therapies, which are being evaluated to improve the outcomes. So, the last decade definitely has seen a lot of new improvements, but we are so excited that several new treatment choices are now available for patients, and several are in clinical evaluation. So, the future is bright for the patients with prostate cancer, where we have several new treatment choices to improve their outcomes.

Brittany Harvey: It sounds like an exciting time for developments in prostate cancer.

So, I want to thank you so much for your time today, Dr. Garje, and thank you for all of the work you did to update this guideline.

Dr. Rohan Garje: Thank you so much. I really thank ASCO leadership and the team for giving me this opportunity, and thank you, Brittany, for hosting me on this podcast.

Brittany Harvey: And thank you to all of our listeners for tuning into ASCO Guidelines Podcast series. To read the full guideline, go to: www.asco.org/genitourinary-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

An interview with Dr. Jun Mao from Memorial Sloan Kettering Cancer Center in New York, NY, lead author on "Integrative Medicine for Pain Management in Oncology: SIO-ASCO Guideline." Dr. Mao reviews the recommendations on integrative approaches, such as acupuncture, yoga, reflexology, massage, guided imagery with progressive muscle relaxation, hypnosis, and music therapy for managing pain in patients with cancer, and the evidence behind these recommendations. He also addresses the implications for clinicians and patients as well as outstanding questions about the use of integrative approaches for pain management. Read the full guideline at www.asco.org/survivorship-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcast.

My name is Brittany Harvey, and today I'm interviewing Dr. Jun Mao from Memorial Sloan Kettering Cancer Center in New York, New York, lead author on ‘Integrative Medicine for Pain Management in Oncology: Society for Integrative Oncology and American Society of Clinical Oncology Guideline’.

Thank you for being here, Dr. Mao.

Dr. Jun Mao: Thank you, Brittany. It's great to be here.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available in line with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Mao, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Jun Mao: No, I don't.

Brittany Harvey: Great. Then I'd like to get into the content of this guideline. So what is the purpose and scope of this joint SIO-ASCO guideline?

Dr. Jun Mao: So Brittany, about one in two cancer patients or survivors experience pain that often are not adequately controlled by conventional medications. So often individuals seek out complementary and alternative medicine, more recently known as integrative medicine, for the relief of pain, but there's a very little synthesized information for oncologists to help guide the patients in choosing evidence-based integrative therapy approach. Therefore, we decided to really do a systematic review and come up with a system of guidelines that can help oncologists and patients make informed decisions about choosing the right type of integrative medicine approaches to manage pain.

The Society for Integrative Oncology and the American Society of Clinical Oncology joined forces that really convene a group of panelists, that represent many fields in conventional oncology in support of integrative medicine. And after reviewing over 200 articles from clinical trials to systematic review have come up with very thoughtful recommendations to help patients and physicians to provide the best evidence-based care on how to manage pain for patients with cancer.

Brittany Harvey: Excellent. And yes, it's great to have SIO and ASCO join forces on this guideline. So then next, I'd like to review those key evidence-based recommendations of this guideline that you just mentioned. The recommendations are provided in the guideline by pain type. So I'd like to review each category for our listeners, starting with: what is recommended for patients experiencing aromatase inhibitor related joint pain?

Dr. Jun Mao: So we recommend acupuncture should be offered to patients experiencing aromatase inhibitors related joint pain in breast cancer. And this is really evidence-based, benefits outweigh the harms. And with intermediate quality of evidence and moderate strength of recommendation. As many of our audience would know, aromatase inhibitors cause very severe types of joint pain that not only affect quality of life and functions, but make many women stop taking these life saving drugs.

So the panelists want to recommend this therapy based on large randomized control trial that hope this can be part of a pain management strategy along with exercise and duloxetine so give people the options so that women can not only have better quality of life, but also hopefully they can stay on aromatase inhibitor to prevent the recurrence of breast cancer. And we also found some weak evidence for yoga to improve joint pain related to AIs. However, the evidence is weak, although the benefit outweighs the harm. So clearly, more studies are needed to make yoga as a part of therapies for cancer patients.

Brittany Harvey: Understood. And thank you for reviewing the level of evidence behind those two interventions for patients experiencing aromatase inhibitor related joint pain. So following those recommendations, what is recommended for patients experiencing general cancer pain or musculoskeletal pain?

Dr. Jun Mao: So in terms of general cancer pain or musculoskeletal pain, there are three therapies that we consider that may be offered to patients experiencing this type of pain: acupuncture, reflexology or acupressure, or massage. So reflexology and acupressure use the same kind of principles like acupuncture, but instead of using needles, by using hands. So that's kind of in between acupuncture and massage. So these are evidence based recommendations with benefits outweigh harms, and the quality of evidence is intermediate with moderate level of evidence and recommendations. So clearly, for cancer patients or survivors that experience this type of general cancer pain or musculoskeletal pain, I think these approaches may be appropriately integrated along with conventional pharmacotherapy or physical therapy.

Brittany Harvey: Definitely. It's great to have options to go along with conventional pharmacologic therapy. So then following those recommendations you just mentioned, what is recommended for patients with chemotherapy-induced peripheral neuropathy?

Dr. Jun Mao: So chemotherapy-induced peripheral neuropathy, also known as CIPN, is a very bothersome symptom resulting from certain types of chemotherapy that can be very functional limiting, and resulting in falls and that also can cut the dosage of chemotherapy. So this is a quite bothersome to patients and also can be really challenging in the practice of oncology. So based on the current evidence, we recommend either acupuncture or reflexology or acupressure may be offered to patients who experience CIPM. So, unfortunately, the evidence base here is weaker. So although it's evidence-based, benefits outweigh harms, but the quality of evidence is low. Therefore, the level recommendation is weak. So basically, there are a number of smaller trials that really provide some good signals that this type of therapies can be beneficial. But we really need more large and definitive trials to establish the strength of the evidence

Brittany Harvey: Understood. It's important to know in which patient populations we have more evidence and where we still need confirmatory results. So following those recommendations, what is recommended for patients who experience procedural or surgical pain?

Dr. Jun Mao: Many surgery procedures or surgery itself can cause acute short-term pain that if not adequately treated, can then become chronic. So in this setting, there is actually a pretty reasonably robust base for hypnosis. So the evidence base really is intermediate with moderate level recommendation. We consider that hypnosis may be offered to patients experiencing procedural pain in cancer treatment or diagnostic workups. However, for other type of therapies like acupuncture or acupressure or music therapy, although there are some smaller trials to show that it could be beneficial, the current evidence base is very low and the strength of recommendation is weak. So clearly, we need more high-quality trials to establish the evidence base for those therapies for surgery or procedure-related pain

Brittany Harvey: Understood, and we'll get into some of those outstanding questions or where there's insufficient evidence a little bit later in the episode. So then the last category of recommendations that the panel made: what is recommended for patients who have pain during palliative and hospice care?

Dr. Jun Mao: So for patients with advanced cancer near the end of life, there is some good evidence that massage may be offered for patients experiencing pain during palliative and hospice care. So we recommend massage should be used with an intermediate level of evidence and moderate level of recommendation. And I do think the caveat is we still don't know the long-term effects for massage. Therefore, many of the trials, the follow up are reasonably short. But the evidence showing that acupuncture in the population of palliative care hospice patients can produce immediate pain relief as well as to enhance coping. Therefore, we suggest massage may be offered to patients experiencing pain during hospice or palliative care settings.

Brittany Harvey: Understood. Well, thank you for reviewing all those recommendations, the level of evidence behind them and the strength of those recommendations. But you've also mentioned that in several areas, there's low evidence or insufficient evidence. So are there interventions that the panel reviewed but found insufficient or inconclusive evidence to make recommendations?

Dr. Jun Mao: Brittany, I feel like the field of integrative medicines research is still in its infancy or adolescence. So there's clearly a lot of gaps, particularly in the area of mindfulness-based interventions. There are studies showing outside oncology settings, it can be very helpful for managing pain and pain coping, but that literature in oncology is very, very limited to make any reasonable recommendation. So I think research is needed.

Another area is in the area of herbal medicine or supplements. A lot of cancer patients have a lot of interest in using supplements or herbs to manage symptoms, improve their sense of well-being. But the trials unfortunately in this setting are just too sparse and the quality is too poor to make any recommendation. Last but not least, is for children that experience pain. This guideline was sought out to develop recommendations for both adults and children. Unfortunately, the trials in the pediatric populations are just too few and some of the quality are just too poor. Therefore, there's inconclusive evidence in that population to recommend any specific therapy to be used to manage pain.

So I do think these represent really important gaps in research that we really need to be developing and designing and conducting rigorous clinical trials to build an evidence base so we can bring integrative medicine into conventional oncology care to help patients with a variety of truths.

Brittany Harvey: Yes, well, we certainly appreciate the panel reviewing this mountain of evidence across several different integrative oncology approaches, even if we ended up not making recommendations for certain interventions because of inconclusive or insufficient evidence because it still demonstrates the need for high-quality trials in those areas. In your view, Dr. Mao, what is the importance of this guideline? And how will it change clinical practice?

Dr. Jun Mao: Brittany, I think this guideline is both important and timely. With the opiate epidemic experienced in the United States, managing pain for cancer patients and survivors is incredibly challenging. This is the first SIO and ASCO joint guideline for integrative medicine for pain. And for the first time, we have solid recommendations for specific integrative medicine modalities to care for patients and survivors with pain. I do think the implementation process will take time. First of all, we need to find ways to educate oncology providers as well as patients about the evidence base of this treatment so they can talk to their patients about this type of therapies.

Second of all, some of the therapies are not uniformly covered by insurance. So we do need better insurance coverage for integrative therapies such as acupuncture, massage, or reflexology for managed pain for cancer patients. So people from across socioeconomic areas can access it.

I think last but not least, as we know, there are disparities in healthcare infrastructures. In large hospitals like Memorial Sloan Kettering Cancer Center, Dana-Farber, or MD Anderson Cancer Center, we do have acupuncture services developed to help cancer patients. But then in smaller community hospitals, especially in those who serve predominantly black and brown populations, those services may not be in existence. So we need to partner with our community partners to develop the necessary resources to overcome those structural barriers for these therapies to be incorporated as part of standard oncology care.

Brittany Harvey: Definitely. Those are key points on the implementation of this guideline and the availability and accessibility of integrative medicine modalities across different hospitals and patients. So then, this leads into my next question, how will these guideline recommendations impact patients?

Dr. Jun Mao: It is my hope this will really help improve patient care, and also patients here in such conventional oncological treatments, whether they're chemo therapies or hormonal treatments. I do think patients in general have a lot of preferences for using therapies that are a little bit more natural or therapies are in addition to drugs to manage their pain or symptoms. So these guidelines clearly provided recommendations based on prior research. And I do think as we engage patients in shared decision making, we need to really acknowledge patients’ beliefs, preferences, as well as availability of treatments in their care settings. So hopefully we can provide both evidence-based and patient-centered care to manage pain.

Brittany Harvey: It's great to have more options beyond conventional treatments to offer patients to help with pain management because it occurs across cancer patients. Finally, Dr. Mao, you've already talked about some interventions where we lacked data such as mindfulness-based interventions, herbal medicines and supplements, and interventions in the pediatric population. But what are the outstanding questions for the use of integrative approaches and managing pain in patients with cancer?

Dr. Jun Mao: Brittany, as a researcher, I'm always thinking about the future questions. I do think with clinical trials in the last 10 years, there's definitely larger and well done trials to demonstrate both efficacy and effectiveness of specific integrative medicine therapies for improving pain. We need to do more of that in the next 10, 20 years. In addition, I think two particular areas of research I hope to see more research as part of these guidelines being implemented, one is what I consider precision pain management. But just because acupuncture works for some patients, it doesn't work for everyone. We need to figure out what type of molecular biomarkers, so psychological attributes can help to predict who may respond to acupuncture or not so we can make sure the right person gets the right care for best pain management and at the least amount of cost to him or herself or to the society.

The second issue I really think we’ve got to do better is I feel like there's wide acknowledgement of health disparity in pain management, particularly in cancer patients. I'd love to see more research designed for and in populations of historically underserved populations, so we can really implement this approaches to narrow the health disparity issues in cancer care.

Brittany Harvey: Absolutely. Those are key points about providing equitable care for pain management in oncology. So I want to thank you for all of your work on these guidelines, Dr. Mao, and thank you for taking the time to speak with me today.

Dr. Jun Mao: Brittany, it’s such a pleasure. Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

An interview with Dr. Beverly Moy from Massachusetts General Hospital in Boston, MA, lead author on "Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update." Dr. Moy reviews data from the recently published DESTINY-Breast04 study, and the ASCO Expert Panel's updated recommendation on the use of trastuzumab deruxtecan. For more information, visit www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guideline podcast series brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today I’m interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, lead author on 'Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update'. Thank you for being here, Dr. Moy.

Dr. Beverly Moy: It’s my pleasure. Thank you for having me.

Brittany Harvey: Great. First, I’d like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Beverly Moy: I do not have any relevant disclosures that are directly relevant to this guideline topic.

Brittany Harvey: Thank you. Then let’s talk about this rapid update. So first, what prompted a rapid update to this guideline on chemotherapy and targeted therapy for patients with HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative, which was last updated in 2021?

Dr. Beverly Moy: First, I would state that ASCO issues rapid guideline recommendation updates when really important advances in the treatment and management of cancer have been presented. This mechanism really allows clinicians to keep up with the rapid advances in cancer management. The fact that a rapid update had to be issued just one year after the full updated guideline that was published in 2021, as you just mentioned, is really a testament to the advances in cancer research and clinical trials that have been made recently.

But I will state that the reason why this rapid update was done was because the result of the DESTINY-Breast04 study were so strong and compelling and showed such a large degree of benefit to a large group of metastatic breast cancer patients that we felt as the guideline panel that this rapid update had to be out there. We really wanted to make sure that the oncology community was aware of these results. That’s based on the strength of the trial. The DESTINY-Breast04 trial was a very large randomized study that showed that trastuzumab deruxtecan significantly improved progression-free survival and overall survival compared to treatment of physician’s choice in patients with metastatic, “HER2-low” breast cancer.

Brittany Harvey: So then based off this new data from the DESTINY-Breast04 trial that you just mentioned, what is the updated recommendation from the guideline expert panel?

Dr. Beverly Moy: So the updated recommendation is that patients with HER2-low, or to be specific, HER2 IHC1+ or 2+ and ISH negative metastatic breast cancer who have received at least one prior chemotherapy for metastatic disease, if they’re hormone receptor-positive, are refractory to endocrine therapy, those patients should be offered treatment with trastuzumab deruxtecan.

Brittany Harvey: And then what should clinicians know as they implement this new recommendation for trastuzumab deruxtecan?

Dr. Beverly Moy: I think that there are a few things that clinicians really need to be aware of. One is that it significantly improved progression-free survival and overall survival, and that’s pretty important. The paper was published in the New England Journal of Medicine, and folks can refer to that study specifically. But to be specific, it improved progression-free survival at a median follow-up of about 18 months from 9.9 months with trastuzumab deruxtecan compared to 5.1 months with treatment of physician choice in the entire study population. Median overall survival was 23.4 months with trastuzumab deruxtecan and 16.8 months with treatment of physician’s choice. So that’s really a marked improvement in both of those outcomes.

It is also important to note that trastuzumab deruxtecan has a very important side effect, and that’s the potential of developing drug-related interstitial lung disease or pneumonitis. And that could be very serious. This side effect was confirmed in about 12% of the patients who received trastuzumab deruxtecan, and about 1.3% of patients actually had severe symptoms requiring oxygen, and three patients in the study, so less than 1% actually died of this side effect. So that’s something that needs to be monitored for very carefully, and clinicians need to be very cognizant of this potential side effect when using this drug.

Brittany Harvey: Thank you for reviewing both the impact on survival and then the adverse event of interstitial lung disease. So how does this guideline update impact patients with breast cancer?

Dr. Beverly Moy: So metastatic breast cancer is incredibly common. And this HER2-low, and I say, “HER2-low” because this is a definition that has never been made before. The patients with HER2 IHC1+ or 2+ and ISH negative disease, that's a very large group of patients. That's a lot of patients. So it's really important that this guideline is going to impact a very large group of patients. Again, it's those who've had at least one prior line of chemotherapy in the metastatic setting. And if they had hormone receptor-positive disease, it has to be refractory to endocrine therapy. But that's a lot of patients. And the results of this randomized study do show that trastuzumab deruxtecan is superior to other treatment of physician’s choices that were available before this study came out in terms of its efficacy. So this guideline is very significant for clinicians and metastatic breast cancer patients across the world.

Brittany Harvey: Definitely. It's great to have a new option and one that has such a great clinical impact for patients.

So then finally, Dr. Moy, what are the outstanding questions regarding chemotherapy and targeted therapy for HER2-negative metastatic breast cancer?

Dr. Beverly Moy: I think like any good study, this raises a lot of other important questions. Again, this HER2-low definition that I described is an interesting one. It’s a very large bucket of patients. One obvious question is, would this drug be as effective in patients who are truly HER2-negative, so HER2 IHC of 0? Kind of, overnight, the results of this study has changed the paradigm for many oncologists because we used to just say HER2-positive or HER2-negative. And now we're looking back at patients' charts to see what their immunohistochemistry results were. Does it really matter if it's IHC 0 or 1+ or 2+? So that would be very interesting.

Another outstanding question is: what about the use of trastuzumab deruxtecan earlier in the treatment? I said that it should be offered for patients who’ve received at least one prior line of chemotherapy? What about first line chemotherapy in the metastatic setting? And there are multiple studies studying this drug in actually early stage breast cancer as well. So lots of unanswered questions about this compound that's pretty remarkable.

Brittany Harvey: Great. Well, I want to thank you so much for your time today, Dr. Moy, for discussing the results of the DESTINY-Breast04 trial with me, and for your work to rapidly update this guideline.

Thank you so much.

Dr. Beverly Moy: Thank you, Brittany. It was a pleasure.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for therapeutic options for patients with stage IV NSCLC with ALK rearrangement or RET rearrangement. They also discuss new agents on the horizon. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, Michigan, and Dr. Andrew Robinson from Kingston General Hospital at Queen's University in Ontario, Canada, authors on 'Therapy for Stage IV Non-small Cell Lung Cancer with Driver Alterations: ASCO Guideline Update'.

Thank you for being here, Dr. Jaiyesimi and Dr. Robinson.

Dr. Ishmael Jaiyesimi: Thank you.

Dr. Andrew Robinson: It’s a pleasure to be here.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Jaiyesimi, do you have any relevant disclosures that are directly related to this guideline?

Dr. Ishmael Jaiyesimi: None.

Brittany Harvey: Thank you. And, Dr. Robinson, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Andrew Robinson: Yes, I have received funding less than $5,000 from AstraZeneca, Merck, and BMS over the past two years.

Brittany Harvey: I appreciate those disclosures. So, then Dr. Jaiyesimi, let's talk about the purpose of this guideline. So, what is the purpose of this guideline update, and what clinical scenarios does this guideline address?

Dr. Ishmael Jaiyesimi: The purpose of therapy for stage IV non-small cell lung cancer with driver alterations, is to rapidly update the ASCO and Ontario Health guideline on the systemic treatment of patients with stage IV non-small cell lung cancer, last published in February of 2021.

The update is a result of potentially practice-changing evidence published since the last publication in February 2021. The update is based on two clinical trials from 2020 to 2021.

The clinical scenario this guideline covers are stage IV non-small cell lung cancer with driver alteration with an ALK gene rearrangement and RET gene rearrangements.

Brittany Harvey: Great. So, then let's review those two clinical scenarios that you just mentioned. So, there are a few new recommendations regarding ALK rearrangement. So, what are the recommended first-line options for patients with stage 4 non-small cell lung cancer in an ALK rearrangement?

Dr. Ishmael Jaiyesimi: In the previous guideline alectinib or brigatinib were recommended as first-line therapy with a strong recommendation and level of evidence in patients with ALK gene rearrangement, and a performance status of zero to two.

In the current update, lorlatinib was cited as the first-line ALK inhibitor that may be offered as an alternative first-line therapy. If alectinib, brigatinib, or lorlatinib are not available, ceritinib or crizotinib should be offered.

This is based on the CROWN study that showed alectinib was superior to crizotinib in the first-line setting. Unfortunately, we don't have head-to-head comparative data with alectinib or brigatinib, so we cannot conclude that any one treatment is more effective than the other, and decisions should be made on experience, toxicity, and on.

Brittany Harvey: Okay, thank you for describing how a clinician should select between those treatments as well. So, then the second clinical scenario that Dr. Jaiyesimi just mentioned, Dr. Robinson, what is recommended for both first-line and second-line treatment for patients with stage IV non-small cell lung cancer and a RET rearrangement.

Dr. Andrew Robinson: Thank you. So, for patients with a RET rearrangement and a good performance status of zero to two and previously untreated non-small cell lung cancer, clinicians may offer selpercatinib or pralsetinib as first-line therapy.

Selpercatinib was recommended in the 2020 guidelines and pralsetinib has been added to that. As with other driver mutation recommendations for scenarios where randomized studies against standard non-driver mutation treatments have not been done or completed, these recommendations are with a lower level of evidence and somewhat weaker recommendations, an alternative approach of first-line standard non-driver mutation treatment may also be offered.

As a guideline group, we listed this approach of non-driver treatment behind the targeted therapies, because there's a belief that the targeted approach may be superior upfront. But we should also continue to, of course, encourage participation in ongoing trials comparing selpercatinib or pralsetinib to standard first-line non-driver mutation treatment to determine whether our assumptions are correct.

For patients with a RET rearrangement who've had previous RET targeted therapy, clinicians may offer treatment as per the non-driver mutation guidelines. And for patients with a RET rearrangement who have had previous chemotherapy, chemoimmunotherapy, clinicians may offer selpercatinib or pralsetinib for them.

Brittany Harvey: Okay. And then you've just mentioned some ongoing trials as well. So, that leads to my next question of what ongoing trials and new agents is the panel monitoring for the next guideline iteration?

Dr. Andrew Robinson: It's really an exciting time with new agents on trials and I think we can divide it into more driver mutations, more lines of therapy, and more certainty with what we're doing.

In terms of driver mutations, there are several phase II and III trials with agents such as sotorasib and adagrasib in KRAS-G12C mutated non-small cell lung cancer, trastuzumab deruxtecan in the DESTINY trials in HER-2 mutated lung cancer, mobicertinib and amivantamab in EGFR, exon 20 insertion lung cancer or HER-2 exon 20 insertion lung cancer, etc.

So, looking at more driver mutations is all of those agents plus a number of others that will be coming out over the next couple of years at ASCO. We're also interested in more lines of therapy.

So, for patients who progress after standard first-line, say osimertinib with EGFR or after progression on ALK therapies such as lorlatinib. So, we're looking forward to studies such as the CHRYSALIS studies of amivantamab and lazertinib in EGFR mutation-positive patients who have progressed after osimertinib, and other studies that are looking at the increasing treatment options for second-line treatment and third-line treatment.

And then we're looking at interest to phase three studies that are comparing targeted agents to docetaxel in the second-line setting such as the sotorasib studies in KRAS-G12C patients and capmatinib and MET exon 14 patients, particularly as many of these patients may do well with non-driver mutated guided first-line treatment.

There are phase three trials comparing RET inhibitors to standard first-line chemoimmunotherapy which will also be keenly awaited to see if our, and when I say our, I mean, the ASCO guideline panel and also the thoracic oncology community writ large, our assumption that targeted therapy will be superior to first-line therapy is actually borne out with clinical trial evidence.

So, there's plenty of evidence that we're excited to keep our eye on and update as soon as possible, which is more driver mutations, more lines of therapy for patients who have established driver mutations, and more certainty, hopefully, regarding the timing of these various interventions.

Brittany Harvey: Definitely, there's a lot going on in this space. So, we'll look forward to the results from these ongoing trials and the panel's review of that evidence, and eventually updated recommendations. So, then Dr. Jaiyesimi, in your view, why is this guideline update important and how will it impact practice?

Dr. Ishmael Jaiyesimi: This guideline is important because it emphasizes rapid development in the research and treatment in advanced non-small cell lung cancer and that non-small cell lung cancer are heterogeneous.

Clinicians need to identify biomarkers of the molecular pathways, including targetable driver mutations, example: epidermal growth factor receptors, the BRAF, the MET, the KRAS, and etcetera, and fusion rearrangement, example: anaplastic lymphoma kinase, c-ROS oncogene 1, RET, and on that drive malignancy in patients with non-small cell lung cancer, especially in those patients with adenocarcinoma histology and a little or never smoking history regardless of histology. Because of the availability of effective targeted agent for many of these cancers, at minimum, determination of epidermal growth factor receptor mutation status and anaplastic lymphoma kinase rearrangement status before initiating therapy because rapid and sensitive tests are available. An initiation of immunotherapy could increase the toxicity of tyrosine kinase inhibitors later in the patient’s course. All this, in my opinion, will impact clinical practice. Furthermore, an opportunity for patients with driver mutation to enrolled in ongoing clinical trials targeting the driver mutations.

Brittany Harvey: Yes. You've just mentioned that this is not a one size fits all approach for patients. And so, in your view, Dr. Jaiyesimi, how do these guideline recommendations affect patients living with stage IV non-small cell lung cancer with driver alterations?

Dr. Ishmael Jaeysimi: I believe along with my associates the improvement in the treatment of stage IV non-small cell lung cancer brings hope to the patient with driver alteration for a possibility to use targeted therapy and no chemotherapy or immunotherapy upfront to some patients and this may enhance their lives, increase longevity with some tolerable side effects, and better quality of life, and a truly wide range of opportunities for patients to participate in clinical trials.

Brittany Harvey: Great! Yes, it seems like the data has come fast, and a lot of new results of recent trials have driven these updated recommendations and we're also looking forward to many of the results from upcoming clinical trials that you both mentioned.

So, I want to thank you so much for your work on these guideline updates, and thank you for taking the time to speak with me today, Dr. Jaiyesimi and Dr. Robinson.

Dr. Ishmael Jaiyesimi: Thank you, Brittany.

Dr. Andrew Robsinson: It was a pleasure to be here and I hope that this was educational.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline go to www.asco.org/thoracic-cancer-guidelines. There's a companion guideline update on therapy for stage IV non-small cell lung cancer without driver alterations available there and on the JCO.

You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO the mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for first-, second-, and third-line therapy in patients with stage IV NSCLC without driver alterations. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, Michigan, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on 'Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Guideline Update'. Thank you for being here, Dr. Jaiyesimi and Dr. Robinson.

Dr. Ishmael Jaiyesimi: Thank you for inviting me.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Jaiyesimi, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Ishmael Jaiyesimi: I do not have any financial disclosures. Thank you.

Brittany Harvey: Thank you. And Dr. Robinson, do you have any relevant disclosures that are directly related to this guideline topic?

Dr: Andrew Robinson: Yes, I do. I have had funding of less than $5,000 from BMS, Merck, and AstraZeneca in the past two years.

Brittany Harvey: Okay. Thank you for those disclosures. So, then let's talk about the content of this guideline update. So, Dr. Jaiyesimi, what prompted this guideline update, and what is the scope of the update?

Dr. Ishmael Jaiyesimi: The purpose of this guideline update is to update the ASCO and Ontario Health guidelines on the systemic treatment of patients with non-driver alteration stage IV non-small cell lung cancer last published in January of 2020.

The update is the result of potentially practice-changing evidence published since the last update. ASCO published the last full clinical practice guideline updates on systemic therapy for patients with stage IV non-small cell lung cancer that included those whose cancer did not have driver alterations in January of 2020.

The scope of evidence for the update guideline is made of ongoing or completed randomized controlled trials for non-driver alterations from 2018 to 2021. These updated algorithms provide recommendations from the ASCO expert panel and emphasized rapid changes in the management of patients with advanced non-small cell lung cancer and the importance of clinical research.

Brittany Harvey: Thank you for that overview, Dr. Jaiyesimi. So, then talking about those changes you just mentioned, I'd like to review the new or changed recommendations for this guideline. So, let's start with for patients with stage IV non-small cell lung cancer without driver alterations, and with high PD-L1 expression and non-squamous cell carcinoma, what are the updated recommendations for first-line therapy?

Dr. Ishmael Jaiyesimi: In addition to 2020 options for patients with high PD-L1, 50% or more expression, non-squamous cell carcinoma, and performance status of zero to one, and absence of targetable oncogenic driver alterations, clinicians may offer a single agent atezolizumab alone, or single agent cemiplimab alone, or a combination of nivolumab and ipilimumab without chemotherapy, or a combination of nivolumab and ipilimumab with two cycles of platinum-based chemotherapy. The number of acceptable options has increased. And each of the recommendations carries a strength of recommendation and quality of evidence with it.

Brittany Harvey: I appreciate you reviewing those options. So, then Dr. Robinson, moving on to the next category of patients addressed in this guideline, for patients with stage IV non-small cell lung cancer without driver alterations and with negative or low positive PD-L1 expression and non-squamous cell carcinoma, what are the updated recommendations for first-line therapy?

Dr. Andrew Robinson: Thank you for that question. So, in addition to the 2020 options for patients with negative, 0%, and low positive PD-L1 expression, with a TPS score of 1 to 49% and I'd add, unknown PD-L1, non-squamous, non-small cell lung cancer and a good performance status, clinicians may offer combination nivolumab and ipilimumab or combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy.

These are the additional recommendations and this gives an increased number of acceptable options, particularly for patients who cannot or choose not to take cytotoxic chemotherapy.

Brittany Harvey: Understood. Thank you for reviewing those options. So. then the next category of patients this guideline addresses, for patients with stage IV non-small cell lung cancer without driver alterations and with high PD-L1 expression and squamous cell carcinoma, what are those updated recommendations for first-line therapy?

Dr. Andrew Robinson: So, similar to the patients with non-squamous cell carcinoma for patients with stage IV non-small cell lung cancer that is squamous cell and a good performance status of zero to one, clinicians may also offer single agent atezolizumab alone or single agent cemiplimab or combination nivolumab and ipilimumab or combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy followed by ongoing nivolumab and ipilimumab. So, these are additional recommendations in this group as acceptable options for treatment.

Brittany Harvey: Great thank you for reviewing those options. So, then Dr. Jaiyesimi, what is recommended for patients with stage four non-small cell lung cancer without driver alterations and with negative or low positive PD-L1 expression and squamous cell carcinoma for first-line therapy?

Dr. Ishmael Jaiyesimi: In addition to 2020 recommendations, for patients with negative, TPS 0%, and low positive, with TPS 1% to 49%, PD-L1 expression, squamous cell carcinoma, and performance status of zero to one, clinicians may offer a combination of nivolumab and ipilimumab alone or a combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy.

Brittany Harvey: Great! So, then we've just reviewed the updates and changes to the first-line therapy recommendations. So, Dr. Jaiyesimi, were there any updates to second- or third-line therapy recommendations for patients with stage IV NSCLC without driver alterations?

Dr. Ishmael Jaiyesimi: For patients with non-squamous cell carcinoma who receive an immune checkpoint inhibitor and chemotherapy as first-line therapy, the clinician may offer paclitaxel plus bevacizumab in the second-line setting.

For the majority of patients with non-squamous cell carcinoma who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, in either sequence, clinicians should offer the option of single-agent pemetrexed (non squamous cell carcinoma, non-small cell lung cancer), or docetaxel (all histologic types), or weekly paclitaxel plus bevacizumab, (non-squamous cell carcinoma, non-small cell lung cancer) in the third-line setting.

For patients in whom the initial treatment was not a chemoimmunotherapy combination should receive the treatment not given earlier that is platinum doublet chemotherapy (if the initial treatment was monotherapy with an immune checkpoint inhibitor, or dual immune checkpoint inhibitor therapy) and immunotherapy with an approved PD-1 or PD-L1 inhibitor in the second line setting (if the initial treatment was platinum doublet chemotherapy).

Brittany Harvey: Okay, thank you for reviewing those recommendations as well. So, then Dr. Robinson, what is the importance of these recommendation updates for practicing clinicians?

Dr. Andrew Robinson: These updates give an increasing menu of choices for patients and physicians, particularly in the first-line setting. The increased list of acceptable first-line options may help us physicians may run into situations where their preferred first-line option isn't available, or for other reasons shouldn't be given.

Now we recognize that given the increasing variety of options in the first line, it would be really nice if we could have guidelines, that say in this certain patient treatment with nivolumab and ipilimumab is recommended and in that certain patient chemotherapy plus pembrolizumab is recommended, and divide things up that way so that the right patient gets the right treatment.

However, the guideline committee did not feel that this was appropriate at that time as the only comparative data with these different strategies is insufficient, either population-based data or cross trial and network comparisons, that, however well done, do not have a defense against confounders and bias that a randomized study has.

So, the advances in drug development and research in non-small cell lung cancer in the past decade have made available multiple treatment options, particularly for first-line therapy for patients, and to some extent, this has also made the process of decision making in this context challenging for practicing clinicians, especially in the community and for patients and caregivers.

Clinicians need to understand patients' comorbidities as well as other variables that can potentially influence treatment decisions prior to making final therapeutic recommendations for any given patient, and also become comfortable handling a few of these regimens. Each of these are somewhat complex regimens with sometimes subtle and sometimes not-so-subtle differences that require expertise and appropriate treatment and monitoring.

So, with so many options available, it's important that clinicians get familiar with a few of them at least given that all of these regimens are now considered as appropriate standard of care regimens suitable for first-line therapy, it may also help justify physicians, researchers and ethics boards who are participating, designing and overseeing simple clinical trials that pragmatically ask the questions as to what should be used when.

So, physicians should simultaneously become familiar with these guidelines, familiar with different therapies, have expertise in a few of these therapies, and continue to stress cancer clinical trials that may improve outcomes, and also may help us determine which treatment for which patient at which time.

Brittany Harvey: Definitely, that makes sense. Thanks for reviewing these recommendations and also the limitations of the evidence around them. So, finally, Dr. Robinson, how will these guideline recommendations affect patients with stage 4 non-small cell lung cancer without driver alterations?

Dr. Andrew Robinson: Well, there are more options available which should be good but we wish what we meant when we say there are more options for patients, what we meant is that if one option doesn't work that other options are then available.

However, in this case, we mean that there are more options for patients for their initial therapy, particularly including more non-chemotherapy or reduced chemotherapy options.

It's difficult to imagine that many patients and clinicians will now discuss, say 8 options with patients with high PD-L1 lung cancer. Pembrolizumab, cemiplimab, atezolizumab, pembrolizumab with platinum doublet, nivolumab, ipilimumab, nivolumab and ipilimumab chemotherapy, and the majority of patients with high PD-L1 will likely continue to have single-agent PD-1 or PD-L1 inhibitors.

For patients with low PD-L1 lung cancer, the inclusion of nivolumab and ipilimumab without chemotherapy as a potential option may allow some patients to avoid chemotherapy toxicity and trade for other toxicities and choose a different therapy.

Patients who enroll on clinical trials where the comparator arm is any one of these therapies should be comfortable knowing that they are considered acceptable standards. The advancement in non-small cell lung cancer diagnosis and treatment would allow patients with stage IV non-small cell lung cancer without driver mutations who are eligible for immunotherapies with or without chemotherapy, a chance of living longer and the opportunity to participate in ongoing research to further move the ball down the field.

Brittany Harvey: Definitely. And, thank you for reviewing that as well. So, I want to thank you both for all of your work to review the rapid changes in evidence in this field and provide these guideline updates. I want to thank you again for your time today, Dr. Robinson and Dr. Jaiyesimi.

Dr. Ishmael Jaiyesimi: Thank you for having me.

Dr. Andrew Robinson: Thank you. It was a pleasure to be here.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. There's a companion guideline update on therapy for stage IV non-small cell lung cancer with driver alterations available there and on the JCO.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Lynn Henry from the University of Michigan in Ann Arbor, MI, lead author on "Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update." Dr. Henry reviews new biomarkers for the purposes of making treatment decisions for triple-negative breast cancer, and hormone receptor-positive, HER2-negative breast cancer, as well as tumor agnostic tumor biomarkers. Specific biomarkers addressed in this conversation include PIK3CA, ESR1, BRCA 1/2, PALB2, HRD, PD-L1, dMMR/MSI-H, TMB, NTRK, ctDNA, and CTCs. Read the full guideline at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Lynn Henry from the University of Michigan in Ann Arbor, Michigan, lead author on 'Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update'.

Thank you for being here, Dr. Henry.

Dr. Lynn Henry: Thank you very much for inviting me to participate.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Henry, do you have any relevant disclosures that are related to this guideline topic?

Dr. Lynn Henry: No, I do not.

Brittany Harvey: Great! Thank you. Then let's talk about the scope of this guideline. So, what prompted this update to the guideline on the use of biomarkers to guide decisions on systemic therapy for patients with metastatic breast cancer, which was last updated in 2015? And what is the scope of this guideline update?

Dr. Lynn Henry: Yes, so a lot has happened in the past six or seven years that influence how we treat metastatic breast cancer. And there are many new drugs that have been approved by the FDA during that time.

When we reviewed the prior guideline and the new treatment landscape, we realized that while much of what was included in the old guideline was still relevant, there were quite a number of new biomarkers related to new drugs that needed to be included.

The newly recommended biomarkers are primarily applicable to making decisions about treatment of estrogen receptor, progesterone receptor, and HER2-negative breast cancer, also called triple-negative breast cancer, as well as for treatment of hormone receptor-positive HER2-negative breast cancer. And finally, there are now some tumor biomarkers that can be tested for that are tumor agnostic, and these were included as well.

Brittany Harvey: Great! So, then let's discuss the updated guideline recommendations based off these new biomarkers for our listeners. The guideline reviews testing for several different biomarkers. So, I would like to review each of the biomarkers that the panel assessed. Let's start with what is the role of PIK3CA mutation testing?

Dr. Lynn Henry: Yeah! So, PIK3CA activating mutations are commonly found in tumors that are hormone receptor-positive and HER2-negative. Based on the results of the SOLAR-1 trial, patients whose tumors have an activating PIK3CA mutation had improved progression-free survival when treated with the PI3 kinase inhibitor alpelisib plus fulvestrant compared to fulvestrant alone.

This improvement was not seen in patients whose cancers didn't have a mutation. So, therefore, this provided the evidence for the clinical utility of evaluating tumors for the somatic PIK3CA mutations.

Testing of either a tumor specimen or plasma to look for PIK3CA mutations can be performed. However, it's important that if the plasma is tested, and no PIK3CA mutations are identified in the circulating tumor DNA, then our tumor specimen should really be tested if possible, because of the possibility of a false negative finding in the plasma.

Also, since these mutations can be acquired over time, a more recent specimen should be tested if possible, as opposed to testing the primary tumor.

Finally, in the SOLAR-1 trial, a patient's tumor had to have one of the 11 pre-specified PIK3CA mutations in exon 7, 9, or 20. And therefore, when mutations are identified using next-generation sequencing, it is important to confirm that the identified mutation is one of those 11 activating mutations and not a different one that may not convey benefit from treatment with a PI3 kinase inhibitor.

Brittany Harvey: Great! I appreciate you're reviewing that recommendation, as well as the clinical utility of it and the evidence behind it. So, then following those recommendations, what is the role of testing for ESR1 mutations?

Dr. Lynn Henry: At this time, there are insufficient data to support routine testing of metastatic hormone receptor-positive HER2-negative tumors for ESR1 mutations. However, the panel did note that there's a retrospective analysis of two different phases three trials that demonstrated that fulvestrant improved progression-free survival compared to the aromatase inhibitor exemestane in patients who had previously progressed on a non-steroidal AI and whose tumors had an ESR1 mutation.

Importantly, there are ongoing clinical trials addressing this issue, including the PADA-1 trial, which is evaluating the effect of the switch of fulvestrant from aromatase inhibitor therapy, versus remaining on that therapy when ESR1 mutations are detected in the blood. However, although preliminary findings were presented at a recent large breast cancer meeting, and were suggestive of a possible progression-free survival benefit from switching therapy, data have not yet been published, and therefore they were not included in this guideline.

Brittany Harvey: Great! So, we'll look forward to those updated data to potentially review that recommendation in the future. So, following those recommendations, what is the role of testing for germline BRCA 1 or 2 and PALB2 pathogenic mutations?

Dr. Lynn Henry: So, the answer for germline BRCA1 and BRCA2 mutations is relatively straightforward. Patients with metastatic HER2-negative breast cancer can be either hormone receptor-positive or negative, and who are candidates for treatment with a PARP inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine whether they should receive treatment with a PARP inhibitor.

This recommendation is based on the results of two large randomized clinical trials comparing PARP inhibitor therapy to physician's choice chemotherapy, although notably, the chemotherapy options did not include taxanes, anthracyclines, or platinums.

In contrast, there remains insufficient evidence to support a recommendation either for or against testing for germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with a PARP inhibitor.

The panel did note, however, that there are small single-arm studies that show that there is high response rate to PARP inhibitors in patients with metastatic breast cancer and coding DNA repair defects, such as either germline PALB2 pathogenic variants or somatic BRCA1 or 2 mutations. It was also noted that it is likely that patients who harbored mutations in these genes will actually be identified through routine testing with panel testing for germline variants.

Brittany Harvey: Okay, understood. So, then following those recommendations, what is the role of testing tumors for homologous recombination deficiency?

Dr. Lynn Henry: So, although there are emerging data from other solid tumors to support the use of homologous recombination deficiency, or HRD testing to guide therapy, current data do not support the assessment of HRD in the management of metastatic breast cancer. Therefore, we did not recommend routine testing of tumors for HRD at this time.

Brittany Harvey: It's important to note where we both have evidence and where we don't have evidence. So, then what is the role of testing for expression of PD-L1 in metastatic breast cancer?

Dr. Lynn Henry: So, the panel recommends that patients who are candidates for treatment with immunotherapy, with either a PD1 or PD-L1 inhibitor, should undergo testing for expression of PD-L1 in the tumor and immune cells with an FDA-approved test.

At present in the United States, pembrolizumab is the only approved immunotherapy for the treatment of metastatic breast cancer, and it is given in combination with chemotherapy.

The FDA-approved test for this drug is the 22C3 assay which evaluates PD-L1 staining in the tumor and surrounding stroma to calculate a combined positive score or CPS, with positive considered to be a score of 10 or greater.

Of note, in other countries, there are different anti PD1 and PD-L1 antibodies that are approved for treatment, and each has been approved with its own companion diagnostic. So, it is important to make sure that you're using the right biomarker test, depending on which drug you are planning to use.

Brittany Harvey: Great! I appreciate you reviewing the test in addition to the role of the biomarker. So, then, following those recommendations, what is the role of testing for deficient mismatch repair microsatellite instability-high?

Dr. Lynn Henry: Similar to PD-L1 testing, it is recommended that patients with metastatic breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for deficient mismatch repair or microsatellite instability-high to determine eligibility for treatment with one of the drugs that is currently FDA approved, either dostarlimab or pembrolizumab.

In contrast to the PD-L1 data, however, there are no randomized studies that have been conducted specifically in patients with breast cancer addressing this question. The testing recommendation was therefore included in these guidelines because of the tumor agnostic FDA approval of these drugs.

In terms of which biomarker methodology to use, it was noted that, while the original studies assessed the deficient mismatch repair and MSI high using immunochemistry, and PCR respectively. The FDA has subsequently approved the next-generation sequencing platform to use in selecting candidates for these treatments. And so, therefore, there are a number of different tests that can be used.

Brittany Harvey: Thank you for reviewing those recommendations as well. So, then following, what is the role of testing for tumor mutational burden?

Dr. Henry Lynn: So, tumor mutational burden describes the quantity of somatic mutations in the tumor. Similar to the biomarkers we were previously discussing, there are minimal data specifically in metastatic breast cancer to support the assessment of tumor mutational burden for making treatment decisions.

However, the testing recommendation was again included in the guidelines because of the tumor agnostic FDA approval of the drug pembrolizumab in the setting of high TMB. And also there is one single arm phase two trial that looked at this specifically.

Importantly, the panel noted that there are a variety of factors that influence assessment of TMB. These include sample type, pre-analytical factors so how the sample was handled, the size of the panel and mutations that are tested, depths of the sequencing, type of the mutations that are included on the panel, and cut point variables.

So, in particular, assessment of TMB in cell-free DNA assays such as circulating tumor DNA is an area of evolving evidence. There are therefore very important caveats to be aware of when selecting a TMB assay and assessing the results, many of which are outlined in the guideline manuscript itself, and different assays can yield different results for the same tissue specimen. It is therefore very important to use the approved companion assay and the approved cut point when making decisions regarding a specific treatment.

Brittany Harvey: Absolutely. I appreciate your reviewing those details. So, then what is the role of testing for neurotrophic tyrosine receptor kinase?

Dr. Lynn Henry: So, I'm going to abbreviate that to NTRK. So, NTRK fusions are rare in metastatic breast cancer. One study said 0.39% of all breast cancers have NTRK fusions.

So, as with the above biomarkers, the NTRK testing recommendation is based on the results of phase 1 and phase 2 studies that were identified by the panel evaluating the efficacy and safety of these inhibitors for the treatment of advanced solid tumors with NTRK gene fusions, noting that there are only minimal data available that are specific to metastatic breast cancer.

Brittany Harvey: Understood. Some of these are very rare in metastatic breast cancer. So, then, following that recommendation, what is the role of using circulating tumor DNA?

Dr. Lynn Henry: So, for circulating tumor DNA, although the ctDNA technology holds promise in metastatic disease, for its ability to potentially identify tumor-specific mutations that are shed into the blood and that may be targetable, to date, neither the measurement of changes in ctDNA as a marker of treatment responsiveness nor identification of specific mutations in the blood to direct therapy has actually been prospectively shown to improve patient outcomes compared to standard imaging-based detection of tumor progression.

Therefore, at present, the guideline does not recommend routine assessment of ctDNA for monitoring response to therapy among patients with metastatic breast cancer, although many studies are underway evaluating this question.

Brittany Harvey: Understood. Then the last biomarker that the panel assessed in this guideline update, what is the role of using circulating tumor cells?

Dr. Lynn Henry: Similar to circulating tumor DNA, there are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among patients with metastatic breast cancer.

To date, studies that have examined the clinical utility of this marker to determine the optimal time for treatment change have not led to improvements in outcomes in metastatic breast cancer.

Brittany Harvey: Great! Well, thank you for reviewing all of these recommendations. The panel certainly took on a lot of biomarkers and performed a critical review of all the evidence to make recommendations in this setting. So, in your view, Dr. Henry, what is the importance of this guideline update and what should clinicians know as they implement these updated recommendations?

Dr. Lynn Henry: Yeah, that's an excellent question. So, this guideline addresses the key questions that we face, as we're making decisions about how best to treat patients with metastatic breast cancer.

Importantly, the guideline highlights the current state of the science, with a focus on the available published data from randomized clinical trials. It also discusses the limitations of our current knowledge, as well as key considerations for different biomarkers.

Of course, we recognize that there are new data emerging on a regular basis. And the panel therefore also highlighted where data are anticipated but not yet available, as well as key questions which we hope will be able to be addressed in the more distant future.

Brittany Harvey: And then finally, how will these guideline recommendations affect patients with metastatic breast cancer?

Dr. Lynn Henry: Yeah, so really, that is the bottom line, isn't it? So, ideally, this guideline will enable the dissemination of best practices in terms of biomarker selection and analysis to guide clinicians as they are making treatment decisions in conjunction with patients.

Treatment of metastatic breast cancer has become more complex, with regimen selection affected by both inherited germline genetics and somatic changes in the cancer that can evolve over time. The assessment of relevant biomarkers should allow patients to receive the optimal therapies that are most likely to be effective based on the individual characteristics of their cancers.

Brittany Harvey: Well, I want to thank you so much for reviewing this guideline with me today, and all of the recommendations and our gaps in evidence, for our listeners. Thank you for your work on this guideline update and thank you for your time today, Dr. Henry.

Dr. Lynn Henry: Thank you so much!

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Tian Zhang from UT Southwester Medical Center in Dallas, TX, author on "Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline." Dr. Zhang reviews the guideline recommendations for the treatment and management of patients with metastatic clear cell renal cell carcinoma and it's implications for clinicians and patients. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Tian Zhang from UT Southwestern Medical Center in Dallas, Texas, one of the authors on 'Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline'. Thank you for being here, Dr. Zhang.

Dr. Tian Zhang: Absolutely. Thank you so much for having me, Brittany.

Brittany Harvey: Great! First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Zhang, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Tian Zhang: Yes, I have received past research funding from Novartis, Merck, and Pfizer, as well as advisory board and consulting fees from Merck, Exelixis, Pfizer, BMS, Eisai, and Aveo. All of these industry partners have approved therapies in renal cancer. For the complete list, our audience can refer to the guideline’s publication.

Brittany Harvey: Great, thank you for those disclosures. Then starting off on the content of this guideline, can you give us an overview of the purpose and scope of this guideline?

Dr. Tian Zhang: Sure. This is a guideline for recommendations for the treatment and management of patients with metastatic clear cell kidney cancer. ASCO gathered 14 colleagues, including myself, that were considered kidney cancer experts from around the world, and we performed a systematic literature review to guide treatment recommendations in metastatic clear cell kidney cancer.

In the series of ASCO clinical practice guidelines for genitourinary cancers, we hope this guideline will provide recommendations for kidney cancer treatment with supporting data and evidence, particularly given the therapeutic landscape changes since about 2017.

Brittany Harvey: Then I'd like to review those recommendations that you just mentioned of this guideline. So, this guideline covers six overarching clinical questions. So, I'd like to go question by question for our listeners, starting with how is metastatic clear cell renal cell carcinoma is defined and how is it diagnosed?

Dr. Tian Zhang: In this portion, we recommended a gold standard of comparing metastatic tissue outside of the primary site to the primary tumor. We discuss adding in staining for PAX8 as well as CA-IX for clarity of clear cell histology.

The timing is also pretty important in the timing of initial diagnosis and nephrectomy until the appearance of metastatic sites on scans, and radiographic diagnosis is therefore used in settings where prior diagnoses of clear cell kidney cancer has been established and when a metastatic lesion is not accessible for biopsy or when there's clear, measurable disease within a year of the initial diagnosis.

Brittany Harvey: Understood. And then in the next section of the guideline, what is the role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma?

Dr. Tian Zhang: In this section, we recommend that cytoreductive nephrectomy should be considered for select patients who present with de novo metastatic clear cell kidney cancer to palliate hematuria or pain or to remove the bulk of tumor burden.

We discuss some past trials in the settings of interferon alpha, and VEGF inhibitors and also recommend consideration of ongoing clinical trials in the era of immunotherapies. There are two such trials that are ongoing, PROBE and Cyto-KIK, that are actively accruing patients.

Brittany Harvey: Great. And then the guideline goes into options for systemic treatment. So, what are the preferred options for first-line systemic treatment?

Dr. Tian Zhang: This is probably our most extensive section, as first-line systemic treatments have changed and expanded greatly over the past five years. First, we recommend considering active surveillance for select patients with the following criteria: those who have IMDC favorable or intermediate-risk disease, those with limited or no disease-related symptoms, and also those with a long interval between nephrectomy and the development of metastasis.

Second, we recommend IMDC risk stratification to then determine treatment selection. Those with IMDC intermediate or poor risk factors should be offered combination treatment with either two immune checkpoint inhibitors or an immune checkpoint inhibitor with an anti-angiogenic VEGF tyrosine kinase inhibitor.

We provide strong level of evidence with the completed phase three trials in this first-line setting of ipilimumab and nivolumab, axitinib with pembrolizumab, axitinib with avelumab, cabozantinib with nivolumab, and lenvatinib with pembrolizumab.

For patients with IMDC favorable-risk disease, we recommend an immune checkpoint inhibitor with a VEGF tyrosine kinase inhibitor which may be offered over VEGF TKI alone for those patients who are candidates for immunotherapy.

In addition, VEGF monotherapy or an immune checkpoint inhibitor monotherapy may be offered for select patients who have certain coexisting medical conditions.

In addition, we have discussed this long history of high dose interleukin-2 treatments and that this may still be considered in first-line treatments for certain patients while discussing the significant toxicity of IL-2 relative to the newer immunotherapy regimens.

And finally, we encourage the participation and enrollment into first-line clinical trials when available. A couple of the current ongoing ones include PDIGREE and the LITESPARK-012 Trial.

Brittany Harvey: I appreciate your reviewing those options and the level of evidence along with those ongoing trials for patients. So, then following those recommendations for first- line that you just went through, what is recommended for the second or later line systemic treatment?

Dr. Tian Zhang: Subsequent treatment in later lines after initial treatment of refractory renal cell carcinoma depends largely on the initial treatment choices.

We recommend nivolumab or cabozantinib for patients who had prior progression on a VEGF TKI alone based on the large phase three trials CheckMate 025 and METEOR respectively that gain the approvals for nivolumab and cabozantinib.

For patients with disease progression on a combination immunotherapy, a VEGF TKI should be considered. Those who progress after initial combination therapy with a VEGF TKI and an immune checkpoint inhibitor should then be offered an alternative VEGF TKI as a single agent.

And finally, for those who have limited sites of disease progression, local treatment with radiation, thermal ablation, or surgical excision could be offered with continuation of the immunotherapy.

Brittany Harvey: Thank you for reviewing those second and later line treatment options. So, then following that, what did the panel recommend regarding metastasis-directed therapy?

Dr. Tian Zhang: There have been some recent studies looking at metastasis-directed treatments, especially for patients with a low volume of metastases. These can include surgical resection, ablation, or radiation therapy. And surgical resection and radiation have not actually been directly compared.

And so, for those patients, we would recommend a tailoring treatment based on sites of disease. For those patients who do have surgical resection, subsequent VEGF TKIs are not usually recommended based on a prior phase two trial.

Brittany Harvey: Understood. And then this guideline addresses a couple special subsets of patients. And so, what are those subsets, and what considerations should be applied to the treatment of these special subsets of metastatic clear cell renal cell carcinoma?

Dr. Tian Zhang: For the special subsets of patients, we considered patients with bone metastases, patients with brain metastases, and also patients with sarcomatoid features on histology.

For those patients with bone metastases, we recommend bone-directed radiation as well as a bone resorption inhibitor with either a bisphosphonate or a RANK ligand inhibitor.

We do not have a recommendation on optimal systemic treatments, although given the presence of the MET receptor on bone metastases, regimens containing cabozantinib, which targets the MET receptor in addition to other receptors, may be preferred.

For those patients who have brain metastases, no definite guidance for treatment can be made given many patients with brain metastases were excluded from the initial trials.

The overall efficacy of the systemic therapies is low for controlling metastatic kidney cancer in patients with brain metastases. We do recommend local treatment with radiation and or surgery to be undertaken based on the pattern of intracranial metastases. And we refer readers and the audience to a recent guideline from ASCO, ASTRO, and SNO on the management of brain metastases.

And finally, for patients who have sarcomatoid features on pathology, an immune checkpoint inhibitor-based combination should be chosen in the first line setting. And this is based on multiple phase three trials that have shown improvement in clinical outcomes for patients treated with immunotherapy combinations compared to sunitinib alone.

Brittany Harvey: Thank you for viewing all these recommendations. The guideline expert panel certainly covered a lot of questions on the treatment and management of metastatic clear cell renal cell carcinoma.

So, then in your opinion, Dr. Zhang, what is the importance of this guideline and how does it impact clinicians?

Dr. Tian Zhang: Sure. You know, in the past 10 years, our treatment options for metastatic kidney cancer have greatly expanded and multiple options are now available. For busy clinicians who may not treat kidney cancer, especially in the metastatic setting often or on a routine basis, this set of guidelines provides a high-level approach to the common management scenarios that clinicians are often faced with.

My fellow committee members and I hope that these guidelines will provide a comprehensive one-stop document that is relevant and updated for the busy clinician taking care of patients with metastatic kidney cancer.

Brittany Harvey: Great! And then finally, how will these guideline recommendations affect patients with metastatic clear cell renal cell carcinoma?

Dr. Tian Zhang: The fact that our treatment options for metastatic kidney cancer have improved clinical outcomes, including extending the time until progression as well as overall survival, is truly wonderful news for patients who are diagnosed with metastatic kidney cancer today.

If patients are directly reading these guidelines, they can also see whether overall recommendations align with their recommended course of treatment, with the caveat that every patient's care is tailored to them based on coexisting medical conditions and concurrent medications. But we hope these guidelines will be helpful for all of our patients.

Brittany Harvey: Yes, it's great to see improved clinical outcomes for patients. So, I want to thank you for all of your work on this guideline and for taking the time to review the guideline recommendations and its impact.

Dr. Tian Zhang: Sure. I really appreciate ASCO giving this time and opportunity, Brittany, and also the audience for their interest in the clinical guidelines for metastatic clear cell renal cell carcinoma.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series.

To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

An interview with Dr. Pauline Funchain from Cleveland Clinic in Cleveland, OH, author on "Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update." Dr. Funchain reviews recent evidence and updated recommendations from the ASCO Expert Panel for the use of tebentafusp in patients with metastatic uveal melanoma. For more information, visit www.asco.org/melanoma-guidelines.

TRANSCRIPT

My name is Brittany Harvey and today I am interviewing Dr. Pauline Funchain from Cleveland Clinic in Cleveland, Ohio, author on Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Funchain.

Dr. Pauline Funchain: It's great to be here with you, Brittany. Thank you!

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Funchain, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Pauline Funchain: I do not have relevant disclosures that relate to this guideline topic.

Brittany Harvey: Great, thank you. Then getting into the rapid update, what prompted this rapid update to the Systemic Therapy for Melanoma: ASCO Guideline published in 2020?

Dr. Pauline: So, earlier this year, on January 25th, the FDA approved tebentafusp for metastatic uveal melanoma. So, this is the first FDA approval for metastatic uveal melanoma. We felt it was really important to put out a rapid update to let both clinicians know about the therapy and also so that more patients can get access to it as quickly as possible.

Brittany Harvey: Understood. So, then based on this new FDA approval, what are the updated recommendations for patients with uveal melanoma?

Dr. Pauline Funchain: So, any patients who have a previously untreated metastatic uveal melanoma, and also who are HLA-A*02:01 positive, this group of patients should be offered tebentafusp as systemic therapy.

This is the only systemic therapy that has been shown to prolong overall survival in patients with metastatic uveal melanoma. And if you look at the kind of benefit that was seen, patients who were on tebentafusp had a median overall survival of 21.7 months versus 16 months in comparison to investigator's choice. In this case, that was either single agent pembrolizumab, ipilimumab, or dacarbazine. So, it is a pretty significant overall survival benefit.

Brittany Harvey: Great! Thank you for reviewing those updated recommendations and the data behind them. So, what should clinicians know as they implement this updated recommendation?

Dr. Pauline Funchain: So, they should know that there was a great overall survival benefit seen, but it doesn't correlate with the objective response rate that was seen in the trial. So, for patients who were treated with tebentafusp, the objective response rate was 9%. And for those patients who were treated with the investigator's choice, again, that was single agent pembrolizumab, ipilimumab, or dacarbazine, the response rate was 5%.

So, that margin was not very different in terms of objective response rate when looking at RECIST-based criteria, so radiologic criteria for response, but the survival was clearly seen. And interestingly, even in those patients that had radiologic progression, there was an improved survival for those patients who were on tebentafusp versus investigator's choice.

So, there is some kind of survival benefit that may not correlate with what is seen on imaging. So, clinicians should know that they may not see a dramatic response in terms of tumor size on imaging, but patients may still benefit from the therapy.

Brittany Harvey: Understood. So, then you've just talked a little bit about responses in patients. So, how does this guideline update affect patients with melanoma?

Dr. Pauline Funchain: So, despite a difference in response rate, long story short, there is an overall survival difference. So, really, this is the first overall survival difference that we have seen in metastatic uveal melanoma.

It is really exciting. It is finally an approved drug for metastatic uveal melanoma, which did not have any approved or standard of care, systemic drugs. So, this is a really big win for a rare disease. I think, in terms of the general melanoma field and also the cancer field in general, this is really an exciting first-in-class drug on two different fronts. It is the first approved T-cell receptor therapy. It is also the first bispecific protein and it works differently than other immunotherapies we have seen. So, hopefully, this is something we see more of in other cancers.

Brittany Harvey: Definitely, it's good to see that these patients finally have an option and we'll look forward to research in other cancers as well. So, then finally, Dr. Funchain, what are the outstanding questions regarding systemic therapy for melanoma?

Dr. Pauline Funchain: Well, there are multiple questions that are outstanding. I think, for metastatic uveal melanoma, I think there are a lot of questions about the dissociation between the radiologic response and survival. I think there are questions about knowing when to stop tebentafusp if it's not working because we don't really have a good sense of what we should be using to know if this is not the right therapy for that patient.

I think we would love to know what the biomarkers of response are, and we may need different ways of looking for how to judge if a patient is benefiting from tebentafusp and other systemic therapies. And I think that there's still a big question in uveal melanoma about whether we start with systemic therapy or local therapy. I don't think that's been answered.

Now, in terms of the entire guideline, I think for melanoma in general, there are new data that are emerging and have been recently published and we will be looking forward to the next ASCO guideline in systemic therapy for melanoma because I think that there are a lot of emerging data that need to be addressed.

Brittany Harvey: Definitely. We'll look forward to that new research in uveal melanoma and to reviewing the updated data with the guideline panel for the next edition of the systemic therapy for melanoma guideline. So, I want to thank you so much for your work to rapidly updating this guideline, and thank you for your time today, Dr. Funchain.

Dr. Pauline Funchain: Thank you for having me. It is really meaningful to us to be able to offer education and get the word out about therapies that can help our patients.

Brittany Harvey: Agreed. And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full rapid recommendation update, go to www.asco.org/melanoma-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

View Details

An interview with Dr. Naren Ramakrishna from Orlando Health Cancer Institute in Orlando, FL, and Dr. Carey Anders from Duke University in Durham, NC, co-chairs on "Management of Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer and Brain Metastases: ASCO Guideline Update." This guideline reviews evidence in both the local therapy management and systemic therapy management for patients with HER2-positive breast cancer and brain metastasis, and provides updated recommendations for these patients. Read the full guideline at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Naren Ramakrishna from Orlando Health Cancer Institute in Orlando, Florida. And Dr. Carey Anders from Duke University in Durham, North Carolina, co-chairs on 'Management of Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer and Brain Metastases: ASCO Guideline Update'. Thank you for being here. Dr. Ramakrishna and Dr. Anders.

Dr. Carey Anders: Thank you.

Dr. Naren Ramakrishna: Thank you.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Ramakrishna, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Naren Ramakrishna: No.

Brittany Harvey: And Dr. Anders, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Carey Anders: I do. I would just like to disclose that I receive research funding, compensated consulting roles, and royalties from several of our industry partners who are developing brain permeable compounds.

Brittany Harvey: Thank you. Let's talk about the content of this guideline. So, Dr. Anders, what prompted an update to this guideline? And what is the scope of this guideline update?

Dr. Carey Anders: Thank you for that question, Brittany. Our previous guideline in the management of HER2-positive breast cancer brain metastasis was published in 2018. And since that time, we've seen significant progress in both the local therapy management and systemic therapy management for our patients with HER2-positive breast cancer and brain metastasis.

I think collectively, this body of work really prompted the panel to think through the changes that we could make to improve the care of our patients taking these updates into account. I'd love to hear Dr. Ramakrishna’s take on the rationale for the update as he was also involved in the 2018 guideline.

Dr. Naren Ramakrishna: Thank you, Carey. Well, it's really an exciting time right now for breast cancer brain metastasis treatment. And the recent data that Dr. Anders referred to has really opened up a whole new era in terms of therapeutic possibilities for breast cancer brain metastasis patients.

In the past, we've relied on traditional methods of treatment like whole-brain radiotherapy, surgery, and stereotactic radiosurgery as mainstays of treatment. But this exciting data that Dr. Anders referred to, has resulted in the possibility of avoiding certain of the local therapy options in select patients, which has the potential to increase patient survival and quality of life, and is a major advancement.

Brittany Harvey: Excellent. It's great to hear about those advancements. So, then next, I'd like to start by reviewing the guideline recommendations for our listeners. Dr. Ramakrishna, what are the key recommendations for local therapy for patients with HER2-positive breast cancer and brain metastases?

Dr. Naren Ramakrishna: Since the 2018 updated guidelines, we've continued with our stratification of patients by prognosis by the number of metastases, size of metastases, and also whether they are symptomatic or asymptomatic.

Overall, the changes include the offering of systemic therapy for patients after multidisciplinary review for asymptomatic metastases, particularly those less than two centimeters in size. In select cases, one might also offer it for patients with metastases larger than that.

The other major change that we see in this update is an increasing reliance on stereotactic radiosurgery rather than whole-brain treatment as a local therapy option, both in the post-operative setting and for single or multiple metastases, for which surgery is not recommended.

Finally, we see a significant change in the application of whole brain radiation, where whole-brain radiation is recommended typically for extensive disease, either with multiple, very large metastases, or many, many small metastases. We recommend whole brain treatment to always be administered with a neuroprotectant, and where possible, with what's called hippocampal sparing, which is thought to reduce the neurocognitive negative effects of whole-brain radiation treatment.

Brittany Harvey: Understood, I appreciate those recommendations for local therapy and that overview that you provided. So then Dr. Anders, in addition to those recommendations, what are the key recommendations for systemic therapy for these patients?

Dr. Carey Andres: Sure, Brittany, happy to review. I think some of the general principles from the 2018 guidelines remain in place. So, for instance, our patients who have progressive disease in the brain, are eligible for local therapy and have controlled extracranial disease, we still recommend continuing the current HER2-directed therapy along with the same algorithm for the treatment of patients with HER2-positive metastatic breast cancer.

There are some interesting and exciting changes to the guidelines with the advent of several of the promising systemic therapies that Dr. Ramakrishna outlines such that we do have the option of leading with systemic therapy for our patients with small asymptomatic lesions in the brain predominantly based on the HER2CLIMB clinical trial which established tucatinib, capecitabine and trastuzumab in this setting.

So, in concert with our local therapist, we have the consideration for moving to the HER2CLIMB regimen in the setting of active asymptomatic brain metastasis in concert with our local therapist. So, that's one key change from the 2018 guidelines.

Another is the introduction of the compound trastuzumab deruxtecan, an antibody-drug conjugate, which has been shown in second line in the setting of metastatic HER2-positive breast cancer to be superior to our traditional T-DM1 therapy in this setting.

In the study, the Destiny-Breast03 study that illustrated the superiority of trastuzumab deruxtecan patients with stable brain metastasis were included and illustrated in this compound, illustrated significant benefit for patients with stable brain metastasis.

So, in addition to the HER2CLIMB regimen in the setting of stable brain metastasis, we also have the option of trastuzumab deruxtecan in this setting. And that was an update in our 2022 guidelines.

So, we essentially have more systemic therapy tools in our toolkit to consider in concert with local therapy. And I just want to emphasize the importance of communication between the systemic therapy team and the local therapy teams, particularly when we're making the decision to move forward with the systemic therapy in the setting of progressive or stable brain metastasis.

Brittany Harvey: Thank you. Yes, that multidisciplinary care is key, and I appreciate your reviewing those updates. So then, in addition to those what is recommended regarding screening for the development of brain metastases for patients with HER2-positive breast cancer?

Dr. Carey Andres: So, this is a very active conversation. And in fact, I had this very conversation with two patients in the clinic just yesterday. So, should we be screening our patients with advanced HER2-positive breast cancer with brain MRIs in the absence of symptoms? I think the bottom line is we just don't have the data yet. I think we will have the data and in fact, there are ongoing prospective studies trying to determine whether or not screening brain MRIs in the absence of symptoms in this setting will improve our patient survival, and also improve our patients' quality of life.

Until we have that data because we do have these new tools in the toolkit for systemic therapy treatment, the panel loosens the guidelines a bit to say that it's not that we no longer recommend screening in the asymptomatic state, but there's not enough data for or against. And I think this really will help the physician and patients as they're making decisions about their screening and restaging studies in a personalized manner.

In addition to the lack of data, we also strongly recommend that clinicians and patients have a very low threshold to obtain a brain MRI in the presence of symptoms and this is really important with regards to communication about symptoms as subtle as they may be. I'd love to hear Dr. Ramakrishna’s take on this challenging space where we clearly need more data.

Dr. Naren Ramakrishna: Yes, Carey, I completely agree that it's quite challenging and the practice patterns are quite diverse throughout the country. It's also a source of a great deal of apprehension and anxiety for patients who automatically typically would assume that more frequent screening is better, especially when they do develop brain metastasis if that's to occur.

So, we do look forward to better data for guidance. And it certainly is an area that should undergo multidisciplinary reviewing recommendations for any particular patient.

Brittany Harvey: Understood, thank you both for reviewing the evidence as it states now and we'll look forward to that emerging data for perhaps a future guideline update. So then, Dr. Ramakrishna, what in your view is the importance of this guideline update and what does it mean for clinicians?

Dr. Naren Ramakrishna: Well, this is a practice-changing update. I mean, I don't think that's an overstatement. Because for the first time, upfront therapy is going to include the possibility of systemic therapy. And this also means that there has to be multidisciplinary and multimodality discussions regarding local versus systemic therapy for a large proportion of HER2-positive breast cancer brain metastasis patients. So, practice patterns are going to shift as a result of the incorporation of systemic therapy into the treatment paradigm.

And finally, the other very important, practice-changing local therapy change is that the use of whole-brain treatment will be reduced relative to stereotactic radiosurgery, but in some cases, also as a result of the use of systemic therapy, and when it is employed, it must be utilized with a neuroprotectant and/or hippocampal sparing.

Brittany Harvey: Great and then finally, how will these guideline recommendations affect patients with HER2-positive metastatic breast cancer and brain metastases?

Dr. Carey Andres: So, I would just echo Dr. Ramakrishna’s comments about the advances that we've seen and the importance of multidisciplinary care. I think from a systemic therapy perspective, we have the wonderful problem of having multiple agents to consider in this space. And as we've seen, really an explosion of HER2-directed therapies that are now approved and available to patients. One of our challenges has been how to sequence these therapies.

And so, we were hopeful that these guidelines will help clinicians and patients determine when to pick individual regimens that best fit the patient's scenario, whether or not their brain metastases are stable at that decision tree, or whether or not they're progressive at that decision tree.

I would also point the listeners to the updated guidelines in the management of patients with HER2-positive metastatic breast cancer, as these guidelines will certainly complement the decision-making and systemic therapy, incorporating the presence or absence of brain metastasis.

Brittany Harvey: Great, and yes, thank you for highlighting that companion guideline. Both are available at asco.org/breast-cancer-guidelines and in the Journal of Clinical Oncology.

So, I want to thank you both so much for your work on these guidelines and for taking the time to speak with me today, Dr. Anders and Dr. Ramakrishna.

Dr. Naren Ramakrishna: Thank you very much, Brittany.

Dr. Carey Andres: Thank you! Thanks for the opportunity.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline go to www.asco.org/breast-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, TX, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, WA, co-chairs on "Systemic Therapy for Advanced HER2-Positive Breast Cancer: ASCO Guideline Update." This guideline updates recommendations on systemic therapies for advanced HER2-positive breast cancer, focusing on second-line, third-line, and greater treatment. Read the full guideline.

TRANSCRIPT

My name is Brittany Harvey and today I'm interviewing Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, Washington, co-chairs on 'Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer: ASCO Guideline Update'. Thank you for being here. Dr. Giordano and Dr. Davidson.

Dr. Sharon Giordano: Thank you.

Dr. Nancy Davidson: Thank you for having us.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Giordano, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Sharon Giordano: No, I do not.

Brittany Harvey: Thank you. And Dr. Davidson, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Nancy Davidson: No, I do not.

Brittany Harvey: Thank you. Let's talk about the content of this guideline update. So first, Dr. Giordano, what prompted an update to this guideline on the systemic therapy for advanced HER2-positive breast cancer, and what is the focus of this update?

Dr. Sharon Giordano: So, we were prompted to update the guidelines for HER2-positive metastatic breast cancer because several new studies have been presented and published, which are really changing our standard of care approaches.

We have new therapies and new combinations that have resulted in improvements in progression-free survival and in overall survival for this patient population. Given the clinical importance of these new studies, we felt that an update of the treatment guidelines was clearly needed. Overall, the focus of our update is really in the title, so, it's systemic therapies for advanced HER2-positive breast cancer. And specifically, what we're focusing on is updating the recommendation for second-line therapy, and then adding multiple new options for systemic therapies for third-line and greater treatment.

Brittany Harvey: Great. Thank you for that overview. So, then I'd like to review the updated recommendations of this guideline for our listeners. Starting with, Dr. Davidson, what is recommended for first-line therapy for patients with advanced HER2-positive breast cancer?

Dr. Nancy Davidson: So, that was the part of this guideline that really did not change. In the previous iteration and in the current iteration, we felt that the evidence suggested that a combination of trastuzumab and a taxane should be the first-line treatment for individuals with metastatic HER2-positive breast cancer unless they have some sort of contraindication to the taxanes.

Now, the evidence supporting that is very strong. The trial that supported this continues to be updated and continues to show benefit. So, that's a very high level of evidence and our recommendation on this was extremely strong.

Brittany Harvey: Great. And then following those first-line recommendations, Dr. Giordano, what is recommended for second-line treatment for these patients?

Dr. Sharon Giordano: So, we did change our recommendation for second-line treatment for HER2-positive patients. The current new recommendation is, and I quote from our guideline, “If a patient's HER2-positive, advanced breast cancer has progressed during or after first-line HER2 targeted therapy, and the patient has not received trastuzumab deruxtecan, clinicians should recommend trastuzumab deruxtecan as a second-line treatment.”

So, as I said before, this recommendation is a change from our prior second-line recommendation. Previously, we had recommended T-DM1. So, this change was really, I think, one of the most important changes to the guidelines with this update.

We made the recommendation based on the initial presentation of the results of the Destiny-Breast03 trial, really given the magnitude of the benefit that was seen in the study. And the manuscript I would note was published this month in the New England Journal of Medicine.

Overall, the study showed statistically significant and highly clinically meaningful reduction in progression-free survival. So, just to give you some of these numbers, to kind of give you a sense of how big the impact was, so 76% of patients who were treated with trastuzumab deruxtecan versus 34% of patients treated with trastuzumab emtansine were alive and without disease progression at a year, with a hazard ratio of 0.28.

The response rates are also quite impressive with 80% versus 34% response rates. And the overall survival data are still immature but do favor treatment with trastuzumab deruxtecan and that hazard was 0.55.

So, I will note though, that toxicity was a bit higher with the new drug, with trastuzumab deruxtecan. So, any grade adverse events were 98% versus 87%. And then if you look at grade three and four drug-related adverse events, it was 45% versus 40%.

I think of note, rather than just kind of the overall numbers, though, one thing that clinicians need to be aware of is the risk of interstitial lung disease with this new drug. And this occurred in about 10% of treated patients in this study, although only 1%, or I think it was two patients, who had grade three or higher pulmonary toxicity. So, this is a toxicity that is specific to this drug that clinicians do need to be aware of.

Dr. Nancy Davidson: I think the other thing on that, Sharon, is that the incidence was lower in the Destiny Breast03 trial than it had been in some of the really early studies of this agent, so, that should be reassuring to us. Although, of course, it doesn't mean that the side effect doesn't happen, you have to take note of it.

Dr. Sharon Giordano: That's a great point. It definitely was lower than we'd seen before. So, a little bit of a relief, but still there.

Brittany Harvey: Great, thank you both for reviewing that data. I appreciate the overview. So then, following those recommendations for second-line treatment, Dr. Davidson, what are the recommended options for third-line therapy for patients with HER2-positive advanced breast cancer that has progressed on second-line or greater HER2 targeted therapy?

Dr. Nancy Davidson: Well, of course, this is the area where there has been considerable change as well. And that's because of the wealth of new anti-HER2 agents that Dr. Giordano talked about earlier.

So, we had a variety of recommendations for clinicians and patients to make decisions about how to proceed. I think certainly one of them, is that if the patient did not receive trastuzumab emtansine (T-DM1) in the second line, as we just talked about, our new recommendation would be that they would not, that they would receive trastuzumab deruxtecan, so you put off for T-DM1 in that [third-line] setting. And that's a new recommendation for us. And the strength of the recommendation is quite high.

Another agent that's come along that's very exciting is tucatinib, one of the small molecule inhibitors. And we think that that is also an alternative, that tucatinib in combination with trastuzumab and capecitabine, again, nice activity and pretty strong recommendation based on analyzed critical trials. And then finally, if for some reason the patient didn't receive the trastuzumab deruxtecan in a second-line setting and you're now in the third-line setting, that would be a very reasonable agent for them as well.

Those are all pretty strong recommendations. And I think the choice of which to proceed will depend a little bit on the decision making between the patient and the doctor about the mode of administration, your side effect profile, what seems the most appropriate, and it might be more one of the order of the recommendation. As opposed to saying, 'This one, but not that one', it might be, 'Pick this one next and know that you will be able to return to some of these in the future.'

Now, there are a lot of other possibilities here. We already had available to us neratinib and capecitabine, that continues to be part of the portfolio. And we also had lapatinib and capecitabine, also part of the portfolio. Other combinations of chemotherapy, trastuzumab could be considered, a new agent called margetuximab with chemotherapy, which has also come on to the market.

And of course, there's the possibility of thinking about the anti-HER2 agents in the context of endocrine therapy for those patients who have estrogen receptor-positive breast cancer as well. And new information suggesting that you might, in some cases, even think about one with CDK 4/6 inhibitors in the context of trastuzumab and fulvestrant.

So, lots of possibilities here that patients and doctors can weigh, and again think about order of administration as opposed to selecting for or against the other. I do think that the leading contenders at the beginning are going to be T-DM1 or trastuzumab deruxtecan, if that hasn't been used, or tucatinib in combination, those would be my personal preferences.

Brittany Harvey: Great. Thank you for reviewing those options and describing where a patient might receive these during their treatment.

Dr. Nancy Davidson: I'd like to hear Dr. Giordano's thoughts on that, how would you stack those up?

Dr. Sharon Giordano: Yeah, well, as you said, I think it does depend on what the patient's been treated with previously. I mean, certainly, T-DM1 or trastuzumab deruxtecan, if they haven't had those agents. Otherwise, I think the data from the tucatinib trastuzumab capecitabine regimen is pretty impressive as it did show an overall survival benefit. And as you know, I think that regimen is also really interesting, because it does seem to have some efficacy for patients with brain metastases. That actually has a very nice advantage.

Then the other ones, I think it just sort of depends on what they've seen previously, what side effects they may be experiencing, and kind of other quality of life issues. I don't see that there's a clear way to sequence the other ones since most of them haven't really been directly compared head-to-head against each other.

Brittany Harvey: It seems like it may be an individual discussion between clinicians and patients at that level. So, then, Dr. Giordano following that, how will this guideline impact clinicians and what should they know as they implement these updated recommendations?

Dr. Sharon Giordano: I think the bottom line is really the clinicians are now going to have more options for the treatment of HER2-positive advanced breast cancer which is fantastic news to have all these different choices and options for our patients.

To me, I think probably the most important changes and recommendations, again, are the addition of trastuzumab deruxtecan in the second-line setting just given the very impressive clinical benefit that’s seen with that drug, or, as Nancy mentioned in the third-line setting if patients, for some reason haven't received it previously.

And then I also think, as we talked about, the tucatinib combination is really an exciting new combination that does seem to have significant clinical benefit. I think the clinicians will need to be aware that that might be an option for patients with CNS metastases that are progressing. And also, just to be aware, as we mentioned before, about the risk of the interstitial lung disease with trastuzumab deruxtecan but it's really encouraging to me to have such a long list of drugs and combinations that we can use to treat our patients.

Brittany Harvey: Excellent. Those are great points. So, then finally, to wrap us up, Dr. Davidson, in your view, how will these guideline recommendations impact patients with advanced HER2-positive breast cancer?

Dr. Nancy Davidson: Well, Brittany, I think one thing we hope, of course, is that those patients will cumulatively have a longer survival, and a better survival as a consequence of all of these new insights that we've been able to make.

I can imagine it would be maybe a little confusing to patients that there are so many things that they might potentially be able to choose from, but this is one where I think that the larger the panel of agents that you have available to you, the happier it is.

So, I hope that patients are going to look at this as an opportunity for partnership with their oncologists to try to figure out of all these possibilities, what's the best one for me now, and they're going to have the comfort of knowing that there'll be other things that they can fall back on in the future, and that, hopefully, these things will improve outcomes. And again, without excessive toxicity.

This last thing I'm going to hope that clinicians and physicians will remember is that we've made a lot of headway here, but that our results are not perfect. And so, right now, we're able to change guidelines, these guidelines today because of clinical trials that have been put together in the last several years and successfully implemented. And I hope that we're going to continue to do that because until we get to a point where survival from HER2-positive breast cancer is 100%, we've got work to do. So, they're going to be other new clinical research strategies, and I hope that doctors and patients will take advantage of those whenever possible.

Brittany Harvey: Absolutely, both hoping for longer survival and better quality of life and looking forward to more clinical trials to give clearer answers. I want to thank you both so much for your time today and for all of your work on updating these guideline recommendations, Dr. Davidson and Dr. Giordano.

Dr. Nancy Davidson: Thanks, Brittany.

Dr. Sharon Giordano: Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guideline Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines.

There's a companion guideline update on the management of advanced HER2-positive breast cancer and brain metastases also just published in the Journal of Clinical Oncology and on asco.org. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast expressed their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Jennifer Ligibel from Dana Farber Cancer Institute in Boston, MA and Dr. Catherine Alfano from Northwell Health Cancer Institute and Feinstein Institutes for Medical Research in New York, NY, co-chairs on "Exercise, Diet and Weight Management During Cancer Treatment: ASCO Guideline." This guideline addresses recommendations for exercise, diet, and weight management for adult patients undergoing active cancer treatment, highlighting where there is evidence to recommend interventions, and where future research is needed. Read the full guideline at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

My name is Brittany Harvey, and today I'm interviewing Dr. Jennifer Ligibel from Dana Farber Cancer Institute in Boston, Massachusetts, and Dr. Catherine Alfano from Northwell Health Cancer Institute, and Feinstein Institutes for Medical Research in New York, New York, co-chairs on 'Exercise, Diet and Weight Management During Cancer Treatment: ASCO Guideline'.

Thank you for being here, Dr. Ligibel and Dr. Alfano.

Dr. Jennifer Ligibel: Thanks for having us.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Ligibel, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Jennifer Ligibel: I have no personal conflicts with this guideline.

Brittany Harvey: Thank you. Dr. Alfano, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Catherine Alfano: I have no conflicts.

Brittany Harvey: Thank you. Then, getting into the content of this guideline. Dr. Ligibel, can you start us off with an overview of the scope of this guideline?

Dr. Jennifer Ligibel: Sure. So, this guideline was developed to provide recommendations around exercise, diet, and weight management for patients undergoing active cancer treatment. We defined active cancer treatment as either the perioperative period or the period of time in which patients were receiving chemotherapy and/or radiation.

This guideline specifically focuses on adult cancer patients and largely focuses on individuals undergoing treatment for curative intent. There were a number of reasons why we thought it was important to develop a guideline specifically for patients who were undergoing cancer treatment.

There are a number of other guidelines that talk about the role of these types of lifestyle factors in preventing cancer, and also information widely available about the potential benefits of exercising more, consuming certain types of diets, or losing weight after cancer treatment is finished. But there's much less information about the feasibility and potential benefits and safety of increasing your exercise, changing your diet, or losing weight during cancer treatment.

This is the time when oncology providers are primarily working with patients in a time when patients have a lot of questions about what they should be eating and what they should be doing. So, this guideline was developed to specifically try to provide guidance during treatment.

Brittany Harvey: Yes, definitely an area in which guidance is very much needed. So, then Dr. Alfano, I'd like to next review the key recommendations of this guideline, starting with what are the recommendations regarding exercise during cancer treatment?

Dr. Catherine Alfano: For exercise, the expert panel felt that the evidence was very strong. And so, oncology providers should recommend aerobic and resistance exercise during active treatment with curative intent because it can mitigate the side effects of cancer treatments.

So, exercise has been shown during active cancer treatment to reduce fatigue, to either improve or preserve a patient's cardiorespiratory fitness, their physical functioning, their strength outcomes, and in some kinds of patients exercise has been shown to improve quality of life and reduce anxiety and depression.

The evidence is not sufficient to recommend exercise specifically for improving cancer control outcomes yet. This is a source of ongoing study, but we felt that the evidence was strong enough that oncology providers should recommend aerobic and resistance exercise, and it should become the standard of care for all cancer patients.

The second recommendation regarding exercise is that oncology providers may recommend pre-operative exercise for patients specifically undergoing surgery for lung cancer. So, this can be called prehab or pre-habilitation exercise. And this exercise has been shown to reduce outcomes like the length of hospital stay and postoperative complications.

Brittany Harvey: Excellent. Thank you for reviewing those recommendations and the level of evidence behind them. So, then, Dr. Ligibel, what did the panel recommend regarding particular dietary patterns or foods for patients during cancer treatment?

Dr. Jennifer Ligibel: One of the things that we recognized as a panel as we reviewed the evidence that shaped these guidelines was that there was much less evidence for both dietary factors and whether that was specific dietary patterns or some specific foods, as well as weight management, how those types of changes during treatment, affected outcomes, or even the feasibility of changing your diet or losing weight during cancer treatment. We, for this guideline, really relied on randomized trials to help shape our guidance, and we realized very quickly that there were few randomized trials testing dietary change or weight management during cancer treatment.

So, as a panel, we debated for a long time about what we should say in this setting. We did find that there were a few randomized trials that specifically looked at neutropenic diets. We defined that as diets that omitted fresh fruits and vegetables for patients who had undergone treatment for hematologic malignancies, and in particular bone marrow transplants.

Those studies were designed to look at whether those types of diets reduce the risk of infection. We did not see evidence that omitting fruits and vegetables during cancer treatment for those malignancies, reduced infection, and so the group provided a recommendation that neutropenic diets not be recommended for patients during cancer treatment, but we were unable to provide specific guidance regarding other dietary factors or the incorporation of specific foods during cancer treatment.

As a group, we recognize the importance of a healthy diet for general health. But given that we were really looking at randomized trials of the effects of changing someone's diet during treatment, we ultimately did not make a recommendation for a particular diet during cancer treatment, but really called for more research with well-designed clinical trials to test the impact of things like plant-based diets, intermittent fasting, other types of diets for which there may be interesting preclinical evidence, but very little information in people about the benefits or even the safety of these types of diets during cancer treatment.

Brittany Harvey: Understood, I appreciate you outlining the nuance of that recommendation, and also the areas for future research, which we can get into a little bit more in a little bit. So then, in the last category of recommendations, Dr. Alfano, what does the guideline state regarding interventions to promote intentional weight loss or avoidance of weight gain during cancer treatment?

Dr. Catherine Alfano: So, when our panel reviewed the evidence for weight loss or the avoidance of weight gain during cancer treatment, unfortunately, we decided that ultimately, there's insufficient evidence right now to recommend either for or against intentional weight loss or the prevention of weight gain during active treatment to improve outcomes related to the quality of life or things like treatment toxicities, or ultimately cancer control outcomes.

Brittany Harvey: Thank you, Dr. Alfano, for that recommendation, as well. So, Dr. Ligibel, in your view, what is the importance of this guideline? And how will it impact both clinicians and patients?

Dr. Jennifer Ligibel: This guideline is really the first large-scale effort to pull together all of the data from randomized trials about the effects of changing your lifestyle, exercising more, in particular, changing your diet, changing your weight during cancer treatment.

I think that as a panel, we found very clear and consistent evidence as Dr. Alfano outlined, that exercise has concrete benefits for patients during cancer treatment. I think that this is really an important call to action, both for providers in speaking about these topics to their patients, but also for payers. And as we think about our healthcare system, about how we're going to support patients in becoming more active in a safe way during their cancer treatment.

I think that it's very important that we recognize that encouraging physical activity is not just telling people that they should go out and do it. We really need to think about how we support patients in making these types of lifestyle changes in a sustained way.

So, I think that this guideline really provides clear evidence that exercise is important. It also provides clear evidence that we need more research in other areas. Patients are asking their oncology providers every day, what they should be eating, whether they should be thinking about losing weight, and we really don't have clear evidence to guide these conversations at this point.

I do think it's important to recognize that as a panel, we all felt very strongly that this guideline should not be interpreted as saying that a healthy diet or maintaining a healthy weight during treatment wasn't important. But we were really struck by the dearth of high-level evidence to be able to help our patients make informed choices and I think that's something that, from this guideline, we really need to come up with a plan be better able to ask the question that comes up in the clinic every day of, 'Doctor, what should I eat?'

Brittany Harvey: Those are excellent points. I appreciate the panel looking critically at the evidence that's actually out there to try and determine recommendations. So then, Dr. Ligibel just mentioned a few areas in which more research is needed. So, Dr. Alfano, what are the outstanding questions regarding optimal diet, weight management, and exercise during active cancer treatment?

Dr. Catherine Alfano: Being treated for cancer makes many patients feel like they have no control over their health and that causes them enormous anxiety. Patients are really looking for things that they can do to take the reins of control back over their health to improve their long-term health and well-being during treatment.

I want to underscore the importance of the oncology team in helping patients improve their exercise. Research has shown that 50% of patients undergoing cancer treatment are not getting enough exercise. Patients want to receive guidance about exercise from their oncology team. And importantly, patients whose oncology clinicians discuss exercise with them are more likely to make these healthy behavior changes.

So, it really underscores the importance of the oncology team in helping patients to access these important components of their health that they're asking for. The appropriate referral for exercise in patients undergoing treatment for cancer can really depend on several factors such as comorbidities, treatment toxicities, and the patient's pre-existing physical activity level. For example, many patients can safely perform unsupervised exercise, but others may need supervised cancer-specific exercise because they've got problems that they need to deal with clinically supervised exercise or to participate in a formal cancer rehabilitation program prior to undertaking exercise on their own.

I want to highlight for everyone that there are national efforts that are focusing on building referral algorithms and clinical decision support tools to help point to the most safe, feasible, and effective intervention for a given patient.

Brittany Harvey: Excellent. Well, thank you both so much for outlining the recommendations here and describing the nuance that the expert panel went through. It was certainly a large effort that you've helped lead. And so, I want to thank you so much for your work on these guidelines, and for your time today, Dr. Ligibel and Dr. Alfano.

Dr. Jennifer Ligibel: Thanks for having us.

Dr. Catherine Alfano: Thank you.

Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO guidelines podcast series. To read the full guideline go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. David Schiff from the University of Virginia Medical Center in Charlottesville, VA, Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, FL, and Dr. Vinai Gondi from Northwestern Medicine Cancer Center Warrenville and Proton Center in Warrenville, IL, authors on "Radiation Therapy for Brain Metastases: American Society of Clinical Oncology Guideline Endorsement of the American Society for Radiation Oncology Guideline." An ASCO endorsement panel endorsed the "Radiation Therapy for Brain Metastases: an ASTRO Clinical Practice Guideline," and the authors review the endorsement process and key points in this episode. Read the full guideline endorsement at www.asco.org/neurooncology-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. David Schiff, from the University of Virginia Medical Center in Charlottesville, Virginia, Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, Florida, and Dr. Vinai Gondi from Northwestern Medicine Cancer Center Warrenville and Proton Center in Warrenville, Illinois, authors on 'Radiation Therapy for Brain Metastases: American Society of Clinical Oncology Guideline Endorsement of the American Society for Radiation Oncology Guideline'.

Thank you for being here, Dr. Schiff, Dr. Vogelbaum, and Dr. Gondi.

Drs. Schiff, Vogelbaum, and Gondi: Our pleasure.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guideline products and ensures that the ASCO conflict of interest policy is followed for each guideline product.

The full conflict of interest information for this guideline endorsement panel is available online with the publication in the Journal of Clinical Oncology. Dr. Schiff, do you have any relevant disclosures that are directly related to this topic?

Dr. David Schiff: No relevant disclosures, Brittany.

Brittany Harvey: Thank you. And Dr. Vogelbaum, do you have any relevant disclosures that are related to this topic?

Dr. Michael Vogelbaum: I have no relevant disclosures.

Brittany Harvey: Thank you. And Dr. Gondi, do you have any relevant disclosures that are related to this topic?

Dr. Vinai Gondi: Brittany, my only relevant disclosure is that I served as vice-chair of the guidelines that we're discussing today, but otherwise, no relevant disclosures.

Brittany Harvey: Excellent! Thank you all. So, then starting us off, Dr. Schiff, what is the scope of this guideline endorsement? And how does it intersect with the recently published 'Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline'?

Dr. David Schiff: Sure. A little bit of background, from the start of the joint ASCO and SNO guideline effort, we had the participation of radiation oncologists, in addition to neurosurgeons, medical oncologists, and neuro-oncologists.

As we were getting underway, ASTRO reached out asking to participate formally as well. They had been planning to update their brain metastasis guidelines but were a year or two away from getting started. And they recognized it would be redundant for them to create comprehensive guidelines that covered chemotherapy, immunotherapy, and surgery as our guidelines were poised to do.

By participating with ASCO and SNO, they were able to have their task force focus specifically on key questions related to radiation oncology practices. In particular, the ASTRO project went into considerable depth on issues of radiation and radiosurgery dose, fractionation schemes, and the risk of radiation complications.

These were areas that our guidelines didn't address. Several members of the ASTRO task force including their chair, Paul Brown, and co-chair Dr. Gondi were members of our committee, and we added Dr. Brown as a co-chair to our committee when ASTRO came on board. The overlap between our two groups helped ensure that our recommendations were in harmony.

Brittany Harvey: So, then, Dr. Vogelbaum, can you provide us with an overview of how the ASCO guideline endorsement process works?

Dr. Michael Vogelbaum: Sure, Brittany. So, as Dr. Schiff mentioned, ASCO had convened a guidelines panel to develop the new 'Treatment for Brain Metastasis: ASCO-SNO-ASTRO Guideline'. And this was a multidisciplinary panel that he and I co-chaired and was anchored by a guideline specialist from ASCO, Hans Messersmith, and the process was that we had evaluated recent literature pertaining to the treatment of the brain metastases, and so, we had a very good understanding of what was supported by high-quality evidence and what was not there yet, as a group. So, when ASTRO came to ASCO and asked whether or not we would be interested in endorsing their guidelines, we were already prepared with all the evidence.

And so, the same panel got together again, to evaluate the ASTRO guidelines. And we did this, again, in a very structured manner. We reviewed the guideline questions and recommendations, compared them to the evidence, and went through the same type of review and polling process that we had when we had developed our own original guidelines.

In the end, we had a conversation with the ASTRO guidelines leadership about some of the points that we raised questions about, and we were able to reach an accommodation that allowed us to fully endorse the ASTRO guidelines.

Brittany Harvey: Thank you, Dr. Vogelbaum for that overview of the endorsement process. So, then, Dr. Gondi, what are the key recommendations of the ASTRO guideline?

Dr. Vinai Gondi: Thank you, Brittany. As Dr. Schiff and Dr. Vogelbaum outlined, ASTRO commissioned a list of key questions that they sought to address specifically to inform the radiotherapeutic management of brain metastases. And to address these questions, ASTRO not only convened a panel of expert radiation oncologists across the country but also engaged with the Agency for Healthcare Research and Quality (AHRQ) to create a comparative effectiveness evidence review, in addition to our own high-level evidence review to address these questions.

The four key questions that were addressed in the ASTRO guidelines are:

Number one: What are the indications for stereotactic radiosurgery alone for patients with intact brain metastases?

Number two: What are the indications for observation, preoperative radiosurgery or post-operative radiosurgery, or whole-brain radiotherapy in patients with resected brain metastases?

Number three: What are the indications for whole-brain radiotherapy for patients with intact brain metastases?

Number four: What are the risks of symptomatic radionecrosis with whole-brain radiotherapy and/or stereotactic radiosurgery for patients with brain metastases?

The recommendations that were made are based on a high-level review of a considerable amount of literature over the past several years that addressed these specific questions. I would encourage the listeners to this podcast to read through the guidelines to understand the specific nuances of each of those recommendations.

Brittany Harvey: Excellent! Thank you for that overview. Then, in addition to what Dr. Gondi just said, Dr. Vogelbaum, were there any additional points of discussion raised by the ASCO endorsement panel?

Dr. Michael Vogelbaum: Brittany, yes, there was an area of discussion where we needed to interact with the ASTRO guidelines leadership, as I mentioned earlier, and it really related to that key question one that Dr. Gondi described, which is what are the indications for SRS alone for patients with intact brain metastasis.

The approach that had been strongly endorsed by ASCO was that there would be a multidisciplinary approach to decision making. And really the benefit of that, the value of that radiosurgery really comes in the form of the interaction between the radiation oncologist and the neurosurgeon.

The way that the original proposal had been formulated, there was a size cut-off that was higher than we thought was appropriate for really endorsing that kind of conversation between the radiation oncologist and the neurosurgeon.

And so really, we proposed that we bring that cut-off down further, there actually was another subpart to the guideline that had looked at a lower cut-off, but did not specifically call out that interaction between the neurosurgeon and the radiation oncologist. And we felt it would be more appropriate to insert that at that cut-off rather than the larger lesion cut-off.

And after a conversation, there was agreement, that was really the only guideline or subpart of the guidelines where there was any real debate or discussion. For the rest of it, the comments that came up from the panel were easily addressed and it really just came down to this one modification. And fortunately, ASTRO agreed, and we were able to go ahead and complete the endorsement.

Brittany Harvey: Great! It's great that this was able to be a complete endorsement of that guideline. So, then, Dr. Gondi, in your view, what is the importance of this guideline endorsement? And how will it affect ASCO members?

Dr. Vinai Gondi: Thank you, Brittany. A number of responses to that. Number one is, as Dr. Vogelbaum, outlined the purpose of these guidelines was meant to be patient-centric and patient-focused, that we had patient champions who had navigated, who are part of the guideline development team, but also to be multidisciplinary. And so, the type of input and feedback we received from the ASCO team was super valued and valuable, as we were formulating these guidelines and Dr. Vogelbaum outlined a good example.

Number two, it had been almost a decade since the last guidelines had come out from ASTRO related to brain metastases management. And much has happened in our field over the past several years that has been practice-changing. We have several novel and innovative radiotherapy technologies and techniques, such as the emergence of radiosurgery, the use of novel radioprotectants, such as hippocampal avoidance, and memantine, but also the emergence of innovative and novel neurosurgical interventions and CNS active systemic therapies.

So, the modern management of brain metastases has really undergone quite a revolution over just the past few years, and it is important that these guidelines be updated to reflect those changes, but also to inform radiation oncologists on the contemporary management of brain metastases and in evidence-based care.

So, we believe that these guidelines will significantly impact ASCO members. Certainly, those who are radiation oncologists, as brain metastases are some of the most common patients that radiation oncologists manage in the community and in academic centers, but also for other members of ASCO medical oncologists, surgeons to understand sort of the nuances of radiotherapy management that is evidence-based, so they can have a patient-centered, patient-focused, multidisciplinary discussion with their radiation oncologist as well.

Brittany Harvey: Those are excellent points for clinicians on the management for brain metastases. So, then finally, Dr. Schiff, Dr. Gondi just mentioned how these guidelines are patient-centric. So, how will these guideline recommendations impact patients with brain metastases?

Dr. David Schiff: Yeah, well, I think what I'm about to say is really going to echo what Dr. Gondi just said. You know, 20 years ago, patients diagnosed with brain metastases were typically immediately referred to a radiation oncologist, they almost always got whole-brain radiation therapy, the median survival was about four months, and many, if not most patients, died from their brain metastases.

The situation has really changed recently. With the rapid advances in management from new therapies, and well-designed clinical trials in recent years, outcomes have markedly improved, it's probably less than a quarter of patients now who succumb to their intracranial disease. But at the same time, decision-making for patients has become much more complicated.

Nowadays, medical oncologists may reach out initially to neurosurgeons for consideration of radiosurgery or surgical resection, or in some circumstances utilize systemic therapy as a first step.

Conversely, a patient might see a neurosurgeon first, who may or may not be aware that there's appropriate immunotherapy or targeted agent that might make sense prior to going on to radiosurgery.

It's obviously a challenge for sub-specialists to keep up with all the emerging clinical trial data and new drugs. Our two sets of guidelines provide a roadmap for physicians of different expertise to help determine what types of therapies or referral should be considered when brain metastases are found. The end result of all this is improved control of intracranial disease and improved quality of life for the patients.

Brittany Harvey: Absolutely. Those are key points. It's excellent to see these guidelines, and the overarching 'Treatment for Brain Metastases: ASCO-ASTRO-SNO Guideline' be published. So, I want to thank you all for your time today, Dr. Schiff, Dr. Vogelbaum, and Dr. Gondi. Thank you for all of your work on these guidelines.

Dr. Michael Vogelbaum: My pleasure.

Dr. Vinai Gondi: Thank you for having us.

Dr. David Schiff: Thank you, Brittany. It was great to participate in this important project.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline endorsement go to www.asco.org/neurooncology-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Fabrice André from Institute Gustave Roussy in Paris, France, and Dr. Komal Jhaveri from Memorial Sloan Kettering Cancer Center in New York, NY, authors on “Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update.” This updated guideline provides precise guidelines on previously endorsed genomic assays and recommendations on the use of new biomarkers to guide endocrine therapy and chemotherapy in patients with ER-positive HER2-negative tumors, and for those with HER2-positive or triple-negative breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Fabrice André from Institut Gustave Roussy in Paris, France, and Dr. Komal Jhaveri from Memorial Sloan Kettering Cancer Center in New York, NY, authors on “Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update.” Thank you for being here Dr. André and Dr. Jhaveri.

Dr. Fabrice André and Dr. Komal Jhaveri: Thank you.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of guidelines and ensuring that the ASCO conflict of interest policies follow each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. André, do you have any relevant disclosures that are directly related to this guideline.

Dr. Fabrice André: No.

Brittany Harvey: Thank you. And Dr. Jhaveri, do you have any relevant disclosures that are related to this guideline topic?

Dr. Komal Jhaveri: No.

Brittany Harvey: Great, then let's talk about the content of this guideline update. So, Dr. Jhaveri, what prompted the update to the biomarkers for adjuvant endocrine therapy and chemotherapy in early-stage breast cancer, and what is the scope of this guideline update?

Dr. Komal Jhaveri: So, since the biomarker guideline published in 2016, there were several new publications that came out between January 2016 and October 2021 that provided perspectives on the use of some of the genomic assays broadly, or specifically in women based on menopausal status, age or number of lymph nodes.

Additionally, new biomarkers such as programmed cell death receptor ligand 1 or PD-L1, stromal TILs, circulating tumor DNA, or circulating tumor cells, or new applications, like extended endocrine therapy have also been developed.

So, this updated guideline provides precise guidelines on previously endorsed genomic assays and also provides recommendations on the use of new biomarkers to guide endocrine therapy and chemotherapy in ER-positive HER2-negative, HER2-positive, and triple negative breast cancer.

Brittany Harvey: Great. Thank you for setting the stage for this guideline. So, then Dr. André, I'd like to review the key recommendations of the guideline for our listeners. So, starting with, which biomarkers should be used to guide decisions on adjuvant endocrine and chemotherapy for patients with newly diagnosed ER-positive HER2-negative breast cancer?

Dr. Fabrice André: Thank you. So, when we are focusing on a newly diagnosed patient with ER-positivity HER-2 negative in the context of the question about deciding on chemotherapy. First, the 21 gene recurrence score should be used in patients with node-negative and in patients with 1-3 node positive who are postmenopausal.

In premenopausal, this test will be used only in patients with node-negative. The second test that is recommended is the MammaPrint 70-gene signature. And here the recommendation is to use this test if the patient is older than 50 and is node-negative or 1-3 node-positive.

If the patient is 50 years or younger, the clinician should not use this test. Then also a recommendation is that the clinician could use the 12 gene risk score EndoPredict if the patient is postmenopausal and has breast cancer node negative or 1-3 positive-node.

And finally, for the genomic test for the patient, the doctor could use PAM50. If the patient is postmenopausal and has breast cancer that is node-negative. Something new in this recommendation is the recommendation that the clinician could use Ki67. If the patient is postmenopausal and has stage I-II breast cancer with very specific recommendations on the cut off for positivity.

Brittany Harvey: Great. Thank you for reviewing those recommendations, Dr. André, and highlighting the new Ki67. So, then, in your introduction, Dr. Jhaveri, you discuss the application of assays for extended endocrine therapy. So, which biomarkers should be used to guide decisions regarding extended endocrine therapy for patients with ER-positive HER2-negative breast cancer?

Dr. Komal Jhaveri: Thank you. So, a quick word about extended endocrine therapy. I think extended adjuvant endocrine therapy, which is beyond five years of primary endocrine therapy, has certainly demonstrated improved outcomes, however, with modest absolute benefit and added toxicity and tolerability issues. Furthermore, while extended endocrine therapy is endorsed by clinical practice guidelines, clear guidance on individualized approaches to optimize patient selection for prolonged endocrine regimens, also remains limited. And this really underscores the need for prognostic and predictive information from genomic assays that can help guide this important clinical question we face.

One such example that has now borne out has been the breast cancer index and really collected evidence from now five studies supports the prognostic and predictive utility of this assay, such that if a patient has node-negative or one to three positive nodes, and has been treated with five years of primary endocrine therapy, to guide decisions about extended endocrine therapy, the clinician may offer Breast Cancer Index with either tamoxifen or aromatase inhibitors or tamoxifen, followed by an aromatase inhibitor.

Brittany Harvey: Great, thank you, Dr. Jhaveri. So, then, Dr. André, which biomarkers should be used to guide decisions on adjuvant therapy for early-stage HER2-positive breast cancer or triple-negative breast cancer?

Dr. Fabrice André: Well, first, we have to be sure that we are good at defining HER2-positive breast cancer and triple-negative breast cancer. So, it's always good to remind colleagues to have quality control assessment in place for HER2, estrogen receptor, and progesterone receptor stainings.

So far, when it's about predicting the benefit of adjuvant chemo or trastuzumab, there is no genomic test that is recommended in patients with HER2-positive or triple-negative breast cancer.

Brittany Harvey: Great, thank you. So, then, Dr. Jhaveri, what recommendations did the expert panel make regarding emerging biomarkers?

Dr. Komal Jhaveri: When we're talking about emerging biomarkers, we're referring to stromal TILs, we’re referring to PD-L1, circulating tumor cells, and circulating tumor DNA. And while there is a lot of emerging data, currently, clinicians should not be utilizing these new biomarkers to guide decisions about adjuvant endocrine therapy or chemotherapy, as we do not have sufficient evidence to support their use.

Brittany Harvey: Great and that's important for clinicians to know. So, then finally, Dr. André, in your view, how will these updated guideline recommendations impact both clinicians and patients?

Dr. Fabrice André: So, we know Komal mentioned this at the beginning that now there is a very large amount of new publications, new data coming every day in the field of cancer. So, the only way for clinicians to deliver the best treatments for patients is to have the right guidelines with the right methodology, and ASCO is really putting in place a very rigorous methodology to deliver guidelines.

And this is the best way to be sure that all patients will have access to the best decision by the doctor. So guidelines are also here to decrease the disparities in terms of the expert decision, and any patient in the world can have access to the best decision, thanks to guidelines delivered by ASCO and all the colleagues of the panel that worked very hard to deliver these guidelines.

Brittany Harvey: Excellent! Well, thank you both so much, and the entire expert panel for your work to update these guidelines, and for taking the time to speak with me today, Dr. André and Dr. Jhaveri.

Dr. Komal Jhaveri: Thank you.

Dr. Fabrice André: Thank you, Brittany.

Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines in interactive resources in the free ASCO guidelines app available in iTunes or Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Lisa Carey from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, NC, panel member on “Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk, Early-stage Triple Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update.” Dr. Carey discusses the updated recommendation on the use of pembrolizumab for patients with T1cN1-2 or T2-4N0 (stage II or III), early-stage triple negative breast cancer. For more information, visit, www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Lisa Carey from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, expert panel member on Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk Early-stage Triple-negative Breast Cancer: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Carey.

Dr. Lisa Carey: It's a pleasure to be here, Brittany. Thank you!

Brittany Harvey: Great! First, I like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Carey, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Lisa Carey: I do not.

Brittany Harvey: Thank you. Then what prompted this rapid update to the Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline, which was last published in 2021?

Dr. Lisa Carey: You know, what prompted it where there were a number of changes that had come out, particularly things like the use of immune checkpoint inhibitors, and the adoption of the neoadjuvant strategy that really made us feel that these were overdue for practice guidelines. And in particular, there were some very important changes that came out early this year, particularly with the pembrolizumab use.

Dr. Brittany Harvey: Great, so, based on these changes in the pembrolizumab use, what is the updated recommendation from the guideline panel?

Dr. Lisa Carey: The recommendation actually is for patients who fulfilled the KEYNOTE-522 trial criteria. KEYNOTE-522 was a seminal trial in early triple-negative breast cancer, meaning, treatment-naive of the use of pembrolizumab incorporated into a chemotherapy-based regimen given neoadjuvantly, and then with the continuation of the immune checkpoint inhibitor pembrolizumab adjuvantly.

This was important because we had been using, for a couple of years now, immune checkpoint inhibitors in PD-L1 positive or immune-activated triple-negative breast cancers in the metastatic setting. But we had not had evidence of improved survival or outcomes in early triple-negative breast cancer, so that's where KEYNOTE-522 comes in. This was a trial in which patients with early untreated triple-negative breast cancer, who fulfilled at least greater than T1N0, - and I want to make that pretty clear, this is a pretty broad net for early triple-negative breast cancer; the vast majority of triple negatives will be eligible for this treatment based on the population that was studied - and they receive four chemotherapy drugs, so, a taxane plus platinum, followed by an anthracycline-based regimen, either with or without pembrolizumab throughout the entire neoadjuvant course. They then went to surgery, and then they went on to receive adjuvant for another nine cycles, adjuvant pembrolizumab.

The trial had already reported an improvement in pathologic complete response with the addition of the immune checkpoint inhibitor, which has also been seen with other immune checkpoint inhibitors. But what was reported a few months ago, and then published early this year, was the impact on event-free survival. So, there was a statistically significant improvement in event-free survival with the addition of pembrolizumab, which, at that point, it's a highly clinically meaningful endpoint, there are now two highly clinically meaningful endpoints. Both of these were the primary endpoints of this study. And so, it has rapidly been adopted on that basis for use and we felt because of that it needed to be addressed in a rapid update for helping clinicians interpret the data and use them effectively.

Brittany Harvey: Understood, and I appreciate your work and the panel's work to rapidly interpret this data. So then, what should clinicians know as they implement this recommendation for the use of pembrolizumab?

Dr. Lisa Carey: I think the key elements are unlike the metastatic setting, there's really no role for PD-L1 testing in the early triple-negative setting because the pembrolizumab seemed to improve outcomes regardless of PD-L1 status, which is a big difference from what's true in the metastatic setting where all of these immune checkpoint inhibitors seem to only benefit patients that are PD-L1 positive. So, it's kind of regardless of PD-L1 status.

It's also true that in the KEYNOTE-522 study when they did do PD-L1 testing, most early triple negatives are PD-L1 positive. There really wasn't a subset of patients in the trial. And again, this is T2 or greater in tumor size or node-positive, who didn't seem to benefit from it.

So, it's a pretty broad recommendation. The 'however' is that, as we all know at this point, when you add immune-directed therapies, you have a different set of toxicities you have to be aware of, specifically what they call immune-related adverse events or irAEs, which are, of course, essentially autoimmune.

The thing that you have to remember is these can be permanent. These are frequently glandular disorders. Typically things like thyroid disease, which can be handled with replacement, but you can sometimes have colitis, myositis of different kinds, pneumonitis, and things like that. And some of these can be permanent.

So, they have to be monitored very carefully. And ASCO has a guideline for managing irAEs and patients treated with immune checkpoint inhibitors - because again, we use these in lots of tumor types - that gives a lot of detailed practice recommendations, that clinicians should really consult frequently, not just in triple-negative, but in other disease types that we use these drugs.

Brittany Harvey: Great. Thanks for explaining that aspect of the guideline. So then, you just mentioned that this recommendation is broadly applicable to many patients with early-stage triple-negative breast cancer. So, how will these guideline recommendations impact patients with early-stage triple-negative breast cancer?

Dr. Lisa Carey: Well, it means that it's a totally new game. So, as you are evaluating a patient, first off, virtually all of these are treated neoadjuvantly now, except for the T1N0s, and pembrolizumab and the addition of pembrolizumab should be considered in all of them.

Again, if they have, particularly organ-threatening autoimmune disorders themselves, they are a poor choice for these drugs, but otherwise, it should at least be considered. It's also true that there's been for many years a debate about the optimal chemotherapy to give in triple-negative breast cancer in the backbone that was used to which pembro was added had four drugs in it. And I think for that reason, that is considered the standard of care now.

I do think one of the challenges for us moving forward is to decide if we need all of those drugs or not. I think a challenge for us also is to figure out who actually benefits from, again, these are five drugs, you know, a lot of therapy, a fair amount of toxicity. And so, I think that's a challenge going forward.

Brittany Harvey: Thank you. And then finally, you just mentioned a couple of upcoming challenges, including the debate about the optimal chemotherapy regimen. But what are the outstanding questions regarding neoadjuvant therapy for patients with breast cancer?

Dr. Lisa Carey: I think the outstanding questions regarding neoadjuvant therapy are one thing. I think neoadjuvant therapy, there isn't a lot of outstanding questions that are medically related other than what's the right backbone and things like that, because I think the neoadjuvant paradigm, if you're just purely talking about whether you're giving drugs before or after surgery, the drugs themselves tend to be the same because the key endpoint for the medical oncologist and for the patient, of course, is their outcome from a relapse standpoint.

But it's also true that the neoadjuvant approach allows tailoring of the medical therapy. Like, in the past before we had immune checkpoint inhibitors, patients who received chemotherapy and had residual disease would get additional chemotherapy.

That wasn't allowed in the KEYNOTE study. So, I think many people, because patients with residual disease in KEYNOTE, still had pretty poor outcomes are incorporating additional chemotherapy, specifically adjuvant capecitabine with the pembrolizumab, but there's no data for that.

So, I think that's a challenge that we do have to address. I think the other challenge is simply surgical management: whether we can use these improved pathologic response and clinical response outcomes to minimize some of the local therapies, in addition to tailoring the medical therapies.

Brittany Harvey: Great! Well, we look forward to maybe tackling some of these challenges when we have more data in upcoming guidelines. I want to thank you so much for your time to rapidly update these guideline recommendations and for your time speaking with me today, Dr. Carey.

Dr. Lisa Carey: It's my pleasure. Thank you so much, Brittany.

Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product service organization activity or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Linus Chuang from Danbury Hospital and Norwalk Hospital, Nuvance Health in Connecticut and New York, co-chair on “Management and Care of Patients with Invasive Cervical Cancer: ASCO Resource-Stratified Guideline Rapid Recommendation Update.” Dr. Chuang discusses the updated recommendation on the use of pembrolizumab in patients with persistent, recurrent, or metastatic cervical carcinoma, based on the results from the KEYNOTE-826 study. For more information, visit, www.asco.org/resource-stratified-guidelines.

Transcript

My name is Brittany Harvey, and today I'm interviewing Dr. Linus Chuang from Danbury Hospital in Norwalk Hospital, Nuvance Health, in Connecticut and New York, Co-Chair on "Management and Care of Patients with Invasive Cervical Cancer-- ASCO Resource-Stratified Guideline Rapid Recommendation Update." Thank you for being here, Dr. Chuang.

LINUS CHUANG: Thank you for having me.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline is available online with a publication in the Journal of Clinical Oncology Global Oncology. Dr. Chuang, do you have any relevant disclosures that are directly related to this guideline topic?

LINUS CHUANG: No, Brittany.

BRITTANY HARVEY: Thank you. Then talking about the content of this publication, so what prompted this rapid update to the "Management and Care of Patients with Invasive Cervical Cancer-- ASCO Resource-Stratified Clinical Practice Guideline," last published in 2016?

LINUS CHUANG: ASCO Rapid Recommendations Updates highlight revisions to ASCO guideline recommendations on "Management and Care of Women with Invasive Cervical Cancer, the ASCO Resource-Stratified Clinical Practice Guideline" that was published in September of 2016. We revised the guidelines to reflect new and practice-changing data on the use of pembrolizumab combination therapy in patients with metastatic, recurrent, or persistent cervical cancer in enhanced and maximal settings.

BRITTANY HARVEY: Great. Then based off this new data for the pembrolizumab combination therapy, what are the updated recommendations from the guideline panel?

LINUS CHUANG: Based on this recently published report about the KEYNOTE-826 study, the checkpoint inhibitor pembrolizumab alongside standard chemotherapy with or without bevacizumab as first-line therapy significantly improved the overall and progression-free survival in patients with persistent, recurrent, or metastatic PD-L1 expressing cervical cancer.

BRITTANY HARVEY: Great. Thank you for providing that recommendation. So what should clinicians know as they implement these recommendations, and for which settings do these recommendations apply?

LINUS CHUANG: This trial included 617 patients, pembrolizumab 200 milligrams delivered intravenously every three weeks in combination with standard chemotherapy and with or without bevacizumab for up to 35 cycles. It's worth emphasizing based on the following study results the median progression-free survival was 2.2 months longer in the pembrolizumab group that have a PD-L1 combined positive score of 1 or more. And the progression-free survival at 12 months was also longer by 20% in the pembrolizumab group when compared to the placebo group. The overall survival rate at 12 and 24 months were higher in the pembrolizumab group-- 75% and 53% respectively-- compared with the placebo cohort-- 63% and 41% respectively.

According to the study, the most common adverse reactions, which occur in more than one in five patients in the pembrolizumab group, are anemia, neutropenia, alopecia, and peripheral neuropathy. Based on this data our rapid communication recommended this regimen be used in the enhanced and maximal settings where the pembrolizumab is available.

BRITTANY HARVEY: Great. Thank you for reviewing that data in the context of this recommendation. So how will these guideline recommendations impact patients?

LINUS CHUANG: So pembrolizumab with the standard chemotherapy with or without bevacizumab demonstrated improvement in the progression-free and overall survival much longer than those without the pembrolizumab group. And this has emerged as a front-line therapy for the group of patients that have persistent, recurrent, or metastatic cervical cancer with PD-L1 expression cervical cancer.

BRITTANY HARVEY: OK, thank you. And then finally, what emerging evidence is the panel anticipating regarding treatment of invasive cervical cancer?

LINUS CHUANG: This is an exciting time. Exploration of other PD-1 and PD-L1 inhibitors, monotherapy, or as part of combination therapy for cervical cancer will expand the management of patients with recurrent or metastatic cervical cancer that progressed after platinum-based chemotherapy. It is also important to explore the ability of pembrolizumab with chemoradiation with or without concurrent and maintenance pembrolizumab to improve outcomes for patients with high-risk locally advanced cervical cancer.

BRITTANY HARVEY: Great. That's very exciting to see that evidence coming to fruition. So I want to thank you so much for your work to rapidly update this guideline and for your time tonight, Dr. Chuang.

LINUS CHUANG: Thank you for having me today.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/resource stratified guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

SPEAKER 3: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Andrea Eisen from Sunnybrook Odette Cancer Centre and Ontario Health in Toronto, Ontario, co-chair on “Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update.” This guideline updates recommendations for which patients with primary breast cancer should be treated with bone-modifying agents, and which bisphosphonates are optimal. Read the full guideline at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

[MUSIC PLAYING]

My name is Brittany Harvey, and today I'm interviewing Dr. Andrea Eisen from Sunnybrook Odette Cancer Center and Ontario Health in Toronto, Ontario, lead author on "Use of Adjuvant Bisphosphonates and other Bone-Modifying Agents in Breast Cancer," American Society of Clinical Oncology and Ontario Health Cancer Care Ontario Guideline Update. Thank you for being here, Dr. Eisen.

ANDREA EISEN: Thanks very much for the opportunity.

BRITTANY HARVEY: And I'd like to note that ASCO takes great care of the development of its guidelines and ensuring that the ASCO conflict-of-interest policy is followed for each guideline. The full conflict-of-interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Eisen, do you have any relevant disclosures that are directly related to this guideline topic?

ANDREA EISEN: I have no disclosures.

BRITTANY HARVEY: Thank you. Then let's talk about the content of this guideline. So what prompted an update to this guideline published in 2017, and what is the scope of this update?

ANDREA EISEN: So ASCO has a guideline update process which triggers updates and reviews when new data are available. And for this particular guideline, an update was prompted by publication of three randomized trials. And during the update process, a fourth trial was published that was relevant for the guidance document.

BRITTANY HARVEY: Great. That's great background. So then next, I'd like to review the key recommendations of this guideline for each clinical question, starting with, which patients with primary breast cancer should be treated with bone-modifying agents?

ANDREA EISEN: The first recommendation for this guideline is that adjuvant bisphosphonate therapy should be discussed with all postmenopausal breast cancer patients, regardless of their hormone receptor status, or HER2 status, who are candidates to receive adjuvant systemic therapy.

BRITTANY HARVEY: Great. And then what is recommended for which bisphosphonates should be used for breast cancer adjuvant therapy, and what doses, duration of administration, time to initial treatment, and routes are optimal?

ANDREA EISEN: For this question, there were a number of different regimens available for review and inclusion in the guideline, because the studies used several different treatment protocols. However, the guideline recommends that adjuvant bisphosphonates should be started early, and ideally within three months of the definitive surgery or within two months of completion of adjuvant chemotherapy. The options for treatment include oral clodronate, oral ibandronate, or several different dosing regimens of zoledronic acid.

BRITTANY HARVEY: Great. So then you've just mentioned three different bisphosphonates. So what is the role of the bone-modifying agent denosumab as an adjuvant therapy for primary breast cancer?

ANDREA EISEN: This was a difficult, and perhaps the most contentious area that the committee considered, because there are two very important clinical trials that were reviewed. The first, the ABCSG trial, and the second was the more recently published D-CARE study. The guideline committee does not recommend the use of adjuvant denosumab for the prevention of breast cancer recurrence in early stage breast cancer patients.

BRITTANY HARVEY: That's helpful for clinicians to know, both which are recommended and which aren't recommended at this time. So then finally, Dr. Eisen, in your view, what is the importance of this guideline update, and how does it impact both clinicians and patients with cancer?

ANDREA EISEN: There are at least two issues that make this guideline particularly timely and important. First, there's new clinical trial guidance available, in particular with respect to scheduling and dosing of bisphosphonates and route of administration. These data also highlight the benefits of bisphosphonates.

The second is that the new evidence confirms our previous recommendation that denosumab is not recommended as adjuvant treatment in early stage breast cancer patients. During the development of this update, it became apparent that the uptake of adjuvant bisphosphonate usage in breast cancer patients is probably suboptimal. And there is a number of reasons for this across different jurisdictions.

Some reasons include variable access to different formulations of the bisphosphonates. For example, oral clodronate, which is well studied, is not available in the United States. The second issue that was highlighted was variable access for patients with respect to insurance coverage. And we also identified that even in jurisdictions where funding is fully provided for adjuvant bisphosphonates, uptake might be suboptimal.

So we hope that publishing this guideline and reviewing the evidence and highlighting the potential benefits in terms of reduction in recurrence and improvement in survival will result in more utilization of the bisphosphonates. We recognize that there are potential toxicities associated with the treatment and that the benefits versus risks have to be weighed carefully. The guideline committee recommended the utilization of an online risk assessment tool to help in those discussions with patients and to determine which patients have sufficient risk to justify using bisphosphonates.

BRITTANY HARVEY: Great. Those access issues are important to highlight. And I appreciate all of the work that you've done on this guideline update and also for taking the time to speak with me today, Dr. Eisen.

ANDREA EISEN: Thanks very much.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.ASCO.org/breast cancer guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Funda Meric-Bernstam and Dr. Amber Johnson from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Mark Robson and Dr. Debyani Chakravarty from Memorial Sloan Kettering Cancer Center in New York, New York, authors on “Somatic Genomic Testing in Patients with Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion.” They discuss the key statements of the provisional clinical opinion, including the topics: multigene panel-based genomic sequencing with disease-specific approved markers, assessment of mismatch repair deficiency and/or microsatellite instability-high status and tumor mutational burden, testing for gene fusions and exon skipping variants, decision making for panel tests with no approved disease-specific markers, and elements to consider while reviewing genomic testing results. Read the full PCO at www.asco.org/assays-and-predictive-markers-guidelines.

View Details

An interview with Dr. Mark Kris from Memorial Sloan Kettering Cancer Center in New York, NY, author on “Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage I to IIIA Completely Resected NSCLC: ASCO Guideline Rapid Recommendation Update.” Dr. Kris discusses the results and impact of two recently published RCTs, and the updated recommendations on the use of osimertinib and atezolizumab. For more information, visit, www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Mark Kris, from Memorial Sloan Kettering Cancer Center in New York, New York, author on Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage One to 3A Completely Resected Non-small Cell Lung Cancer ASCO guideline rapid recommendation update. Thank you for being here, Dr. Kris.

MARK KRIS: You're very welcome. And on behalf of the Adjuvant Guideline Committee, thank you for giving this opportunity today to speak to you. I have had financial report from AstraZeneca, Pfizer, Sanofi Genzyme, and also editorial support from Hoffman-La Roche.

Every year, 35,000 Americans received the diagnosis for early stage lung cancers. And that is, lung cancers that could be helped by surgery. It's a large number of patients. Many of them can be cured by operations, but not all. When people fail to be cured by surgery, the problem is not an unsuccessful surgery, but rather the spread of cancer to other parts of the body, very often cancer that's not suspected by any test that we have in 2022.

What physicians do is to give medicines before or after surgery to try to increase the chance of cure with a successful surgery. And the guideline we're talking about today deals with the recommendations of the American Society of Clinical Oncology Adjuvant Lung Cancer Guideline Committee for new treatments to increase the chance of cure in patients that have successful lung cancer surgeries.

BRITTANY HARVEY: Great. Thank you, Dr. Kris, for both that background and for providing your disclosures for this guideline. You just mentioned what this guideline's purpose is, but this is specifically a rapid update. So what prompted this rapid update to the adjuvant systemic therapy and adjuvant radiation therapy for stage one to 3A completely resected non-small cell lung cancers, which was last updated in 2017?

MARK KRIS: In the last year, there have been extremely important developments in the lung cancer field. There have been two medicines that have been proven to delay or prevent the recurrence of lung cancer after a successful surgery. One of them is a targeted therapy, the other an immunotherapeutic. And both of these medicines have had the clinical trials that discovered them presented at major meetings, including the ASCO meeting.

They also have had major publications in medical journals. And both of these medicines are now FDA approved. This is a new therapy, great addition to our therapy, and it includes drugs that are available to every doctor in the United States for patients in this situation. So there was the need to get this information out early and to get the word out to doctors everywhere to consider these medicines for the appropriate patients.

BRITTANY HARVEY: Understood. Then based off this new data for these new therapies that you just mentioned, what are the updated recommendations from the guideline panel?

MARK KRIS: The current recommendations, and I'll break it up into two settings. One of them is for stage 1B, B as in boy. And these are larger tumors, but only tumors in the lung. And the second set of recommendations are for lung cancers that also have evidence of spread to the adjacent lymph nodes or lymph glands.

Now up until these new recommendations, for the people with the 1B cancer, and that is the larger tumor only in the lung, the recommendation was there was no routine recommendation. That each case got discussed individually and a decision was made whether or not to recommend a chemotherapy program based on the drug cisplatin. It's not right for every patient and requires a fair amount of discussion and evaluation to decide who it's right for.

What the guideline adds now, though, is for genetic testing of the tumor tissue removed at surgery to search for the presence of a certain mutation, the EGFR mutation, in the tumor tissue. And if that mutation is found, the recommendation is to give the drug osimertinib, a pill, for three years following a successful surgery and following chemotherapy. What they found in that trial was that people who received this pill had a clear and dramatic improvement in the return of the cancer.

The cancer was greatly delayed or, hopefully as time goes on, we'll learn did not return at all. This is an important change, because up until then, there was no specific recommendation for patients in this 1B group. Now if you have the EGFR mutation in the tumor, we are recommending that every patient could receive osimertinib.

The other big change here is because there is the need to know if a mutation is present, part and parcel of that is the routine testing of tumor tissue. To make this happen, your surgeon and medical oncologist need to obtain tumor testing on every person to see if these EGFR mutations are present. And if indeed they are, to recommend osimertinib.

The second development was the identification of a drug called atezolizumab. And this is a drug that energizes the immune system. They call it a checkpoint inhibitor, an anti-PD-1 PD-L1 drug, a lot of different names. What they found in this second trial is that patients whose tumor tissue had some identified presence of this particular protein, the PD-L1 protein, again, a routine test, if you had this protein present and you received the atezolizumab, you, again, had improvement in the delay of cancer and as time goes on, hopefully that the cancer won't return at all.

Again in that trial, the use of the atezolizumab followed cisplatin-based chemotherapy, our old recommendation. So these two papers led to these really important changes in our recommendations to all patients with this illness. Patients with EGFR mutations get osimertinib. Patients that don't have an EGFR mutation but instead have expression of pd-l1 and have a lung cancer that's in a lymph gland as well as the lung, they routinely now have the checkpoint inhibitor, atezolizumab recommended.

BRITTANY HARVEY: Thank you for that summary of these new recommendations. So then what should clinicians know as they implement these recommendations for osimertinib and atezolizumab?

MARK KRIS: One change in treatment that these new medicines have brought about is the need to do genetic testing, generally a comprehensive panel of genetic testing, some call it NGS testing, multiplex testing, on the tumor tissue removed at surgery. You need to know if this EGFR mutation is present. And if so, you're a candidate to receive the osimertinib stages 1B, stage two, and stage 3A.

Conversely, if that EGFR mutation is present, the benefit from atezolizumab is much less. And for those patients, to know if atezolizumab could be useful, you need to do a separate test, a so-called immunohistochemistry test. That can be done in any pathology department in the US. And this test looks for the presence of this pd-l1 protein. And if the protein is there, it means that the drug atezolizumab can be useful. And that mutation is found really in the majority of patients that don't have the EGFR mutation.

BRITTANY HARVEY: Great. And then in your view, how will these guideline recommendations impact patients?

MARK KRIS: Well, we are very interested in delivering to our patients what they want. And that is, after surgery to live lives free of cancer and to live lives as they choose and a life not dictated by the cancer. The way to do that is to prevent the recurrence of the cancer, extend the time that they are free of cancer so they can live their normal life. And both of these medicines have been able to do that. What we can do now is offer patients the chance for a more normal life, or extension of their normal life without cancer by adding on these new medicines after cisplatin-based chemotherapy and after their surgery.

BRITTANY HARVEY: Definitely. This is an important intervention for patients. So then finally, Dr. Kris, what are the outstanding questions regarding adjuvant therapy for patients with stage one to 3A completely resected non-small cell lung cancer?

MARK KRIS: I think the biggest question that remains is what do we do for those patients that don't have the EGFR and don't have this pd-l1 standing? At present, our recommendation is that we would recommend cisplatin-based chemotherapy. And there would be some consideration for radiation as well if there's a spread to mediastinal lymph glands, and I would urge a consultation with the radiation oncologist when the mediastinal lymph glands were involved with the cancer to see if that can be helpful. But we don't have this extra treatment today to recommend to these patients like we do for the ones with EGFR and pd-l1.

The second thing we'd like to do would be able to better tell who needs these extra treatments and who needs more intensive extra treatments. Some people are cured by surgery alone. And it would be fantastic to know who those people were so as to focus our efforts on those people that need additional therapy and spare the people that don't need additional therapy the lifestyle disruption that comes on with treatment. And there are a bunch of emerging technologies, and I want folks to know that docs across the country, researchers, are working hard to find ways to say, who needs the treatments.

And three things are being tested now. One of them is a more detailed examination of the tumor tissues. This is particularly important in patients that got their chemotherapy before surgery, and our pathology colleagues are working to see how effective treatments are given the drugs before surgery. And there's more and more a push to give drugs not after surgery, but before surgery, because then we can tell in the tumor specimen that's removed at the time of surgery if they worked or not.

The second thing is to examine these tissues, not just with the eye of the pathologist under the microscope, but to use digital images and to use artificial intelligence to look at the tumors that are present, and perhaps also tumor that's present after initial therapy, and take the appearance of that cancer and correlated with the long term outcome. So to be able to tell using machine learning, artificial intelligence, advanced computing systems, whether or not the cancer is likely to recur.

And there's been some preliminary work in this presented at the ASCO meeting last year that this promise appears to be inching toward reality. It's not simply pi in the sky. The last thing that's being developed is the ability to look for traces of cancerous DNA in the bloodstream. What you would do is check for cancerous DNA before surgery and check again after surgery.

And if we find that cancerous DNA persists in the bloodstream, that would be a trigger to give therapy or give more intensive therapy. And a number of clinical trials have already reported on this that it is feasible and possible, and the early results are that it likely will be another way to tell who will benefit from therapy, who needs it most, and hopefully who doesn't need it, if we can. So a lot of questions to be answered, a huge amount of research. I'm quite confident that it's going to lead to more effective therapies. It's going to lead to more targeted therapies and it's going to lead to sparing patients from getting treatments when their cancer is already taken care of.

BRITTANY HARVEY: Absolutely. We look forward to that promising research to improve outcomes for patients. So I really want to thank you for all your work on this guideline rapid recommendation update and for taking the time to speak with me today, Dr. Kris.

MARK KRIS: And if I could just say a final word, I'm doing this today on behalf of the Guideline Committee led by Laurie Gaspar from University of Colorado in Denver and Katherine Pisters from M.D. Anderson. They and the other panel members very quickly did this. This whole process happened in just a few months. It was very quickly brought together and posted on the ASCO website. I believe it was posted on January 10th and will shortly appear in the Journal of Clinical Oncology to get the word out.

I think to me it's a testimony to ASCO's willingness to quickly get out cancer advances to our patients and the process that ASCO has put in place, I think, worked really well here, going from an idea to get this information out to getting it out to practitioners all over the country in just a few months.

BRITTANY HARVEY: Absolutely. We thank the co-chairs and the entire panel for their work on this guideline. And also, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/thoracic cancer guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

View Details

An interview with Dr. Nancy Baxter from the University of Melbourne in Melbourne, Australia, and Dr. Jeffrey Meyerhardt from Dana-Farber Cancer Institute in Boston, MA, co-chairs on “Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update.” This guideline updates recommendations for adjuvant therapy for patients with resected stage II colon cancer. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

[MUSIC PLAYING]

ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

My name is Brittany Harvey, and today, I'm interviewing Dr. Nancy Baxter from the University of Melbourne in Melbourne, Australia, and Dr. Jeffrey Meyerhardt from the Dana-Farber Cancer Institute in Boston, Massachusetts, co-chairs on adjuvant therapy for stage II colon cancer ASCO guideline update. Thank you for being here, Dr. Baxter and Dr. Meyerhardt.

NANCY BAXTER: Thank you for having us.

JEFFREY MEYERHARDT: Thanks.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Baxter, do you have any relevant disclosures that are directly related to this guideline topic?

NANCY BAXTER: I don't, Brittany.

BRITTANY HARVEY: Thank you. And Dr. Meyerhardt, do you have any relevant disclosures that are directly related to this guideline topic?

JEFFREY MEYERHARDT: I don't, either. Thank you.

BRITTANY HARVEY: Thank you, both. And getting into the content of this guideline, what prompted this guideline update, and what is the scope of this guideline?

NANCY BAXTER: Well, it's been since 2004 that we've had a guideline that gives us advice about stage II colon cancer and the use of adjuvant therapy in this group of patients. And it's one where clinicians often have a lot of challenges in helping patients make decisions about what's best for them in terms of long-term survival from colon cancer. There have been changes in guidelines for stage III colon cancer. And so we thought it was timely to reevaluate our best practice recommendations for stage II colon cancer patients.

JEFFREY MEYERHARDT: Yeah, I agree, Dr. Baxter. I think that this is one of the most challenging conversations that oncologists have with patients. Should they get chemotherapy? What type of chemotherapy? And as you know, there are a variety of higher risk features, of which we're able to sort of tease out a little better relatively, in terms of thinking about someone's stage II disease and trying to bring all that data together and provide some framework in the conversation for clinicians to have with patients.

BRITTANY HARVEY: Great, thank you both for that background information. So then this guideline covers four clinical questions. And I'd like to review the recommendations for each question. So Dr. Baxter, starting with question 1, what does the guideline recommend for patients with resected stage II colon cancer regarding the benefit of fluoropyrimidine-based adjuvant chemotherapy versus surgery alone?

NANCY BAXTER: So overall, what we did was we looked at the risk that individual patients with stage II colon cancer have. So for patients that are at low risk of recurrence-- and so those are patients with stage IIA or T3 tumors that have at least 12 sample lymph nodes in the surgical specimen and don't have any high-risk features, and I'll go over those with the later recommendations-- these patients do not need adjuvant chemotherapy.

It should not be routinely offered to them because the harms may outweigh the benefits. And so the evidence of that, although the quality of the evidence was relatively low, there is quite a bit of evidence that, really, the benefits do not outweigh the risks in this particular group.

That is different for patients that are at higher risk, though, within the stage II group. And so those are the patients with stage IIB or stage IIC colon cancer. So those are T4 lesions that either penetrate through the visceral peritoneum or invade surrounding organs.

And in those patients, adjuvant chemotherapy may have more benefit. And so a discussion of the potential benefits and risks of harms associated with chemotherapy should be had with patients. And those are patients that should be offered adjuvant chemotherapy for their disease.

Now, there's a group of patients with high-risk features-- so not the stage IIB or stage IIC-- but there's a group of patients within stage IIA. So these are patients that are T3 patients where there are high-risk features. And chemotherapy may be offered to these patients, based on their risk features.

So I'll go over a little bit about what the high-risk features are that might make patients included in this group. So that is sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphatic invasion, poor or undifferentiated tumor grade, intestinal obstruction, tumor perforation, and grade BD3 tumor budding. That's more than, or equal to, 10 buds in the tumor.

And so that's because these patients are at higher risk of recurrence, and the chemotherapy may be more beneficial in these patients because they have a higher baseline risk of recurrence. There were a few risk factors that it was really challenging to make any decision on.

And that was specifically circulating DNA. We know that that's an area of great interest, but there really was not enough evidence of the predictive value of ctDNA when you're looking at adjuvant chemotherapy in this group to make a recommendation. We'd expect future versions of this guideline to have some recommendations about that.

We do know that there is controversy around the timing of chemotherapy. So we didn't include reports on this for the guideline because we didn't have enough related to stage II colon cancer and the role of adjuvant therapy. But the trials have generally started patients on chemotherapy within six to seven weeks of surgery.

And finally, all of this needs to be a part of shared decision-making. So particularly for patients at higher risk-- so stage 2A at higher risk-- it's important that this is discussed-- the risks and benefits of chemotherapy, and the possible benefits with respect to the risk of recurrence for these patients-- is discussed as part of the shared decision-making process to come to an ultimate decision about the use of chemotherapy.

BRITTANY HARVEY: Understood. Thanks for detailing those recommendations stratified by risk and identifying what those high-risk features are. So then, additionally, Dr. Meyerhardt, is there a benefit of fluoropyrimidine-based adjuvant chemotherapy for patients with tumors that exhibit mismatch repair deficiency or microsatellite instability or patients with proficient mismatch repair, or microsatellite-stable, tumors?

JEFFREY MEYERHARDT: Yeah, so this was a specific question that we also looked at. What we know is about 15% of stage II colon cancers have evidence of mismatch repair or microsatellite insufficiency. And data that was realized now several decades ago on several different papers-- one larger one published in The New England Journal by Dan Sargent-- showed that patients who have stage II disease who receive a fluoropyrimidine only seem to not benefit if they have microsat instability.

And there was actually some evidence that they may actually have harm, or have a worse outcome. So it is not a routine recommendation to use a fluoropyrimidine-only treatment regimen in patients who have MSI-high or deficiency of mismatch repair in stage II disease.

However, there are some qualifying statements that we reviewed and were important to think about in patients. So what we know is, again, some of those patients will have some high-risk features and particularly T4 tumors or some other high-risk features, except for poor differentiation, that the use of oxaliplatin may actually be a consideration in those patients. And that's basically from indirect evidence of a disease-free survival benefit with the addition of oxaliplatin in the population of patients with stage II disease that were included in the MOSAIC trial, one of the original trials that looked at the addition of oxaliplatin to a fluoropyrimidine as adjuvant therapy for colon cancer.

We specifically carved out poor differentiate is not considered a high-risk prognostic feature in those patients. And so poorly differentiated tumors alone should not be a part of the decision in offering adjuvant therapy with a fluoropyrimidine or fluoropyrimidine-oxaliplatin for MSI-high or deficient mismatch repair protein tumors. And the other patients who have either proficient mismatch repair proteins or microsatellite instability are actually including the other parts of the guideline, so what Dr. Baxter just talked about and some of the other questions that we tackled that you'll be going to next.

BRITTANY HARVEY: Great. Thank you for covering those recommendations for that particular patient population. So then, Dr. Baxter, if adjuvant therapy is recommended, is there a benefit to adding oxaliplatin to fluoropyrimidine-based chemotherapy?

NANCY BAXTER: Well, this is obviously a question that oncologists will face when they're deciding to give adjuvant chemotherapy to high-risk stage II colon cancers or people with T4 stage IIB or C colon cancers. And you know, here's where it's challenging to make recommendations. Because we don't have a lot of evidence for this specific group. And this is why clinicians have such a challenge making recommendations for these patients.

Because actually, there's insufficient evidence to routinely recommend the addition of oxaliplatin, meaning that we have to base our decisions on the best evidence that we have. And the best evidence we have, as we've talked about, is the MOSAIC trial. And so in the MOSAIC trial, a time to recurrence was longer with oxaliplatin-based adjuvant chemotherapy.

And so it may be for some patients that the addition of oxaliplatin makes sense in terms of improving their overall outcome. And again, it needs to be a shared decision-making approach with the discussion of the potential benefits and risks of harms of the addition of oxaliplatin to fluoropyrimidine-based chemotherapy, so again, discussions between the oncologist and the patient.

But that is with the exception of patients who are MSI-high. So those patients need oxaliplatin. If they're going to get chemotherapy, they shouldn't have 5FU-based chemotherapy alone, as we've just discussed.

BRITTANY HARVEY: Great. And definitely, that shared decision-making is key. And I appreciate you reviewing the evidence behind these recommendations, as well. So then, the last clinical question addressed in this guideline, Dr. Meyerhardt, if adjuvant oxaliplatin-containing chemotherapy is considered, are outcomes affected by reducing the treatment duration from six months to three months?

JEFFREY MEYERHARDT: Sure. So this was the last clinical question that the committee considered. And it is based on the IDEA collaboration. So the IDEA collaboration was the International Duration Evaluation of Adjuvant Chemotherapy. It was six trials that were done internationally-- one in the United States, one in Japan, and four in Europe-- that included patients both with stage II and stage III colon cancer. They receive three versus six months of therapy.

Each of the trials had different chemotherapy choices in the sense that the United States trial, FOLFOX was the only choice that could be offered to patients, where in all the other trials, it was a physician and patient choice regarding the use of FOLFOX or capecitabine and oxaliplatin. And that, as people who know the data, is relevant to some of the discussion.

And so the goal of the collaboration was to look at if we can give patients three months of therapy and not compromise outcome. And the main reason for that is we know that the peripheral neuropathy that's cumulative with oxaliplatin increases with more months of treatment. So patients who only receive three months of oxaliplatin have less likelihood of more significant cumulative neuropathy and will have less impact on function by receiving less oxaliplatin overall.

Four of the trials included patients with stage II disease. And those trials, again, pooled their data and looked at the duration question in terms of for stage II patients. Those patients had high-risk disease, some high-risk feature, as discussed earlier.

And what was shown is that for the patients, overall, there was not clear evidence of noninferiority with three versus six months. But when you looked at the patients who received capecitabine and oxaliplatin, the absolute five-year disease-free survival was 81.7% versus 82% for three versus six months of CAPOX, so essentially the same, with a hazard ratio of 1.02, and the confidence interval spanned across 1. And so those really didn't look like there was any compromise in outcome for patients to receive CAPOX for three months versus six months.

For those patients who received FOLFOX, three months of chemotherapy led to a five-year disease-free survival of 79.2% versus 86.5% if you received six months of FOLFOX with a hazard ratio 1.41. So again, those data would suggest that if one was to choose FOLFOX, giving six months of therapy for high-risk stage II patients may be preferable to not potentially compromise some benefit in terms of disease-free survival.

So again, the overall conclusion was it's a discussion with a patient regarding choice of therapy, whether receiving capecitabine, oxaliplatin or FOLFOX and then, based on that, consideration of the duration where we were most comfortable saying that three months of capecitabine, oxaliplatin is sufficient for high-risk patients when appropriate discussion between the clinician and the patient.

BRITTANY HARVEY: Great. Thank you for explaining the nuance of that trial and your recommendation. So finally, to wrap us up, in your view, how does this guideline impact both clinicians and patients?

JEFFREY MEYERHARDT: Yeah, so again, the last time ASCO had addressed guidelines for stage II patients was over 15 years ago. And there are more data. It was really early in the days of understanding the incorporation of oxaliplatin. There was no data versus the three versus six months. And there were less analyses trying to look at some of those particular high-risk features.

So these are all important considerations in those discussions with stage II patients. And the importance of the guidelines are really to provide that framework on the various things you think about when you have a stage II patient and how to have those shared decision-making discussions with the patient.

Again, it's not, probably, appropriate for all patients to receive adjuvant therapy, particularly lower risk. And even for higher risk patients, it is weighing the plus or minuses of the potential toxicities with what we know potentially are benefits.

NANCY BAXTER: Yeah, I think that's very true. And I think, as anyone who treats colon cancer, or stage II colon cancer patients, is aware, this is not a homogeneous population. So in terms of the outcomes, there are people that do extremely well with surgery alone and people who, unfortunately, recur even after chemotherapy and surgery. And the future needs to focus on being able to differentiate those patients most likely to benefit from chemotherapy from those that are not likely to benefit.

What we found in reviewing the evidence is we've moved forward from 2004, but we still have a long way to go. So I really hope when the next guideline is written that we're much closer to being able to identify those patients who would most benefit from chemotherapy in this group.

Because we know there are patients who benefit from chemotherapy in this group. It's just we're still not perfect at identifying those people. So again, these conversations with patients are so important to talk about the limits of our knowledge, which I think is another important thing of this guideline is establishing what the limits of our knowledge are.

But I think there are patients that you can confidently not give chemotherapy to. And that's very reassuring, both to clinician and to patients. And then this guideline kind of outlines the limits of our knowledge. And that's also important for clinicians and patients to understand.

BRITTANY HARVEY: Definitely. I appreciate you both highlighting the importance of shared decision-making throughout this conversation that we've had. So I want to thank you so much for your work on this important guideline update and for taking the time to speak with me today, Dr. Baxter and Dr. Meyerhardt.

NANCY BAXTER: Thank you very much.

JEFFREY MEYERHARDT: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/gastrointestinal cancer guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Megan Daly from University of California in Davis, California and Dr. Navneet Singh from the Postgraduate Institute of Medical Education & Research in Chandigarh, India, co-chairs on “Management of Stage III Non–Small-Cell Lung Cancer: ASCO Guideline.” They summarize guideline recommendations on five subtopics – evaluation & staging, surgery, neoadjuvant therapy, adjuvant therapy, and unresectable disease. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

[MUSIC PLAYING]

ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

My name is Brittany Harvey, and today, I'm interviewing Dr. Megan Daley from University of California in Davis, California, and Dr. Navneet Singh from the Post-Graduate Institute of Medical Education and Research in Chandigarh, India, co-chairs on management of stage III non-small cell lung cancer ASCO guideline. Thank you for being here, Dr. Daley and Dr. Singh.

MEGAN DALEY: Thank you for having us.

NAVNEET SINGH: Thank you for having us, too.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Daley, do you have any relevant disclosures that are directly related to this guideline topic?

MEGAN DALEY: I have research funding from EMD Serono, Merck, and Genentech.

BRITTANY HARVEY: Thank you for those disclosures. Then Dr. Singh, do you have any relevant disclosures that are directly related to this guideline?

NAVNEET SINGH: No, I have no financial conflicts of interest.

BRITTANY HARVEY: Thank you. Getting into the content of this guideline, Dr. Singh, can you give us an overview of both the scope and the purpose of this guideline?

NAVNEET SINGH: Yes, absolutely. So this guideline has been developed to assist clinicians involved in the management of patients with stage III non-small-cell lung cancer, or NSCLC, as we call it briefly.

Now, stage III NSCLC represents one of the most heterogeneous subgroups of lung cancer. Consequently, it is also the subgroup in which the choice of multimodality treatment and the sequence of multimodality treatment varies significantly amongst clinicians, with variations being observed across institutes, as well as within an institute. And we sincerely hope that, with the help of this guideline, clinicians can accurately confirm the presence of stage III disease and offer the most appropriate treatment based on clinical and radiographic characteristics, as well as other medical factors that influence treatment decision-making. This evidence-based guidance also seeks to provide clarification on the common clinical dilemmas that clinicians may have while evaluating a patient with suspected or known stage III NSCLC.

BRITTANY HARVEY: Thank you for that background information, Dr. Singh. Then, Dr. Daley, this guideline addresses five main sections, evaluation and staging, surgery, neoadjuvant therapy, adjuvant therapy, and unresectable disease. So starting with evaluation and staging, what are the key recommendations for workup for patients with suspected stage III non-small cell lung cancer?

MEGAN DALEY: Our first recommendation for such patients is that they should undergo a history and physical exam and a CT scan of the chest and upper abdomen with contrast, unless it's contraindicated. If metastatic disease is not identified on CT, those patients should go on to a PET CT scan and MRI of the brain. If the patients are being considered for curative intent treatment, the guideline recommends pathologic mediastinal lymph node assessment.

And we recommend that endoscopic techniques should be offered as the initial staging modality, if available. If not available, invasive surgical mediastinal staging should be offered. And finally, for patients who have suspected or confirmed stage III lung cancer, we recommend that multidisciplinary discussion should occur prior to any initiation of a treatment plan.

BRITTANY HARVEY: Great, I appreciate your reviewing those recommendations. So following that, Dr. Singh, what does the guideline recommend regarding which patients with stage III non-small-cell lung cancer should be considered for surgical resection?

NAVNEET SINGH: So in this guideline, the recommendation which has come forth is that for patients with stage IIIA, basically N2 disease, induction therapy should be followed by surgery with or without adjuvant therapy if several conditions are met. Basically, a complete resection of the primary tumor and the involved lymph nodes is deemed feasible, and three nodes or contralateral lymph nodes are deemed to be not involved, and the expected perioperative 90-day mortality is low, typically 5% or less.

Another recommendation is that for selected patients with the P4N0 disease, surgical resection may be offered if medically and surgically feasible following multidisciplinary review. We would like to emphasize here that surgeons should always be involved in decisions regarding the feasibility of surgical resection. And they are an integral part of a multidisciplinary evaluation for surgical resection for stage III NSCLC patients.

BRITTANY HARVEY: Great. Then Dr. Singh just reviewed who should be considered for surgical resection. So Dr. Daley, for patients with potentially resectable stage III non-small-cell lung cancer, what are the key recommendations for neoadjuvant therapy?

MEGAN DALEY: Our first recommendation is that patients who are planned for a multimodality approach that will incorporate surgery should receive systemic neoadjuvant therapy. Second, that those patients with N2 disease who are planned for surgical resection should receive either neoadjuvant chemotherapy or neoadjuvant concurrent chemoradiation. And finally, for patients with a resectable superior sulcus tumor, neoadjuvant concurrent chemoradiation should be administered.

BRITTANY HARVEY: Understood. Then in addition, Dr. Singh, for patients with resected stage III non-small-cell lung cancer, what are the key recommendations for adjuvant therapy?

NAVNEET SINGH: So the panel came up with three recommendations for adjuvant treatment. The first is that patients with resected stage III NSCLC who did not receive neoadjuvant systemic therapy should be offered adjuvant platinum-based chemotherapy. The second recommendation which we came up was that for patients with resected stage III disease and presence of a sensitizing EGFR mutation-- classically, exon 19 deletion or the L858R exon 21 point mutation-- they may be offered adjuvant osimertinib, which is an EGFR inhibitor, after platinum-based chemotherapy. And this is based upon the ADAURA trial, which was published last year. And the third recommendation was that for patients with completely resected NSCLC and mediastinal involvement N2 disease, but without extracapsular extension, post-operative radiotherapy should not be routinely offered.

BRITTANY HARVEY: OK. And then the last section of recommendations covers unresectable disease. So Dr. Daley, what does the guideline recommend regarding the management of unresectable stage III non-small-cell lung cancer?

MEGAN DALEY: The guideline first recommends that these patients who have a good performance status should be offered concurrent, rather than sequential, chemoradiation, that concurrent chemotherapy delivered with radiation should include a platinum-based doublet, preferably cisplatin-etoposide, carboplatin-paclitaxel, or cisplatin-pemetrexed or cisplatin-vinorelbine. The patients who are not candidates for concurrent chemoradiation, but who are potentially candidates for chemotherapy, should be offered sequential chemoradiation, rather than radiation alone, that patients receiving concurrent chemoradiation should be treated to 60 gray. And that's based on the results of RTOG 0617.

We also recommend within the guideline that doses higher than 60 gray and up to 70 gray could be considered for selected patients, with careful attention to doses to the heart, lung, and esophagus, among other organs. The guideline also recommends that patients receiving definitive radiation without chemotherapy, that hypofractionation using slightly larger doses could be considered-- over 2 gray per fraction, and up to 4 gray per fraction, and that patients without disease progression during concurrent chemoradiation should be offered consolidation durvalumab, based on the PACIFIC trial.

BRITTANY HARVEY: Thank you both, then, for reviewing the key recommendations of this guideline. So, Dr. Singh, in your view, what is the importance of this guideline, and how does it impact clinicians?

NAVNEET SINGH: I think this guideline will go a long way in helping clinicians who are involved in the diagnosis and treatment of lung cancer, especially stage III NSCLC. As mentioned earlier, this is a very heterogeneous disease. And there are several challenging situations, both in the context of diagnosis, as well as treatment. And using this guideline, which has an extensive evidence review, as well as the development of two very helpful algorithms, we sincerely hope that clinicians who are both in academic centers as well as in practice in the community are able to accurately diagnose stage III, appropriately stage it, and offer the best treatment, given the patient characteristics and the disease characteristics and available resources.

BRITTANY HARVEY: Great. Those are important points. So then, finally, Dr. Daley, how will these guideline recommendations affect patients?

MEGAN DALEY: Well, we hope very much that these guidelines will help patients consistently receive high-quality care for their stage III lung cancer. In particular, we're hoping that the recommendation from multidisciplinary assessment of patients prior to treatment is carefully followed. We're hoping that some of the recommendations surrounding the appropriate workup for patients may help ensure that all patients receive a thorough and complete workup prior to initiation of treatment.

And the guideline, in particular, is highlighting some of the more recent developments in stage III lung cancer, such as the use of consolidation durvalumab based on the PACIFIC trial, the use of osimertinib in resectable disease based on the ADAURA trial. And we're hoping to make sure that these results are disseminated to practitioners everywhere so that patients can receive the latest and best care for their stage III lung cancer.

BRITTANY HARVEY: Understood. Yeah, as you both mentioned, we hope that this has a positive impact for both clinicians and patients. So I want to thank you both for all of your hard work to develop this guideline and the evidence-based recommendations along with it. And thank you for taking the time to speak with me today, Dr. Daley and Dr. Singh.

MEGAN DALEY: Thank you so much for having us.

NAVNEET SINGH: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. David Schiff from the University of Virginia Medical Center in Charlottesville, VA, and Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, FL, co-chairs on “Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline.” This guideline comprehensively addresses the treatment of brain metastases from non-hematologic solid tumors, including surgery, systemic therapy, radiation therapy, and timing of therapy. Read the full guideline at www.asco.org/neurooncology-guidelines.

TRANSCRIPT

[MUSIC PLAYING]

SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, Florida, and Dr. David Schiff from the University of Virginia Medical Center in Charlottesville, Virginia, Co-chairs on Treatment for Brain Metastases, American Society of Clinical Oncology, Society for Neuro-Oncology, and American Society for Radiation Oncology Guideline. Thank you for being here, Dr. Vogelbaum and Dr. Schiff.

MICHAEL VOGELBAUM: My pleasure.

BRITTANY HARVEY: Before we begin, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in The Journal of Clinical Oncology Dr. Vogelbaum, do you have any relevant disclosures that are directly related to this guideline topic?

MICHAEL VOGELBAUM: I have no disclosures relevant to this guideline.

BRITTANY HARVEY: Thank you. Then, Dr. Schiff, do you have any relevant disclosures that are directly related to this guideline topic.

DAVID SCHIFF: Hi, Brittany. No, I do not.

BRITTANY HARVEY: Great. Then first, Dr. Schiff, can you give us an overview of the scope and the purpose of this guideline?

DAVID SCHIFF: Sure. Our overall purpose was to provide guidance on the appropriate treatment of adult patients with parenchymal brain metastases from solid tumors, encompassing surgery, radiation, and systemic therapy, as well. Previous guidelines in this area were for the most part produced by neurosurgeons and radiation oncologists for their respective professional organizations, although they did incorporate multidisciplinary input. But over the last decade, treatment options for certain types of brain metastases have undergone a substantial change.

The expanding armamentarium for medical oncologists in treating both extra-CNS disease as well as brain metastases highlighted the need for a new set of guidelines to evaluate the role of systemic approaches, such as targeted agents and immunotherapy, for the primary treatment of brain metastases in the context of more established treatments like surgical resection, radiosurgery, and fractionated radiotherapy.

Additionally, recent studies have clarified the role of radiation techniques like whole brain radiation with hippocampal avoidance and radiosurgery to surgical resection cavities. By assembling a multidisciplinary group of experts from surgical neuro-oncologists, medical oncologists, neuro-oncologists, and radiation oncologists, we sought to provide as comprehensive and up to date a set of therapeutic guidelines as possible.

In order to accomplish this, the panel performed a systematic review of randomized as well as nonrandomized evidence from 2008 through April, 2020. We focused on the roles of surgery, systemic therapy, and radiation therapy, as well as the timing and interactions among these modalities. And we included all randomized clinical trials, as well as large single arm phase II studies and institutional case series, and we also reviewed case control and cohort studies.

BRITTANY HARVEY: OK, great. That's helpful background. And then you mentioned a couple focus areas, as well, of the systematic review. And so I'd like to review the key recommendations that were based off that evidence.

So, starting with surgery, Dr. Vogelbaum, what are the key recommendations for surgery in adult patients with brain metastases?

MICHAEL VOGELBAUM: So, the role of surgery, I think, was well established via randomized trials to some degree, and then via some of the larger single arm studies. Patients with suspected brain metastases without a primary cancer diagnosis were felt to benefit from surgery to obtain a diagnosis and undergo removal of the tumor. But more to the point, patients with larger tumors with mass effect-related symptoms are the ones most likely to benefit from surgery. What we also noted was that patients who have multiple brain metastases with extensive and uncontrolled systemic disease are unlikely to benefit from surgery unless the remaining disease is controlled via other measures, typically medical measures.

We also contemplated the type of resection performed, the technique being used. There was some developing literature looking at the techniques of either an en bloc resection or a piecemeal resection. And when we critically evaluated the literature, we felt that no recommendation could be made regarding the method of resection, as there was not sufficient evidence to support one approach over another.

Another technique that is being used more recently is the use of laser interstitial thermal therapy, which is a minimally invasive technique to treat tumors in general. But again, there was insufficient evidence to really be able to make a recommendation for or against the use of LITT, as it's called.

BRITTANY HARVEY: OK, thank you for reviewing both those techniques and those recommendations and highlighting where there wasn't enough evidence to actually make a recommendation. So, then, following that, Dr. Schiff, what does the guideline recommend for patients with brain metastases regarding systemic therapy, including chemotherapy, immunotherapy, and targeted agents?

DAVID SCHIFF: Brittany, there is a role for systemic therapy as the initial or primary modality in some cases, but I think it's really important to emphasize this only pertains to patients whose brain metastases are asymptomatic and those with particular histologies or molecular profiles. So, there are really-- there are three primary sites for which targeted or immunotherapy can be considered.

The first is non-small cell lung cancer, for which osimertinib, or if you're in China, where there's access to another drug called icotinib, specifically for EGFR-mutated disease, alectinib, brigatinib, and ceritinib are appropriate approaches in ALK-rearranged asymptomatic brain metastases. And finally, pembrolizumab in combination with pemetrexed and a platinum agent in immunotherapy naive patients whose tumors express PD-L1.

The second primary tumor is melanoma. And for melanoma patients who have asymptomatic BRAF V600E mutant brain metastases, dabrafenib with trametinib is an appropriate option to consider. For all melanoma patients with asymptomatic brain metastases, ipilimumab with nivolumab is also an option. And finally, for breast cancer, the combination of tucatinib, trastuzumab, and capecitabine for HER2 positive asymptomatic brain metastases in patients who have progressed on previous anti-HER2 antibody therapy. When patients treated with systemic therapy progress intracranially, local therapies such as surgery, radiation, and radiosurgery should not be deferred.

BRITTANY HARVEY: OK, those are helpful notes for clinicians, and particularly around the primary tumor sites. So, then, Dr. Vogelbaum, what are the key recommendations for radiation therapy in patients with brain metastases?

MICHAEL VOGELBAUM: So, Brittany, the panel started by noting which patients would not benefit from radiation therapy, in particular, those with asymptomatic brain metastases and a poor performance status, with a Karnofsky Performance Score, or KPS, of less than or equal to 50, or performance status of less than 70 and no systemic therapy options. In those cases, radiation therapy is unlikely to be of real benefit.

But then when speaking to the different modalities of radiation to be used, a lot of the review focused on the two most commonly used modalities, which is Stereotactic Radiosurgery, or SRS, versus Whole Brain Radiotherapy, or WBRT. And the first recommendation was that SRS alone as opposed to either whole brain radiotherapy alone or a combination of the two should be offered to patients with one to four unresected brain metastases, except for the situation of small cell carcinoma, which has a different approach that's used often with prophylactic cranial irradiation. So, that's a separate group. But for others, SRS is the modality that should be offered.

And then for patients who underwent surgical resection of their brain metastases, we know that there needs to be some form of radiation treatment to the surgical cavity. And the recommendation was that SRS alone should be offered to those patients if the surgical cavity can be safely treated, and considering the extent of remaining intracranial disease. Obviously, for patients who have a lot of disease but otherwise have a treatable systemic disease, then whole brain radiotherapy may make more sense. But for the ones that are more limited after surgery, it should be SRS.

And then when the panel considered a situation where you have patients with more than four unresected metastases and the options included radiosurgery, whole brain radiotherapy, or radiosurgery plus whole brain radiotherapy-- and in general, these are reasonable options. But it was felt that SRS may be preferred for patients with better prognosis or where systemic therapy that is known to be active in the central nervous system is available.

Additional recommendations revolved around both protective, radioprotective, and radiosensitizing agents. So, in terms of trying to protect memory, there are two approaches that are used. One is to give memantine during whole brain radiotherapy, or to do whole brain radiotherapy using a hippocampal avoidance technique. And it was felt that either one of those or both should be offered to patients who will receive whole brain radiotherapy and have no tumors in the hippocampus, and they're expected to live more than four months. And then finally, that radiation sensitizing agents should not be offered to patients, because they've not been shown to be effective.

BRITTANY HARVEY: Understood. And it's helpful to know both what those recommendations are for specific approaches, and as you said, critical to know who will and who will not benefit from radiation therapy. So, then we've just reviewed the key surgery, systemic therapy, and radiation therapy recommendations. Dr. Schiff, did the panel recommend anything regarding the timing of surgery, radiation therapy, and systemic therapy?

MICHAEL VOGELBAUM: The panel had just a couple of points in this regard. Although there are some recent data suggesting a decreased incidence of leptomeningeal metastases in patients who undergo radiosurgery before craniotomy, as compared to the reverse sequence, the panel concluded no recommendation on this point regarding the specific sequence of therapy could be made. And to reiterate, for those circumstances in which systemic therapy may be of use for brain metastases, that therapy should proceed, local therapy like surgery or radiation, only if the brain metastases are asymptomatic.

BRITTANY HARVEY: Great. Thank you both for reviewing these recommendations. In your view, Dr. Vogelbaum, what is the importance of this guideline, and how will it impact clinicians?

MICHAEL VOGELBAUM: I think one of the important points that David raised that at the beginning was that this really is the most comprehensive look at the evidence revolving around the treatment of patients with brain metastases and leptomeningeal disease. And in particular, this may be new information for an audience that has not been involved in that treatment for many decades, the medical oncology community.

So, I think some of the impact on clinicians may be that the guidelines will help them understand the durability of surgery and radiosurgery, and those had been the only treatments available for a long time. And so now we have these new medical therapies that are showing activity in the brain, but one needs to balance that against what is known about the effective treatments in the past. Some of the new targeted immunotherapies may not provide as consistent or durable of a benefit as has been shown previously with surgery and radiotherapy.

Hopefully, understanding this challenge with respect to consistency and durability will serve to support the development of phase 0 or window of opportunity clinical trials to better understand the determinants the biological determinants of response or resistance to systemic therapies we want to improve on that, for sure, and those clinical trials are going to be essential for us to be able to do that.

And then ultimately, also, identify opportunities to synergistically combine radiation and medical therapies and better understand the timing of these combinations. This is a great area for clinical trial development in the future.

BRITTANY HARVEY: Definitely. We'll look forward to future research in those areas. So then, finally, Dr. Schiff, to wrap us up, how will these guideline recommendations affect patients?

DAVID SCHIFF: Yeah. Over the last 30 years, the management of brain metastases have involved hugely, from an area where almost everyone got whole brain radiation therapy and many patients died from their brain disease. The use of local therapies like surgical resection and radiosurgery has greatly improved local control of brain metastases. And with options like radiosurgery alone for a limited number of brain metastases, systemic therapies as the initial approach, and hippocampal avoidant whole brain radiation therapy with memantine, patients are experiencing improved long term cognitive function and quality of life, as well. So, I think the careful delineation of the role of each of these modalities that these guidelines provide will really help maximize benefit and minimize the risk for this very large number of cancer patients.

BRITTANY HARVEY: Definitely, improve quality of life is always a goal. So, I want to thank you both for your work on these guidelines and thank you for taking the time to speak with me today, Dr. Vogelbaum and Dr. Schiff.

DAVID SCHIFF: My pleasure.

MICHAEL VOGELBAUM: Thank you, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/neurooncology guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Jaishri Blakeley from Johns Hopkins University School of Medicine in Baltimore, MD, and Dr. Nimish Mohile from the University of Rochester Medical Center in Rochester, NY, co-chairs on “Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline”. This guideline addresses evidence-based therapies for patients with newly diagnosed and recurrent gliomas. Read the full guideline at www.asco.org/neurooncology-guidelines.

TRANSCRIPT

[MUSIC PLAYING]

SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

SPEAKER 2: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Jaishri Blakeley from Johns Hopkins University School of Medicine in Baltimore, Maryland, and Dr. Nimish Mohile from the University of Rochester Medical Center in Rochester, New York, co-chairs on therapy for diffuse astrocytic and oligodendroglial tumors in adults American Society of Clinical Oncology and Society for Neuro-Oncology guideline. Thank you for being here, Dr. Blakeley and Dr. Mohile.

SPEAKER 3: Thank you.

SPEAKER 4: Thank you.

SPEAKER 2: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with a publication of the guideline in the Journal of Clinical Oncology. Dr. Blakeley, do you have any relevant disclosures that are directly related to this guideline topic?

SPEAKER 3: No, I do not.

SPEAKER 2: Thank you. And Dr. Mohile, do you have any relevant disclosures that are related to this guideline topic?

SPEAKER 4: No, I don't have any relevant disclosures.

SPEAKER 2: Great. Thank you. Then let's get into the content of this guideline. So Dr. Mohile, can you start by giving us a general overview of the scope and purpose of this guideline?

SPEAKER 4: Yeah, so over the past 10 years, there have been several positive clinical trials in various glioma subtypes, and several of them have demonstrated a benefit for chemotherapy. The primary purpose of this guideline is to help practicing clinicians understand how these trials might impact treatment for patients with gliomas. During this period, there's also been two updates to the World Health Organization classification of gliomas, and the terminology of gliomas has changed. So what we call tumors today is different from what we might have called them 10 years ago. And so a second purpose of our guideline is essentially to provide a key or a translator so a clinician can look at a pathology report today in 2021 with a current terminology and know what to do with that patient and what treatment best fits for that patient today based on what they would have been called in a trial several years ago.

SPEAKER 2: Great. That makes a lot of sense. So then Dr. Blakeley, looking at this guideline, it addresses four clinical questions, which are after maximal safe surgical resection, what are the evidence-based therapies for adults with newly diagnosed glioma including optimal regimens, settings, and timing of therapy? Then also, what are the appropriate therapies for adults with recurrent glioma, including optimal regimens, settings, and timing of therapy, followed by what should the effect of MGMT promoter methylation status be on choice of therapy and if there are subpopulations that should affect the choice of therapy.

I'd like to review the key recommendations for those clinical questions. In reading through the guideline, the expert panel provided recommendations based on the IDH mutation status and the diagnostic categories in the WHO 2016 and 2021 classification systems for tumors of the central nervous system. So it seems appropriate to review the recommendations in this manner as well. Starting with IDH mutant astrocytic and oligodendroglial tumors, what is recommended for patients with oligodendroglioma, IDH mutant, 1p19q deleted CNS WHO grade 2 or 3?

SPEAKER 3: Absolutely, and I'll just summarize for our listeners to help simplify that as you said, essentially, all of the guidelines are divided along molecular markers. And the first cohort are 1p19q co-deleted gliomas. Something that is a 1p19q deleted gliomas also an oligodendroglioma. Those are interchangeable.

If you are 1p19q co-deleted, you have oligodendroglioma and vise versa. In general, 1p19q co-deleted tumors also are IDH mutant. So you can consider that one bundle. And oligodendroglioma is something that is 1p19q co-deleted and IDH mutant.

And for that whole classification, whether it's WHO grade 2 or WHO grade 3, the recommendation is for radiation followed by the combination of procarbazine, CCNU, and vincristine, based on two prospective studies that showed similar results at different time points. There are a couple of modifications to that guideline. There is a statement that if people feel that the combination of Procarbazine, CCNU, and Vincristine, also called PCV, is too toxic, they can consider temozolomide as an alternative for this subclass of tumors 1p19q co-deleted IDH mutant.

And also, importantly, the 1p19q co-deleted grade 2 gliomas are some of the best performing tumors in terms of prognosis of all glial tumors and maybe all CNS tumors. And so there is a statement in the recommendations that say-- it says it is reasonable to defer therapy under appropriate circumstances. And the text goes into what those appropriate circumstances might be, including how much of a resection could be achieved, what the functional status of the person is, how old they are, et cetera.

But big picture-- 1p19q co-deleted tumor equals an oligodendroglioma, and those are almost all IDH mutant. And the bottom line recommendation is radiation followed by PCV with the parentheses saying temozolomide might be a reasonable alternative to PCV, and if you have a particularly benign presentation with a grade 2 tumor, you can consider deferring that therapy start for a time. The next big bundle is astrocytic tumors that are not 1p19q co-deleted.

So in the guidelines, those are termed as 1p19q non-co-deleted. And those tumors do come in two flavors-- IDH mutant or IDH wild type. And I'm going to focus on the IDH mutant because they track closer to the oligodendroglioma, but they are kind of a bridge between the very good prognosis associated with oligodendrogliomas and the more aggressive prognosis associated with malignant gliomas.

And for this cohort, the 1p19q non-co-deleted IDH mutant cohort, the recommendation is for radiation therapy with adjuvant chemotherapy, and there is data that supports that adjuvant chemotherapy being either PCV or temozolomide. We don't prioritize between those two regimens. And why I'm highlighting the word adjuvant is in some centers, there is a tendency to use temozolomide concurrent with radiation therapy. And the recommendation for these 1p19q non-co-deleted IDH mutant WHO grade 2 tumors is not to use it concurrent but to use it in the adjuvant setting.

And then I will round out with talking about IDH wild type. So now we're, again, 1p19q non-co-deleted but IDH wild type. Those tumors may act closer to the glioblastoma. And in that setting, we would say-- the recommendations say to treat with radiation and consider concurrent temozolomide as you would with glioblastoma or only adjuvant temozolomide as you would with the lower grade astrocytoma.

SPEAKER 2: Great. Thank you for going through that and providing such clarity to those recommendations. Then following that, Dr. Mohile, moving on to glioblastoma and other IDH wild type diffuse glioma, what are the key recommendations for people with newly diagnosed glioblastoma IDH wild type CNS WHO grade 4?

SPEAKER 4: So in the current classification, IDH wild type CNS World Health Organization grade 4 is what we've known of classically as glioblastoma. And for patients with glioblastoma who are fit and can tolerate therapy, we recommend treatment with radiation, concurrent temozolomide, and a six month course of adjuvant temozolomide. We also recommend that they can receive alternating electric field therapy along with the adjuvant temozolomide.

Now the recommendations become a little bit more complicated for patients who might not be as fit-- so patients who might be older, have poor performance status, have other measures of frailty. And the way we wrote this is we said that if a patient who is undergoing a six week course of radiation, if that course of radiation, if the benefits did not outweigh the harm, then you could consider alternate regimens. And these include shorter courses or hypofractionated courses of radiation with or without chemotherapy and also includes courses that are chemotherapy alone.

So in people who have tumors that have MGMT promoter methylation, we can consider the option of temozolomide alone. So this would be specifically for patients who either are older, more frail, who we feel are going to have difficulty going through a radiation course. There is some data to support this temozolomide alone approach.

SPEAKER 2: Thank you. I appreciate you going through those recommendations very clearly as well. You clearly put a lot of effort into these recommendations. So then, Dr. Blakeley, what is recommended for patients with astrocytomas IDH wild type CNS WHO grade 2 or 3?

SPEAKER 3: Yes, thank you. So as Dr. Mohile was just saying, for glioblastoma, you can really think about the recommendations for WHO grade 4 very similarly for IDH wild type independent of grade. And that is a new shift in the management of gliomas in adults. Previously, the histologic grading had a lot of weight on whether or not we would offer radiation and chemotherapy. But with the new prognostic and predictive value known associated with the IDH1 mutation or lack of mutation being IDH wild type, the recommendation is if somebody is IDH wild type CNS WHO grade 2 astrocytoma or grade 2 or grade 3, they would be offered treatment similar to a glioblastoma, which would be concurrent radiation and temozolomide followed by adjuvant temozolomide as long as performance status and all other factors support doing so.

SPEAKER 2: Understood. I appreciate you providing that information as well. So were there additional areas where the expert panel found evidence either insufficient or was unable to make a recommendation?

SPEAKER 4: Yeah, so there's two tumor types where we didn't have enough data to make a specific therapeutic recommendation. The first, unfortunately, is in recurrent glioblastoma. And there were no randomized controlled trials that demonstrated a benefit of one therapy over another. And so our recommendation is that when available, patients should be referred for a clinical trial.

The other area is in a tumor type called diffuse midline glioma. This is a tumor characterized by the h3k27 mutation more commonly seen in children. But we do see this in adults. And here as well, there were no randomized trials that could clearly give us guidance on what the best therapy was even in the newly diagnosed setting. And our recommendation here also was, if available, to be considering a clinical trial.

SPEAKER 2: Understood. It's important to recognize where there are areas where we're lacking evidence as well. So then, Dr. Blakeley, in your view, why is this guideline important and how will it change practice?

SPEAKER 3: Thank you. Well, as Dr. Mohile said at the start, it is quite challenging to review the literature for gliomas in adults because we've had different nomenclature applied across clinical trials and diagnostic studies over the last 10 to 15 years. And this document and these guidelines really seek to be the clearinghouse to help clinicians match up what they see on the pathology report for their patient to the data that is published on phase III studies that has influenced our current standards of care.

So I think the most important way it will change practice is bringing clarity to the data that already exists but has not been accessible to providers trying to help patients make the best decisions for them. It also importantly highlighted how much more work is needed. We desperately need new clinical trials for patients with glioblastoma and patients with astrocytoma IDH wild type 1p19q non-co-deleted WHO grade 2 and 3 and the other areas that Dr. Mohile highlighted. But we're hopeful that this will help provide clarity on both what we do know to help us identify patients who have the best chance of truly meaningful benefit from chemotherapy and where we need to invest more resources.

SPEAKER 2: Absolutely. It seems like this will be a helpful resource for how to treat now and a guide as to what areas of research should be investigated in the future. So in addition to that, Dr. Mohile, finally, how do you view that these guideline recommendations will impact patients?

SPEAKER 4: Yeah, my hope is that this will help standardize our approach to patients with gliomas. In the United States, patients with gliomas get care in all kinds of different settings. And when they're seeing an oncologist, particularly in the community, this might be a very small percentage of the types of cancers that they might be seeing, and it's hard to keep up with all of these trials and hard to keep up with the changes in classification. So our hope is that this guideline helps that oncologist in providing them the clarity, as Dr. Blakeley said, on how to approach treatment here so that all of our patients are getting the best standard of care based on the best available evidence and that they're being considered in those areas where there is not good evidence or referral for clinical trials so that in 10 years, when we put together the next guideline, that we're able to make some progress on some of these questions.

SPEAKER 2: Great. Well, thank you both for all of your work that you did to review the literature and produce these evidence-based recommendations and, as you said, provide a real clear and helpful resource to both clinicians and to improve the quality of care for patients. And thank you for taking the time to speak with me today, Dr. Mohile and Dr. Blakeley.

Finally, thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/neurooncology guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Sharon Giordano, co-chair on “Abemaciclib with Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer: ASCO Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Rapid Recommendation Update.” Dr. Giordano discusses the results and impact of the monarchE trial, the updated recommendations on the use of abemaciclib, and impact for clinicians and patients. For more information, visit www.asco.org/breast-cancer-guidelines.

View Details

An interview with Dr. Leslie Fecher from the University of Michigan Health System, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews considerations for the use of steroids to manage immune-related adverse events in patients treated with immune checkpoint inhibitor therapy in the final episode of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

My name is Brittany Harvey, and today we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Leslie Fecher from the University of Michigan Health System in Ann Arbor, Michigan, author on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update, and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.

And today we're focusing on considerations for the use of steroids to manage immune-related adverse events in patients treated with immune checkpoint inhibitor therapy.

Thank you for being here, Dr. Fecher.

LESLIE FECHER: Thank you, Brittany, for this invitation.

BRITTANY HARVEY: Great. Then I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with a publication of the guidelines in the Journal of Clinical Oncology. Dr. Fecher, do you have any relevant disclosures that are related to these guidelines?

LESLIE FECHER: The details of my disclosures are included in the manuscript, but I'd just like to note that I have received research funding, specifically in the form of clinical trial funding, from companies that do manufacture these immunotherapies.

BRITTANY HARVEY: Thank you.

Then getting into the content, so steroids are valuable agents in the management of immunotherapy-related adverse events. So first, what should clinicians consider pretreatment with steroids?

LESLIE FECHER: So I think one of the first things is obviously going back to the traditional history and physical exam, and making sure you understand any preexisting comorbid conditions, such as diabetes, high blood pressure, preexisting cataracts or glaucoma, infections, osteopenia, or osteoporosis. It's always good to try and optimize things before getting started on steroids.

Additionally, it's typically considered very reasonable to check hepatitis B and C serologies prior to starting immunotherapy treatment. And also consideration of assessment for tuberculosis, if there are specific risk factors, understanding if somebody already carries a diagnosis of HIV, and understanding the status of that in advance would be relevant.

BRITTANY HARVEY: Those are important considerations. Then in addition to that, how should opportunistic infections be prevented?

LESLIE FECHER: So one of the most common infections that we tend to try and prevent is pneumocystis jirovecii pneumonia, or PJP, previously known as PCP pneumonia. And this is one of the more common things that we recommend prevention for.

So in patients who have received the equivalent of prednisone dosing of 20 milligrams per day for four or more weeks, or greater than 30 milligrams per day for three weeks or more, that's when it would reasonably be indicated. There are obviously specific institutional guidelines for the preferred regimen, but I think that's important to consider.

The role of viral prophylaxis as well as antifungal prophylaxis is a bit less clear, but is something to be considered, especially depending on the duration of the steroid course. And whether or not in the setting of herpes zoster, for example, if the patient has had issues with zoster in the past.

BRITTANY HARVEY: OK. and then the use of these steroids is to treat immunotherapy-related adverse events. But what are the key recommendations for monitoring both the short-term and long-term adverse effects from steroids?

LESLIE FECHER: So I think being aware of the side effects as well as making sure that the patients and the family members or loved ones that are helping them are aware of them as well. From a short-term standpoint, typically we recommend things such as GI prophylaxis, with either a proton pump inhibitor or a histamine 2 antagonist, to reduce or prevent gastric ulcers or duodenal ulcers, or gastritis.

Given some of the long-term effects, such as bone loss as well as steroid myopathies, we encourage exercise as well as physical therapy in some circumstances.

But really one of the most important things is to make sure that you're constantly both assessing and eliciting from the patient and family members for any other side effects. So often, common acute short-term side effects can be increased risk of infection. So making sure you're asking about it. They may not have the typical manifestations of infection, such as fevers or chills. insomnia or difficulty with anxiety, irritability, skin changes for sure, or high blood pressure.

And then obviously being aware that laboratory evaluation for glucose intolerance is important as well.

BRITTANY HARVEY: Definitely. Those are important points for clinicians, patients, and caregivers.

So then we've had some of the other authors on this guideline talk about tapering steroids. So what are those recommendations on how clinicians should taper steroids?

LESLIE FECHER: So tapering is an art in and of itself in my opinion, and there's lots of different ways to do it. Some general concepts are you want to really try and understand what the side effect is that you are managing, because that will require frequent reassessment.

And so when we talk about reassessing patients during the treatment of their toxicities, the management of the toxicities, in my opinion, is almost as important as the management of the immunotherapy itself. And so patients still need to be seen, still need to be assessed, still need blood work done.

And so reassessment for the toxicity that you're managing, given that we can see rebounding of symptoms. So for example, if they were getting treated for diarrhea or colitis, having a really good understanding of what their baseline bowel movements were, how bad they got, and then a constant reassessment and making sure that the patient, as well as the family, knows that this should not come back again, if you will, in the midst of the taper.

I think the other things to be aware of is that I tend to always reassess before giving the next decrease in dose of the steroids rather than having an automatic decrease. Because again, patients sometimes will follow those, even if their symptoms recur. So ensuring that there's that, again, reassessment.

When we're on oral steroids, some of the general concepts we say is that the course should be at least usually about four weeks total, sometimes as long as six weeks or even longer, depending on the toxicity. And we think about, on average, decreasing from a prednisone or prednisolone amount roughly 10 milligrams every three to seven days, depending on the side effect that you're managing.

The longer the taper, the slower you might need to go, depending at the end. And also being aware of the risk of adrenal insufficiency towards the end of a long steroid course is also an important thing to assess for.

BRITTANY HARVEY: Great. I appreciate you reviewing those considerations.

So then in your view, Dr. Fecher, how will these recommendations for the use of steroids in the management of immune-related adverse effects impact both clinicians and patients?

LESLIE FECHER: I think it will bring ongoing awareness to the physician and their team, as well as the patient and their team. I think that this is obviously really important that everybody is involved and aware.

And I use the term engagement from a patient and family member standpoint. It's really critical to have an understanding of the side effects, have an understanding of the prednisone management. And explaining that not only to the physician team and nurses and other people involved in their care, but when patients call in, that they know to look out for rebounding of their symptoms and to report them immediately, as that can impact steroid tapering.

I think, again, the awareness and engagement is going to ensure that patients get the best care and best results.

BRITTANY HARVEY: Absolutely, and thanks for highlighting both that awareness and engagement.

So thank you so much for your work on these guidelines, and for taking the time to speak with me today, Dr. Fecher.

LESLIE FECHER: Thank you so much, Brittany. I appreciate your time.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Marc Ernstoff from the National Cancer Institute, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” He reviews identification, evaluation & management of ocular toxicities in patients receiving ICPis, including uveitis, iritis, and episcleritis in Part 12 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

My name is Brittany Harvey, and today we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Marc Ernstoff from the National Cancer Institute in Bethesda, Maryland, author on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update, and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.

And today we're focusing on ocular toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Ernstoff.

MARC ERNSTOFF: Thank you, Brittany.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology.

Dr. Ernstoff, do you have any relevant disclosures that are directly related to this guideline?

MARC ERNSTOFF: I have no further disclosures at this time.

BRITTANY HARVEY: Great. Thank you.

Then let's get into these ocular toxicities. So first, what are the immune-related ocular toxicities addressed in this guideline?

MARC ERNSTOFF: So the ocular toxicity is addressed in the guidelines represent a relatively uncommon side effect of immune checkpoint inhibition, and represents inflammation of all components of the eye from the superficial component to the internal uveal component. So there is iritis. There's episcleritis and uveitis, are the ones that are usually identified by physical examination and by complaints.

BRITTANY HARVEY: Understood. Then so let's start with what are the key recommendations for identification, evaluation, and management of uveitis and iritis?

MARC ERNSTOFF: So those are excellent questions. I think that it's important for clinicians to recognize that while most of the eye toxicities are relatively minor, low grade, and can be managed effectively, there are some that are very important to identify, particularly as they may lead to blindness, particularly uveitis or pan uveitis.

So identification of these symptoms and signs are important. So evaluation of the patient by asking whether there are any eye symptoms-- dryness or irritation-- is important in your evaluation of the patient's side effects.

In addition, looking at the eye, both with a penlight, looking for any inflammatory signs, and doing a ophthalmologic examination to make sure there's no cloudiness or anything identified in the retina is important.

BRITTANY HARVEY: Great. And then furthermore, what are the key recommendations for identification, evaluation, and management of episcleritis?

MARC ERNSTOFF: So episcleritis can usually be seen by irritation in the superficial areas of the eye. It usually can be managed. If it's low grade, it can be managed with topical steroids and continuation of the immune checkpoint inhibitor.

On the other hand, if it's more bothersome and not responding to topical therapy, evaluation by an ophthalmologist, potentially interruption of immune checkpoint inhibitor, is important. And if it's severe, systemic steroids might be required at that time.

BRITTANY HARVEY: Great. Thank you for reviewing how to best identify and manage that particular toxicity.

So then in your view, how will these recommendations for the management of ocular toxicities impact both clinicians and patients?

MARC ERNSTOFF: So again, I think it's important that both from symptom management, that these, many times, can be managed with topical steroids and tears effectively, and that a patient's therapy can continue, which I believe is important.

On the other hand, identifying areas that may be beyond the expertise of an oncologist, would require evaluation by an ophthalmologist, including a slit light examination. It is important to recognize that uveitis can have minimal symptoms and yet be more severe in its condition, requiring intervention and holding of immune checkpoint.

And if really severe-- grade 3 or 4-- the interruption and discontinuation of immune checkpoint inhibition is probably going to be required to manage the side effect.

Again, if undiagnosed and untreated, it can lead to blindness. So while not quote life-threatening, clearly a major impact in quality of life of a patient that is preventable, if identified.

BRITTANY HARVEY: Great. Thank you so much for viewing these recommendations for the management of ocular toxicities, to ensure both the quality of life of patients and the best practices for management of these toxicities.

So I want to thank you for your work on these guidelines and for taking the time to speak to you today, Dr. Ernstoff.

MARC ERNSTOFF: Thank, you very much, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune related-adverse events. To read the full guideline, go to www.asco.org/supportive-care-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Pauline Funchain from Cleveland Clinic, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews the recommendations for cardiovascular toxicities in patients receiving ICPis, including overall cardiac toxicities (i.e., myocarditis, pericarditis & arrhythmias), and VTE in Part 11 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

My name is Brittany Harvey, and today we're continuing our series on the management of immune related adverse events. I am joined by Dr. Pauline Funchain from the Cleveland Clinic in Cleveland, Ohio, author on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update, and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.

And today we're focusing on the cardiovascular toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Funchain.

PAULINE FUNCHAIN: Thank you, Brittany, for the invitation.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Funchain, do you have any relevant disclosures that are directly related to these guidelines?

PAULINE FUNCHAIN: So I do. My institution receives research funding from Pfizer and Bristol Myers Squibb for clinical trials where I'm a primary investigator. And I have done some consultation work with Eisai.

BRITTANY HARVEY: OK. thank you for those disclosures.

Then talking about the content of this guideline, what are the immune-related cardiovascular toxicities addressed in this guideline?

PAULINE FUNCHAIN: So there are two major categories. One is an overall cardiovascular category. That includes myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis. That's overall. And there's a second category of venous thromboembolism.

BRITTANY HARVEY: Great. Then starting with that overall category, what are the key recommendations for identification, evaluation, and management of myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis?

PAULINE FUNCHAIN: So in that overall category, I think it's important to recognize that there are symptoms that are a little bit more general. They may be cardiovascular. They may be pulmonary. But we have to be aware that some of these can be cardiovascular.

So that would include worsening fatigue, progressive or acute dyspnea. I think they're generally going to be other things, but you really have to recognize a potential cardiac IRAE, as those can have major medical consequences.

I mean there are other things that are more obviously cardiac, like chest pain, arrhythmia, palpitations, acute onset peripheral edema. And it is important to note that they can, like every other IRAE, happen at any time. In the literature, the median time to onset is 6 weeks, but the range is somewhere between 1.4 to 54, and we know that it can be all over the place with IRAEs in terms of presentation.

Then next would be evaluation. So with evaluation, whenever you see this type of side effect, fatigue, dyspnea, chest pain, it's natural to want to get an EKG troponin. I think that's a great place to start. And I think if there's more concern for cardiac type of IRAE, then an echocardiogram, a chest X-ray, I think, are probably the next easiest evaluations to assess for cardiac IRAE.

One of the important things to note is that cardiac IRAEs, especially myocarditis, tend to happen along with concurrent myositis, so it's important to check a CPK to rule that in or rule that out. And typically, then if people need more evaluation, the cardiac MRI is the next step, but things like cardiac catheterization may be involved.

And so that's where I think it's really important with management to have cardiology involved early. I mentioned this briefly before, but it's really important to know that myocarditis has a very high fatality rate, up to about 50% in published series. I think as we get better at recognizing myocarditis, that fatality rate will likely go down, but catching a cardiac IRAE late can have some very serious implications for our patients.

So immediately recognizing that a cardiac workup is necessary, and referring early to cardiology is really important, no matter what grade of cardiac IRAE we see.

And I do think that with cardiac IRAEs, it's really, is it an inpatient workup? Does it require immediate cardiac consultation and workup? If there are elevated troponins that are going up, or conduction abnormalities, does that patient need to be in a cardiac unit? I think those are the major things to keep in mind with management.

Another thing, I think, that is really important because of the high fatality rate: starting corticosteroids early. So like our other IRAEs, you can start corticosteroids that 1 to 2 mgs per kg per day. And doing that early has the potential to quickly improve cardiac inflammation, keep people from the very serious and potentially fatal side effects for cardiac IRAEs. And it really doesn't have that much of a consequence in the short term.

So I think in discussions about this guideline, we all felt that if a patient has a Grade 2 or higher IRAE-- so that's anything that has a cardiac biomarker that's abnormal plus symptoms of any kind-- it's important to keep in mind early steroids and early cardiac consultation.

For very, very severe cases where management with corticosteroids is not improving the patient's status, then we highly recommend considering cardiac transplant rejection doses, which would be methyl pred at 1 gram daily, or adding other immunosuppressants.

So there are not as many studies as we would like, but mycophenolate, infliximab, antithymocyte globulin have all been reported. There have also been case reports on abatacept or alemtuzumab, with good outcomes. So those are things to consider, of course, with cardiology input for severe cases.

BRITTANY HARVEY: Thank you. Those are important notes for clinicians to keep in mind for management and evaluation.

So then, the second category that you mentioned, what are the key recommendations for identification, evaluation, and management of venous thromboembolism?

PAULINE FUNCHAIN: So for identification, most everyone listening to this podcast knows what a venous thromboembolism looks like. That's extremity swelling, extremity pain, sometimes accompanied by fever, pleuritic pain, cough, dyspnea.

And the evaluation is the same as what you would see in clinic. That would be venous ultrasounds for any suspected deep vein thromboembolisms. And CT, PE for any suspected pulmonary embolism. And of course, a VQ scan if you can't do that type of CT.

And the management is the same as what you would normally do in clinic. So if it's a superficial thrombosis, that would be a grade 1. You would do a warm compress, do supportive care. But importantly, you can continue the immune checkpoint inhibitor per our recommendations.

For grade 2, so a symptomatic thrombosis, a deep vein thrombosis, that would require anticoagulation. But again, once anticoagulation has been started, the recommendation is that it is safe to continue the immune checkpoint inhibitor therapy, because at this point, you're protected. Should be, in theory, protected from future embolic events.

And then, I think the major thing is that for management in general once there is anticoagulation on board, then there isn't necessarily a reason to hold immune checkpoint inhibitor therapy. I think that the major reasons we would recommend to hold it are life-threatening consequences, organ damage. So grade 4 embolic event, where you would have to admit the patient. And then it becomes a risk-benefit discussion after an admission.

In general, I think the recognition and treatment are the same in terms of venous thromboemboli that are identified in the context of immune checkpoint inhibitor therapy. The major thing is just to know that it exists as a potential side effect, that the incidences appear to be higher, and that there is something about immune checkpoint inhibitor therapy that may put our patients at higher risk for these embolic events.

BRITTANY HARVEY: Definitely. That's key to know, and particularly also when to hold or continue ICPI therapy.

So then in your view, Dr. Funchain, how will these recommendations for management of cardiovascular toxicities impact both clinicians and patients?

PAULINE FUNCHAIN: I think the major thing is to know that these exist. The overall cardiac toxicities are less common, so if we're talking about myocarditis, that is a pretty rare event. But it's important to know that this is an event that is potentially fatal, that that fatality happens often, and that myocarditis can occur along with a myositis, and in some cases with myasthenia gravis.

So these are three different rare side effects that can happen together, sometimes in pairs, sometimes in triplets, sometimes just one of them. But any one of these three has a higher risk for fatality.

So I think just to know that it's out there. So that that is just hanging around in the differential for someone who is tired or out of breath. It may be pulmonary, but also keep in mind that it could be cardiac, and that is serious, and that should be worked up early and treated early.

I think that's the major thing that I hope these guidelines do, is put these important but rare side effects out there and potentially save lives.

I will say for VTEs, for venous thromboemboli, again, so PE can happen, and it can be fatal. I think this is not as rare, but of course, it's not rare in our patient population either. So these are things that we already look out for. Just, I think, if this podcast and the guidelines can add to the education that immune checkpoint inhibitors will increase the risk of thromboembolism, I think that those are the important takeaways.

BRITTANY HARVEY: Absolutely. Recognition of these IRAEs is a common theme across the affected organ sites that we've heard in many of these podcast episodes.

So I want to thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Funchain.

PAULINE FUNCHAIN: Thank you for having me.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune related adverse events.

To read the full guideline, go to www.asco.org/supportive-care-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Loretta Nastoupil from MD Anderson Cancer Center, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She discusses the identification, evaluation, and management of hematologic toxicities in patients receiving ICPis, including hemolytic anemia among others in Part 10 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

I am joined by Dr. Loretta Nastoupil from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, author on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update, and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on hematologic toxicities in patients treated with immune-checkpoint inhibitor therapy. Thank you for being here, Dr. Nastoupil.

LORETTA NASTOUPIL: Thanks, Brittany. I'm happy to be here.

BRITTANY HARVEY: Great. Then first I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Nastoupil, do you have any relevant disclosures that are related to these guidelines?

LORETTA NASTOUPIL: Yes, Brittany. So I have received honorarium for participation in advisory boards from the following companies, including BMS/Celgene, Genentech, Janssen, Novartis, Merck, MorphoSys TG Therapeutics, and Takeda. And I've also received research funding support from BMS/Celgene, Gilead Kite, Genentech, Janssen, Novartis and Takeda.

BRITTANY HARVEY: Thank you for those disclosures. Then let's get into what we're here today to talk about. So what are the immune-related hematologic toxicities addressed in this guideline?

LORETTA NASTOUPIL: So it's important to recognize that hematologic toxicities that are immune-related as a result of immune therapy are infrequent occurrences. So it's important to recognize when they do occur and some of the unique workups given that they are so infrequent. So probably one of the most common is hemolytic anemia.

It's important to recognize that these are cancer patients. And they may have multiple reasons for the development of acute or new onset anemia, but recognizing if they're on either checkpoint inhibitors or immune therapies, it's important to recognize that it might be spurred on as a result of immune-mediated anemia. We advise in terms of history and workup to consider whether or not they've been exposed to new drugs, whether or not they've had a recent insect or snakebite exposure.

The recommended workup includes a CBC with also a peripheral blood smear to look for evidence of hemolysis or macrocytosis. In addition, other hemolytic anemia workup includes evaluation for LDH, haptoglobin, reticulocyte count, bilirubin, and free hemoglobin. Other potential diagnoses on the differential include DIC, so a panel, including coags, PT, INR, and PTT, exploring autoimmune serologies, PNH screening, evaluation for infection such as viral or bacterial causes of hemolysis, and also consideration for bone marrow failure syndrome, including evaluation for potentially reversible causes, such as B12, folate, copper, parvovirus, iron, thyroid, infection, et cetera.

G6PD level is helpful in the evaluation, as well as exploration as I mentioned of potentially new drugs that might be linked, including ribavirin, rifampin, dapsone, interferon, some of the antibiotics, such as cephalosporins, penicillins, NSAIDs, ciprofloxacin, for instance, et cetera. So as part of the workup, if we have excluded alternative causes and we think that the immune-checkpoint inhibitor might be the underlying cause of the autoimmune hemolytic anemia, then generally we will continue unless they have grade 2 or higher toxicity, which is generally a hemoglobin less than 10. In which case, we would recommend to hold the immune-checkpoint inhibitor, again, with significant anemia.

So those with grade 2 or higher, you might consider initiating corticosteroids, including 1.5 to 1 milligram per kilogram per day until improvement. For grade 3 or higher-- so this is more severe anemia, so hemoglobin is less than 8. Generally, we're recommending permanent discontinuation of the checkpoint inhibitor and potentially higher doses, including up to 2 milligrams per kilogram per day of prednisone or corticosteroid equivalent to speed up the recovery.

In regards to transfusion requirements or consideration, we are suggesting you evaluate or consider your local or regional guidelines. We generally do not transfuse for a target hemoglobin greater than seven to eight. And we also recommend supplementation with folic acid.

BRITTANY HARVEY: Great. And then beyond those recommendations for hemolytic anemia, what are the key recommendations for identification, evaluation, and management of acquired thrombotic thrombocytopenia purpura?

LORETTA NASTOUPIL: Sure. So fortunately, TTP is quite rare, but, again, something that is worth exploring. Some of the challenges are in the clinical syndrome. And that it can mimic some of the other toxicities that are covered in other sections, particularly the neurotoxicity section.

But essentially, for patients who have pretty dramatic change in platelet count, again, they may have additional clinical sequelae such as neurologic toxicity or adverse events. It's important to recognize that TTP might be an underlying cause, again, for patients who are on immune-checkpoint inhibitors. This is where a hematology consult early in the clinical course would be particularly of importance to recognize it and potentially to minimize offending agents.

Drug exposure is always important, because many of these patients might have other drugs, in addition to their immune-checkpoint inhibitors, such as chemotherapy, sirolimus, tacrolimus, antibiotics et cetera. And so exploring offending agents is important. An ADAMTS13 level, an inhibitor titer, would be important to send if you're considering TTP, in addition to evaluating the peripheral smear, and the hemolytic anemia workup, as I just mentioned, including LDH, haptoglobin and reticulocyte count.

Exploring infectious etiology, including CMV titers or serology, would be particularly helpful, an additional clinical evaluation, such as brain imaging with CT or MRI, echocardiogram, and EKG would be of help. For all grades of TTP, again, even with a clinical suspicion for the diagnosis, in addition to hematology consult, we recommend stabilizing the patient. That might require care in an acute care setting, making sure that they have adequate organ function and that this is stabilized. For grade 1 or higher, we recommend holding the immune-checkpoint inhibitor.

And you might consider, again, initiation of corticosteroids with 0.5 to 1 milligram per kilogram per day of prednisone or an equivalent. For grade 3 or higher, we would, again, in addition to holding the checkpoint inhibitor and in conjunction with your hematology colleagues, you might initiate a therapeutic plasma exchange. Again, in accordance with existing guidelines, you may consider higher doses of steroids, including methylprednisolone 1 gram IV daily for three days. You could consider some additional supportive agents, such as rituximab or pembrolizumab if the ADAMTS13 level is less than 10 or less than 10% of normal and an inhibitor or elevated ADAMTS13 IgG has been detected.

BRITTANY HARVEY: I appreciate you going through the details for TTP. So then, additionally, this guideline addresses aplastic anemia. So what are the key recommendations for identification, evaluation, and management of aplastic anemia?

LORETTA NASTOUPIL: Yeah. So, fortunately, again, these are quite rare situations. So with aplastic anemia, similar to what we've discussed in terms of workup of anemia, globally, it's important to explore potentially causes of, again, bone marrow failure syndrome. And aplastic anemia is one of those such causes. Exploration of a bone marrow biopsy in conjunction, again, with your hematology consult would be critically important, and exploring potentially reversible causes, again, such as deficiencies and important nutrients, viral etiologies, in addition to parvovirus, CMV, HHV-6 is important to consider and rule out.

But I think the end of the day, a bone marrow biopsy and aspirate is going to be the most helpful assessment to ensure that aplastic anemia has been considered and worked up. In regards to management of aplastic anemia, we're going to hold the immune-checkpoint inhibitor. You may need to provide additional support such as growth factors. And close follow-up, I think is the most critical aspect of this. Sometimes we initiate patients on corticosteroids. We hold the checkpoint inhibitor. And then we may monitor them less frequently. Oftentimes, these patients with high malignancies are going to need to be followed very closely, sometimes weekly or multiple times a week. So in regards to management of aplastic anemia that might be immune-mediated as a result of immune-checkpoint inhibitors and in conjunction with your hematology and colleagues, consideration of management might include administration of horse ATG and cyclosporine, but again transfusion support, growth factor support, even consideration for HLA typing and evaluation first. Stem cell transplantation might be appropriate, particularly for a young patient with minimal comorbidities.

For grade 3 or higher, in addition to these considerations, we're going to hold the checkpoint inhibitor and monitor weekly for improvement. If no response, you might consider repeating immune suppression with Rabbit ATG plus cyclosporine or cyclophosphamide. And for refractory patients, consider eltrombopag plus best supportive care.

BRITTANY HARVEY: Great. Thank you. Those are important notes on the management of aplastic anemia. So then, additionally, what are the key recommendations for the identification, evaluation, and management of lymphopenia?

LORETTA NASTOUPIL: Yeah. I think one of the challenges with lymphopenia, it's common for patients who've had cancer-directed therapy, particularly things like chemotherapy. And so understanding whether or not this is a new onset after exposure to checkpoint inhibitors is one of the critical aspects, in addition to considering alternative causes.

But for patients in which we do think the lymphopenia is a result of the immune-checkpoint inhibitor, we're not generally advising discontinuation or holding of the immune-checkpoint inhibitor, but it is important to consider best supportive measures, including whether or not patients might benefit from monitoring for reactivation of certain viral etiologies, including CMV and HHV-6, for instance, in addition to potential consideration for prophylactic strategies, such as PJP prophylaxis. Also, zoster reactivation might be something that these patients might indeed be at risk for. So as opposed to holding your checkpoint inhibitor and initiating things like corticosteroids, if we have excluded alternative causes and think lymphopenia is a result of the immune-checkpoint inhibitor or as immune-mediated, ensuring that they are receiving best supportive care to mitigate some of their toxicity that may result as the result of the lymphopenia.

BRITTANY HARVEY: Understood. And it's important to note for clinicians that management is different from a lot of the management of the other hematologic toxicities. So then the last hematologic toxicity that was addressed in this guideline was acquired hemophilia A. So what are those key recommendations?

LORETTA NASTOUPIL: Acquired hemophilia A, again, fortunately is very rare and uncommon, but this is one situation where engagement of a hematologist, who is an expert in management of hemophilia, will be critical. So that would potentially be step one. In terms of laboratory assessment, that would be helpful, in addition to your CBC, where you're assessing things like platelet count, coagulation workup, including fibrinogen, PT, PTT, INR, that would be informative.

Patients with acquired hemophilia A will likely have a prolonged activated PTT with a normal PT. So that might be one of the clues. Imaging would be helpful to ensure the patients don't have any signs of spontaneous bleeding or hematosis, such as MRI, CT, or ultrasound, if particularly they have any localizing symptoms. Medication review to look for alternative causes would always be helpful. And determination of the Bethesda unit level of inhibitor would be critical.

In regards to management, we would hold the checkpoint inhibitor, initiate corticosteroids, transfusion support as indicated, and you want to treat the underlying acquired hemophilia with conjunction of a hematologist. For grade 2 or higher, this may require factor replacement. And the choice is usually based on the Bethesda unit of the titer.

Administration of prednisone, in addition to rituximab 375 milligrams per meter squared weekly for four weeks or cyclophosphamide dosed at 1 to 2 milligrams per kilogram per day may be patient-specific. And, again, that decision should be made in conjunction with your hematology consult. Prednisone, rituximab, and cyclophosphamide should be given for a minimum of five weeks.

And factors should be prescribed to increase the level, particularly during bleeding episodes. And, again, the choice of the factor is based on the presence or absence of an inhibitor. For grade 3 or higher, we advise to permanently discontinue the immune-checkpoint inhibitor.

These patients generally will be admitted for stabilization. They do require factor replacement. Bypassing agents may also be required, including factor VII. Caution should be taken in elderly patients and those with coronary artery disease. Corticosteroids, rituximab, and cyclophosphamide should also be considered, transfusion support, if they're having active bleeding.

And if worsening or no improvement, you could consider adding cyclosporine or immune suppression to try and stabilize these patients. Again, acquired hemophilia A requires special clinical and laboratory expertise. This would require consult and potentially even transfer to a specialized center, and consultation with a hemophilia center should be initiated as soon as this is considered or confirmed.

BRITTANY HARVEY: That's a great summary of these recommendations. The expert panel and you clearly put in a lot of work into these recommendations. So then in your view, how will these recommendations for the management of hematologic toxicities impact both clinicians and patients?

LORETTA NASTOUPIL: I think the most important thing are disseminating this information. I think ASCO plays a critical role in helping clinicians first recognize some of the toxicities that are different from what we have traditionally seen with chemotherapy and may have different management strategies. So guidelines, such as this, are critically helpful. Podcasts, such as this, are incredibly helpful to get the information out, recognizing that all of us authors are more than willing to provide additional guidance and are willing to be contacted in this situation where someone's facing one of these unique and rare toxicities and would like some additional guidance in terms of further management.

Hematologic toxicities are sometimes hard to distinguish or maybe potentially hard to recognize, given many of these patients may have been on prior chemotherapy agents, and anemia or thrombocytopenia may not be unusual, but recognizing if it's new or more severe than what has been seen previously and that, at least, consideration of an immune-mediated hematologic toxicity, be considered, because the management might be unique. And so I hope that we've outlined today some of the hematologic toxicities that are rare that may be seen with immune therapy and some of the strategies to work up alternative diagnoses and management if it is indeed immune-mediated toxicity.

BRITTANY HARVEY: Definitely. And I really appreciate you going through these rare but very important toxicities. So thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Nastoupil.

LORETTA NASTOUPIL: Thanks, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews neurologic toxicities in patients receiving ICPis, such as myasthenia gravis, Guillain-Barre Syndrome, peripheral neuropathy, aseptic meningitis & encephalitis in Part 9 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center in New York, New York, author on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update, and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T Cell Therapy: ASCO Guideline. And today, we're focusing on nervous system toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Santomasso.

BIANCA SANTOMASSO: Thank you for having me.

BRITTANY HARVEY: Then I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Santomasso, do you have any relevant disclosures that are directly related to these guidelines?

BIANCA SANTOMASSO: Yes, I'd like to disclose that I've served as a paid consultant for Celgene, Janssen Pharmaceutical, and Legend Biotech for advising them on the topics of CAR T cell therapy side effects.

BRITTANY HARVEY: Thank you. Then getting into the content of this guideline, what are the immune-related nervous system toxicities addressed in this guideline? And what are the overarching recommendations for evaluation of these neurologic immune-related adverse events?

BIANCA SANTOMASSO: So neurologic immune-related adverse events actually encompass a very diverse spectrum of neurologic syndromes that can occur as a complication of treatment with checkpoint inhibitors. So the spectrum that is covered by this guideline includes myasthenia gravis, Guillain-Barre syndrome, polyneuropathy, aseptic meningitis, and encephalitis.

And although these are rarer than many of the other immune-related adverse event types affecting other organ systems, they're increasingly being encountered due to more patients being treated with novel combinations of immunotherapies. And they're important to recognize, because along with myocarditis, they have generally more morbidity and even more mortality than irAEs affecting other organ systems. So it's important for clinical care providers to have a high index of suspicion for these events.

Studies have suggested that these tend to occur in about 3% to 12% of patients, probably between 1% and 2% of patients developing severe events. So they're rare. But again, the events are probably more commonly seen in patients treated with combination checkpoint blockade. And we're increasingly seeing more combinations. So we should be on the lookout for these.

Neurologic immune-related adverse events can be divided into syndromes that affect the peripheral nervous system, so meaning the peripheral nerves, the neuromuscular junction, and muscle. So that would be Guillain-Barre syndrome, myasthenia gravis, and myositis. And those that affect the central nervous system, such as the brain, spinal cord, or leptomeninges. So those would be aseptic meningitis and encephalitis.

The peripheral nervous system irAE appear to be more common than those affecting the central nervous system. And patients can present with a number of different symptoms that kind of relate to these syndromes. That can be as diverse as a headache to numbness, tingling, or focal weakness, such as a foot drop or facial weakness. You may see patients with severe altered mental status or personality changes or gait difficulty, walking difficulty, which could actually mean any number of syndromes.

It's generally important to be aware that the timing of onset is generally early, a median of four weeks after the start of treatment, but can range anywhere from one week after the start of treatment to greater than a year. And because we know that cancer can spread to many parts of the nervous system, neurologic toxicity should be considered a diagnosis of exclusion.

So that means that as part of the workup for neurologic immune-related adverse events, it's imperative to rule out nervous system metastasis, stroke, and infection, which we know can occur at higher rates in patients with cancer. So for most neurologic immune-related adverse events, diagnostic workup is similar. It should include MRI brain and/or of the spine, with and without contrast, and often a lumbar puncture for cerebrospinal fluid analysis, including cytology to rule out leptomeningeal metastasis.

BRITTANY HARVEY: Thank you for that overview. In addition to those points for evaluation for all nervous system toxicities, what are the key recommendations for identification, evaluation, and management of myasthenia gravis?

BIANCA SANTOMASSO: So for myasthenia gravis, presenting symptoms usually include fatiguable or fluctuating muscle weakness. It's generally more proximal than distal. And there's frequently ocular and/or bulbar involvement. So that means either ptosis, like a droopy eyelid, diplopia, or double vision, difficulty swallowing, dysarthria, facial muscle weakness, and/or head drop or neck weakness. Again, for any patient with new neurologic symptoms, an MRI of the brain or spine should be performed depending upon the symptoms to rule out central nervous system involvement by disease or some alternative diagnosis.

And similar to idiopathic myasthenia gravis, acetylcholine receptor antibodies can be positive. So these should be checked. This is a blood test. But it's important to note that while these antibodies may be confirmatory, their absence does not rule out the syndrome. The rate of acetylcholine receptor antibody positivity in immune-related myasthenia gravis has not been definitively established. So depending on the presentation, one might also consider sending a paraneoplastic panel for Lambert-Eaton myasthenic syndrome.

The single most important point I'd like to make regarding suspected immune-related myasthenia gravis is that orbital myositis and generalized myositis from immune checkpoint inhibitors can present similarly. For this reason, early neurology consultation and electrodiagnostic testing with repetitive stimulation or single fiber EMG becomes important and helpful to distinguish the two. And to make matters even more complicated, we've learned that there's an overlap syndrome, where patients may develop not only myasthenia gravis, but also myositis and/or myocarditis at the same time.

So basically, the neuromuscular junction is affected. But the local muscle and myocardium, which is heart muscle that's kind of related, may be affected all at once. And this overlap of syndromes may increase disease severity and mortality. So they're important to recognize. So what this means is that when you encounter a patient with suspected myasthenia gravis, you should also be checking CPK, muscle enzymes, aldolase to evaluate for myositis, and troponin and electrocardiogram to evaluate for myocarditis. And this should be done even if there are no obvious symptoms.

So onto the treatment of myasthenia gravis, this is similar to the management of the idiopathic form. Therefore, it's helpful to have the involvement of a neurologist. The immune checkpoint inhibitor therapy should be held. And patients with mild symptoms are often started on pyridostigmine and corticosteroids. And patients with more severe symptoms should initiate IVIG or plasmapheresis.

And patients with more severe symptoms may need to be admitted to the hospital. So that their neurologic and pulmonary status can be monitored closely for improvement. Some patients may require ICU level of monitoring. And considering adding rituximab if symptoms are refractory, and often, as symptoms improve, the steroids can be de-escalated.

BRITTANY HARVEY: Understood. Those are all very important points for clinicians to consider. So then following that, what are the key recommendations for identification, evaluation, and management of Guillain-Barre syndrome?

BIANCA SANTOMASSO: So Guillain-Barre syndrome, like myasthenia gravis, also presents with weakness. Most often, patients present with a progressive ascending muscle weakness. The syndrome can start with sensory symptoms or neuropathic pain that can be localized to the lower back and thighs. In addition to the classic ascending weakness, there may be facial weakness, double vision, numbness or tingling in the hands or feet, loss of balance, and coordination.

And shortness of breath may occur due to respiratory muscle weakness. The autonomic nerves can also be affected and can present as new severe constipation or nausea, urinary problems, or orthostatic hypotension. The reflexes are often reduced or absent, deep tendon reflexes. So again, as for all of the syndromes, early involvement by a neurologist is recommended, if possible.

Usually, MRI imaging of the spine is important to rule out spinal cord compression. And it also may show cauda nerve thickening or enhancement, which can occur with this syndrome. And the second aspect is cerebrospinal fluid analysis is important for diagnosis. This is important really for ruling out leptomeningeal metastasis, since that could present similarly. And often, what can be seen in GBS is an elevated protein level in the cerebrospinal fluid.

In addition, unlike idiopathic GBS, there can be an elevated white blood cell count in the cerebrospinal fluid. Electrode diagnostic testing can also be helpful for confirmation, and serum tests for antiganglioside antibodies, and a paraneoplastic antibody workup may also be considered. Bedside pulmonary function test and swallowing evaluation should be performed if there's a concern for respiratory or swallowing dysfunction.

And some patients do need to have inpatient admission and monitoring if symptoms are severe or if they appear to be progressing from mild. For management, the checkpoint inhibitor therapy should be held. And patients are most often treated with IVIG or plasmapheresis. Corticosteroids can be added to the IVIG or plasmapheresis. These are not usually recommended for idiopathic Guillain-Barre syndrome. However, in immune checkpoint inhibitor-related forms, a trial is reasonable. And steroids are usually given at a higher dose for five days and then tapered over several weeks.

BRITTANY HARVEY: Understood. I appreciate that overview. So then what are the key recommendations for identification, evaluation, and management of peripheral neuropathy?

BIANCA SANTOMASSO: So peripheral neuropathy, or polyneuropathy, is a rare but likely underreported complication of immune checkpoint inhibitor therapy. So in the large databases and meta-analyses, those have really focused on Guillain-Barre syndrome for reporting. But other types of neuropathies, such as painful length dependent sensory and motor axonal neuropathies, or polyradiculopathies or sensory neuropathies do occur after immune checkpoint inhibitors and are probably under-recognized.

So evaluation of immune related neuropathy should include neurology consultation to guide the neurology phenotype determination and also the workup. The evaluation primarily relies on a combination of electrodiagnostic studies, serologic tests, and MRI neuroimaging. Because peripheral nervous syndromes can overlap, screening for neuromuscular junction dysfunction with electrodiagnostic testing and myopathy is recommended for any patient who presents with at least motor symptoms that are thought to be peripheral.

Serum testing can be helpful for ruling out reversible causes of neuropathy. Spinal imaging is recommended to exclude metastatic disease. And for management, it usually involves holding the checkpoint inhibitor in mild cases, using neuropathic pain medication or steroids in more severe cases. And very severe cases that kind of resembled GBS would be managed as per the GBS algorithm with IVIG or plasmapheresis.

BRITTANY HARVEY: Understood. And it's key to look out for those overlapping adverse events. So then following that, what are the key recommendations for aseptic meningitis?

BIANCA SANTOMASSO: Right, so now we're getting into the central nervous system toxicity. So aseptic meningitis is an inflammation of the meninges. And it can present with headache, photophobia, neck stiffness. Patients can have nausea, and vomiting, and occasionally fever. The mental status is usually normal.

And in patients presenting with headache, which in isolation, could suggest an aseptic meningitis, it's important to evaluate if they have any confusion or altered behavior, which might suggest an encephalitis. And this distinction is important, because suspected encephalitis triggers a different workup, which we'll be discussing later, and also even different management. So the workup for aseptic meningitis includes neuroimaging, usually an MRI of the brain.

And on that imaging, we sometimes see abnormal leptomeningeal enhancement. It's important not to assume that this is cancer and to do a lumbar puncture to evaluate cerebrospinal fluid both for inflammation and to exclude other causes of meningeal disease, particularly neoplastic and infectious causes. So cytology, Gram stain, and culture, and other infectious studies should be negative. And it's recommended that empiric antibiotics or antiviral therapy be considered to cover for infectious meningitis until the cerebrospinal fluid results return negative.

What's seen in the cerebrospinal fluid in aseptic meningitis is typically reactive lymphocytes, but also neutrophils or histiocytes may be prominent on the cytology. And while the symptoms can be severe, sometimes requiring hospitalization, the management of this entity, these are usually quite treatable. Aseptic meningitis generally responds very well to corticosteroids. So management involves holding the checkpoint inhibitor. And you can often get away with starting a fairly modest dose of corticosteroids, such as oral prednisone, 0.5 to 1 milligram per kilogram or the equivalent. And steroids can usually be tapered over two to four weeks.

BRITTANY HARVEY: Great, thank you for reviewing those recommendations. So then you just mentioned the distinction of aseptic meningitis and encephalitis. So what are those key recommendations for identification, evaluation, and management of encephalitis?

BIANCA SANTOMASSO: So in encephalitis, the mental status is not normal. It's characterized by, really, an acute or subacute confusion, altered mental status, altered behavior, memory deficits, including working memory and short-term memory. There can be, as associated symptoms, headaches, new onset seizures, psychiatric symptoms, which can include delusions or hallucinations. There could be weakness, sensory changes, imbalance, or gait instability, along with the mental status changes.

And so similar to aseptic meningitis, the other central nervous system toxicity, it's important to distinguish encephalitis from other causes of altered mental status, such as CNS metastases, stroke, or infection. And as for the other syndromes, it's very helpful to have neurologic consultation early, if possible.

An MRI of the brain is critical. And in addition, MRI of the spine may be obtained to evaluate for inflammatory demyelinating ischemic or metastatic lesions. In immune related encephalitis, MRI brain imaging may reveal T2 flare changes, typical of what can be seen in idiopathic autoimmune or limbic encephalitis. But most often, the MRI imaging is normal. So in this situation, a lumbar puncture for CSF studies to evaluate for evidence of inflammation can be very helpful.

You can expect to see either a lymphocytic pleocytosis or an elevated protein, or CSF restricted oligoclonal bands. CSF analysis is also helpful for excluding other causes of encephalitis, particularly viral encephalitis. So HSV, Herpes Simplex Virus, or varicella zoster virus encephalitis should be ruled out and treated with antivirals while the tests are pending. So typically, these entities can be excluded by PCR testing for HSV and VZV.

Electroencephalogram, or EEG, can also be helpful for revealing subclinical seizures or status epilepticus, which can occur as a complication of encephalitis or as a cause of persistently depressed sensorium. But these are not specific to encephalitis. Other testing that's done includes screening metabolic tests to look for alternative etiologies. And for this entity, serum and CSF autoimmune antibody evaluation should be sent to assess for malignancy associated neurologic syndromes.

And your neurologist can help you with the workup and management, in particular which tests to send. There have been reported cases of antibody positive checkpoint inhibitor related encephalitis. For management, in contrast to aseptic meningitis, these are generally not as steroid sensitive. So you often have to treat with either higher steroid doses, even pulsed steroid doses, along with IVIG or plasmapheresis.

If no improvement, escalation to rituximab and cyclophosphamide can be considered, with the assistance of neurology. This management guidance is taken from how to treat autoimmune encephalitities that are not related to checkpoint inhibitors. Unfortunately, these can be difficult to treat. The response may only be partial. So this is one area in need of better understanding of best therapeutics.

BRITTANY HARVEY: OK, thank you for reviewing that and pointing out where there's future research needed as well. And I appreciate your reviewing the recommendations for each of these neurologic immune-related adverse events. So then to wrap us up, in your view, how will these recommendations for the management of nervous system toxicities impact both clinicians and patients?

BIANCA SANTOMASSO: Yeah, so I think this is a daunting list of toxicities. But I'll say that in most situations, the immune checkpoint inhibitor side effects are often manageable and reversible with proper supportive care. They can be serious, and they require close vigilance and prompt treatment and identification. But by knowing what to look for in early identification, that allows early intervention, which is really the key to reversibility and the best outcomes.

So having these toxicities on your differential diagnosis is critical. And I think these guidelines really help inform both clinicians, and care providers, and patients on what the possible manifestations are. So we believe this guideline and its recommendations will help members of clinical teams with the recognition and the management of these unique toxicities. And again, it's timely recognition and early intervention that helps patients, really, by increasing their safety with early management.

BRITTANY HARVEY: Great, well, thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Santomasso.

BIANCA SANTOMASSO: My pleasure. Thank you so much.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive-care-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe. So you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Umang Swami from the Huntsman Cancer Institute, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” He discusses the identification, evaluation, and management of renal toxicities in patients receiving ICPis, focusing on nephritis/acute kidney injury in Part 8 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

I am joined by Dr. Umang Swami from the Huntsman Cancer Institute at the University of Utah in Salt Lake City, Utah, author on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update, and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T Cell Therapy: ASCO Guideline. And today, we're focusing on renal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Swami.

UMANG SWAMI: Thank you, Brittany. And I appreciate the invitation to be here today.

BRITTANY HARVEY: Great. Then first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Swami, do you have any relevant disclosures that are directly related to these guidelines?

UMANG SWAMI: No, I do not have any relevant disclosures that are directly related to these guidelines.

BRITTANY HARVEY: Thank you. Then let's dive into what we're here today to talk about. So what are these immune-related renal toxicities that are addressed in this guideline?

UMANG SWAMI: So this guideline focuses on nephritis, or acute kidney injury, as an adverse event due to immunotherapy. Acute kidney injury, or AKI, is an uncommon complication of immune checkpoint inhibitor therapy. Just to give a little context before we start, the incidence of any grade AKI is around 1% to 2% in patients treated with a single agent immune checkpoint inhibitor, such as ipilimumab, nivolumab, or pembrolizumab, and 4.5% in those treated with anti-CTLA-4 for and anti-PD-1 combination of nivolumab plus ipilimumab therapy. The incidence of grade 3 or grade 4 AKI is very low. I will say less than 1% with single agents, and around 1.6% with the combination of nivolumab plus ipilimumab.

While initial studies had quoted a small incidence of AKI with immune checkpoint inhibitor use, emerging data now suggests that a higher incidence might be present, which might range between 9.9% to around 29% of AKI with the immune checkpoint inhibitors. However, most of this extra toxicity is grade 1. The median time to onset of renal toxicity with these agents is around 14 weeks, but can range from 6.5 to 21 weeks.

BRITTANY HARVEY: Thank you for that background information. I think it's helpful for clinicians to understand how rare or common these adverse events are. So then, what are the key recommendations for identification, evaluation, and management of nephritis or acute kidney injury?

UMANG SWAMI: That's a great question. Presenting symptoms related to immune therapy-induced renal toxicities may include urinary frequency, dark, cloudy urine, fluid retention, or edema of face, abdomen, extremities. There might be sudden weight gain. There might be associated abdominal or pelvic pain. Patients might have nausea, vomiting, high blood pressure, or they may have a change in mental status such as drowsiness. However, we should remember that a vast majority of them will be asymptomatic at presentation. Therefore, patients should have their renal function, that is, serum creatinine, checked prior to administration of each dose of checkpoint inhibitor therapy.

For patients with new elevations in creatinine, one should consider holding checkpoint inhibitor therapy while other potential causes are evaluated. These other causes may include recent IV radiographic contrast administration, dehydration, urinary tract infection, other natural toxic medications, including concurrent chemotherapy, herbals, or other supplements. Patients without their obvious causes or who don't respond to alternative treatment measures should be presumed to have immune-related renal toxicity and treated empirically depending on the grade of AKI.

Safe treatment of autoimmune component is important. So with regards to the grading of AKI, grade 1 means a creatinine level increase of more than 0.3 milligrams per deciliter, or creatinine 1.5 to two times above baseline. And in this situation, physicians should consider temporarily holding checkpoint inhibitor therapy and evaluating other potential contributing agents in combination regimes, pending consideration of potential alternative pathologies. A change that is still less than 1.5 times of upper limit of normal could be meaningful and should be remembered.

For grade 2 AKI, which is creatinine two to three times above baseline, apart from holding immune checkpoint inhibitor and evaluating for alternative causes, nephrology should be consulted. If other etiologies are ruled out, administer 0.5 to 1 milligram per kg per day prednisone or its equivalent. If kidney function worsens or does not improve after one week, increase the dose of prednisone to 1 to 2 milligrams per kg per day or its equivalent, and permanently discontinue immune checkpoint inhibitor.

If the AKI improves to grade 1 or less, taper steroids over at least four weeks, otherwise we might see recurrence. If there is no recurrence, a physician might discuss resumption of immune checkpoint inhibitor with patient after taking into account what are the risks and what are the benefits. Resumption of immune checkpoint inhibitor can be considered once steroids have been successfully tapered to 10 milligrams per day or less, or discontinued. However, if elevation persists for more than seven days or worsens, and no cause is found, then the grade 2 AKI needs to be treated as grade 3.

Now grade 3 and grade 4 AKI are managed similarly. Grade 3 AKI is defined as creatinine more than three times the baseline, or more than 4 milligrams per deciliter, or when hospitalization is indicated. And grade 4 AKI defined as an AKI associated with life-threatening consequences, when dialysis is indicated, or creatinine six times above baseline.

Management includes nephrology consult, evaluation for alternative causes, and permanent discontinuation of immune checkpoint inhibitor. If they are directly implicated in renal toxicity, the administration of corticosteroids in grade 3 or grade 4 AKI is at an initial dose of 1 to 2 milligrams per kg per day of prednisone or its equivalent. If and when the AKI improves to grade 1, corticosteroids can be tapered over at least four weeks.

However, if elevation persists for more than three to five days for grade 3 or more than two to three days for grade 4 or worsens, we should consider additional immunosuppression, such as infliximab as a time frame, cyclophosphamide, cyclosporine, or mycophenolate. Usually, reflex renal biopsy is typically not necessary or recommended unless the AKI is refractory to steroids or other immunosuppressive agents.

BRITTANY HARVEY: I appreciate your reviewing those details for immune-related renal toxicity. So then, in your view, Dr. Swami, how will these recommendations for the management of renal toxicities impact both clinicians and patients?

UMANG SWAMI: This guideline presents a concise, up to date, and a stepwise approach to diagnose, grade, and treat this rare, but serious side effect of immunotherapy. In my view, this would be immensely helpful to clinicians in busy practices.

Prompt identification and treatment is also expected to help our patients experiencing immune related kidney injury. For patients, it will provide a readily available document to refer to for information regarding side effects of immune checkpoint inhibitor therapy. I applaud the efforts by the ASCO and the authorship team in developing the patient-focused version of this guideline. This may allow patients, especially when between clinic visits, to identify this unusual condition and seek medical help in a timely fashion.

BRITTANY HARVEY: Great. Thank you for highlighting the importance of this guideline, for all your work you did on this guideline, and for your time today, Dr. Swami.

UMANG SWAMI: Thanks so much, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can find many of our guidelines and interactive resources in the free ASCO guidelines app, available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Maria Suarez-Almazor from MD Anderson Cancer Center, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews identification, evaluation & management of musculoskeletal toxicities in patients receiving ICPis, including inflammatory arthritis, myositis & polymyalgia-like syndrome in Part 7 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at ASCO.org/podcasts.

My name is Brittany Harvey, and today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Maria Suarez-Almazor from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on musculoskeletal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Suarez-Almazor.

MARIA SUAREZ-ALMAZOR: Thank you.

BRITTANY HARVEY: First I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for the guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Suarez-Almazor, do you have any relevant disclosures that are directly related to these guidelines?

MARIA SUAREZ-ALMAZOR: Thank you, Brittany. I don't have any disclosures directly related to the guidelines.

BRITTANY HARVEY: Thanks very much. Then getting into the content of this, what are the immune-related musculoskeletal toxicities addressed in this guideline?

MARIA SUAREZ-ALMAZOR: There are three major musculoskeletal syndromes covered in this guideline-- inflammatory arthritis, myositis, and polymyalgia rheumatica.

BRITTANY HARVEY: Great. Then let's start with that first one that you mentioned. So what are the key recommendations for identification, evaluation, and management of inflammatory arthritis?

MARIA SUAREZ-ALMAZOR: The diagnosis of inflammatory arthritis is primarily based on a thorough joint exam to detect the presence of synovitis and how many joints and what joints are actually involved. For this reason, we recommend early referral to a rheumatologist. From a diagnostic perspective, we recommend testing for antinuclear antibodies or ANA, rheumatoid factor, and cyclic citrullinated peptide antibodies or anti-CCP. These are only positive in 10% to 20% of patients but may be indicative of a more persistent disease.

As inflammatory arthritis does not have any specific biochemical parameters for follow up, we use inflammatory markers such as sed rate and CRP in conjunction with the clinical exam as indicators of disease activity. For grades 1 and 2, we recommend treatment with nonsteroidal anti-inflammatory drugs or NSAIDs, or low-dose steroids up to 20 milligrams of oral prednisone or equivalent. If there is involvement of only one or two joints, local treatment with steroid injections can be indicated.

For grade 3 and higher, the dose of steroids can be increased up to 0.5 to 1 milligram per kilogram of body weight. And if there is no improvement within two weeks or if the steroids cannot be satisfactorily tapered, we recommend early initiation of a disease-modifying antirheumatic drug or a DMARD, such as methotrexate, hydroxychloroquine, or sulfasalazine. We need to understand though that these may take up to two or three months to be effective.

Alternatively, we can use biologic agents which have a faster onset of action. Recommended agents include tumor necrosis factor or interleukin 6 receptor inhibitors. In severe cases, immune checkpoint inhibitors may need to be permanently discontinued. But the overall goal is to try to continue therapy while we treat the adverse event.

BRITTANY HARVEY: Understood. Appreciate your reviewing that information for inflammatory arthritis. Following that, what are the key recommendations for identification, evaluation, and management of myositis?

MARIA SUAREZ-ALMAZOR: Well, myositis is really the most serious of the musculoskeletal toxicities. And it can be life threatening, especially when it's associated with myocarditis and with myasthenia gravis features. It usually presents with proximal weakness of the upper and lower extremities and sometimes with myalgia and even rhabdomyolysis.

It usually is very acute in its presentation. Specific testing includes muscle enzymes, creatine kinase and aldolase, and electromyography and muscle biopsy if the diagnosis is uncertain. MRI can be useful as it can show muscle inflammation. And it can also assist in identifying a location for a biopsy if needed.

Consultation with rheumatology and neurology should be requested early on. We also recommend that all patients undergo testing of cardiac enzymes such as troponin. And if elevated, a cardiology consultation should be placed right away and further testing performed. For grades 1 and 2, if patient has symptoms, treatment with corticosteroids are 0.5 to 1 milligram per kilogram should be initiated.

For patients with grade 3 or 4, checkpoint inhibitors should be discontinued and the patient should be hospitalized. Corticosteroids should be initiated at a dose of 1 milligram per kilogram of prednisone or equivalent. And patients with severe compromise may need intravenous corticosteroid doses at higher doses of 1 or 2 milligrams per kilogram or even higher. For severe disease or if there is myocarditis or concomitant myasthenia gravis, we can consider plasmapheresis.

IVIG can also be used, but it has a slower onset of action. And it is important to remember that plasmapheresis can remove immunoglobulins. So if it is to be used, the IVIG should be administered after the plasmapheresis is completed. There are other immunosuppressant therapies such as biologic agents that can also be considered. And sometimes for maintenance, oral immunosuppressants such as azathioprine, methotrexate, or mycophenolate mofetil can also be considered. Patients with severe disease may need to permanently discontinue the checkpoint therapy.

BRITTANY HARVEY: OK, those details are helpful for clinicians. So then, for the last category, addressed in this guideline that you mentioned, what are the key recommendations for identification, evaluation, and management of polymyalgia-like syndrome.

MARIA SUAREZ-ALMAZOR: Polymyalgia rheumatica syndromes present with marked pain and stiffness of the muscles in the shoulder and hip girdles. But some patients can also present with concomitant inflammatory arthritis. The workup is very similar to that of arthritis. In these patients, it is very important though to obtain a creatine kinase so that the muscle enzyme to be certain that the myalgia is not from myositis, as a treatment would be very different. Although very rare, polymyalgia, in some instances can be associated with giant cell arteritis which, if present, would require more aggressive treatment. For this reason, it is important to ask the patient about symptoms such as headache, visual disturbances, or jaw claudication.

The management of polymyalgia-like immune adverse events alone, without any associated vasculitis, is very similar to that of arthritis. So we would use NSAIDs and low-dose steroids for grade 1 and 2. Higher doses of steroids and disease modifying agents, including biologics, might be needed for grades 3 and 4. But overall, very similar management as that of inflammatory arthritis.

BRITTANY HARVEY: Great. Thanks for reviewing all of those recommendations for those three different categories. So then, in your view, Dr. Suarez-Almazor, how will these recommendations for the management of musculoskeletal toxicities impact both clinicians and patients?

MARIA SUAREZ-ALMAZOR: Thank you, Brittany. For the most common rheumatologic adverse events, such as arthralgia, inflammatory arthritis, or polymyalgia-like syndromes, because they are not life threatening, we may not be as worried. But we need to recognize that they can greatly impair quality of life. So we really hope that these recommendations can assist patients and clinicians in the early recognition of symptoms and also in initiating prompt treatment so our goal to be able to continue checkpoint inhibitor therapy can be achieved by controlling the symptoms that really impair quality of life.

Myositis is a much more serious adverse event that can lead to death. Patients may not be able to restart immune checkpoint inhibitor therapy again after they develop myositis. So we hope that these recommendations do highlight the need for very prompt diagnosis, consultation with specialists, and very aggressive treatment early on to control and manage these devastating, life-threatening adverse event.

BRITTANY HARVEY: Definitely. Early recognition, treatment, and improved quality of life are key. So I want to thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Suarez-Almazor.

MARIA SUAREZ-ALMAZOR: Thank you, Brittany.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Jennifer Mammen from Johns Hopkins University, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She discusses the identification, evaluation, and management of endocrine toxicities in patients receiving ICPis, including thyroid-related irAEs, primary AI, hypophysitis, and diabetes in Part 6 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, we're continuing our series on the management of immune-related adverse events.

I am joined by Dr. Jennifer Mammen from Johns Hopkins University in Baltimore, Maryland, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on endocrine toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Mammen.

JENNIFER MAMMEN: My pleasure, Brittany.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Mammen, do you have any relevant disclosures that are related to these guidelines?

JENNIFER MAMMEN: I do not.

BRITTANY HARVEY: OK. Thank you. Then, to start us off, what are the immune-related endocrine toxicities addressed in this guideline?

JENNIFER MAMMEN: Yeah. So irAEs affect the thyroid and the pituitary most commonly. But we also addressed the possibility of primary adrenal toxicity and also the emerging toxicity of insulin-dependent type 1 diabetes, which, while rare, can present with grade 4 toxicity in the form of diabetic ketoacidosis.

BRITTANY HARVEY: Understood. Then, starting with adverse events affecting the thyroid, what are the key recommendations for identification, evaluation, and management of thyrotoxicosis?

JENNIFER MAMMEN: So thyrotoxicosis after ICI exposure is almost entirely due to subacute thyroiditis. That's a transient inflammation of the thyroid gland that causes a few weeks of high levels of thyroid hormone, followed by at least several weeks of hypothyroidism as the stores of thyroid hormone are replenished. In the irAE context, many patients do not ever actually recover adequate thyroid function and will remain hypothyroid, requiring thyroid hormone long term. Because the thyrotoxicosis is transient and results from the release of preformed thyroid hormone, anti-thyroid drugs do not help and actually can even make the hypothyroidism phase worse. Therefore, the treatment is really supportive care with beta blockers in particular to control symptoms of the hypothyroidism, such as tachycardia, tremor, or anxiety.

BRITTANY HARVEY: In addition to those points for thyrotoxicosis, what are the key recommendations for primary hypothyroidism?

JENNIFER MAMMEN: Yeah. So primary hypothyroidism is very common both in the general population and now in this population as a result of thyroiditis. Many patients might actually already be on thyroid hormone when starting immunotherapy. When the pituitary is working, the pituitary hormone thyrotropin or TSH is a reliable indicator of the adequacy of thyroid hormone replacement. And the goal is to use a dose of thyroid hormone that maintains the TSH in the mid reference range, generally between 1 and 3 million international units per liter.

When a patient is first presenting or diagnosed with hypothyroidism, for example, in that second phase of thyroiditis, a weight-based dose can be used to estimate the needed replacement dose. For those with higher BMI, generally, an ideal body weight rather than an actual body weight gives a better estimate. And those specific recommendations are in the guidelines.

Proton pump inhibitors, calcium/iron supplementation, or GI inflammation can all decrease the absorption of thyroid hormone. And so even the thyroid hormone is really common, and many oncologists are used to managing it, it can be tricky in these patients if there's issues with malabsorption. And so, therefore, an endocrinology consultation can be helpful to titrate and ensure that the dosing is adequate. Once that adequate dose, that stable dose is found, if other factors don't change, dose requirements are generally quite stable and can be monitored annually either by a primary care physician or an oncologist.

BRITTANY HARVEY: Great. Those are important points. Then, addressing the immune-related adverse event that impacts the pituitary, what are the key recommendations for identification, evaluation, and management of hypophysitis?

JENNIFER MAMMEN: So hypophysitis is inflammation of the pituitary, as you said. And although there are five hormone systems at risk, it's actually most common that the thyroid and the adrenal gland axes are what are affected. The diagnosis is made by a combination of assessing the pituitary hormone and the primary hormone, in this case, the thyroid hormone and cortisol along with the TSH and ACTH, which is the pituitary hormone that regulates the adrenal gland. With primary gland failure, as we said, the pituitary hormones will be elevated. But in hypophysitis, the problem actually comes from the pituitary. And so TSH and ACTH will be low or inappropriately normal for the low primary thyroid hormone level.

There are several key points for oncologists who might need to initiate therapy before the patient can see endocrinology. First, thyroid hormone increases the metabolism of cortisol. And so if you've diagnosed central hypothyroidism due to hypophysitis, it's really important to replace cortisol, if needed, before replacing thyroid hormone, because in someone with both deficits, thyroid hormone alone can precipitate an adrenal crisis. Thus, the ASCO Guidelines really emphasize the need to assess both before starting thyroid hormone and also give the option to use steroids empirically, if needed, since the diagnosis can be sorted out later by an endocrinologist.

A second important point is that headaches, visual changes, and diabetes insipidus, which is loss of fluid and generally marked by hypernatremia, those are much more common with metastatic disease in the pituitary rather than hypophysitis. And so such symptoms should really prompt a pituitary MRI when they're found in the setting of hormonal losses. The management of central hypothyroidism is similar to that of primary hypothyroidism. But as I said, the TSH is no longer a reliable marker for adequate replacement. So the goal, then, shifts from a TSH in the reference range to a free T4 at the upper half of the reference range.

Adrenal insufficiency, as with thyroid hormone insufficiency, is managed by physiologic hormone replacement, and that's best done using hydrocortisone. This is a short-acting steroid that can be given in a way to imitate the natural diurnal rhythm. We use 2/3 of the dose in the morning and 1/3 in the early afternoon, allowing levels to fall as they naturally would overnight. Dose-titration is based on symptoms. And usually, 15 to 25 milligrams of a total daily dose is adequate to control symptoms from adrenal insufficiency. I do think all patients should see endocrinology at some point if they have been diagnosed with hypophysitis because they do need education on sick day rules, otherwise known as stress dosing, and also to be instructed on wearing an emergency alert bracelet or necklace or something.

Long-acting steroids can be used for patients who have adherence problems. And of course, those long-acting steroids are more appropriate for the treatment of any other irAE that a patient may develop. While on higher doses of prednisone, patients can discontinue hydrocortisone and then restart it when the prednisone dose is weaned down below 5 milligrams daily. If there's a question about whether the central adrenal insufficiency is from hypophysitis or due to suppression after weaning off high-dose exposure, use of hydrocortisone because of the diurnal rhythm actually allows the adrenal axis to recover normally. And so after weeks, you can test for adrenal recovery using a morning endogenous level 24 hours after the last dose is given, which is another advantage to using the hydrocortisone mode of hormone replacement.

BRITTANY HARVEY: Understood. And I appreciate you highlighting those key points for oncologists. Then, following that, what are the key recommendations for primary adrenal insufficiency?

JENNIFER MAMMEN: Yeah. So primary adrenal insufficiency, you'll see the ACTH elevated just like in primary thyroid disease, and the cortisol will be low. Again, this situation is actually much more common with metastatic disease, and therefore, imaging is called for if you find that pattern of hormonal changes. It's been case-reported to happen with irAEs, but in general, this is incredibly rare. The management of hydrocortisone replacement for people with primary adrenal insufficiency is really the same as for hypophysitis. We're using hydrocortisone with that diurnal physiologic replacement pattern. Primary adrenal insufficiency, however, also generally results in the loss of mineralocorticoid function. And so most patients also need at least a low dose of fludrocortisone replacement.

BRITTANY HARVEY: OK. And then the last adverse event addressed in the endocrine toxicity section of this guideline, what are the key recommendations for identification, evaluation, and management of diabetes?

JENNIFER MAMMEN: Yeah. So diabetes in this patient population is very tricky because so many of these patients are getting high-dose steroids as part of their chemotherapy regimens, and this can cause a lot of hyperglycemia. And I think it's actually easy to become complacent about seeing blood glucoses in the 200s. And in fact, most of the hyperglycemia will be just that, secondary to steroid exposure and worsening type 2 diabetes. It can be managed with a titration of routine medications. But they are now increasingly less rare but still rare events of acute loss of pancreatic function, presumably autoimmune, that can be accompanied by life-threatening diabetic ketoacidosis.

And the challenge for oncologists, I think, is to have a low enough threshold to investigate a suspicious pattern of hyperglycemia, for example, hyperglycemia with complaints of polyurea or, on physical exam, a more rapid respiratory rate that could indicate compensation for metabolic acidosis. So it's really a question of being a good clinician and taking the diabetes in context and not just assuming that it's due to steroid exposure. This is, I think, important because, like I said, diabetic ketoacidosis can be a grade 4 emergency, and patients can end up in the intensive care unit, needing a lot of intervention, which if we have a higher suspicion in clinic, we might be able to avert by getting rapid communication with endocrinology, starting people on insulin and that kind of an approach.

BRITTANY HARVEY: Definitely. A common theme with these toxicities seems to be early identification is key. So thank you for reviewing the high-level recommendations for each of these toxicities. In your view, how will these recommendations for the management of endocrine toxicities impact both clinicians and patients?

JENNIFER MAMMEN: Yeah. So I think making diagnoses in the hormonal systems can be complex and does require attention to the interactions, like we were talking about, between the pituitary and the primary gland. It's not something that oncologists necessarily have front of mind. And yet hormone replacement is actually quite straightforward. Once the need for it is recognized, since there's no side effects from replacing a hormone at an appropriate dose, it's just a replacement. And so, therefore, rapid diagnosis and initiation of hormone replacement can really allow patients to continue immunotherapy with a very minimal disruption, even in the face of an endocrine irAE.

Although at our institution the close coordination between treating oncologists and endocrinologists is available, that's certainly not true everywhere. And I think that the ASCO Guidelines are designed to try and help oncologists make these diagnoses and initiate therapy to stabilize patients and even allow them to continue treatment while awaiting any necessary consultations, even in the case of thyroiditis, perhaps, managing what's a self-limited event and then moving on, which reduces the burden on patients with other priorities to focus on.

BRITTANY HARVEY: Great. Those are very important points. So I really want to thank you for all of your work on these guidelines. And I appreciate you taking the time to speak with me today, Dr. Mammen.

JENNIFER MAMMEN: It's my pleasure.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Jarushka Naidoo from Johns Hopkins University, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She discusses the identification, evaluation, and management of lung toxicities in patients receiving ICPis, focusing on pneumonitis in Part 5 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network-- a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Jarushka Naidoo from Johns Hopkins University in Baltimore, Maryland, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And, today, we're focusing on lung toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Naidoo.

JARUSHKA NAIDOO: Thank you. It's my pleasure to share updates on this guideline.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with a publication of the guidelines in the Journal of Clinical Oncology. Dr. Naidoo, do you have any relevant disclosures that are directly related to these guidelines?

JARUSHKA NAIDOO: Yes. So I have research funding in the last two years from Merck, AstraZeneca, and Bristol Myers Squibb. And I also have served in a consulting role-- or an advisory board capacity-- for Merck, AstraZeneca, Bristol Myers. And not specifically related to this work, but also Pfizer, Takeda, Daiichi Sankyo, and Kaleido Biosciences.

BRITTANY HARVEY: OK. Thank you for those disclosures. Then-- getting into the content of this guideline-- what are the immune-related lung toxicities addressed in this guideline?

JARUSHKA NAIDOO: Thanks, Brittany. So the main lung toxicity that is addressed in this guideline is immune checkpoint inhibitor pneumonitis, which-- as this audience knows-- is an uncommon, but potentially fatal toxicity particularly associated with anti-PD-1 or PD-L1 monotherapy, but can also occur with combination immunotherapy approaches.

In the guideline, we go through what is known about the natural history, risk factors, and then, of course, our comprehensive approach to identifying, evaluating, and managing this toxicity, which is defined as a focal or diffuse inflammation of the lung parenchyma.

We also identify that, while pneumonitis is the quintessential lung toxicity that can occur with immune checkpoint inhibitors, we also note that there are some other lung toxicities that have been reported on, but for which known we relatively little.

And this includes sarcoid-like granulomatous reactions, including subpleural micronodular opacities and hilar lymphadenopathy, as well as pleural effusions. And these have been associated with both CTLA-4 and the PD-1, PD-L1 immune checkpoint inhibitor therapies.

BRITTANY HARVEY: I appreciate that overview. So then, you mentioned the main toxicity here is pneumonitis. What are the key recommendations for identification, evaluation, and management of pneumonitis?

JARUSHKA NAIDOO: Thanks, Brittany. So yeah, this is a key focus of the guideline. So, as we're aware, pneumonitis is defined as a focal or diffused inflammation of the lung parenchyma and is a toxicity that was identified as one of the early toxicities in the early clinical trials of the PD-1 inhibitors.

The incidence of this toxicity is estimated at anywhere between 0% and 10%, and in large meta analyses, looks to be around 2% to 3% in terms of incidence. In terms of how to evaluate patients with suspected immune-related pneumonitis, the common symptoms would be cough, shortness of breath, fever, and chest pain.

And in a patient who has suspected pneumonitis, some of the first tests to be done would be to take a pulse oximetry and to do some chest imaging. Chest imaging is preferable with a CT scan with contrast in order to rule out alternative etiology, such as pulmonary embolus

For patients who are symptomatic-- which means CTCAE grade 2 or greater-- we also recommend a standard infectious workup, which is guided by institutional guidelines. But based on our ASCO guideline, we outline that this should include, at a minimum, a nasal swab, sputum culture and sensitivity, blood culture and sensitivity, and urine culture and sensitivity, as well as a standard COVID-19 evaluation.

When we come to the diagnosis of pneumonitis, we then evaluate that in terms of CTCAE grade. Where the grade of pneumonitis refers, firstly, to whether a patient has symptoms, and the proportion of the lung parenchyma that may be involved with pneumonitis on chest imaging.

Broadly speaking, patients with grade 1 pneumonitis are asymptomatic and usually identified on radiographic imaging almost incidentally. For these patients, we would recommend either holding immunotherapy or proceeding with close monitoring.

And we recommend that patients should have weekly physical exams and pulse oximetry offered, and consideration of further chest imaging if the diagnosis is uncertain, or to follow progress-- usually around every three to four weeks-- or, if a patient becomes symptomatic, it may be more often than this.

We also recommend that we may consider doing spirometry or DLCO evaluation as a repeat in these patients. Broadly, again, in terms of the evaluation of patients-- if patients are symptomatic from pneumonitis, which means they have a symptom related to radiographic features, then this would be called grade 2.

And usually, radiographically, patients have more of the lung parenchyma involved-- greater than 25%-- and require a medical intervention. And the management would be prednisone, 1 to 2 milligrams per kilogram per day, that is then tapered over 4 to six weeks, and immunotherapy is held during that time.

Importantly, in order to knuckle down the diagnosis of pneumonitis, we recommend consideration of doing a bronchoscopy with bronchoalveolar lavage sampling in order to truly rule out alternative infectious diagnoses or lymphangitis carcinomatosis. And for this reason, a transbronchial biopsy can also be considered. In some cases, we also consider treating with empiric antibiotics to cover infection if we feel that this remains in the differential diagnosis.

If patients do not clinically improve after 48 to 72 hours on prednisone, then we recommend treating at a higher grade, meaning grade 3, where patients have severe symptoms, hospitalization is required, and a larger proportion of the lung parenchyma is involved.

For these patients who have grade 3 or greater pneumonitis, we recommend permanently discontinuing immunotherapy, administering a higher dose of steroids at methylprednisolone, 1 to 2 milligrams per kilogram per day. And, once again-- if there is no improvement after 48 hours, we recommend a range of potential additional immunosuppressive approaches, which include either infliximab, mycophenolate mofetil, intravenous immunoglobulin, or cyclophosphamide.

And there are currently no recommendations as to which may be the optimum immunosuppressive approach, but there are a number of clinical trials aiming to elucidate the answer to this. Importantly, overall in patients who are symptomatic, it may also be appropriate to consult pulmonary medicine and infectious diseases teams to weigh in on the diagnosis and management going forward.

BRITTANY HARVEY: Great. Thank you for that clear, step-wise approach to the evaluation and management of pneumonitis. So then, in your view, Dr. Naidoo-- how will these recommendations for the management of lung toxicities impact both clinicians and patients?

JARUSHKA NAIDOO: I think it's very important for both clinicians and patients to be aware of the potential side effects of the treatment that patients are receiving with immune checkpoint inhibitors. We know that some toxicities from immunotherapy tend to be mild and can be managed quite well with corticosteroids or other approaches.

What we understand about lung toxicities is that, thankfully-- in the majority of cases-- pneumonitis will be well-controlled with corticosteroids and holding of immunotherapy. However, in a proportion of patients, pneumonitis may become severe and may even lead to treatment-related deaths.

And for that reason, both patients and clinicians need to be aware of what to look out for in terms of the symptoms of pneumonitis, and how to diagnose and manage this toxicity quickly and efficiently in order to avoid poor outcomes.

BRITTANY HARVEY: Absolutely. Those are excellent points for both clinicians and patients to keep in mind. So I really want to thank you for all of your work on these guidelines and for taking the time to speak with me today, Dr. Naidoo.

JARUSHKA NAIDOO: You're very welcome, Brittany. And thank you to the ASCO oncology community for the opportunity to share this important work.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Yinghong Wang from MD Anderson Cancer Center, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She discusses the identification, evaluation, and management of gastrointestinal toxicities in patients receiving ICPis, including colitis and hepatitis in Part 4 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey. And today, we're continuing our series on the management of immune-related adverse events.

I am joined by Dr. Yinghong Wang from the University of Texas MD Anderson Cancer Center in Houston, Texas, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on gastrointestinal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Wang.

YINGHONG WANG: Thank you, Brittany. It's my great pleasure to be invited to participate in this education event. I'm happy to share my experience and the knowledge that I learned over all the research studies in this field and share with the readers or the community providers on this specific topic.

BRITTANY HARVEY: Great. Thank you. Then, first, before we get into the content, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Wang, do you have any relevant disclosures that are directly related to these guidelines?

YINGHONG WANG: I do have consulting services to two pharmaceuticals, but they're not related to the current guidelines that are published from the ASCO. They're Tillotts Pharma and Athenex Pharma.

BRITTANY HARVEY: OK. Thank you. Then, let's talk about these gastrointestinal toxicities. So first, what are the immune-related gastrointestinal toxicities addressed in this guideline?

YINGHONG WANG: So these particular guidelines have provided very detailed description on the incidence and clinical presentations and also recommendations on the evaluation and treatment for the upper and the lower gastrointestinal adverse events and the liver and even other organ toxicity, including the exocrine pancreas toxicities that are being categorized as GI field related to checkpoint inhibitor treatments.

BRITTANY HARVEY: OK. And then what are the key recommendations for the identification, evaluation, and management of colitis?

YINGHONG WANG: So colitis is definitely one of the most common organ to be involved in this category of toxicity-related checkpoint inhibitors. And that's why a lot more studies have been studied because the patient volume can allow enough power to run a lot of analysis. I think the summary that I would say-- the recommendations from the current ASCO Guidelines include the early recognition and evaluation with close monitoring for people who had suspicious symptoms for gastrointestinal adverse events and early stool inflammatory marker evaluation even in patients who had grade 1 symptoms. And very important to rule out alternative causes of the symptom presented, like infections or cancer metastases or some other medication-related side effects other than checkpoint inhibitors.

And the other important component of evaluation is endoscopy and the pathological evaluation for patients who had a positive stool inflammatory markers or if the patient has a presentation of colitis symptoms like bleeding. And also, the presence of ulcers on the endoscopy usually has been found to predict a steroid refractory disease course. Therefore, the early initiation of more potent treatment like biologic agents, such as infliximab or vedolizumab, is very critical. The other alternative medical treatment, like ustekinumab or tofacitinib or even fecal transplantation for refractory cases, should also be considered in the small portion of patients.

The disease monitoring while on the medical treatment is critical via the repeat endoscopy or following the fecal calprotectin level to guide the duration of treatment and the time to resume immune checkpoint inhibitor treatments if indicated. The rechallenge of these checkpoint inhibitors is possible among patients with GI toxicities, and the risk of GI toxicities is completely manageable. That's the brief summary of the GI recommendations.

BRITTANY HARVEY: Yeah. Thank you for that summary. And then just in addition to those key recommendations, is there anything additional about the identification, evaluation, and management of hepatitis?

YINGHONG WANG: Yeah. The hepatitis-- the incidence is not as common as colitis but can be severe in extreme cases. So it requires the equal attention to recognize and evaluate for liver toxicity after checkpoint inhibitors with close monitoring. We also need to rule out other alternative causes of the symptoms, including the infections, alcohols, iron overload, thromboembolic events, cancer metastases, et cetera. The imaging, on the other hand, is more critical for liver toxicity evaluation. This is a little bit different from using the endoscopy and biopsy for luminal GI tract toxicities. And the liver biopsy should also be considered in certain select cases through all other differential diagnosis and also the other alternative treatment other than corticosteroid, including azathioprine and mycophenolate mofetil, that are mentioned in the small case series and also listed in the current ASCO Guidelines.

BRITTANY HARVEY: Great. Thank you for that overview for both colitis and hepatitis. So then, in your view, how will these recommendations for the management of gastrointestinal toxicities impact both clinicians and patients?

YINGHONG WANG: Yeah. Given the increasing volume of patients experiencing the GI adverse events related to the checkpoint inhibitor cancer therapies and their related morbidities, so both the clinicians and patients need to be familiar with the clinical presentations and the time frame of onset to ensure early recognition and early diagnosis, especially serious complication and even mortality can occur due to the significant delay in appropriate treatment in extreme cases. So the updated guideline provided by ASCO and also other professional societies in the US or internationally can provide a great resources to the academic and community clinicians when they encounter these cases in their practice.

So ultimately, the implementation of appropriate management and future prospective clinical trials in this field for these challenging conditions should improve the patient's outcome of toxicities and also cancer. And that's the goal of our clinicians and academia providers, to be able to serve the patient better in the future.

BRITTANY HARVEY: Definitely. Well, thank you for sharing this summary with us today, for all of your work on these guidelines, and for taking the time to speak with me today, Dr. Wang.

YINGHONG WANG: Thank you very much for this opportunity. Please let me know if you have any questions.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Milan Anadkat from Washington University & Dr. Aung Naing from MD Anderson Cancer Center, authors on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” They discuss recommendations for cutaneous toxicities in patients receiving ICPis, including rash, bullous dermatoses & SCAR in Part 3 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey. And today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Milan Anadkat from Washington University in St. Louis, Missouri. And Dr. Aung Naing from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, authors on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.

And today, we're focusing on cutaneous toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here Dr. Anadkat and Dr. Naing.

AUNG NAING: Thank you for having us.

MILAN ANADKAT: Thank you.

BRITTANY HARVEY: I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Anadkat, do you have any relevant disclosures that are directly related to these guidelines?

MILAN ANADKAT: As listed in the document, I don't have any direct disclosures. I do have a number of indirect disclosures, as I've consulted on similar topics in the past.

BRITTANY HARVEY: Thank you. Then Dr. Naing, do you have any relevant disclosures that are related to these guidelines?

AUNG NAING: I do not have.

BRITTANY HARVEY: Great, then let's get into the content of this guideline and the cutaneous toxicities that we're here today to talk about. So Dr. Naing, what are the immune-related cutaneous toxicities addressed in this guideline?

AUNG NAING: Well, with the advancement of immunotherapy, we've seen better response in our cancer patients. However, together with such positive outcomes, we are also seeing side effects caused by the immunotherapy. Disruption of the homeostatic mechanisms include a unique spectrum of side effects or immune related adverse events, commonly called IRAEs. The most common immune related adverse events in patients receiving checkpoint inhibitors are dermatitis, enterocolitis, transmitis, and endocrinopathies.

However, if you look at the most commonly reported IRAE of any grade, it is dermatologic toxicity. So here in this guideline, we addressed how to take care of the patients when they are having these side effects, particularly with the cutaneous toxicities. So when you look at that time to median onset of skin toxicities, it ranges from two to five weeks. And using CTCAE criteria for grading is a challenge for skin toxicity, as it may not reflect the true picture.

So, therefore, severity may be graded based on body surface area, tolerability, mobility, and durations. Those are the points also we discuss in this guideline. Broadly speaking, they are three groups of cutaneous IRAEs. They are rash inflammatory dermatitis, bullous dermatoses, and finally, Severe Cutaneous Adverse Reactions, SCAR. It is important to have thorough physical exam and rule out any other etiology of skin problems.

In general, it's also important to work closely with our colleagues from dermatology. While some of those low grade skin toxicities could be treated in outpatient setting, consulting the cases with dermatologists is important for higher grades of skin toxicities, such as bullous dermatoses and SCAR. My colleague, Dr. Milan Anadkat, will follow with a discussion on the role of dermatologists in taking care of patients with cutaneous toxicities caused by immunotherapy.

BRITTANY HARVEY: Thank you, Dr. Naing for reviewing those. So then you just mentioned three categories of toxicity. And I'd like to review the key recommendations for each. So Dr. Anadkat, starting with what is recommended for the identification, evaluation, and management of rash or inflammatory dermatitis?

MILAN ANADKAT: Thank you, Brittany. And thank you Dr. Naing for teeing up this discussion. I think, as was mentioned, there are three major categories of cutaneous toxicity that are seen from immunotherapy. By and large, the most common is rash or inflammatory dermatitis, from which there are multiple different phenotypes or looks by which physicians may be seeing.

The most common phenotypes within rash or inflammatory dermatitis, which account for over 90% of the cutaneous toxicity seen from immunotherapy, include lichenoid, which is a purple, flat topped bumpy rash that can involve the skin or the mucosal membranes. The psoriasiform, which resembles psoriasis, morbilliform, or oftentimes, maculopapular, which resembles a measles-like pink exanthem over the trunk, or generalized eczema and itching. So what's important is identifying the particular phenotype and categorizing it as an inflammatory dermatosis and excluding the other two phenotypes of cutaneous toxicity, such as bullous dermatoses or Severe Cutaneous Adverse Reactions.

BRITTANY HARVEY: Great, and then moving into that second category that you both mentioned, what are the key recommendations for bullous dermatoses?

MILAN ANADKAT: And so the key phenotypes for bullous dermatoses, by and large, is bullous pemphagoid, which is the most common phenotype seen in this category. Although other phenotypes resembling autoimmune bullous diseases, such as pemphigus or bullous drug reactions may also be seen. With bullous pemphigoid we see tense blisters, or tense bullae, frequently overlying a bed of erythema on the skin. Patients typically complain of considerable itching, far more than pain, with this category of eruption.

BRITTANY HARVEY: Got it. Thank you for reviewing that for bullous dermatoses. So then the third group is Severe Cutaneous Adverse Reactions. So what are the key recommendations there?

MILAN ANADKAT: And so the third group, being Severe Cutaneous Adverse Reactions, is a term used worldwide to encompass conditions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and DRESS or drug reaction with eosinophilia and systemic symptoms. These are, fortunately, rare, but can be life threatening skin eruptions.

They account for less than 1% of all skin reactions seen from immunotherapy. When practitioners are approaching a patient who may potentially have one of these conditions, patients typically will exhibit symptoms of malaise, fatigue, fever, and a dramatic cutaneous eruption, which will either present with peeling or sloughing of the top layers of the skin, or a generalized erythema covered with multiple sterile pinpoint pustules. Oftentimes, there are associated symptoms of lymphadenopathy and organ toxicity that is noticed simultaneously, such as hepatotoxicity, or eosinophilia, or acute renal failure.

BRITTANY HARVEY: Great, I appreciate you reviewing the identification of all three of those groups. So then I'd like to hear from you both on this last question. But in your view, how will these recommendations for the management of cutaneous toxicities impact both clinicians and patients?

AUNG NAING: I would say that recognition of the toxicity is really important, particularly if you can actually catch the toxicity when it is in the mild grade. If you take care of them, then you can actually stop them from being mild to severe toxicity. That's number one. Number 2 is in that way, we may not have to halt or stop the immunotherapy treatment that could be beneficial to the patients.

And also, working together with the dermatologists is very important, because as I discussed earlier, some of them, we could take care of as an outpatient. But there will be certain dermatology toxicities, where we need to work closely with our dermatologists. And please also remember that these are the guidelines. You will be seeing the patient in the setting. So I think using that guideline and clinical judgment, that would actually help our patients at large.

MILAN ANADKAT: I think that's excellent. One, I think, important aspect of these guidelines is not only to correctly identify the phenotypes of cutaneous toxicity, but as Dr. Naing mentioned, it assists in management of these toxicities. The goal of these guidelines, especially as it pertains to the skin toxicity, is to accurately identify what toxicity is occurring for the patient, but then more importantly, to guide on appropriate management strategies to allow the patient to continue on immunotherapy and minimize or avoid unnecessary treatment interruption or treatment discontinuation.

The guidelines assist in management strategies according to the severity by which patients present. And as mentioned, I think ultimate priority will be given to the practitioner directly treating the patient. But consideration towards not only extent of body surface area involved, but severity of cutaneous eruption is thoroughly reviewed. And in addition to phenotype, including such patient reported outcomes, such as degree of pain, itch, or interruption on activities of daily living help guide the degree of management that can be provided.

BRITTANY HARVEY: Those are excellent points. I want to thank you so much for your work on these guidelines and for taking the time to speak with me today, Dr. Naing and Dr. Anadkat.

AUNG NAING: Thank you.

MILAN ANADKAT: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe, so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Bryan Schneider from the University of Michigan Health System and Dr. Kathryn Bollin from Scripps MD Anderson Cancer Center, co-chairs of the Management of Immune-Related Adverse Events Guideline Expert Panel. They discuss an overview of the “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update” in Part 1 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and I want to introduce you to our series on the Management of Immune-Related Adverse Events. ASCO has developed two guidelines for the management of immune-related adverse events, one for patients treated with immune checkpoint inhibitor therapy and a second for patients treated with CAR T-cell therapy.

Today, we'll be focusing on an overview of the Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. And we'll have authors join us for future episodes to discuss the key recommendations for organ-specific management for patients treated with immune checkpoint inhibitor therapy and an episode to discuss the management of immune-related adverse effects in patients treated with CAR T-cell therapy.

Today, I am joined by Dr. Bryan Schneider from the University of Michigan Health System in Ann Arbor, Michigan, and Dr. Kathryn Bollin from Scripps MD Anderson Cancer Center in San Diego, California, co-chairs on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy, ASCO Guideline Update and authors of the Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy, ASCO Guideline. Thank you for being here, Dr. Schneider and Dr. Bollin.

BRYAN SCHNEIDER: Thank you, Brittany.

KATHRYN BOLLIN: Thank you for having us.

BRITTANY HARVEY: I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Schneider, do you have any relevant disclosures that are related to this guideline?

BRYAN SCHNEIDER: I have research funding to my institution from Bristol Myers Squibb and Genentech Roche at the time of panel formation.

BRITTANY HARVEY: Thank you. And, Dr. Bollin, do you have any relevant disclosures that are directly related to this guideline?

KATHRYN BOLLIN: No disclosures.

BRITTANY HARVEY: Thank you. Then, let's talk about this guideline. So first, Dr. Schneider, what prompted this update to the Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy Guideline last published in 2018?

BRYAN SCHNEIDER: Yeah. The previous guideline was widely used and consistently one of the top read articles of the JCO over the last couple of years. And since the original guideline publication in 2018, new data have emerged on the management of immune checkpoint inhibitor toxicities. So our goal was to build on the original guideline with more treatment options, especially for patients who fail initial steroid treatment. New strategies have developed for the management of many toxicities, especially GI, cardiac, and heme toxicities. And ASCO and the panel felt it was important to present these new options to the providers in the community.

We also wanted to add sections that the providers would find valuable, including a table with many of the immunosuppressive agents used with typical dosages and schedules. We also added a table of commonly conducted testing while patients are on high-dose steroids as this is something many medical oncologists may not be used to handling as we typically do not have patients on steroids at high doses for several weeks or even months.

BRITTANY HARVEY: Understood. Then, in addition to those updates that Dr. Schneider just mentioned, Dr. Bollin, what is the general scope and purpose of this guideline?

KATHRYN BOLLIN: Yes. So the immune-related adverse event management guideline update and the CAR T-cell toxicity guideline serve to provide physicians that are prescribing these therapies with an understanding of the wide range of known potential toxicities of these agents and the best available evidence-based and expert opinion recommendations for their management. So up to 70% of patients treated with immune checkpoints will experience some form of immune-related adverse event, and nearly all patients getting CAR T-cell therapies experience toxicity. So recognition of the occurrence of these toxicities and appropriate management are essential for optimizing patient outcomes.

BRITTANY HARVEY: Definitely, those are key points. So then, Dr. Schneider, what are the overarching recommendations for the management of immune-related adverse events irrespective of the affected organ?

BRYAN SCHNEIDER: I think early recognition of the side effect is critical. So the guideline has typical signs and symptoms of each toxicity to help clinicians decide if this is occurring in their patients. Second, I think it's critical to grade the toxicity. We often don't do that with side effects related to traditional chemotherapy outside of clinical trials. So for example, if a patient has a platelet count of 75, I can't think off the top of my head what grade that is. I just know I'm going to hold chemotherapy for a week or two. But grading of the toxicity of these immune checkpoint therapies really is very important to decide whether patients can just be watched, whether they need to start steroids or whether they need to be admitted.

I think still corticosteroids and dose holds are the first steps that clinicians will do. The majority of these toxicities-- although it would be nice if we could personalize the treatment based on the particular side effect and what we see under the microscope if the particular affected organ is biopsied, I think, in broad strokes, corticosteroids can be implemented easily, and a lot of our oncologists can be comfortable doing this potentially without subspecialty help.

Having said that, I think multidisciplinary care is a must for the higher-grade side effects as, in oncology, we can't pretend to also be cardiologists, gastroenterologists, neurologists, dermatologist, and so on. And although there may be varying degrees of comfort from our subspecialists regarding the management of these toxicities, we do need their help for shared decision making, especially for the steroid refractory toxicities. We always want to emphasize a slow steroid taper oftentimes over at least four to six weeks. We get into trouble when we try to get them off the steroid quickly because they do have side effects that the patient may not enjoy. But oftentimes, we try to taper them quickly, and the side effect comes roaring back.

And then, finally, to escalate immunosuppression quickly if no improvement with high-dose steroids is observed, oftentimes, that's done even within just a few days. But commonly, in practice, there's still hope that the steroid will kick in two or three weeks down the road, and that's not a good strategy. If the patient's having significant symptoms and steroids aren't helping, they do need to go on to a more important immunosuppressant.

BRITTANY HARVEY: Those are important notes on the overarching management, particularly on how the adverse effects are different than those in patients treated with chemotherapy and the importance of multidisciplinary care. So then, Dr. Bollin, in your view, how will this guideline impact clinical practice?

KATHRYN BOLLIN: So the impact of this guideline update is actually very broad. As with the previous guideline, as Dr. Schneider alluded to earlier, it's been very frequently accessed by readers since it offers symptom outlines and algorithmic recommendations for early identification and the management of immune-related adverse events based on the severity and organ system involved. What's really important to understand is that while initially, as hematology-oncology physicians prescribing these agents, we're doing so in the setting of early phase clinical trials. We were learning about the toxicities, and those physicians were often managing the toxicities themselves. But now, with the exponential increase and the therapeutic indications for immune checkpoint therapies in cancer, the experience with the toxicities and their management and the questions have also followed suit with an exponential rise.

With this guideline update, we have experts among all of the internal medicine subspecialties that are now guiding the hematology-oncology physicians in immune-related adverse event management. We enlisted the experts in crafting this guideline update. So in summary, this serves not only as a tool for the prescribing hematology-oncology physicians but also for all of the subspecialists in the community and within academic centers for optimizing patient outcomes in the setting of immune-related adverse events.

BRITTANY HARVEY: Great. Yeah, it sounds like this update will be hugely important for practicing clinicians. So then, in addition to those points raised by Dr. Bollin, Dr. Schneider, what are the implications for patients receiving immune checkpoint inhibitor therapy?

BRYAN SCHNEIDER: So we really hope this will be an essential tool to help providers quickly treat patients when these toxicities present. Often, this is unexpected, and busy clinicians may be blindsided by these issues. So these guidelines will provide a quick resource to guide the workup and formulate a treatment plan that will expedite patient recovery. And ultimately, this should help promote quality of life for patients on these therapies and may help reduce trips to the emergency department, hospitalizations, and potentially allow the safe rechallenge of immune checkpoint therapy after resolution of the side effect.

Many centers have the advantage of subspecialty support with experience in managing these toxicities. But for providers who may not have immediate access to, say, hepatology or endocrinology, we hope these guidelines will help the oncology providers provide the best treatment to facilitate the optimal clinical outcome.

BRITTANY HARVEY: Absolutely, those are key for optimal care. Then, finally, Dr. Bollin, looking toward the future, what are the important outstanding questions and developing areas of research for the management of immune-related adverse events?

KATHRYN BOLLIN: So while our recognition of immune-related adverse events, the testing for them, and management strategies have greatly improved with the expanded use of and experience with these therapies, large gaps in our knowledge remain. Translational and basic science research efforts are underway to understand these gaps, such as with the intrinsic and extrinsic drivers of autoimmunity, such as those with HLA allelic variations and the microbiomes interplay with our immune systems.

There are also research efforts underway to develop rapid diagnostic tests to deploy early in the onset of irAE signs and symptoms and for the development of biomarkers and modeling tools that will aid us in predicting which patients are likely to experience immune-related adverse events. There have also been some interventional protocols that have attempted to prevent these immune-related adverse events by incorporating immune suppressants along with therapeutic agents. But so far, promising results with this strategy remain elusive.

In regard to treatment for immune-related adverse events, investigators are working to learn the best strategies for selective immune suppression rather than just the use of glucocorticoids that will control immune-related adverse events while maintaining the clinical benefit of these incredible anticancer therapies.

BRITTANY HARVEY: Thank you for highlighting those research gaps and both of you for your efforts to lead this guideline update. We'll be joined by authors on the guideline over the next episodes to review the key recommendations for organ-specific management in patients treated with immune checkpoint inhibitors and to review the recommendations for patients receiving CAR T-cell therapy. Stay tuned for these episodes highlighting the sections of the guidelines. And thank you for your time today, Dr. Schneider and Dr. Bollin.

KATHRYN BOLLIN: Thank you so much.

BRYAN SCHNEIDER: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center and Dr. Monalisa Ghosh from the University of Michigan Health System, authors on “Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.” They discuss recommendations for management of irAEs in patients treated with CAR T-Cell Therapy in Part 2 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network. A collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today we're continuing our series on the management of immune-related adverse events. ASCO has developed two guidelines for the management of immune-related adverse events-- one for patients treated with immune checkpoint inhibitor therapy and a second for patients treated with CAR T-cell therapy.

In our last episode, you heard an overview of the Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Today, we'll be focusing on the Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline, and we'll have authors join us for future episodes to discuss the key recommendations for organ-specific management for patients treated with immune checkpoint inhibitor therapy.

Today, I am joined by Dr. Monalisa Ghosh, from the University of Michigan Health System in Ann Arbor, Michigan and Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center in New York, New York, authors on both Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline and Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.

Thank you both for being here, Dr. Ghosh and Dr. Santomasso. In addition, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline.

The full Conflict of Interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Ghosh, do you have any relevant disclosures that are directly related to this guideline?

MONALISA GHOSH: No. I do not have any relevant disclosures.

BRITTANY HARVEY: Thank you. And, Dr. Santomasso, do you have any relevant disclosures that are directly related to this guideline?

BIANCA SANTOMASSO: Yes. I'd like to disclose that I've served as a paid consultant for Celgene, Janssen Pharmaceutical, and Legend Biotech for advising them on the topics of CAR T-cell therapy side effects.

BRITTANY HARVEY: Thank you. Then, getting into these immune-related adverse events-- first, Dr. Ghosh, can you give us an overview of the scope and purpose of this guideline?

MONALISA GHOSH: Sure. The purpose of this guideline is to offer expert guidance and recommendations on the management of immune-related adverse events in patients treated with chimeric antigen receptor or CAR T-cell therapy.

This guideline offers guidance on the diagnosis, evaluation, and management of the most common toxicities of CAR T-cell therapy, which includes Cytokine Release Syndrome-- or CRS-- and immune effector associated neurologic syndrome-- or ICANS.

As well as other potential, but less common toxicities, such as Hemophagocytic Lymphohistiocytosis-- or HLH-- B-cell aplasia, prolonged and recurrent cytopenias, Disseminated Intravascular Coagulation-- or DIC-- and infections.

BRITTANY HARVEY: Great. Thank you. Then, Dr. Santomasso-- looking at this guideline, there's a few overarching recommendations. So, what are those general recommendations for the management of immune-related adverse events in patients receiving CAR T-cell therapy?

BIANCA SANTOMASSO: Yes. The overarching recommendations are, really, first to recognize that these side effects exist. And that, as such, it's important to recognize that patients who develop these toxicities or side effects after CAR T-cell therapy need to be evaluated, or managed in, or transferred to a specialty center that has experience with the management of these toxicities.

They're new toxicities. This is a new therapy. And patients are increasingly going to be managed in, or treated in, the outpatient setting, and, as such, they need to remain within a short distance of the treating center for about four to eight weeks post-therapy, and they should then return to their treating center upon experiencing any toxicities.

Finally, as its flu season and infection season, it is recommended that inactivated influenza and COVID-19 vaccination be performed on patients and also family members as well. And any patient who does have an active infection, the CAR T-cell infusion should be delayed until that infection has been successfully treated or controlled.

I often make a final point, which is that the immunogenicity of and efficacy of COVID-19 vaccines is uncertain in these patients with these agents, but the potential benefits outweigh the risks and uncertainties for most patients.

BRITTANY HARVEY: Thank you. Those are important points for patients and treating clinicians. So then, Dr. Ghosh-- as you mentioned, this guideline addresses the seven most common CAR-T-related toxicities, and I'd like to review the key recommendations for each of those.

So let's start with, what are the key recommendations for identification, evaluation, and management of cytokine-release syndrome?

MONALISA GHOSH: Well, Cytokine Release Syndrome is one of the two major toxicities that occur immediately or within a short time period after infusion of CAR T-cells. We have defined Cytokine Release Syndrome, or CRS, as an immune-mediated phenomenon that's characterized by various symptoms that are indicative of immune activation and inflammation.

And patients may experience signs and symptoms that could include fever, hypotension, hypoxia, tachycardia, shortness of breath, rash, nausea, headache, and various other symptoms that are a little less common. These symptoms are caused primarily by the release of cytokines.

Cytokines are the messengers of the immune system, and most of them are released by bystander immune and non-immune cells. We know that the onset of Cytokine Release Syndrome is variable depending on the CAR T-cell product that's used, as well as the patient population that's treated.

But it generally occurs anywhere from two to seven days after infusion of CAR T-cells, and in some rare cases can occur even a little bit later. A standard grading system has been developed and grade CRS, or Cytokine Release Syndrome, based on three parameters-- fever, hypotension, or low blood pressure; and hypoxia or low oxygen levels.

CRS is primarily managed with IL-6 antagonists because IL-6 is an inflammatory cytokine that has been shown to mediate a lot of the systemic effects that we see from Cytokine Release Syndrome. And one of the treatments is the monoclonal antibody tocilizumab, which acts against-- or blocks-- the IL-6 receptor.

CRS that is refractory to tocilizumab is generally treated with steroids. Then there's limited experience with additional therapies, especially in the setting of CRS, that does not respond to tocilizumab or steroids. There are other anti IL-6 therapies available. For example, siltuximab, which binds to IL-6 itself rather than the IL-6 receptor. However, there have been no direct comparative studies of these agents. Anakinra, which is also an IL-1 receptor antagonist has also been shown to mitigate CRS in some CAR T-cell recipients that have high grade CRS.

BRITTANY HARVEY: OK. Thank you for reviewing those management strategies. So, following that-- Dr. Santomasso, what are key recommendations for identification, evaluation, and management of immune effector cell-associated neurotoxicity syndrome?

BIANCA SANTOMASSO: Sure. Immune Effector Cell-associated Neurotoxicity Syndrome-- also known as ICANS-- is the second most frequent severe toxicity that can be seen after CAR T-cell therapy. So, what is ICANS? These are transient neurological symptoms that occur in the days after infusion, most commonly with CD19 CAR T-cell therapy.

And the clinical manifestations of ICANS include encephalopathy, which is confusion, behavioral changes, expressive aphasia, or other language disturbance, change in handwriting or other fine motor impairment or weakness, and tremor and headache can also be seen.

In more severe cases, patients can become obtunded with a depressed level of consciousness or even develop seizures, and they may require a higher level of ICU care, such as intubation for airway protection. And in very rare cases, malignant cerebral edema may develop, which may be fatal.

ICANS can occur at the same time as Cytokine Release Syndrome, or can also occur several days after or shortly after CRS resolves, so it's important to have a high index of suspicion even after Cytokine Release Syndrome has resolved, but typically the side effects are self-limited and occur within the one month after infusion.

Most symptoms lasts between 5 and 17 days, and the time of onset duration and severity of ICANS may really vary depending on the CAR T-cell product used or the disease state of the patient. So, what do I mean by that? Patients with high disease burden seem to be at increased risk for severe ICANS, so kind of knowing the disease that the patient has and the burden of disease is important.

And then also there may be product-specific differences as well, so reviewing the product label is important as well because each may have its own risk evaluation and mitigation strategies that inform both the duration and the frequency of monitoring for ICANS after infusion.

For evaluation of ICANS, we recommend, again, the ASTCT ICANS grading system. These allow for monitoring of several different aspects of neurologic function in these patients. Mental status changes are really what define the onset of ICANS.

So for CRS, it's fever; for ICANS, it's mental status changes. And the severity of the mental status change can be determined by a standardized score known as the ICE score, which stands for Immune Effector Cell-associated Encephalopathy score.

This is a simple 10-point scoring metric where points are assigned for orientation to year, month, city, hospital, ability to name three objects, ability to follow simple commands, write a standard sentence, and count backwards from 100 by tens.

And for children younger than age 12 or those with developmental delay, The Cornell Assessment of Pediatric Delirium, also known as the CAPD, can be used in placement of the ICE assessment. Prior to CAR infusion, patients should be evaluated, including with an ICE score, for their baseline neurologic status.

And what's nice is that this ICE assessment can be used as a daily screen after CAR infusion for the onset of ICANS during at-risk period. Then, other than the ICE score, there are four other neurologic domains that contribute to ICANS grading, and that's level of consciousness, seizures, severe motor weakness, and signs and symptoms of elevated intracranial pressure or cerebral edema, and patients are graded according to the most severe symptom in any of the five domains.

So for patients who develop ICANS, it's recommended that they have workup, including blood work, CRP, CBC, comprehensive metabolic panel, fibrinogen, and coagulation tests. Neuroimaging with a non-contrast CT of the brain should be done and considering MRI of the brain in patients who are stable enough.

In addition, electroencephalogram and lumbar puncture should be considered. And the electroencephalogram is really to rule out subclinical seizures, and the lumbar puncture is to assess the opening pressure-- or the pressure within the central nervous system-- and also to send studies to rule out infection. And again, these all have to be considered on an individual case by case basis, but are things to keep in mind.

So for treatment of ICANS, the mainstay of treatment is, really, supportive care and corticosteroids. Tocilizumab, while it seems to rapidly resolve Cytokine Release Syndrome and most symptoms, actually does not resolve ICANS and may worsen it, so steroids are really typically used.

The typical steroid is dexamethasone at a dose of 10 milligrams, and the interval really depends on the grade of the ICANS. Because of the possibility that tocilizumab may worsen neurotoxicity, ICANS really takes precedence over low grade CRS when the two occur simultaneously.

And patients who don't show improvement within 24 hours after starting steroids or other supportive measures should have CSF evaluation and neuroimaging. Often treatment of seizures-- many patients are put on Keppra and levetiracetam or other anti-seizure medicine if they develop ICANS, and patients with grade 3 or greater ICANS may need an ICU level of care and escalation of steroid doses.

The steroids are continued until ICANS improves to grade 1 and then tapered as clinically appropriate. And the most important thing to remember is that ICANS just needs to be monitored very closely as patients may worsen as some steroids are tapered. They also may improve rapidly after steroids are started, so steroids should be tapered quickly as patients improve.

And, again, as with CRS, there's limited experience with other agents, such as Anakinra and siltuximab, but those could be considered in severe or refractory cases.

BRITTANY HARVEY: Understood. I appreciate you going through when and how clinicians should screen for ICANS and those key management points. So, in addition to that-- Dr. Ghosh, what are the key recommendations regarding cytopenias?

MONALISA GHOSH: So cytopenias can occur post-CAR T-cell infusion, and they can occur either in the early phase or in the later phase after CAR T-cell infusion. Meaning that they can occur early within the first few days to weeks post-CAR T-cell therapy or could even occur months to years later.

These cytopenias include anemia, thrombocytopenia, leukopenia, neutropenia. Many patients may present with fatigue, weakness, shortness of breath, lightheadedness, frequent infections, fevers, bruising, and bleeding, and the symptoms usually are consistent with how they would present otherwise with anemia, thrombocytopenia, or neutropenia.

Acute cytopenias within three months of CAR T-cell therapy are more common. This is due to usually the lymphodepleting chemotherapy that is administered prior to CAR T-cell therapy. Most patients receive a combination of fludarabine and cyclophosphamide prior to CAR T-cell infusion, or they may receive another agent, such as bendamustine. Most patients also come into CAR T-cell therapy with low lymphocyte counts from previous therapies.

Early cytopenias, as I mentioned, are generally due to lymphodepleting chemotherapy or other recent therapies. There also could be an immune-mediated process due to the CAR T-cells. Usually prolonged cytopenias which occur beyond three months post-CAR T-cell infusion can be seen in a small number of patients.

And the mechanism of prolonged cytopenias is really unclear at this time, but likely multifactorial. Most recipients of CAR T-cells who have prolonged cytopenias beyond three months post-CAR T-cell infusion should have a standard workup to rule out other common causes, such as vitamin or nutritional deficiencies.

They should also have testing such as bone marrow biopsy and scans to rule out relapse disease-- relapse lymphoma or leukemia, for instance, that could be causing these cytopenias. Other examples would be myelodysplastic syndrome or other bone marrow failure syndromes. So cytopenias are generally managed with supportive care including growth factor and transfusion support. This applies to both cytopenias in the early period post-CAR T-cell therapy or more delayed prolonged cytopenias.

In patients who have prolonged cytopenias of unclear cause that could be immune-mediated, other interventions such as high dose IVIG or even steroids could be considered depending on the situation. For those that have cytopenias in the first few months post-CAR T-cell therapy, generally they are monitored and treated with supportive care, and these cytopenias eventually resolve in the majority of patients.

BRITTANY HARVEY: Great. Those are important considerations. Then, Dr. Santomasso, what are the key recommendations regarding Hemophagocytic Lymphohistiocytosis?

BIANCA SANTOMASSO: The major recommendations for the identification, evaluation, and management of Hemophagocytic Lymphohistiocytosis, or HLH-- this is also known as macrophage activation syndrome. First, let's just start by saying that this is a dysfunctional immune response, and it's basically characterized by macrophages which are revved up and hyperactive and also possibly lymphocytes as well.

There are high levels of pro-inflammatory cytokines during this state and tissue infiltration, and hemophagocytosis, and organ damage. This can occur outside of the context of CAR T-cell therapy, either as a primary HLH or secondary HLH that can be either triggered by infections, or autoimmune disease, or cancer-- especially hematological malignancies, but HLH has also been observed as a rare complication of CAR T-cell therapy. And outside of the setting of CAR T-cell therapy, HLH is defined by fever, cytopenias, hyperferritinemia-- or high ferritin level-- as well as bone marrow hemophagocytosis.

And what's interesting is that this is very similar to what's seen during Cytokine Release Syndrome, and that can make it difficult for patients who have moderate to severe CRS to distinguish that from HLH. The laboratory results may be very similar. So the key to recognizing HLH is really to have it on your differential even though it occurs rarely after CAR T-cell therapy. It may occur with slightly different timing and may require more aggressive treatment.

The lab alterations can include, again, as I mentioned, these elevated levels of several cytokines, such as interferon gamma. We can't normally send those in the hospital or the clinic, but sometimes soluble IL-2 receptor alpha can be sent and serum ferritin can be sent, and that's an especially useful marker.

There have been diagnostic criteria for CAR T-cell-induced HLH that have been proposed, and these conclude very high ferritin levels-- over 10,000-- and at least two organ toxicities that are at least grade 3, such as transaminitis, increased bilirubin, renal insufficiency or oliguria, or a pulmonary edema, or evidence of hemophagocytosis in bone marrow or organs.

Unlike other forms of HLH that occur outside of the context of CAR T-cell therapy, the patients may not have hepatosplenomegaly, lymphadenopathy, or overt evidence of hemophagocytosis. So just because a patient may not show those yet doesn't mean that HLH shouldn't be considered.

If we see patients that have a persistent fever without an identified infection source or worsening fever, we basically should be considering HLH and doing the appropriate workup and treatment. Patients with HLH often have low fibrinogen, high triglycerides, and also cytopenias as well.

The treatment-- just as there's an overlap kind of in the signs and symptoms, the treatment and the clinical management overlaps as well with CRS, so tocilizumab is typically administered. But corticosteroids should really be added for these patients, especially if there's clinical worsening or grade 3 or greater organ toxicity.

And if there's insufficient response after 48 hours of corticosteroid therapy plus tocilizumab, many centers consider adding another medication such as Anakinra. I'll finally make a comment that, outside of the context of CAR T-cell therapy, HLH is sometimes treated with cytotoxic chemotherapy, such as etoposide.

This approach generally is not used as a first line for patients undergoing CAR T-cell therapy due to etopiside's documented toxicity to T lymphocytes. And generally, the corticosteroids, plus the anti IL-6 agent, plus Anakinra is considered the first line of management.

BRITTANY HARVEY: Got it. That's an important note on the management of HLH, and a great note on distinguishing CRS and HLH. So in addition, Dr. Ghosh-- what are the recommendations for management of B-cell aplasia?

MONALISA GHOSH: B-cell aplasia, it's a disorder that's caused by low numbers or absent B-cells. And this is particularly relevant to CD19 directed CAR T-cell therapy, which is what most of the CAR T-cell therapies that are available right now target. They target CD19, and CD19 is present on normal as well as malignant B-cells.

So most patients who receive anti-CD19 CAR T-cell therapy will develop B-cell aplasia at some point, and B-cell aplasia may be temporary or prolonged. It usually does, on one hand, indicate ongoing activity of the CD19 CAR T-cells and can be used as a surrogate marker.

And increase in CD19 CAR T-cells could, in some patients, signal impending relapse, or dysfunction, or absence of activity of CD19 CAR T-cells. B-cell aplasia in CAR T-cell recipients is really due to, as I mentioned, an on-target, off-tumor effect. It can be prolonged and there is variability in rates of prolonged B-cell aplasia.

The most significant consequence of B-cell aplasia is that it can lead to low immunoglobulin production. And immunoglobulin production is a very important part of the immune response by providing antibody-mediated immunity, so patients may present with frequent infections and low immunoglobulin levels.

For most CAR T-cell recipients, this can be managed with infusions of Intravenous Immunoglobulins-- IVIG. However, the presence of B-cell aplasia can also present other challenges-- especially during this current pandemic, as Dr. Santomasso alluded to earlier, that it is unclear if patients will be able to mount a sufficient enough antibody response to the COVID-19 vaccines available since they cannot produce significant amounts of antibodies. This is an active area of research. However, we do advise that all CAR T-cell recipients do get the COVID vaccine and also other seasonal vaccines, such as the influenza vaccine.

So it remains to be seen. We need some more long-term follow-up studies on how many people who receive CD19-directed CAR T-cell therapy will have prolonged B-cell aplasia and what the consequences will be. At this time, it is suggested that patients have their IgG levels monitored and-- if possible-- their actual B-cell numbers monitored.

And if their IgG levels drop below a certain number, then they may receive IVIG infusions intermittently. We recommend in this guideline using 400 as a possible cutoff for IgG levels prior to administering IVIG. However, if patients have higher IgG levels and they have recurrent or life threatening infections, infusion of IVIG is recommended as a consideration to help boost the antibody response.

BRITTANY HARVEY: OK. As you mentioned, those challenges are particularly relevant now. So then, Dr. Santomasso, what are the key recommendations regarding Disseminated Intravascular Coagulation?

BIANCA SANTOMASSO: Disseminated Intravascular Coagulation is a disorder that's characterized by systemic pathological activation of blood clotting mechanisms, which results in both clot formation throughout the body and also bleeding. There's an increased risk of hemorrhage as the body is depleted of platelets and other coagulation factors.

So it's basically important for clinicians to be aware that DIC-- or Disseminated Intravascular Coagulation-- can occur after CAR T-cell therapy, and it can occur either with or without concurrent Cytokine Release Syndrome. The treatment is primarily supportive care and replacing the factors, such as fibrinogen-- based on the levels-- and also replacing factors based on partial thromboplastin time and bleeding occurrences.

But corticosteroids and IL-6 antagonist therapy can be used if there is concurrent CRS or in the setting of severe bleeding complications. There is limited evidence for other interventions.

BRITTANY HARVEY: Great. Appreciate you reviewing those. So then, the last category of toxicity addressed in this guideline-- Dr. Ghosh, what are the key recommendations for identification, evaluation, and management of infections?

MONALISA GHOSH: So a variety of infections can be seen after CAR T-cell therapy. And there are many factors that can lead to infection after CAR T-cell therapy including the presence of cytokines, such as neutropenia or leukopenia and B-cell aplasia that we earlier discussed-- leading to low immunoglobulin production and protection.

As well as the increased risk of infection due to use of high-dose steroids to treat CAR T-cell-related toxicities, such as ICANS or CRS. Early after the infusion of CAR T-cell therapy-- that is, within three months-- patients often develop neutropenia due to lymphodepleting chemotherapy and/or the CAR T-cells themselves.

And these patients are particularly susceptible to infection, so most of the infections that occur early on tend to be bacterial infections, and a few fungal infections have been observed as well. Patients who receive high-dose steroids for high grade CRS or ICANS have been shown to have increased serious infectious complications including bacterial infections, fungal infections, as well as viral reactivations.

Infectious complications that occur later are often due to hypogammaglobulinemia due to B-cell aplasia and reduced production of immunoglobulins. And treatment is typically directed at the infectious source, as it would be even if these patients did not have CAR T-cell therapy.

There are some prophylactic antimicrobials that are recommended for CAR T-cell recipients who have prolonged cytopenias. Especially those with prolonged neutropenia should be on some sort of bacterial and/or fungal prophylactic antimicrobials.

Patients should also be monitored for hypogammaglobulinemia long term and should receive intravenous immunoglobulins as needed. As we have mentioned a couple of times already, being very aware that these patients are also more susceptible to seasonal infection, such as influenza, is important, and so vaccinations are very important for this patient population. Vaccinating against influenza and vaccinating against COVID-19.

BRITTANY HARVEY: Thank you both for reviewing those key points for the most common CAR T-related toxicities. So, just to wrap us up-- Dr. Santomasso-- in your view, how will this guideline impact both clinicians and patients?

BIANCA SANTOMASSO: Well, I think we've seen now that cell therapy is really one of the major advances in cancer treatment in the past decade. And I think it's reasonable to expect more of these cell therapies to be developed, and we'll hopefully see their use extend beyond very specialized centers.

But CAR T-cell therapy side effects are manageable if they're recognized, so I think this guideline helps that, and they're reversible with proper supportive care. They can be serious and they require close vigilance and prompt treatment. But, again, we believe this guideline and recommendations will help members of clinical teams with both the recognition and management of all of these toxicities, and that will help patients by increasing their safety.

BRITTANY HARVEY: Great. That's important to note that these toxicities can be severe, but are also manageable. So I want to thank you both for your work on these guidelines and for taking the time to speak with me today, Dr. Santomasso and Dr. Ghosh.

BIANCA SANTOMASSO: Our pleasure.

MONALISA GHOSH: Absolutely. It was my pleasure.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events in patients treated with immune checkpoint inhibitors. To read the full guidelines, go to www.asco.org/supportive care guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Manish Shah from New York Hospital and Weill Cornell Medicine, co-chair on “Immunotherapy in Patients with Locally Advanced Esophageal Carcinoma: ASCO Guideline Rapid Recommendation Update.” He discusses the results of the Checkmate 577 trial and the updated recommendation of the Treatment of Locally Advanced Esophageal Carcinoma Guideline. For more information, visit www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

[MUSIC PLAYING]

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at ASCO.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Manish Shah from New York Hospital and Weill Cornell Medicine in New York, NY, co-chair of the Locally Advanced Esophageal Carcinoma guideline expert panel and lead author on the Immunotherapy in Patients with Locally Advanced Esophageal Carcinoma: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Shah.

MANISH SHAH: Absolutely. Thank you very much for having me.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline is available online. Dr. Shah, do you have any relevant disclosures that are directly related to this guideline?

MANISH SHAH: Yes, so I do have relationships with many of the companies that make checkpoint inhibitors. And in fact, we are being supported by Bristol Myers Squibb on a first-line study of chemotherapy with nivolumab. We've also been supported by Merck on a pre-operative study of chemotherapy with radiation and pembrolizumab.

BRITTANY HARVEY: Thank you for that information. Then so what prompted this rapid update to the Treatment of Locally Advanced Esophageal Carcinoma: ASCO Guideline?

MANISH SHAH: Yes, so recently there was a landmark study that was practice-changing in the space, published in the New England Journal of Medicine by Ronan Kelly and colleagues. And this was the report of CheckMate 577, the use of adjuvant nivolumab in resected esophageal or gastroesophageal junction carcinoma. And this was a positive study that led to important changes in practice. And we felt that this was worthy and worthwhile of getting it out there to the community.

BRITTANY HARVEY: Great. Then based off this new data from CheckMate 577 on nivolumab, what is the updated recommendation?

MANISH SHAH: Sure. So previously, the data available was that patients who receive chemotherapy and radiation and then went on to receive surgery, that those patients with esophageal cancer had no further treatment recommendations. This study, CheckMate 577, actually examined nivolumab in that context. So patients who received chemotherapy and radiation and then underwent surgery, if they had some residual disease at the time of the surgical resection, even if they had a major response but there was some residual cancer in the surgical specimen, patients were eligible for randomization. And about 800 patients were randomized, 2 to 1, to receive nivolumab versus placebo in this context.

And the primary endpoint in the study was disease-free survival. And patients who received nivolumab had a median disease-free survival of 22.4 months compared to placebo, which was the previous standard of care. The median disease-free survival in that group was 11.0 months, so almost a doubling of the disease-free survival. The hazard ratio was 0.69. And that was highly significant, with a p value of 0.001. So there was a 31% improvement in reducing the risk of recurrence with adjuvant nivolumab. So based on that trial, we have updated the guideline to recommend adjuvant nivolumab for patients who have received chemotherapy and radiation and surgery, and then had some residual disease in the surgical specimen.

A key distinction is that about 20% to 30% of patients will have had a pathologic complete response. These patients were not eligible for the trial. And so at this time, patients who have had a complete response, the current guidelines remain the same, where there's no further treatment indicated.

BRITTANY HARVEY: OK, it seems like this study provided a strong signal to update that recommendation. I appreciate you going through the details of that study, and particularly the patients that were eligible to participate. So then, how will this guideline impact patients with locally advanced esophageal cancer?

MANISH SHAH: Yeah, I think that this is a key thing. Because 70% to 75% of patients have residual disease at the time of resection. And still, even if you've had a major pathologic response, the risk of recurrence for many patients is still high, greater than 50%.

Of note also I'd highlight that the study included adenocarcinoma and squamous cell cancer. And the results were positive in both groups. So based on that, I think that this will be highly impactful for a majority of patients with esophageal cancer, both adenocarcinoma and squamous cell cancer, who, as I said, underwent chemoradiation and surgery and had residual disease in the surgical pathologic specimen.

BRITTANY HARVEY: That's good to hear that this will have a positive impact for these patients. So then what are the outstanding clinical questions regarding treatment of these patients?

MANISH SHAH: Yeah, so I think that there are a lot of outstanding questions. I think one question which is currently being studied is the use or integration of checkpoint inhibition therapy prior to surgery. So that's being examined in an inter-group study in the United States, as well as several company-sponsored studies across the globe. And a concept there is that, if you're giving chemotherapy with radiation and a checkpoint inhibitor all combined, you might be able to have even the higher benefit from activation of the immune system against the cancer than in the adjuvant setting where you're trying to treat microscopic minimal disease. So that's one question.

And the other key question, which was actually raised by the clinical trial itself was the CPS scoring system. So CPS means Combined Positive Score. This is a way to examine the level of PD-L1 expression in the tumor and its microenvironment. And it's not a great biomarker, but it's the best biomarker available. And it is predictive of who would benefit. So patients who have a higher CPS score are more likely to benefit from a checkpoint inhibitor. A post hoc analysis of this study suggested that tumors that had a CPS score of less than 5 had less benefit. So although the FDA approval for adjuvant nivolumab was independent of the CPS score, I think, with time, we'll have more information on the potential impact of CPS or other biomarkers on which patients really may benefit from adjuvant therapy.

So I think, on the positive end, patients now have options. And I think they're clinically significant and meaningful. But it does, as you point out, highlight new questions that will be answered in due course.

BRITTANY HARVEY: Great. And we'll look forward to the results of those studies that address some of those questions. So thank you for your efforts to issue this rapid update and for taking the time to speak with me today, Dr. Shah.

MANISH SHAH: Oh, absolutely. It was a pleasure to be here. Thanks so much, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.ASCO.org/gastrointestinal-cancer-guidelines. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Nadine Tung and Dr. Dana Zakalik, co-chairs on ”Adjuvant PARP Inhibitors in Patients with High-risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update.” They discuss the results and impact of the OlympiA trial, the updated recommendation, and outstanding questions on the use of PARP inhibitors in the adjuvant setting. For more information, visit www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

[MUSIC PLAYING]

ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.ASCO.org. My name is Brittany Harvey, and today I'm interviewing Dr. Nadine Tung from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and Dr. Dana Zakalik from Beaumont Health in Royal Oak, Michigan, co-chairs of the Management of Hereditary Breast Cancer Guideline Expert Panel and this rapid recommendation update, Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Guideline Recommendation Update. Thank you for being here, Dr. Tung and Dr. Zakalik.

DR. ZAKALIK: Thank you for having us.

DR. TUNG: Thank you so much. Pleasure to be here.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online. Dr. Tung, do you have any relevant disclosures that are directly related to this guideline topic?

DR. TUNG: I do receive research funding from AstraZeneca, as I run a trial using a PARP inhibitor in breast cancer.

BRITTANY HARVEY: Thank you. And Dr. Zakalik, do you have any relevant disclosures?

DR. ZAKALIK: I do not.

BRITTANY HARVEY: Thank you. Then let's get into the meat of this rapid recommendation update. So, Dr. Tung, what prompted this rapid update to a recommendation from the Management of Hereditary Breast Cancer Guideline?

DR. TUNG: The OlympiA Trial, which was presented at ASCO this past June and published the same day in the "New England Journal of Medicine." OlympiA was a large Phase III trial, which demonstrated that a year of adjuvant olaparib, a PARP inhibitor, significantly improved both invasive disease-free survival by nearly 9%, and distant disease-free survival by a similar improvement, in germline BRCA mutation carriers with HER2-negative breast cancer and a high risk of recurrence. Overall survival was numerically better with olaparib, but it didn't yet reach significant improvement as a stringent p-value was required for this early reporting.

And I say early reporting because the trial was reported early after the first event-driven interim analysis showed a benefit with olaparib. 1,800 patients had been enrolled with a median follow up of 2 and 1/2 years at the reporting. But the follow up was 3 and 1/2 years for the first 900 patients enrolled, known as the maturity cohort. And it was comforting that the significant improvement in invasive disease-free survival and distant disease-free survival was also seen when just looking at that maturity cohort. So for those who might think that it's too early and that these benefits might not hold up with longer follow up, it's very comforting that in that maturity cohort with longer follow up, the results were really the same.

And last year, ASCO published guidelines on managing patients with hereditary breast cancer, including women with inherited BRCA mutations, meaning a pathogenic or likely pathogenic variant. At that time, PARP inhibitors were recommended only for BRCA carriers with metastatic disease, based on the OlympiAD and EMBRACE trials. So when OlympiA was published, we felt the need to update the guidelines to recommend olaparib in the early-stage setting for some germline BRCA carriers.

BRITTANY HARVEY: So then, based off this new data from the OlympiA trial, Dr. Zakalik, what is the updated recommendation from the guideline expert panel?

DR. ZAKALIK: The updated recommendation states that for patients with early-stage, HER2-negative breast cancer with a high risk of recurrence, and who carry a germline BRCA1 or 2 mutation, one year of adjuvant olaparib should be offered after completion of adjuvant or neoadjuvant chemotherapy and local treatment, including radiation therapy. And this data was specific to a high risk of recurrence subgroup of these patients, defined as, for those with triple-negative breast cancer having a tumor over two centimeters, or with any involved lymph nodes, or for those who received neoadjuvant chemo, any residual disease in the triple-negative setting was sufficient to qualify.

For patients with hormone receptor positive disease, these were high-risk patients for recurrence, again, and that was defined as having at least four positive lymph nodes, or any residual disease following neoadjuvant therapy. But in addition, having a clinical stage and pathologic stage estrogen receptor status and tumor grade, otherwise called the CPS+EG score, of greater than or equal to three, which is really defined as looking at estrogen receptor status grade and clinical and pathologic stage. So again, a high-risk group for risk of recurrence was included in this study. And again, in order to apply these findings, we have to be mindful of patients who meet these inclusion criteria as being high-risk for recurrence. Again, both in the triple-negative hormone receptor-positive setting, if they met these criteria, there was a significant benefit in terms of outcome in lowering the risk of recurrence.

BRITTANY HARVEY: I appreciate you going through that recommendation. So then, given that updated recommendation. Dr. Tung, what should clinicians know as they implement the use of adjuvant olaparib into clinical practice?

DR. TUNG: For those who have not used olaparib, it's worth saying that it's an oral medication. Typically patients take two pills twice a day. And it's important to be familiar with the side effects. I would say that generally, olaparib is well-tolerated. But it can have side effects. And the two most common are nausea, and then anemia. So for the nausea, we use the typical antiemetics we would use for any chemotherapy. And it's worth saying to patients who do have nausea that quite often, that lessens with time. It decreases. So I would say nausea's one of the side effects. Some patients can have fatigue, although I don't think that's all that common.

And anemia is the other one. And we do check bloodwork monthly for patients on olaparib. The anemia can come suddenly, even after months of really not having any. And grade 3 anemia was probably the most common, grade 3 or higher, toxicity that was seen in OlympiA, although it's only 9% of patients that had grade 3 or higher anemia. But I would say those are the two side effects to look for most. And then I think one other thing that's worth saying is that for the BRCA carriers with triple-negative breast cancer, currently our standard therapy for patients who have residual disease after neoadjuvant chemotherapy is capecitabine. But olaparib should not be given with capecitabine. There is no safety data for that. So oncologists are going to need to choose between what I think is our standard therapy right now, capecitabine, and olaparib. And there's no data directly comparing these two medications in the early-stage setting.

But in the metastatic setting in BRCA carriers, in both OlympiAD and EMBRACE, olaparib was compared to chemotherapy. And olaparib with superior. And in both of those studies, about half the women in the chemotherapy arms received capecitabine. And olaparib, again was superior. So olaparib may be the better choice in the early-stage setting. But I can't say that there's any direct data. But the message would be not to give them together. And I think it would be better probably not to give capecitabine first and then olaparib, because there's some data that the earlier you give a PARP inhibitor the better.

BRITTANY HARVEY: Those are important notes for clinicians and particularly for safety. So then building on that, Dr. Zakalik, how will this update impact patients with breast cancer?

DR. ZAKALIK: This data will significantly impact the therapeutic options that we have for patients with high-risk disease in the setting of a BRCA germline mutation. And that will happen in the sense that patients who have these certain specific features that render them high-risk will now be able to be offered a very impactful therapy that has been shown in this landmark study to significantly decrease their risk of recurrence. And these are patients who otherwise would face a significant risk of potentially facing a recurrence in the future. So the outcomes we anticipate to be dramatically improved for patients who have triple-negative or high-risk hormone receptor-positive breast cancer in the setting of a BRCA germline mutation.

But furthermore, whereas genetic testing in the past was predominantly focused on identifying individuals who are at high risk for developing breast cancer so that we can offer early detection or prevention options, this is the first time that we're able to broadly apply the benefit of molecular genetic testing for hereditary risk to therapy for patients with early nonmetastatic breast cancer. So as clinicians who see patients with breast cancer, it is further made more important to recognize what the guidelines are for genetic testing. To think of whether a patient meets criteria that are currently outlined for genetic testing, as this will have a significant potentially major impact on patients' outcome. And already in the clinic, we have been focused on recognizing who may have a BRCA mutation. Obviously, this data will make that even more important, because this therapy is so beneficial for patients. And I think going forward, it will fuel a discussion of possibly reevaluating who gets genetic testing, now that it's particularly important not to miss patients who have BRCA mutations when they develop breast cancer.

So I think that physicians who are in the clinic will not only have a therapeutic option, but also will be hopefully recognizing more patients who have a BRCA mutation in that the therapy is so markedly better now with this new data. And in the future, we may possibly expand our guidelines for testing. And I think that remains to be determined, based on a number of factors that go into this decision.

BRITTANY HARVEY: Well then, you've both touched on this a bit, regarding outstanding questions for both genetic testing and the use of capecitabine. But finally, Dr. Tung, given this recent study and guideline update, what are the outstanding questions regarding the use of PARP inhibitors in the adjuvant setting?

DR. TUNG: Right. We have already listed a couple. The capecitabine question is one that I won't repeat. And I think who gets tested would be another one that Dana just mentioned. I think a big one, as of yesterday, is immune therapy. Yesterday, the FDA approved pembrolizumab, based on the KEYNOTE-522 study for patients with triple-negative breast cancer. And that population in KEYNOTE was very similar to the one in OlympiA for BRCA carriers, namely patients with T2 tumors, or involved axillary lymph nodes. So for BRCA carriers, we're going to have to make some decisions here, namely, should they receive pembrolizumab and olaparib together, for those who have residual disease after neoadjuvant chemotherapy. I think everyone right now is digesting KEYNOTE-522 and this FDA approval. And so that's something that will have to be worked out.

I know in other diseases there is safety data for the combination of pembrolizumab and olaparib. But again, I think that's something that we're all going to have to sort out. I don't think there's going to be any data forthcoming immediately about the use of pembro, olaparib, and the combination, et cetera for our patients. So that's a big one I think another question that comes up is, how long after a BRCA carrier finishes their chemotherapy and local therapy are they eligible to take olaparib? What about patients that finished six months ago, or a year ago, or longer? And again, I don't think there are any data for that, and we're going to have to use some clinical judgment. There was precedent for this kind of question when adjuvant trastuzumab was approved and in 2005, when the adjuvant trials demonstrating such an impressive benefit for trastuzumab were announced and published.

I remember that we were administering trastuzumab to patients who'd completed their chemotherapy within the last year. So I think for many, that may be a timeline that makes sense. But again, there are no data. So still questions, and we're going to as always have to use some clinical judgment. And others, Dana, that you can think of?

DR. ZAKALIK: No. I think this is tremendously exciting new data. It really provides hope for patients who are young, often, when they're diagnosed. Because hereditary breast cancer tends to manifest itself at a young age. And so for our women in the prime of their life, when they have high risk and develop breast cancer, I think this just really gives us tremendous hope and opportunity for improving the lives and saving lives in the future of patients who have high-risk disease. Very exciting data.

DR. TUNG: Yeah, I agree completely. I think the investigators are really to be congratulated. This was a very large study. 1,800 BRCA carriers, international study. Very hard to do with a situation, a disease that's relatively uncommon. Only 3% to 5% of all breast cancer. So really a terrific effort with a significant, major impact for our BRCA carriers with breast cancer.

BRITTANY HARVEY: Definitely. This is an exciting update for patients with breast cancer. And we'll look forward to hearing more research about those outstanding questions that you mentioned. So I want to thank you both for your efforts to update this guideline recommendation so quickly, and provide evidence-based recommendations for both clinicians and patients. And thank you for taking the time to speak with me today, Dr. Zakalik and Dr. Tung.

DR. ZAKALIK: Thank you.

DR. TUNG: My pleasure.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. For more information, visit www.ASCO.org/breast-cancer-guidelines. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Harold Burstein from Dana Farber Cancer Institute in Boston, MA, chair on “Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Update.” This guideline updates recommendations on use of alpelisib, and the role of biomarkers and CDK4/6 inhibitors. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

[MUSIC PLAYING]

My name is Brittany Harvey. And today I'm interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute in Boston, Massachusetts, chair and lead author on endocrine treatment and targeted therapy for hormone receptor-positive HER2 negative metastatic breast cancer ASCO guideline update. Thank you for being here, Dr. Burstein.

HAROLD BURSTEIN: Glad to be with you.

BRITTANY HARVEY: First I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Burstein, do you have any relevant disclosures that are related to this guideline topic?

HAROLD BURSTEIN: I do not.

BRITTANY HARVEY: Great, thank you. Then let's delve into the content of this guideline. So first, what prompted the update of this guideline and what is the focus of this update?

HAROLD BURSTEIN: So this guideline focuses on metastatic breast cancer, and in particular, estrogen receptor-positive HER2 negative metastatic breast cancer. Worldwide in 2021, actually breast cancer became the most commonly diagnosed cancer in the world, excepting superficial skin cancers.

And so it is a true global health problem. And the most common type of breast cancer is estrogen receptor-positive HER2 negative breast cancer, which accounts for 70% to 75% of all cancer diagnoses in the breast cancer space, and as a consequence, also accounts for 70% to 75% of the cases of metastatic breast cancer. So it's really important from a public health point of view and a quality point of view, both in the United States and globally, to have current up-to-date guidance for the management of this most common form of breast cancer that we have.

In addition, there have been several innovations in the way of targeted therapies that are coming into place for advanced ER-positive breast cancer. And increasingly, we are using genomic tests to help us understand how best to treat patients with advanced ER-positive breast cancer. So those two initiatives-- the interest in genomic testing and the use of targeted therapies-- all warranted and justified an update to the guidelines.

BRITTANY HARVEY: Great. Thank you for reviewing that landscape of where we are in clinical practice for this guideline. So then I'd like to review the key recommendations that this guideline addresses. So first, should alpelisib be given to post-menopausal women and to male patients with hormone receptor-positive HER2 negative PIK3CA-mutated advanced or metastatic breast cancer?

HAROLD BURSTEIN: So alpelisib, as you indicated, is a new drug. It is now FDA approved. And it is a protein kinase targeted inhibitor. And it goes after the PIK3CA-mutated tumors. And in a seminal study called the SOLAR-1 study, there was randomization to endocrine therapy alone with fulvestrant or endocrine therapy plus alpelisib for ER-positive HER2 negative breast cancer.

And that study showed two important things. First was that in women whose tumors did not have a PIK3CA mutation, there was no benefit for alpelisib. However, in the women whose tumors did have a PIK3CA mutation, there was an improvement in progression-free survival with the use of this targeted drug alpelisib.

So based on that, the guidelines now incorporate alpelisib into the treatment algorithm. And as a corollary, it means that all patients who have ER-positive metastatic breast cancer now need testing of the tumor to see if they have a PIK3CA mutation because that's going to guide therapy.

In the guideline, we now suggest that this be a standard thing to do-- to test all tumors for PIK3CA mutation. And in those cases where there is a PIK3CA mutation to add alpelisib-based therapy with endocrine treatment typically in second or subsequent lines of therapy.

BRITTANY HARVEY: Great. And thank you for reviewing the evidence base behind that recommendation. So next, what is recommended regarding the role of biomarkers in treatment selection for patients with hormone receptor-positive metastatic breast cancer?

HAROLD BURSTEIN: So there are two different ways of thinking about biomarkers. One is traditional biomarkers, such as estrogen receptor, progesterone receptor, and HER2. Those are familiar to all clinicians who have been dealing with breast cancer. The second is to think about some of the newer technologies, including tumor genomic sequencing and the kind of mutational analysis we just discussed with the PIK3CA mutations.

So in the breast cancer space, there are some important innovations in that latter genomic or genetic testing. One, of course, is the PIK3CA mutation testing that we now recommend for all cancers. That can be done on the primary tumor, or it can be done on cell-free or circulating tumor DNA samples from the bloodstream in most cases.

The other kind of testing we do relates to ESR1 mutations. And one of the reasons that tumors become resistant to aromatase inhibitors is that they acquire mutations in the estrogen receptor itself, so-called ESR1 activating mutations. Those mutations mean that the estrogen receptor is on even in the absence of estrogen. And that accounts for probably 50% to 60% of the resistance that we see in treatment with aromatase inhibitors.

So the panel really struggled with this because, on the one hand, this is not a uniformly accepted way to decide how to treat patients. On the other hand, there are a lot of data that women whose tumors have ESR1 mutations get negligible benefit from ongoing use of aromatase inhibitor therapy.

So this recommendation fell into sort of our practice suggestions, which is that if you have the information on ESR1, then it probably is the case that there's very little, if any, role for ongoing aromatase inhibitor treatment. This fell short of the highest level in endorsement because, first, it's not a uniformly tested assay. And secondly, it's important to remember that these tumors can still benefit from ongoing anti-estrogen therapy with different anti-estrogens like fulvestrant.

And finally, and perhaps this is the most practical issue, the way you become ESR1 mutated is usually through exposure to aromatase inhibitors. And if you've already had a patient with extensive exposure to AIs, and they need ongoing anti-estrogen therapy in the metastatic setting, it usually means you're switching treatment anyway. So that's an example of where we're sort of on the frontier of thinking about dynamic changes in the tumor as a way to select treatment for ER-positive metastatic disease.

BRITTANY HARVEY: Great. That's helpful for a clinical interpretation of the recommendations and incorporating these into practice. So the final question that was addressed in this focused update was, what is the role of CDK4/6 inhibitors in the treatment of patients with hormone receptor-positive metastatic breast cancer?

HAROLD BURSTEIN: So CDK4/6 inhibitors are another tyrosine kinase inhibitor class of drugs that has really emerged as an important part of first-line therapy for ER-positive metastatic disease. There have been multiple randomized trials looking at either first-line therapy with an aromatase inhibitor with or without a CDKI4/6 inhibitor, or second-line treatment typically with fulvestrant with or without a CDKI4/6 inhibitor in the metastatic setting. And the panel was able to update the guidance here based on the maturation of multiple randomized trials, as well as extensive subset analyses that have been performed by investigators associated with the individual pharmaceutical-led studies and by the FDA itself.

So here are some important takeaways. The first is that in long-term follow-up, these drugs as a class are improving overall survival for women with ER-positive HER2 negative metastatic breast cancer. And for that reason, they are a very important part of the standard armamentarium for ER-positive disease. It's important to say that they also delay the onset of need for chemotherapy, and in general, are associated with a very well preserved quality of life. So this is a big win for patients with ER-positive metastatic breast cancer.

We typically recommend them in the first-line setting. So if a patient has de novo metastatic disease, then they should get an endocrine therapy such as an aromatase inhibitor with a CDK4/6 inhibitor. If they've previously had adjuvant aromatase inhibitor treatment or recur while on adjuvant endocrine therapy, we often move to fulvestrant plus a CDKI4/6 inhibitor. Both settings have shown substantial benefit for this class of drugs.

It's important that clinicians understand the side effects of these drugs. Neutropenia and diarrhea are common side effects associated with the various drugs. And because of the prevalence of ER-positive metastatic disease, it's really important for clinicians and all those who care for advanced breast cancer patients to know how to manage those side effects carefully.

The panel discussed controversial issues, I suppose you might say, in the management. What about patients who have truly minimal metastatic disease? There aren't a lot of data on how best to think about those patients. And we all can imagine on a case-by-case basis an individual who might not need a CDK4/6 inhibitor at a given moment in time.

But what was impressive when we pulled all the data was that in subset analyses, it's really hard to find a group of patients that does not benefit from the incorporation of these drugs. So that included premenopausal women who also get concurrent ovarian suppression and then endocrine therapy plus the CDK4/6 inhibitor. It included women with bone-only metastatic disease. It included women whose tumors were ER-positive but PR negative, or had other variations in ER expression. It included patients who had less rather than more metastatic cancer, including visceral disease.

So in the literature, one is hard-pressed to see a subset that does not benefit meaningfully from this class of drugs. So we really wanted to reiterate in the algorithms just how important these are. They should be the standard first-line treatment for metastatic disease either paired with an AI or with fulvestrant.

And so one of the other nice things that the update gave us was the opportunity to put in some fresh sort of algorithm flow sheets. I would very much encourage people to look at that. They make fantastic PowerPoint or downloadable Twitter documents if you are so inclined. But it's very clear the way the treatment should flow, which is the initial therapy is endocrine treatment plus a CDK4/6 inhibitor. While the patients are getting that, we typically test for PIK3CA mutations. In second line, if it's a PIK3CA mutated, you have the option of using alpelisib. You also might consider an older drug for PIK3CA wild type tumors called everolimus. We reiterated that recommendation in the guideline.

Finally, one more thing to touch on that is emerging in the guidelines we generated and in the parallel guideline process for the ASCO guidance on chemotherapy-resistant or refractory breast cancer is the importance of genetic testing all patients who have metastatic breast cancer to look for the possibility of a BRCA1 or BRCA2 deleterious mutation, because there now is FDA approval for PARP inhibitors in the setting of metastatic disease.

And one of the interesting things is that as we test more and more, we're seeing that not all the patients who are found to have a BRCA1 or 2 mutation meet the classic criteria for genetic testing-- strong family history, or say, triple-negative breast cancer. So it's really important to test, because that class of drugs, the PARP inhibitors, can be immensely helpful in women with ER-positive metastatic disease when they harbor a BRCA1 or 2 mutation.

One of the things the guideline panel wrestled with and ended up putting into the sort of clinical discussion, as opposed to the strong guidance, was the 1% of patients who have PALB2 mutations. So PALB2 mutation, another hereditary predisposing factor for breast cancer. Most tumors that arise in PALB2 mutation carriers are in fact estrogen receptor positive.

And a very small study, now published in the JCO, has suggested that those patients have a very high likelihood of response to PARP inhibitors. Because there were only like 15 patients in that cohort, we didn't feel that this warranted clear endorsement in the guidelines. But at the same time, everyone on the panel acknowledges that this is an active drug in that rare subset of tumors with PALB2 mutations in addition to the BRCA1 or 2 mutations.

So the takeaway here is that genetic testing should be standard for all patients with advanced metastatic breast cancer to see if the patient is a candidate for a PARP inhibitor-based therapy.

BRITTANY HARVEY: Definitely. Well, thank you for reviewing all of those updated recommendations and highlighting some of the ones that were still relevant to this guideline.

HAROLD BURSTEIN: Work in progress.

BRITTANY HARVEY: Yeah, definitely. And then finally, what is the importance of this guideline update? And how will it impact both clinical practice and what does it mean for patients?

HAROLD BURSTEIN: Well, I think guidelines like this have multiple purposes. The first is to sort of describe the state of the art. And while breast cancer is a very common disease, and most clinicians who take care of a lot of cancer patients will see a lot of advanced breast cancer, I think it's still helpful to articulate the rationale for these treatment recommendations.

And one of the great things about the ASCO guideline process is the thoroughness of the literature review, the thoroughness of the search to make sure we're including all important publications, and the thoughtfulness that the panel, which includes experts, patient advocates, quality of life expertise, all those things bring to bear on really thinking through what makes sense and what does not for our patients based on the best science available. So I think it is an important activity to really sort of benchmark where we're at.

The second thing we've tried to do in the guideline is to introduce areas of nuanced discussion, because not every patient is the same. And I think for those who are interested and take the time to read the guideline, there really is a very nice discussion about how our panel thought about when best to use this approach and when to use a different approach.

Third, there's extensive discussion of the side effects and the appropriate management of the side effects. These are drugs that do carry risks. And while by oncology standards, many of them are, quote, "well tolerated," unquote, there's no doubt that there are side effects to these drugs. And it's important for clinical teams to know how to manage them.

Finally, I think by putting forward all the evidence, you make clear to investigators, to drug companies, to patients and advocates, and others who are involved in the review of new drugs what the benchmarks are and what the criteria should be for designing clinical trials and for approving new drugs. And I think we've done a nice job of framing that discussion quite handsomely in this guideline and to all of the ASCO guidelines.

BRITTANY HARVEY: Great. Well, thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Burstein.

HAROLD BURSTEIN: Happy to join you and thanks very much.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at SurveyMonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Beverly Moy from Massachusetts General Hospital, co-chair on “Chemotherapy and Targeted Therapy for Patients With HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update.” Updated guidance addresses optimal sequence of therapy & indications for treatment regimens. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

[MUSIC PLAYING]

My name is Brittany Harvey. And today I'm interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, co-chair and lead author on chemotherapy and targeted therapy for patients with HER2 negative metastatic breast cancer that is either endocrine pre-treated or hormone receptor negative ASCO guideline update. Thank you for being here, Dr. Moy.

BEVERLY MOY: Thanks for having me, Brittany.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic?

BEVERLY MOY: I do not have any relevant disclosures related to this guideline topic.

BRITTANY HARVEY: Great. Thanks so much. Then let's get into what this update covers. So first, what prompted the update of this ASCO guideline and what does the scope of this guideline update?

BEVERLY MOY: So this guideline update was developed to address both chemotherapy and targeted therapy for women with advanced HER2 negative breast cancer that is either endocrine pre-treated or hormone receptor negative. So it really focuses on chemo and targeted therapy.

The original ASCO clinical treatment guideline was published in 2014 and really focused on chemotherapy, since that was generally the standard of care at that time. Since 2014, however, there have been several important new therapies that have become available based on robust evidence from numerous clinical trials.

These include, but are not limited to, BOLERO-6 and PEARL trials for hormone receptor positive HER2 negative metastatic breast cancer, the ASCENT and EMBRACE trials for triple negative metastatic breast cancer, and the EMBRACA trial for metastatic breast cancer associated with germline BRCA1 or 2 mutations. So it really was important to update the guideline in a fairly urgent matter.

BRITTANY HARVEY: Great. Well, then this guideline addresses four overarching clinical questions. For each of these, I'd like to review the key recommendations for our listeners. So starting with question one, is there an optimal sequence of chemotherapy and/or targeted therapy for patients with triple negative metastatic breast cancer either with or without BRCA1 or BRCA2 germline mutations?

BEVERLY MOY: So clinical question one really focused on patients with metastatic triple negative breast cancer. So for patients with metastatic triple negative disease, the first key question is, what is the Programmed cell Death Ligand 1, or what we call PD-L1 status? If the disease is PD-L1 positive, then patients may be offered first line therapy with an immune checkpoint inhibitor plus chemotherapy. And that's a very important development.

If the disease, however, is PD-L1 negative, patients should be offered single agent chemotherapy rather than combination chemotherapy, unless they have symptomatic or immediately life-threatening disease, and you really need to get a response more quickly. In those cases, combination chemotherapy can be used.

After the first line, if patients with metastatic triple negative breast cancer have received at least two prior therapies, then they should be offered treatment with the new antibody drug conjugate called sacituzumab govitecan, which is a very exciting development in the treatment of metastatic triple negative breast cancer.

If the patient has a germline BRCA1 or 2 mutation and has metastatic triple negative disease and have been previously treated with chemotherapy, then they may be offered treatment with an oral PARP inhibitor rather than chemotherapy, also a very exciting development that this guideline update addresses.

BRITTANY HARVEY: Great. Thank you for reviewing those recommendations for triple negative metastatic breast cancer. So then next for clinical question two, what are the indications for chemotherapy versus endocrine therapy in endocrine pre-treated estrogen receptor positive metastatic breast cancer?

BEVERLY MOY: So clinical question two focuses on women or patients with metastatic hormone receptor positive breast cancer who have developed progressive disease on a prior endocrine therapy with or without targeted therapy. So really is focusing on patients with metastatic hormone receptor positive breast cancer that have become fairly resistant to endocrine therapy alone. These patients may be offered treatment with either endocrine therapy with or without a targeted therapy or single agent chemotherapy.

Brittany, I think it's important for listeners to realize that there is another important clinical practice guideline update that's being released simultaneously with this guideline. And that one is called endocrine therapy and targeted therapy for hormone receptor positive metastatic breast cancer. This other guideline update will describe in detail recommendations for the various targeted therapies that can be used with endocrine therapy, such as CDK4/6 inhibitors, PI 3-kinase inhibitors, and others.

So I encourage everyone to read this guideline as well. Importantly, both guidelines state that treatment choice should be based on individualized patient and provider assessment of preferences, risks, and benefits.

BRITTANY HARVEY: Great. And thank you for pointing out that companion guideline. Listeners can also listen to a podcast episode with Dr. Burstein on that particular guideline, which will be available in our podcast feed.

So then next, what are the key recommendations for the third question in the guideline, which is, is there an optimal sequence of non-endocrine agents for patients with hormone receptor positive but HER2 negative metastatic breast cancer who are no longer benefiting from endocrine therapy, either with or without BRCA1 or BRCA2 germline mutations?

BEVERLY MOY: So this third question really focuses on patients with hormone receptor positive HER2 negative disease and the optimal sequence. Essentially what we recommend is that germline BRCA1 or 2 patients with metastatic hormone receptor positive HER2 negative breast cancer who are no longer benefiting from endocrine therapy, those patients may be offered an oral PARP inhibitor in the first through third line setting rather than chemotherapy. And that is evidence that is evolving and important, and that's what the guideline recommends at this time.

BRITTANY HARVEY: Great. And then clinical question four was the last question addressed in this guideline update. And what did the panel say regarding at what point should a patient be transitioned to hospice or best supportive care only?

BEVERLY MOY: So this obviously is an incredibly important question for clinicians and oncologists to consider. The current literature and evidence does not allow us, at this time, to make a firm recommendation regarding at which point a patient's care should be transitioned to hospice or best supportive care only.

When to transition is a decision that really needs to be shared between the patient and clinician in the context of an ongoing conversation regarding goals of care. The conversation of that integration of supportive care and eventual consideration of hospice care really should start early in the management of metastatic breast cancer. And these conversations have to occur throughout.

I would also refer listeners to other important clinical treatment guidelines on the ASCO website about incorporation of palliative and supportive care for patients with metastatic cancer. I think those are incredibly valuable guidelines.

BRITTANY HARVEY: And then you've touched on this a bit as you've talked about the recommendations, but in your view, what is the importance of this guideline update? And how will these updated recommendations impact both clinicians and patients?

BEVERLY MOY: I think that this is an extremely important guideline update. It provides really important clinical guidance about the new use of immune checkpoint inhibitors, which really is the first time immune checkpoint inhibitors are clearly recommended for the treatment of breast cancer. It also provides important clinical guidance about this new antibody drug conjugate, sacituzumab govitecan, and PARP inhibitors for the treatment of metastatic breast cancer.

These are all important and effective new treatments for breast cancer. And every clinician should be aware of their optimal uses. I will point out that many unanswered questions remain. And that was really an exciting part of doing this guideline update to look at these unanswered questions, such as what we described earlier, the optimal time to transition to best supportive care only and the widespread use of molecular tumor profiling. As treatments get more complicated and the entire oncology community are increasingly tasked to absorb new data, ASCO guidelines are enormously helpful in giving people an easy to access tool that takes into account the latest data.

BRITTANY HARVEY: Great. Thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Moy.

BEVERLY MOY: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at surveymonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Robin Zon from Michiana Hematology Oncology in Mishawaka, IN, co-chair on “Telehealth in Oncology: ASCO Standards and Practice Recommendations.” The standards address telehealth implementation, doctor-patient relationships, roles of advanced practice providers & allied health professionals, multidisciplinary cancer conferences, and teletrials. Read the standards at www.asco.org/standards. Suggest a topic for standards development at www.surveymonkey.com/r/standardssurvey.

TRANSCRIPT

[MUSIC PLAYING]

ROBIN ZON: Thank you so very much for having me here with you, to discuss this very important topic and work, which was undertaken by an expert panel of ASCO incredible volunteers and ASCO staff lead, Erin Kennedy.

BRITTANY HARVEY: Great. Then first I'd like to note that ASCO takes great care in the development of its standards and ensuring that the ASCO conflict of interest policy is followed. The full conflict of interest information for the expert panel is available online with the publication of the standards in the JCO Oncology Practice. Dr. Zon, do you have any relevant disclosures that are directly related to these standards?

DR. ROBIN ZON: No. I do not have any relationships to disclose related to the subject.

BRITTANY HARVEY: Thank you. Then let's get into the content of these telehealth standards. So first, can you give us a general overview of the purpose and scope of these standards for telehealth in oncology?

DR. ROBIN ZON: Well, absolutely. The service background, pre-pandemic, telehealth was utilized less than 1% of the time for oncology ambulatory visits. With, of course, a subsequent rapid adoption of digital health, in response to the public health emergency. This uptake of technology intervention was then further facilitated by the Centers for Medicare and Medicaid Services increased flexibility and reimbursement for these services.

In response to the COVID-19 pandemic, ASCO published an interim policy statement on telemedicine. The signal is positions on emerging policy issues, as well as the road to recovery report, which presented ASCO's recommendations for modifying pre-pandemic policies and practices to improve high-quality patient care, wherein ASCO membership identified a need for more detailed oncology-based telemedicine. So these standards were created in response to this need. It is important to note that these standards include an endorsement of existing general guidelines as published by the American Medical Association Telehealth Implementation Playbook and the American Telemedicine Association's Quickstart Guide.

BRITTANY HARVEY: That background and context is helpful for our listeners. So, then these standards, reading through them, they address six questions. I'd like to review the key points in each section for our listeners. So the first section, which patients should be seen via telehealth versus in-person? And what are the important implementation considerations for oncology telehealth visits?

DR. ROBIN ZON: Those are great questions, Brittany. Generally speaking, patients should always have the option for in-person visits when feasible. But when appropriate infrastructure and personnel are available, telehealth visits are suitable for treatment or long term management visits, in addition to family conferences, genetic counseling, second opinion evaluations, consent form discussions for pre-research trial participation, or when care access issues exist. I would refer the audience to the bottom line box which highlights the 18 described visits, as well as the preferred in-person consultation recommendations.

So from an operations standpoint, the standards include recommendations for practices to develop their own policies and procedures for these types of visits, frequency of visits, and documentation requirements for all clinical visits. Additionally, patients need to be oriented to the technology being utilized and have real time access to troubleshoot and support, if there are technology issues. The panel strongly advocated the quality of care should be equivalent to in-person visits. Thus to support this concept, the standards include, key performance indicators evaluation, policies for interventions delivered asynchronously, automated reminders, and inclusion of patients and caregivers involvement, if new technologic interventions are developed.

BRITTANY HARVEY: Great. I think those specifics you outlined will be helpful both for clinicians and practices, as they implement telehealth. So then, how should the establishment of the physician-patient relationship occur within the context of telehealth in oncology.

DR. ROBIN ZON: Well, both state and federal policies permitting telemedicine to cross state lines, should include a provision requiring that the doctor-patient relationship be established, prior to provision of any telemedicine services. As a reminder to the listener, the ASCO position statement, Telemedicine Cross-State Licensure, was recently approved by the Board of Directors and references a valid doctor-patient relationship as outlined by the American Medical Association.

This includes establishment of relationship by face-to-face examination or consultation with another physician, who has an ongoing doctor-patient relationship with the patient, or meets the standards of establishing a doctor-patient relationship, if included, in clinical practice guidelines developed by a major medical specialty society. I would refer the audience then to this ASCO position statement, for a much more detailed discussion regarding this topic. Importantly, the doctor-patient relationship should include the usual follow-up and care responsibilities and include opportunity for in-person visits at the physical location of the physician practice.

BRITTANY HARVEY: Then following those recommendations for the physician-patient relationship, what is the guidance for when patients may see an advanced practice provider?

DR. ROBIN ZON: Well, the panel recommends that practices follow established standards, policies, and algorithms that govern when Advanced Practice Providers, also known as APPs, or physicians should conduct the televisit based on the disease, treatment, or decision inflection point. However, the panel advises that practices should also review and comply with state and local regulations, for advanced practice provider supervision, including on how the APPs and physicians form teams.

BRITTANY HARVEY: Understood. And then further, in addition to those, what is the role of allied health professionals in oncology-specific telehealth interventions?

DR. ROBIN ZON: And just to orient the audience, when we refer to allied health professionals, we are referring to health professionals who are valued oncology team members. But they're distinct from physicians and nurses. That said, the expert panel referred to the Clinical Oncology Society of Australia, also known as COSA, Tele-oncology Guidelines, which provides guidance for oncology telehealth in rural and remote Australia. This evidence base was the largest for allied health professionals supportive interventions, delivered by both telephone and video conferencing. So due to the strength of the COSA evidence base, the expert panel endorses these recommendations, and refers to the utilization of telephone-based support systems, computerized screening, hybrid tele-practice systems, and video conferencing, as instruments for allied services delivery.

BRITTANY HARVEY: Great. And then the standards went into specifics regarding multidisciplinary cancer conferences. So how should discussion occur at virtual multidisciplinary cancer conferences, compared to in-person MCC meetings?

DR. ROBIN ZON: Well, as many of you know, many practices, in both academia and community settings, consider cancer conferences, which we also refer to as tumor boards, as essential for high quality patient care. Therefore, virtual cancer conferences replace these face-to-face meetings. The expert panel endorses the recommendations by the University of Pittsburgh Medical Center, for implementation of a virtual cancer conference. These include finalization of the agenda, one day in advance, secure video conferencing software, prioritizing complicated cases, and documentation and evaluation guidance. The expert panel also suggests that practices follow institutional guidelines, allowing the discussion to be directed by the presenter. And that there be no recording of the conference taking place without prior legal review.

BRITTANY HARVEY: Once again I find those specifics will be very helpful and explicit for clinicians. So then the last question that was addressed in these standards, how can telehealth be incorporated into clinical trials in oncology?

DR. ROBIN ZON: Well, utilization of telehealth and clinical trials are recommended, as a method for increasing recruitment, while reducing patient burden. Importantly, I want to emphasize that the expert panel endorses these recommendations prevail, beyond COVID-19 pandemic restrictions. This includes consideration for a hub and spoke model for patient enlistment. As well as recommendations to facilitate the conduct of teletrials, which are modifications intended to reduce risk during the pandemic, but also results in increased accessibility, reduced costs, and are less time-consuming.

BRITTANY HARVEY: Thank you for reviewing all of those key statements that were highlighted in the standards. So then, in your view, Dr. Zon, what is the importance of these standards to clinicians, and how will their implementation impact clinical practice?

DR. ROBIN ZON: Well, as I mentioned earlier, telehealth was very uncommonly utilized in cancer care, prior to the pandemic. However, with the soaring use of this intervention, there was a noted gap specific to oncology standards beyond the general telehealth guidance. These standards, then, are designed to assist the cancer care team in delivering the highest quality patient care, similar to the face-to-face quality care the oncologists strive to provide on a daily basis.

Furthermore, what we have witnessed, from both the practice responses and the convening of many experts in the delivery of telecare, is the flexibility to swiftly change and harness innovation among our colleagues worldwide. Telehealth, then, has the potential to improve care beyond the pandemic. And these standards serve as a roadmap for telecare best practices to continue to develop and address the needs for rural communities, patients with poor access to care, increase overall clinical trial participation, support patient education, and become one strategy, in a toolbox of other strategies, to help narrow the gap in disparate care.

BRITTANY HARVEY: Great. And then you've started to touch on this already, and talking about access to telehealth and how that impacts patients. But finally, how will these standards affect patients?

DR. ROBIN ZON: With regards to patients, what we learned from this evidence review, is that patient satisfaction is high. And they appreciate the convenience, flexibilities, and time and cost savings, as a result of telehealth options. I can share from my own practice that my patients were very grateful that we were able to provide telecare during the pandemic, and even now, as restrictions lessen, they're very thankful to have that opportunity. Many oncology patients want this option to continue for the future, and do not believe their clinical care was compromised.

However, oncology patient-reported outcomes and ongoing patient satisfaction evaluations must continue, along with the assessment of how the continuing challenges of broadband access, lack of technologic devices, or even familiarity with some technology, may serve as barriers to this care model. These standards are meant to assure the same high quality care for patients who choose to use this intervention, as they would if it were in person.

BRITTANY HARVEY: Definitely. Well, thank you for your work on these evidence-based standards directed at delivering high quality and accessible oncology care. And thank you for taking the time to speak with me today Dr. Zon.

DR. ROBIN ZON: And thank you so very much for this opportunity.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the standards go to www.asco.org/standards. Additionally, our annual survey for standard topics is open for submissions suggest a topic for standard development at www.surveymonkey.com/r/standardssurvey. Our standards survey. The link is also available in the episode notes of this podcast. If you have enjoyed what you heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Valeria Mercadante from University College London, Dr. Siri Beier Jensen from Aarhus University, and Dr. Douglas Peterson from UConn Health, authors on “Salivary Gland Hypofunction and/or Xerostomia Induced by Non-Surgical Cancer Therapies: ISOO/MASCC/ASCO Guideline.” This guideline provides evidence-based recommendations for interventions to prevent, minimize, and manage salivary gland hypofunction and xerostomia in patients receiving nonsurgical cancer therapy. Read the full guideline at www.asco.org/supportive-care-guidelines. Suggest a topic for guideline development at www.surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

[MUSIC PLAYING]

My name is Brittany Harvey, and today I'm interviewing Dr. Valeria Mercadante from University College London and University College London Hospitals Trust in London, United Kingdom, Dr. Siri Beier Jensen from Aarhus University in Aarhus, Denmark, and Dr. Douglas Peterson from the School of Dental Medicine and Neag Comprehensive Cancer Center UConn Health in Farmington, Connecticut, authors on "Salivary Gland Hypofunction and/or Xerostomia Induced by Non-Surgical Cancer Therapies: International Society of Oral Oncology, Multinational Association of Supportive Care in Cancer, and American Society of Clinical Oncology Guideline."

Thank you for being here, Dr. Mercadante, Dr. Beier Jensen, and Dr. Petersen.

DR. VALERIA MERCADANTE: Thank you. It's a pleasure to be here.

DR. DOUGLAS PETERSON: Thank you.

DR. SIRI BEIER JENSEN: Thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Mercadante, do you have any relevant disclosures that are directly related to this guideline topic?

DR. VALERIA MERCADANTE: No, I do not have any relevant disclosure.

BRITTANY HARVEY: Thank you. And Dr. Beier Jensen, do you have any relevant disclosures that are directly related to this guideline?

DR. SIRI BEIER JENSEN: No, I have no conflicts to declare related to this guideline topic.

BRITTANY HARVEY: Thank you. And finally, Dr. Peterson, do you have any relevant disclosures that are related to this guideline topic?

DR. DOUGLAS PETERSON: No. No related conflicts to declare.

BRITTANY HARVEY: Thank you. Then let's delve into some of the content of the guideline. First, Dr. Mercadante, can you give us an overview of this guideline's scope and purpose?

DR. VALERIA MERCADANTE: Of course. These clinical practice guidelines focus on the prevention and management of salivary gland hypofunction and xerostomia due to non-surgical cancer therapies. This is something we are deeply passionate about because nonsurgical cancer therapies, including all type of radiation regimens, chemotherapy, and biological cancer therapy, can damage the glands in our mouth that produce saliva, resulting in xerostomia, which we define as patient-reported subjective sensation of dryness and salivary gland hypofunction, which we define as reduced salivary flow rate as measured objectively.

And this condition may last for several months or may become permanent. And because saliva serves so many important function, xerostomia may lead to a range of other symptoms that can impact patient quality of life. And therefore, ASCO, MASCC, and ISOO decided to update the findings of their two previous systematic reviews published in 2010 and provide a practical, evidence-based approach in a multidisciplinary setting to address this important topic.

BRITTANY HARVEY: Great. Thank you for that background. So then I'd like to review the key recommendations of this guideline. This guideline covers two clinical questions, one on prevention and one on management. So Dr. Peterson, starting with prevention, what are the key recommendations regarding pharmacologic and non-pharmacologic interventions for the prevention of salivary gland hypofunction and/or xerostomia induced by non-surgical cancer therapies?

DR. DOUGLAS PETERSON: Thank you, Brittany. As you've noted, the guideline is framed in the context of two clinical questions, prevention, and then followed by the management once the condition has occurred. Relative to prevention, there were eight recommendations, all of which were directed to reducing the risk of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer. And as with other ASCO guidelines, each of these recommendations was in turn supported by text directed to literature review and analysis and clinical interpretation.

So let me just briefly highlight the eight recommendations on prevention. Recommendation 1.1 was that intensity-modulated radiation therapy, IMRT, should be used to spare major and minor salivary glands from a higher dose of radiation. This was a very strong, well-evidenced recommendation. The evidence quality was high. The strength of the recommendation was strong.

Recommendation 1.2 is that other radiation modalities that limit cumulative dose to an irradiated volume of major and minor salivary glands as one or more effectively than IMRT may be offered. Recommendation 1.3 reads that acupuncture may be offered during radiation therapy for head and neck cancer to reduce the risk of developing the symptom of xerostomia.

Recommendation 1.4, systemic administration of the sialogogue bethanechol may be offered during radiation therapy for head and neck cancer. Recommendation 1.5-- and this is an important different type of recommendation-- vitamin E or other antioxidants should not be used to reduce the risk of radiation-induced salivary gland hypofunction and xerostomia. And this is because of the potential adverse impact of these antioxidants on cancer-related outcomes and the lack of evidence of benefit.

In addition to those five recommendations, there were three recommendations for which the evidence was insufficient. In the panel's view, it was important to delineate these three recommendations in the context of current clinical practice as well as opportunities for future research that we'll talk about in a little bit.

The three recommendations for which there was insufficient evidence are 1.6. -- The panel was unable to make a recommendation for or against the use of submandibular gland transfer administered before head and neck cancer treatment. This limitation is due to the current amount of evidence associated with this surgical intervention, submandibular gland transfer, in relation to ever-evolving contemporary radiation modalities.

Recommendation 1.7-- evidence remains insufficient for a recommendation for or against use of the following three interventions during radiotherapy for head and neck cancer. The three interventions are oral pilocarpine, amifostine in association with contemporary radiation modalities, and low-level laser therapy.

And then, finally, Recommendation 1.8-- the evidence remains insufficient for or against the use of several interventions, including selected radiation technology, for example, boost radiation or hyper or hypofractionated radiation therapy, Transcutaneous Electrical Nerve Stimulation or TENS, human epidermal growth factor, and selected complementary medicines. And again, the evidence is insufficient in the panel's view for a recommendation for or against these and several other interventions that are listed in the guideline.

So I'll now turn the microphone back to Brittany.

BRITTANY HARVEY: Great. Thank you for reviewing those prevention recommendations and explaining the evidence that supported those as well. That's very helpful. So following that, Dr. Beier Jensen, what are the key recommendations on pharmacologic and non-pharmacologic interventions for the management of salivary gland hypofunction and/or xerostomia induced by non-surgical cancer therapies?

DR. SIRI BEIER JENSEN: The key recommendations for the management of salivary gland hypofunction and xerostomia induced by cancer therapies are based on the principles of stimulation of the salivary reflex and lubrication of the oral tissues of, say, the mucosa and the teeth. The recommendations 2.2, 2.3, 2.4, and 2.5 address this stimulatory approach.

If there is residual secretory capacity of the salivary glands, stimulation of natural saliva secretion may be provided by chewing or taste stimuli. This can be regular use of sugar-free lozenges, sugar-free candies, or sugar-free non-acidic chewing gum. In patients who have their natural teeth, it's important to be aware that if acidic candies are used to stimulate saliva secretion, then it should be a special nonerosive preparation for dentate patients that will say that they do not dissolve the tooth substance.

Pharmacological stimulation is also an option by prescription medication such as oral pilocarpine and cevimeline in countries where this is available. This may result in systemic adverse effects that limit use in some patients. So the gustatory and masticatory salivary reflex stimulation, Recommendation 2.2, the evidence-based quality was intermediate, and the strength of the recommendation was moderate.

And for the pharmacological stimulation by pilocarpine and cevimeline, it was evidence-based, high-quality, and strong recommendation strength. For patients who have salivary gland hypofunction or xerostomia induced by radiation therapy for head and neck cancer, stimulation of saliva secretion may also be provided by acupuncture, transcutaneous electrical stimulation, or acupuncture-like transcutaneous electrical stimulation, although the evidence base here is less strong than for the other stimulatory management options mentioned. This is addressed in Recommendation 2.4 and 2.5.

If the residual secretory capacity of the salivary glands is low or maybe even nonexistent, then regular lubrication of the oral mucosa and teeth is of relevance. This is addressed in Recommendation 2.1. Such lubrication may be provided by topical application of mucosal lubricants and saliva substitutes, which are agents directed at ameliorating xerostomia and other salivary gland hypofunction-related symptoms.

It is of importance to notice that available stimulatory and lubricating options all provide transitory increased salivary flow rates and transitory relief from xerostomia. If you would like to review the specific recommendations, they can be found in the manuscript.

BRITTANY HARVEY: Great. Thank you for reviewing those recommendations on the management of salivary gland hypofunction and/or xerostomia. So Dr. Peterson, you mentioned this earlier, but there are some cases in the guideline in which evidence was insufficient to make recommendations. And you went through a few of these areas. So what areas of future research did the panel discuss?

DR. DOUGLAS PETERSON: Thanks, Brittany. The panel worked very carefully to relate the quality of evidence to strength of each of the recommendations. In addition to providing important context regarding clinical prevention and treatment of xerostomia salivary hypofunction, novel directions for future research were therefore identified. And I'll just briefly delineate these future directions.

Studies directed to the continued, rapidly-evolving radiation technology such as proton therapy and volumetric modulated art therapy or VMAT, as well as the length of time after this treatment is completed, for example, one to five years after completion of treatment, these studies are needed to assess the relationship of this rapidly-evolving technology to the long-term adverse oral events such as salivary gland hypofunction and xerostomia as well as advanced dental disease and osteoradionecrosis as well.

Importantly, and the panel spent quite a bit of time deliberating this, ethical considerations must continue to be paramount in the study designs. And this is pertinent relative to this guideline. An important issue is that implementation of randomized clinical trials comparing current and novel radiation therapy modalities is typically precluded for ethical reasons. So this is a barrier to address, and the panel wanted to call attention to the scientific and clinical community.

In addition to the radiation technology itself, two additional future research directions also represent potential strategic advances in the field as well. First, radiosensitivity of parotid gland stem cells. For example, it has been recently shown that not all constituents of the parotid gland are equally radiosensitive because of an unequal distribution of the stem cells within the gland. This and related biologic concepts should be incorporated in future randomized controlled trials of head and neck cancer patients.

Secondly, novel regenerative medicine options may be used to spare, optimize, or restore salivary gland function after treatment. The guideline addresses these innovative treatment approaches in the context of both the current state of the science as well as opportunities for future research. I'll turn the microphone back to Brittany.

BRITTANY HARVEY: Great. Thank you, Dr. Peterson, for reviewing those areas where additional research would be helpful. So next, in your view, Dr. Mercadante, what is this guideline's importance and how will it affect clinicians?

DR. VALERIA MERCADANTE: Thank you for this question. We believe these guidelines offer an opportunity for any clinician involved in non-surgical cancer therapies-- oncologists, dentists, dental specialists, dental hygienists, oncology nurses, clinical researchers, advanced practitioners. We all have an essential role in supporting our patients for the entire journey by optimizing symptoms management and improve our patients quality of life.

These guidelines thus suggest a preventative and treatment course, but we've also delineated what we feel is common practice between experts and what areas would need further research to provide, as Dr. Peterson beautifully described, an ethical framework for future studies in this field.

BRITTANY HARVEY: Great. Thank you so much. So finally, Dr. Beier Jensen, how will these guideline recommendations impact patients?

DR. SIRI BEIER JENSEN: Well, for patients who live with these complications during cancer treatment or as [INAUDIBLE] of cancer therapies, these guideline recommendations on prevention and management of salivary gland hypofunction and xerostomia will enable them evidence-based and with the help of professional health care providers to support the natural functions of saliva and promote their oral comfort and health.

BRITTANY HARVEY: Great. Well, thank you all, Dr. Mercadante, Dr. Beier Jensen, and Dr. Peterson for taking the time to work on this guideline and produce evidence-based recommendations for clinicians and patients. And thank you for taking the time to speak with me today.

DR. BEIER JENSEN: Thank you.

DR. DOUGLAS PETERSON: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at www.SurveyMonkey.com/r/ascoguidelinesurvey by August 1st. The link is also available in the episode notes of this podcast.

If you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Muriel Brackstone from London Health Sciences Centre and Dr. Tari King from Dana Farber and Brigham and Women’s Cancer Center, authors on “Management of the Axilla in Early-Stage Breast Cancer: OH (CCO) and ASCO Guideline.” This guideline addresses management & timing of surgical and radiotherapeutic treatment of the axilla in early breast cancer. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

[MUSIC PLAYING]

My name is Brittany Harvey, and today I am interviewing Dr. Muriel Brackstone from London Health Sciences Center in London, Ontario and Dr. Tari King from Dana-Farber and Brigham and Women's Cancer Center in Boston, Massachusetts, authors on "Management of the Axilla in Early-Stage Breast Cancer" Ontario Health (Cancer Care Ontario) and American Society of Clinical Oncology Guideline." Thank you for being here Dr. Brackstone and Dr. King.

DR. MURIEL BRACKSTONE: Thank you.

DR. TARI KING: Thank you for having us.

BRITTANY HARVEY: First, I'd like to note that we take great care in the development of our guidelines in both the ASCO and Ontario Health Cancer Care Ontario program and evidence-based care. Conflict of interest policies were followed for this guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Brackstone, do you have any relevant disclosures that are directly related to this guideline topic?

DR. MURIEL BRACKSTONE: No, I don't have any conflicts to disclose.

BRITTANY HARVEY: Thank you. And Dr. King, do you have any relevant disclosures that are directly related to this guideline topic?

DR. TARI KING: No, I do not have any relevant disclosures.

BRITTANY HARVEY: Great, thank you. Then let's get into some of the content of this guideline. So first, Dr. Brackstone, can you give us a general overview of what this guideline covers?

DR. MURIEL BRACKSTONE: Sure. This guideline reviews how best to diagnose and treat any lymph node spread in breast cancer patients with early-stage disease. It also reviews the role of radiation and surgery in treating the axilla to reduce the risk of regional cancer recurrence in these patients.

BRITTANY HARVEY: Great, thank you. Then I'd like to review some of the key recommendations that this guideline covers. So this guideline addresses five specific objectives. So I'd like it if we could go through each of those.

So for each of these objectives, could you give an overview of those high level recommendations? First, Dr. King, the first objective is about which patients with early-stage breast cancer require auxiliary staging.

DR. TARI KING: Yes, thank you. So I think the two main takeaway points from this objective-- the first is that sentinel lymph node biopsy really is the standard of care for axillary staging for all breast cancer patients when it is felt that information about the lymph node status is necessary. So this really is in the majority of patients that we see and care for with early-stage breast cancer.

We want to know the status of the axillary lymph nodes. That's important in our subsequent treatment recommendations. And there's really no role for axillary lymph node dissection as a staging procedure any longer. Sentinel lymph node biopsy is the staging procedure of choice.

Now, there are some patient populations, however, where we may decide that we don't need the information from the axillary lymph nodes to make subsequent treatment recommendations. And one particular group which is called out in this guideline is for those women who are over the age of 70 with early-stage, again, clinically node-negative hormone receptor-positive, HER2-negative breast cancer, where the information from the sentinel lymph node biopsy is not going to alter subsequent systemic therapy recommendations.

And this is really based on several lines of work demonstrating that omitting sentinel node in these older women, again, with hormone receptor-positive, HER2-negative breast cancer, does not negatively impact their long term outcomes. And so this is an opportunity for us to tailor our approach to a particular patient population without having a negative impact.

BRITTANY HARVEY: Great, thank you, and thank you for reviewing for which patients this is specifically targeted to. So then for the second objective, Dr. Brackstone, is further auxiliary treatment indicated for women with early-stage breast cancer who did not receive neoadjuvant chemotherapy and are sentinel lymph node-negative at diagnosis?

DR. MURIEL BRACKSTONE: No. We use this guideline to confirm that in patients who have early-stage disease and go to surgery first, so they're not having neoadjuvant chemotherapy. And in those patients, if their sentinel lymph node excision for staging is negative, that no further axillary surgery is required. Now, with regards to axillary radiation, it may be considered in the subset of patients whose breast cancer risk is high for recurrence-- so the triple negative subtype, patients who are under 50 years of age, or those with medial tumors.

BRITTANY HARVEY: OK. And then Dr. King, for the third objective, which axillary strategy is indicated for women with early-stage breast cancer who did not receive neoadjuvant chemotherapy and are pathologically sentinel lymph node-positive at diagnosis after a clinically known negative presentation?

DR. TARI KING: Thank you. Yes, so this recommendation really addresses a very large population of our breast cancer patients. Those that present with clinical T1 and T2 but node-negative early-stage breast cancer, we take them to the operating room. We perform a sentinel biopsy, and about 20% to 30% of them will actually end up having positive lymph nodes.

And traditionally, we thought that we needed to do axillary lymph node dissection in the setting of positive nodes. But we now have multiple clinical trials that have addressed this question. And we now know that it is safe to avoid lymph node dissection in women found to have one or two positive sentinel nodes.

We've had trials that have compared lymph node dissection to axillary radiotherapy or lymph node dissection to observation alone. And with either of those strategies, we've seen excellent local control in the women who have not undergone lymph node dissection. And so it really provides us, again, an opportunity to dial back or tailor our therapies to the patient's individual disease burden.

Now, certainly, patients that have more than one or two positive nodes, and the guideline specifically states how to manage patients with three or more positive nodes. And those patients do need additional axillary treatment, either in the form of lymph node dissection or lymph node dissection plus axillary radiotherapy and in some scenarios. Also, the guideline is very clear to define that there are some differences in the level of recommendation for women undergoing breast-conserving surgery and found to have one or two positive nodes as opposed to women undergoing mastectomy and found to have positive nodes.

So certainly, we have the larger body of data in the breast-conserving therapy group, but the guideline is very clear to also highlight the data that is available for the mastectomy group. And again, the overall recommendation is that not everybody with positive nodes needs additional lymph node dissection. And that we have alternatives which we know minimize the morbidity of our treatments.

BRITTANY HARVEY: Great. Thank you for addressing the evidence base behind both of those recommendations as well. So following that, Dr. Brackstone, for the fourth objective, what axillary treatment is indicated? And what is the best timing of axillary treatment for women with early-stage breast cancer? And when is neoadjuvant chemotherapy used?

DR. MURIEL BRACKSTONE: Right. So this guideline was really used to formalize a recommendation against repeating the sentinel lymph node biopsy procedure twice in patients, before and after chemotherapy. We really found that the risk of false negativity in a repeat procedure was too high. So for patients who are having neoadjuvant chemotherapy-- so patients with higher risk cancers-- the axillary ultrasound is useful to guide a biopsy of any suspicious lymph nodes to document if they're positive.

If the clinical exam and the ultrasound are both negative, then the sentinel lymph node excision should be done at the time of surgery after chemotherapy. If they do have a positive lymph node that's confirmed by biopsy before their chemotherapy, and those lymph nodes respond really well to chemotherapy and are no longer palpable, then their staging can occur by sentinel lymph node procedure at the time of surgery. And that avoids what we have standardly done up to now, which is the axillary dissection and the risk of lymphedema that comes with that.

If the sentinel lymph nodes are negative when you're doing your surgery after neoadjuvant chemotherapy, then we are recommending that no axillary lymph node dissection is required. If any of the lymph nodes are positive after neoadjuvant chemotherapy through the sampling technique, then a completion axillary lymph node dissection is still recommended, at least for now, until the results of some ongoing clinical trials looking at avoiding axillary node dissection are completed, which will be in the next several years. In both of those scenarios, however, locoregional radiation is still recommended.

BRITTANY HARVEY: Great, thank you for providing some clarity around those specific scenarios. So then finally, Dr. King, regarding the fifth and last objective, what are the best methods for identifying sentinel nodes?

DR. TARI KING: Thank you. Yes, so this objective encompasses several different clinical scenarios as well. The first being, when you are performing a sentinel lymph node biopsy procedure, do you need to use single tracer or do you need to use dual tracers to help you identify the lymph nodes? We know that in the up upfront surgery setting that you can absolutely identify the nodes with a very low false-negative rate with a single tracer. And this guideline highlights that single tracer is appropriate in patients who are undergoing upfront surgery.

The guideline suggests that the physicians start with radiocolloid, and if there is a good signal, then blue dye can be omitted. In contrast, though, in patients that are receiving neoadjuvant chemotherapy, the data there supports really that the use of dual tracer is important and improves the identification rate, as well as decreases the false-negative rate of the procedure. This recommendation also includes guidance on when ultrasound should be used.

As you just heard from Dr. Brackstone that they do recommend ultrasound prior to neoadjuvant chemotherapy. But in patients undergoing upfront surgery, again, with early-stage disease, clinically node-negative disease, the guidelines states that preoperative axillary ultrasound staging is not recommended. But in anybody who has suspicious or potentially abnormal nodes, then preoperative axillary ultrasound is recommended to confirm nodal status.

And then finally, it is important to note that nodal staging cannot be solely performed with axillary ultrasound. So sentinel lymph node biopsy is still, again, indicated even if the ultrasound is negative. There are many clinical trials going on around the world right now to address that question.

But right now, the evidence still certainly supports that we cannot rely on a negative axillary ultrasound, and sentinel lymph node biopsy should be performed.

BRITTANY HARVEY: Great. Well, thank you both for reviewing those key recommendations around the objectives. So then Dr. Brackstone, in your view, what is the importance of this guideline? And how will it both impact clinicians and patients?

DR. MURIEL BRACKSTONE: Thank you. I would say for clinicians that the guideline was written in an effort to collate all of the clinical trial data and the variable practice patterns across institutions in an effort to standardize treatment. In order to deescalate therapies that don't improve patient outcomes. And hopefully, provide some clarity for clinicians who treat breast cancer.

For patients, I would say that deescalating treatments that are entrenched as standard, but where data demonstrates no known significant disease-free survival or overall survival benefit, that these are important because patients can suffer long term side effects from treatments, such as lymphedema, that could potentially be avoided if they're not clinically indicated.

BRITTANY HARVEY: Great. Thank you both so much for your work on these evidence-based recommendations. And for taking the time to give a summary to our listeners, Dr. Brackstone and Dr. King.

DR. TARI KING: Thank you.

Suggest a topic for guideline development at www.surveymonkey.com/r/ascoguidelinesurvey by August 1. The link is also available in the episode notes of this podcast. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Kim Woofter, RN from Advanced Centers for Cancer Care and John V. Cox, DO, MBA from UT Southwestern Medical Center, co-chairs on “Oncology Medical Home: ASCO and COA Standards.” They review the standards for the OMH model, which is a system of care delivery that features coordinated, efficient, accessible, evidence-based care and includes a process for measurement of outcomes to facilitate continuous quality improvement. For more information, visit www.asco.org/standards.

TRANSCRIPT

[MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

My name is Brittany Harvey, and today I'm interviewing Kim Woofter, RN from the Advanced Centers for Cancer Care in South Bend, Indiana, and John Cox, DO, MBA, from UT Southwestern Medical Center in Dallas, Texas, co-chairs on Oncology Medical Homes, American Society of Clinical Oncology, and Community Oncology Alliance Standards. Thank you for being here, Ms. Woofter and Dr. Cox.

JOHN COX: You bet.

KIM WOOFTER: Thank you for having us.

BRITTANY HARVEY: I'd like to note that ASCO takes great care in the development of its standards and ensuring that the ASCO conflict of interest policy is followed. The full conflict of interest information for the expert panel is available online with the publication of the standards in JCO Oncology Practice. Ms. Woofter, do you have any relevant disclosures that are directly related to these standards?

KIM WOOFTER: No, I don't have anything to disclose.

BRITTANY HARVEY: Thank you. And Dr. Cox, do you have any relevant disclosures that are related to these standards?

JOHN COX: I do not.

BRITTANY HARVEY: Great. Then let's talk a little bit about these standards. So first, can you give us a general overview of the purpose and scope of these standards for the Oncology Medical Home or OMH model?

KIM WOOFTER: Sure. I'll start this one out. The purpose was to collaboratively define a care delivery system with a standardized set of expectations and goals, and it all centered around the delivery of high quality, cost-effective care. And one of the reasons this is so important to all of us right now is to be ready for value-based care. We all need to really have a care delivery system that's patient-centric and has a standardized set for all of us to follow. Dr. Cox, do you see this any differently, or what would you have to say?

JOHN COX: No, I think you've said it well, Kim. I think one of the challenges we all have when we talk about Oncology Medical Home or a system of care is to be challenged to address that question in a simple answer. I would give the predicate that we have had a blossoming of the complexity of oncology care in our science, yet one of the thorny issues that faces oncology practice is how do we equitably and efficiently provide quality oncology care.

And if you were to challenge many clinicians to define how they provide quality oncology care, you get diverse opinions about that. The Oncology Medical Home certification program and the system of care that Kim highlighted attempts to put forward a comprehensive set of standards that helps us define what quality oncology care looks like and to answer those questions in care delivery.

BRITTANY HARVEY: Great. Then, given that scope, what are the key statements made by the expert panel in these standards?

JOHN COX: I'll take a stab at that, but also offer a little bit of insight into the development of Oncology Medical Home. We actually had some 20 years of history with different medical home certification programs to draw on, including significant contributions by oncologists who have worked in different programs to help define what Oncology Medical Home is. So when we took on this project, a collaborative project between ASCO and the Community Oncology Alliance, COA, we drew upon that great history of previous certification programs.

These programs focused on different aspects of care delivery, including aspects that are focused on improving patient engagement and access to practice, ensuring that evidence-based medicine is provided in a practice, looking at how quality is measured and how that feedback is given to practices and how that feedback is used to have quality improvement programs, focusing on palliative and end-of-life care, and addressing one of the unique features of medical oncology delivery, which is the delivery of chemotherapy and how we do that safely. So this was a very comprehensive set of standards. Kim, I don't know if you want to add to this.

KIM WOOFTER: No, I think you stated that very well. And the piece that I really love about this project, and what we focused heavily on, is the equitable delivery of care. We all fundamentally believe that every cancer patient deserves and has the right to high quality, cost-effective care, and this was just the baseline. And I think Dr. Cox explained it very well, that one of the key elements is the quality improvement process, or the re-evaluation continually of how we deliver care, the outcomes of care, the patient satisfaction with that care.

So as we developed this, we knew this was just the foundation. This is the starting point. We've brought some unity around the discussion. We've used evidence to come up with these standards and really defined what's gone on prior to this time. And what's exciting is this is just the beginning of what will evolve over the years to come.

BRITTANY HARVEY: Great. It sounds like this is a really comprehensive document. So I'm reading through the standards. It looks like there's a little bit of a deeper dive on two subcomponents of the OMH model-- first, clinical pathways, and second, survivorship care plans. How do the standards address these two?

JOHN COX: Oh, I'll dive in first again. And not to step on Kim at all about this, but many of the listeners to this podcast will be very familiar with ASCO guideline development. And the traditional clinical guidelines are completely infused and based on an evaluation of what the evidence base is. Care delivery is a bit more complex. Much of care delivery focuses on best practices that have been learned in practice through trial and error-- observation, if you will.

So many of the standards that are in Oncology Medical Home certifications are really based on best practices. However, we knew that we would be challenged to evaluate those standards that had significant cost or significant resource dedication in a practice. If we were going to build those aspects of a certification program forward as being a best practice in a care delivery model, we would need to justify, or at least examine, what evidence base is present to show that it had value.

Two of the most consequential standards that are going to require significant resource development by any practice is the measurement of evidence base through a pathway program. The other one was the significant discussion that has been around survivorship and survivorship care plans. So those two areas of the standards we took a deep dive in in this process. Kim, do you want to add to this?

KIM WOOFTER: Yeah. I really appreciate Dr. Cox's description. He's spot on, as always. I think having managed to practice myself for many, many years, the struggle with the implementation of a clinical pathway program and survivorship care plans or for survivorship program have always been somewhat difficult. And what I love about the standards is we clearly define that pathways are no longer a homegrown list of what I like to do or how I like to treat. It is absolutely evidence-based. Your pathways have to truly reflect the importance of clinical research and what that has done to lead up to the intelligence of that delivery.

What I think is so important, too, is ASCO still did a little bit of work and set the pathway for us on this in that it needs to be a comprehensive list. It needs to have systematic review. We have to demonstrate adherence to pathways and also document when somebody goes off a pathway. And I think that's very important as you manage a practice and as you prepare for this delivery system. It's no longer what we do in the back room. It's very well-defined and very measurable.

As far as survivor care plans, I love that we have migrated a little bit on this standard. I think the nation has migrated. Over the years-- and I'll include the COC in this discussion. Originally, it was check the box, have a survivorship care plan and a visit to explain what the future would look like. And we now know that isn't the best way to handle survivorship.

Patient satisfaction and outcomes are much better when we have a survivorship program. And that's what the standard calls out. It is not just a care plan or a piece of paper. It is support. It is ongoing evaluation of the patient. It's integration with the primary care and when to transition back to primary care. So what's exciting is it is now a program versus just a care plan.

BRITTANY HARVEY: Thank you both for explaining the evidence-based reasoning behind those two components. So then you've both noted earlier the importance of these standards for quality oncology care. So why are these standards important, and how will their implementation impact clinicians?

KIM WOOFTER: I'll jump in to why I think they're important-- and I think the whole industry, the whole ecosystem of oncology care thinks they're important-- is we need standardization. We need real, evidence-based standardization. And we need to prepare ourselves in all settings-- community oncology practice settings, academic settings-- for the value-based care that we're going to be required to deliver every day, all day. And clinicians, I believe, will embrace this. They'll embrace this because it's taken away some of the ambiguity of what care delivery should look like, and it levels the playing field, if you will.

It also helps with the dialogue with patients and their employers. I think we could all argue that patients and employers are the ultimate payers. And they now have a mechanism by which they can evaluate, am I getting the highest quality, most affordable care? And these Oncology Medical Home standards will be the foundation for that discussion. And I'm excited that everyone will be involved in that discussion. So I think that's why they're very important.

BRITTANY HARVEY: Great. And then, finally, how will these standards impact patients?

JOHN COX: Well, I think our whole goal in delivering efficient and quality oncology care is to be very patient focused. I would underline that this entire concept of an Oncology Medical Home is built around a patient centered care. So every standard that this program identifies has the patient at the center of care. And I think anybody who reads through the standards can see that every aspect of this is focused on some issue that they can relate to patients in their practice stumbling over.

We have this wonderful technology of care. But right now, I would challenge oncology practice universally that as our science has become more complex, patients are having to jump through more hoops to get that quality care. Specialization breeds fragmentation. What we want this program to do is to define what a oncology practice must do to help that patient have a coordinated care approach for all aspects of their cancer journey.

And I want to come back and just put a coda, a real strong statement, is this is a care delivery system. We are trying to take as comprehensive view of the delivery of oncology practice in the certification program as we can. It's not intended to parse. It's intended to focus on the patient and to provide a comprehensive system of care.

The other challenge is we know that the only way there can be efficient and easily accessible practices that can provide this kind of care is that they be adequately funded. And though this certification program does not speak to funding directly-- this is about the quality of care delivery-- we wanted to build a program that payers in industry could look at and build their reimbursement systems around. We hope that as new reimbursement models, alternative payment models come to bare, that if practices are pursuing this certification program, they will be able to meet the demands of the payer and apply this toward a comprehensive, meeting the standards of any alternative payment program.

And to that end, I really want to defer maybe a little more discussion of this to Kim. Kim, we sort of present two ends of the barbell, if you will, of care delivery. I, a practitioner, Kim is on the point of the sword in dealing with her practice about the reimbursement issues and contracting. So when we talk about this, what is the impact for patients?

Part of that is recognizing that patients have insurance. They have employers. They have people who are paying for this care. And that's really important to address. Kim, I'm long-winded. Maybe I'm trying to wrap too much into this answer. But I'll let you add to the issues of reimbursement and how this affects patients.

KIM WOOFTER: Well, thank you, Dr. Cox. You're never too long-winded. I always love to hear you speak, and your insight is spot on. And I think, from a patient's perspective, what's exciting about this program is it engages and empowers patients right from the beginning. You'll see, very well spelled out in the standards, that one of the requirements is that you educate that patient about what an Oncology Medical Home really means, what the components are. And that empowerment of the patient allows them to be part of the voice for quality oncology.

As we work with their payers, their employers, the patient themselves understand the value of what we are doing in collaboration. They understand that we provide them access, 24/7 access, you'll see, as part of the requirement. And they understand very well and can help us communicate to everybody in the ecosystem that this comprehensive package is what gives them the highest quality, allows them, like I said, the most access. It allows them safe chemo delivery. And as they communicate that, it will become the desired standard.

The patient is absolutely the ultimate winner here. Everything we do as clinicians and administrators is based around the patient. Outcomes, satisfaction, end-of-life initiatives. And I believe by putting this comprehensively and well-defined into one set of standards, we have helped the patient to achieve that goal.

BRITTANY HARVEY: Well, it sounds like these standards will have a real positive impact for patients and quality oncology care delivery. So I want to thank you both for your work on the development of these Oncology Medical Home standards and for taking the time to speak with me today, Dr. Cox and Ms. Woofter.

KIM WOOFTER: It was our pleasure.

JOHN COX: It's our pleasure.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the standards, go to www.asco.org/standards. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Zeba Aziz from Hameed Latif Hospital in Lahore, Pakistan, Dr. William Burke from Stony Brook University Hospital in Stony Brook, NY, and Dr. Keiichi Fujiwara from Saitama Medical University International Medical Center in Saitama, Japan, authors on "Assessment of Adult Women with Ovarian Masses and Treatment of Epithelial Ovarian Cancer: ASCO Resource Stratified Guideline." This guideline provides recommendations in three resource-constrained settings on diagnosis and staging of adult women with ovarian masses and treatment of patients with epithelial ovarian (including fallopian tube and primary peritoneal) cancer. Read the full guideline at www.asco.org/resource-stratified-guideline.

TRANSCRIPT

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today, I'm interviewing Dr. Zeba Aziz from Hameed Latif Hospital in Lahore, Pakistan, Dr. William Burke from Stony Brook University Hospital in Stony Brook, New York, and Dr. Keiichi Fujiwara from Saitama Medical University International Medical Center in Saitama, Japan, authors on Assessment of Adult Women with Ovarian Masses in Treatment of Epithelial Ovarian Cancer: ASCO Resource Stratified Guideline.

Thank you for being here, Doctors Aziz, Burke, and Fujiwara. First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline and the Journal of Clinical Oncology, Global Oncology. Dr. Burke, do you have any relevant disclosures that are directly related to this guideline topic?

DR. WILLIAM BURKE: I do not.

BRITTANY HARVEY: And Dr. Fujiwara, do you have any relevant disclosures that are related to this guideline topic?

DR. KEIICHI FUJIWARA: Yes. I have the consultancy for the PARP inhibitors development.

BRITTANY HARVEY: Thank you. And then Dr. Aziz, do you have any relevant disclosures that are related to this guideline?

DR. ZEBA AZIZ: No, I don't.

BRITTANY HARVEY: Thank you. OK, so first, Dr. Burke, can you give us a general overview of what this guideline covers?

DR. WILLIAM BURKE: Sure, Brittany. The purpose of this guideline is to provide expert guidance in treatment of adult women 18 years and older with epithelial ovarian cancer, including fallopian tube and primary peritoneal cancer, to clinicians, public health leaders, patients, and policymakers in a resource-constrained setting. To do this, ASCO has established a process for development of resource stratified guidelines, which includes a mixed methods of evidence-based guideline development, adaptation of the clinical practice guidelines to other organizations, and formal expert consensus. This guideline summarizes the results of this process and presents resource-stratified recommendations. The recommendation of this guideline centers around the four key clinical questions pertaining to the care of women with ovarian cancer.

BRITTANY HARVEY: Great. And then, as you just mentioned, this is a resource-stratified guideline. So Dr. Fujiwara, can you tell our listeners about the four-tier resource stratification used for the development of this guideline?

DR. KEIICHI FUJIWARA: Oh, yes. So we have the four tiers resource stratification, which were basic, limited, enhanced, and maximum. So for the basic, it's the core resources or fundamental services that are absolutely necessary for any public health or primary health care systems to function. So the basic levels of this typically are applied in our single clinical interactions. For the limited, so this is the second tier resources or services that are intended to produce major improvements in outcomes such as, for instance, cost-effectiveness, and are attainable with a limited financial means and modest infrastructures. So the limited level of service may involve single or multiple interactions. And the third tier is enhanced. The third tier resources or services that are optional, that are important, enhance the level of resources should produce further improvements in the outcome and to increase the number of the quality of options in the individual choices. Lastly, the fourth tier is a maximal, so high-level or state of the art resources, or services that may be used or are available in some high-resource countries, and/or may be recommended for the high resource setting guidelines that do not adapt to resource constraints, but that nonetheless should be considered for a lower priority than those resources or services listed in the other categories on the basis of extreme cost and/or impracticality for the broad use of the resource-limited environment.

BRITTANY HARVEY: Great. Thank you for going over those. So next, I'd like to review the key recommendations of this guideline. This guideline addresses four overarching clinical questions. So first, Dr. Aziz, what are the key diagnostic and staging recommendations for patients with symptoms of epithelial ovarian cancer?

DR. ZEBA AZIZ: Thanks, Brittany. Basically, as pointed out, we have three levels. The basic level usually involves one or two encounters, and at the basic level, the doctor makes a clinical assessment of a suspected ovarian mass, takes a good history and physical, and the family history is also important at the same time. At the basic level, one can do a chest X-ray and an ultrasound to confirm the suspicion, and then the doctor should ideally send the patient to a limited or an enhanced level-- wherever the patient can go. At the limited and enhanced level, again, you have to do diagnostics, which include a CT scan and an MRI if it's available and feasible.

You can do the biomarker studies for CA125 and CEA level, and to make a diagnosis, you can do a CT-guided biopsy. You can also do a cell cytology and if a cell block preparation can be made through cell block. Very rarely, if need be, and if you think that you need to make a diagnosis and you can't do anything else, laparoscopy can be done. Once the diagnosis is made, you then go for staging. And the staging is usually done when you're doing a CT scan and you do an abdominal and pelvic CT scan. You do a CT scan of the chest if you think it's needed. Otherwise, a chest ray will suffice. And then you go forward and get a diagnostic workup done and send it to the surgeon for either and decide on a multidisciplinary with a neoadjuvant or surgical assessment testing.

BRITTANY HARVEY: Great. Then so next, Dr. Fujiwara, what are the overarching recommendations for surgery with women with stage one to four epithelial ovarian cancer?

DR. KEIICHI FUJIWARA: Yes. So the purpose of the surgery is to diagnose, stage, and/or for treatment. So we strongly recommended the ovarian cancer surgery should be performed by trained gynecological oncologists or surgeons with oncologists' surgical expertise. If it is not suitable, we strongly recommend to refer those patients to the highest-resourced level center with an oncology surgical care capacity.

For the staging purpose, where the feasible patients with a presumed early stage ovarian cancer should undergo surgical staging by train surgeons. In basic setting, surgical staging is not feasible. Thus, it is not recommended. For the treatment purpose of the women with advanced ovarian cancer, which is a stage three or four, should receive optimal surgical debulking to remove all visible disease to improve overall survival by trained surgeons.

BRITTANY HARVEY: Great. And then Dr. Burke, what are the key recommendations for optimal adjuvant and systemic therapy for patients with stage one to four epithelial ovarian cancer?

DR. WILLIAM BURKE: Sure. Well, one of the most important things is that access to appropriate evidence-based chemotherapy agents, contraindications to chemotherapy, and potential side effects of chemotherapy should be evaluated and managed in every patient. Basic resource settings that most likely lack the capacity to provide safe administration of chemotherapy should refer patients to a higher level center for evaluation. Limited settings without skilled capacity should refer patients to settings with access to specialized care. Some other notes include that clinicians should be able to document pathology and stage to determine eligibility for adjuvant chemotherapy.

If pathology confirmation is not possible due to patient or resource limitation, alternatives can be discussed. Clinicians should not administer systemic treatment, adjuvant chemotherapy, to patients with ovarian low malignant potential tumors or early stage, microinvasive borderline tumors, independent of stage. Combination chemotherapy with paclitaxel and carboplatin is the standard of care for adjuvant therapy in ovarian cancer. However, single agent carboplatin may be utilized due to resource limitation or patient characteristics. Only in enhanced settings, highly selected cases can be assessed for appropriate evidence based intraperitoneal chemotherapy following optimal debulking, where there are resources and expertise to manage the toxicities.

BRITTANY HARVEY: Great. And then the last overarching clinical question-- Dr. Aziz, what is recommended for patients with recurrent epithelial ovarian cancer?

DR. ZEBA AZIZ: You know, with recurrent ovarian epithelial cancer is a tough option, especially in patients residing in the low-middle income countries. Supportive care treatment should be started together with whatever we have to do. So there are three options. There's one patient who presents with a rising CA125 with no evidence of disease and asymptomatic. We can elect to follow these patients, and it's easier to follow them until they become symptomatic or they have evidence of disease. If you have small volume disease which is resectable, you send them to an enhanced level setting, ideally where surgery can be done.

Then you also look at patients and divide them into platinum resistant or platinum sensitive. If they're platinum sensitive, you can give a platinum-containing regimen, but if they're platinum resistant, you can put them on a non-platinum chemotherapy-- a single agent or whatever-- but these patients are tough to manage in that part of the world.

BRITTANY HARVEY: Definitely. Well, thank you all for reviewing each of those key recommendations. The full recommendations are available in the guideline, but those are some important highlights. Thank you very much. So Dr. Burke, in your view, what is the importance of this guideline, and how will it change practice?

DR. WILLIAM BURKE: Sure. Well, I think the importance of this guideline is that it globally targets health care providers, including gynecologic oncologists, surgeons, nurses, and palliative care clinicians, as well as non-medical community members, including patients, caregivers, and members of advocacy groups, providing them with resource-stratified clinical guidelines, recommendations that can be implemented across many health settings. The guideline will hopefully raise awareness among frontline practitioners, and provide guidance to provide adequate services in the face of varied and sometimes limited resources we see throughout the world.

BRITTANY HARVEY: Great. And Dr. Aziz, how do you envision that these guidelines can be applied in low and middle income regions?

DR. ZEBA AZIZ: These are extremely important guidelines for our part of the world. Remember that there are about 70 low-middle income countries, and all these countries-- and within each country-- there's marked variability in training of physicians who encounter cancer patients. There's also difficulty by the patients in accessing a few tertiary care centers, cancer care centers which are present, and most of all, financial implications, because you have to go there, you have to stay there, you have to get your chemotherapy, and this is true for the marginalized population.

You also have to remember that more than 50% of our patients are treated in a limited resource setting, and the availability of enhanced resources are very difficult for them. And these limited settings are in public sector hospitals, where the doctors-- some of the doctors are very good, but the physicians or surgeons are overworked. They have resources ranging from minimal to moderate, depending on the funds available. And because they're overworked and there are few working hours, detailed counseling of the patient is infrequent because there are a large number of patients there. And the majority of surgeries, which is the cornerstone of ovarian cancer, is done by the postgraduate fellows who are there. Sometimes the senior consultants do surgeries, but most of the time, it is done by them.

First time chemotherapy is easier to deliver because it does not have any expensive medicines. There are a lot of generics for carboplatin and taxanes regimen available, so it's not a major problem. But treating the side effects, again, becomes very expensive, and the patients have to come back and forth. The relapsed disease is very difficult to treat because we don't have too many options there and it is expensive. We've also seen that patients who are treated at an enhanced level do much better. Their survival outcomes are better, the supportive care treatment is better, and the progression-free survival is also better.

BRITTANY HARVEY: Great. Thank you for reviewing that information. And then finally, Dr. Fujiwara, Dr. Aziz touched on this a bit on how it impacts patients, but how else do you view that these guideline recommendations will affect patients?

DR. KEIICHI FUJIWARA: Yes. As Dr. Aziz said and Dr. Burke said, this guideline is written for the patients around the world in a different medical environment. So I think that it is very useful resource of information for patients to receive the best ovarian cancer treatment that suits the actual situation of each country or regions.

BRITTANY HARVEY: Great. Well, thank you all for your work on these important guidelines. It sounds like they're going to have a real impact globally, and so I really appreciate both all of your work on these guidelines, and also for taking the time to speak with me today, Dr. Aziz, Dr. Burke, and Dr. Fujiwara.

DR. ZEBA AZIZ: Thank you, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/resource-stratified-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Jennifer Griggs from University of Michigan and Dr. Gary Lyman from Fred Hutchinson Cancer Research Center & University of Washington, co-chairs on “Appropriate Systemic Therapy Dosing for Obese Adult Patients with Cancer: ASCO Guideline Update.” This guideline updates recommendations on appropriate dosing of systemic antineoplastic agents – including cytotoxic chemotherapy, checkpoint inhibitors, and targeted therapies – for obese adults with cancer. Read the full guideline at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at podcasts.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Jennifer Griggs from the University of Michigan and Dr. Gary Lyman from Fred Hutchinson Cancer Research Center and University of Washington, co-chairs on appropriate systemic therapy dosing for obese adult patients with cancer ASCO guideline update. Thank you for being here, Dr. Griggs and Dr. Lyman.

DR. GARY LYMAN: Thank you, Brittany.

DR. JENNIFER GRIGGS: Thanks for having us.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Griggs, do you have any relevant disclosures that are directly related to this guideline topic?

DR. JENNIFER GRIGGS: No, I don't.

BRITTANY HARVEY: And Dr. Lyman, do you have any relevant disclosures related to this guideline?

DR. GARY LYMAN: I have no relevant disclosures to this guideline.

BRITTANY HARVEY: Great. Thank you, both. Then let's get into the substance of this guideline update.

So Dr. Lyman, can you explain what prompted an update to this guideline on appropriate dosing for obese adult patients with cancer last published in 2012, and what is the scope of this update?

DR. GARY LYMAN: Thank you, Brittany. Yes, this is an update of a previous guideline, several years old, that was prompted by evidence that there was wide variation in how chemotherapies at that time were being dosed, particularly in the overweight and obese population. Some were capping the dose, some were giving the full weight-based dosing, and all sorts of permutations in between. So that guideline was greeted, I think quite favorably, and, in fact, led to changes in clinical practice in many institutions and I believe also in the cooperative group research networks.

Since that time, however, a whole array of new therapies have come along. These, we'll talk about briefly in this podcast, include the novel targeted therapies based on molecular targets, as well as the new checkpoint inhibitors, and other monoclonal antibody therapies, where the dosing issues, in general, are different for many of these agents. And specifically for patients who are overweight and obese, we thought it was important that we update this guideline, review the evidence in total appropriate to the dosing of these new agents in overweight and obese patients, and make updated recommendations that would be more relevant to that practice of oncology in 2021.

BRITTANY HARVEY: Great. Thank you for explaining the previous version of the guideline and for explaining the expanded scope. So given that, I'd like to review those key recommendations made in this guideline. So Dr. Griggs, what are the recommendations regarding dosing of cytotoxic chemotherapy in obese adults with cancer?

DR. JENNIFER GRIGGS: With rare exception, we recommend, and the evidence supports, using actual body weight when we calculate doses. So whether it's just per kilogram, milligrams per kilogram for example, or per meter squared, using body surface area, we recommend that the actual body weight of the patient be used with no compromise or capping, no maximizing the dose as if it were calculated using 2 meter squared for example. There's no evidence that that's necessary to avoid side effects, and, in fact, there's increasing evidence that doing so, that limiting the doses in patients, is associated with decreased benefit of the treatment.

Since the original guideline came out, there's been no convincing evidence that has made us change our recommendation. So again, in brief, we recommend that actual body weight be used in calculating the target dose for cytotoxic chemotherapy.

BRITTANY HARVEY: Great. Thank you. That's very clear for clinicians. So Dr. Lyman, you mentioned this in your introduction to the scope of this guideline, what are the recommendations for dosing of checkpoint inhibitors and targeted therapy in obese adults with cancer?

DR. GARY LYMAN: Well, Brittany, these are the new agents that I referred to in the introduction that have appeared in broad usage in oncology and other disciplines since our 2012 guideline recommendation. Many of these are monoclonal antibodies, and they just generally have a wider therapeutic index and distribute an extracellular fluid and plasma with less correlation with body size descriptors, such as weight or body surface area. They may be, in fact, in some cases are amenable to fixed dosing schedules.

So this has all led to a whole array of new agents approved by the FDA for cancer therapies that are being dosed on a wide variety of means, some based on dosing like we have done for classical chemotherapy that Dr. Griggs discussed using body surface area, in some cases body weight, and then some being dosed base on fixed dosing-- fixed size regardless of the body size that the patient represents. So it gets a little complicated, because currently the monoclonal antibodies and many of these therapies are dosed in different ways, versus fixed dosing is recommended for some of the immunotherapies, alemtuzumab, afatinib, as well as targeted therapies like pertuzumab, which are relatively recent.

And then weight-based dosing, milligram per kilogram, is used for other checkpoint inhibitors, like ipilumumab, as well as other monoclonals like bevacizumab and trastuzumab among others. And then again some were still dosing based on body surface area, such as rituximab and cetuximab. So the bottom line is these agents will be dosed and the approved dosing by the FDA will generally be based on the schedule and dosing that was used in the pivotal clinical trials. And different companies in different disease areas have chosen different ways of dosing these.

So for us, with this guideline, and this is true of overweight and obese patients in particular, we recommend dosing these agents based on the FDA approved dose and schedule for that agent. But be aware, as I indicated, that it will vary from agent to agent and category of agent from one to the other. Because of the convenience and perhaps some safety issues related to fixed dosing, additional data has been submitted to the FDA for some agents, nivolumab, for instance, and pembrolizumab, to suggest that a different dosing schema, fixed dose schema can be used, and that has led to a modification in those dosing recommendations.

So even if you think you know, if you're not using these agents day in and day out, you really should check and make sure you're using the currently recommended dosing. And final point is, in the overweight and obese patient, any dose modification because of adverse events or scheduling changes should be applied independent of the patient's obesity or overweight status. In other words, any dose modification that you would apply a healthy weight patient is the same type of dose modification you should apply in the overweight and obese patient and not modify solely based on the patient's weight or obesity status.

BRITTANY HARVEY: Definitely. Great. That was actually going to be my next question. So Dr. Griggs, do you have anything to add about for obese adult patients with cancer who experience high grade toxicity-- should clinicians modify dosing and schedules differently than they would for non obese patients?

DR. JENNIFER GRIGGS: Well, as Dr. Lyman says, the same with checkpoint inhibitors and targeted therapies, we don't recommend and the evidence doesn't support making changes in a different way. That is, there's no interaction between obesity status and the recommendation through dose modification. So in a patient who has severe toxicity related to chemotherapy as well as the targeted agents and checkpoint inhibitors, we recommend that standard dose modifications be made, and moreover that if the patient does better that one consider dose escalation again, if there were for example another concurrent illness that might have contributed in part to the toxicity. So if that other factor resolves, let the dose be increased again to try to maintain that relative intensity dose over time that we consider ideal.

BRITTANY HARVEY: Great. Thank you for reviewing that for the cytotoxic agents in addition to the immune checkpoint inhibitors and targeted therapies. So then, Dr. Lyman, the last clinical question of this guideline-- how should body surface area be calculated?

DR. GARY LYMAN: Well, this is the issue alluding to when I mentioned that there could be safety concerns with these complex calculations. And we tried to make it simple in the guidelines. There are multiple BSA-- Body Surface Area-- calculators out there. You can search them on the web, you can go to textbooks, and there's a whole range of them.

And we actually looked at this. This goes back to the original guideline, and it holds true today, that if you compare that the dose calculated by these different calculators, it's very close to one another. So our bottom line recommendation-- if you're going to use body surface area for calculating the dose of conventional cytotoxic therapy or any of these other agents where that dosing approach is recommended, any of these calculators are going to give you a safe and hopefully effective dose of the therapy. And we don't prefer or recommend one over the other.

Again, there are many on the web. Many institutions have their preferred and may even have embedded the calculator within the EMR or computer order entry system. Many prefer the Mosteller, the Du Bois, the Boyd, there's a whole variety of these, but all of them will generally yield very similar calculations. We haven't mentioned, and just to point out, as most oncologist know certainly, is one drug group, a specific agent, carboplatin is dosed differently. And for carboplatin, we calculate the dose based on a target area under the curve and GFR, so that the Calvert formula calculates the dose differently for carboplatin. And that's for historical as well as pharmacologic reasons.

So again, as Dr. Griggs mentioned, for classical chemotherapy, body surface area is the most common one. But any of the approved calculators or available calculators will give you essentially the same dosing recommendation. And I would follow what's recommended by your institution.

BRITTANY HARVEY: OK. Well, thank you both for reviewing the key recommendations in this guideline update. So finally, Dr. Griggs, in your view, why is this guideline update important, and how will it impact both clinicians and patients with cancer?

DR. JENNIFER GRIGGS: Dr. Lyman and I have viewed this as a really important guideline and guideline update. Because, as we know, the prevalence of obesity is increasing and obesity is associated with an increase in the risk of cancer-- many cancers, not all. And moreover, people who are obese tend to have worse outcomes. And so to try to level out and keep people from systematically what we consider underdosing people who are obese with chemotherapy is very likely to improve outcomes for an important group of our patients.

In addition, the update, because it's been updated now since 2012, we have more evidence that what we're recommending, what the evidence has supported thus far historically and in trials, is actually safe. There's been no signals, in other words, that the original guideline needed to be altered for certain patients or drugs. And now, with this update, we're pretty confident, based on what we know from the FDA and clinical trials, that using actual body weight is not just appropriate, but it's also recommended. So it's an important issue for the population and for our patients, and it's important for clinicians to have the confidence to use actual body weight when calculating anticancer drug doses.

BRITTANY HARVEY: Great. Thank you, both, for all the work you did to update this evidence-based guideline and thank you for taking the time today to speak with me on the podcast, Dr. Griggs and Dr. Lyman.

DR. GARY LYMAN: Thank you, Brittany.

DR. JENNIFER GRIGGS: Thanks, Brittany. We want to thank our co-authors on the guidelines, as well as the ASCO staff for their tremendous work.

DR. GARY LYMAN: Yes, we couldn't do it without all of them, and it's a tremendous team effort.

BRITTANY HARVEY: Definitely. We thank them all as well. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Jessica Geiger, MD, from Cleveland Clinic and Patrick Ha, MD, from the University of California, San Francisco, co-chairs on “Management of Salivary Gland Malignancy: ASCO Guideline.” This guideline provides recommendations for preoperative evaluation, surgical procedures, radiotherapy techniques, the role of systemic therapy, and follow-up evaluations for patients with salivary gland malignancies. Read the full guideline at www.asco.org/head-neck-cancer-guidelines.

TRANSCRIPT

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Jessica Geiger from Cleveland Clinic and Dr. Patrick Ha from the University of California San Francisco, co-chairs of management of salivary gland malignancy ASCO guideline. Thank you for being here, Dr. Geiger and Dr. Ha.

DR. PATRICK HA: Thank you, Brittany.

DR. JESSICA GEIGER: Thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Geiger, do you have any relevant disclosures that are directly related to this guideline?

DR. JESSICA GEIGER: No, I don't.

BRITTANY HARVEY: And Dr. Ha, do you have any relevant disclosures that are related to this guideline?

DR. PATRICK HA: No, I do not.

BRITTANY HARVEY: Thank you both. Then let's talk about some of the content of this guideline. So first, Dr. Geiger, can you give us a general overview of the purpose and the scope of this evidence-based guideline on the management of salivary gland malignancy?

DR. JESSICA GEIGER: Sure. So salivary gland cancers-- they're relatively rare, and they encompass a wide variety of both histologies, but also biologic behaviors of cancers. This is a very multidisciplinary tumor, so surgeons, radiation oncologists, pathologists, medical oncologists-- they all play an integral role in treating these patients. And the purpose of this guideline was to bring all of these disciplines together and to develop an as strong as possible, evidence-based way of approaching the diagnosis of such cancers and then approaching it from all modalities of therapy-- surgical, radiotherapy, systemic therapy-- in a very evidence-based and organized fashion.

BRITTANY HARVEY: Great, then as you just mentioned, this is a multidisciplinary guideline, and it covers six different subtopics on the management of salivary gland malignancy-- preoperative evaluation, surgical management, radiotherapy, systemic therapy, follow up, and treatment options for recurrent and metastatic disease. I'd like to go through and review the key recommendations from each of those sections for our listeners.

So first, Dr. Ha, what is the guideline recommend regarding preoperative evaluation for patients with salivary gland malignancy?

DR. PATRICK HA: Great, so I'd first like to start off by saying that we were focusing on salivary gland malignancy. So again, these are tumors where we may not know the diagnosis, but we're suspicious of this being cancer as opposed to a benign tumor.

So along those lines, there are many different imaging recommendations-- first off, that some sort of imaging would be helpful if there's a suspicion of cancer, and then drilling down a little bit more specifically if there is concern about bone involvement. And then CT scan was recommended if it was more of a concern about the soft tissue or perineural invasion or skull-based invasion, then MRI was suggested. And we did spend some time focusing on the strength of and the importance of tissue biopsies, either with fine needle aspiration biopsy or core needle biopsy as a real helpful tool to help clinicians determine what sort of procedures and care this patient might need.

Additionally, with the onset of more understanding of the pathology in the markers, it was felt that using these biopsies-- these FNAs or core biopsies-- to perform either molecular or immunohistochemical studies could further help clarify what the diagnosis would be and thus lead to sort of more specific and defined treatment subsequently.

BRITTANY HARVEY: And then following those evaluation and imaging and biopsy recommendations, what are the key surgical recommendations?

DR. PATRICK HA: Yeah, so again this is probably known to most people-- that when it is considered resectable, the surgery is really the mainstay upfront management option for these patients. We spent some time looking at the different types of surgeries and felt that it was a bit up to the discretion of the surgeon, but it depends on the location as to what type of surgery exactly needs to be done. But the idea is obviously we would want a complete resection of it and margins where possible.

And then we address the nodes and the ability for these cancers to sometimes spread regionally. And basically, if these are high risk or high grade cancers, specifically if there are things like the grade of the tumor itself-- the type-- and then whether there were other concerning features about it, than a neck dissection electively would be offered.

If there were N positive disease, then the neck dissection definitely should be performed. And then there was discussion as well about the facial nerve and how to manage that, wherein the evidence mostly reported trying to preserve the facial nerve whenever possible.

And then we did talk a little bit about the possibility of palliative resection, which can occur sometimes in the presence of distant metastatic disease upon presentation. And it was felt again that there is a palliative component to surgery if the metastatic disease didn't seem to be rapidly progressive or imminently lethal. So these are all the difficult decisions that we discussed regarding surgery.

BRITTANY HARVEY: OK, thank you. Then Dr. Geiger, how does this guideline address radiotherapy for patients with salivary gland malignancy?

DR. JESSICA GEIGER: Well, as Dr. Ha mentioned, this is primarily a surgical disease. So most of the recommendations regarding radiotherapy involve the post-operative setting. But if you look at the guideline, we have actually laid out 10 recommendations regarding radiation, and they're dependent on various factors with each cancer, so the histology of the disease, other tumor pathologic factors, such as T-stage, vascular, lymphatic invasion, margin status, perineural invasion-- all of that goes into the recommendation here. There's also considerations for what nodal basins to cover, based on where the tumor is, and even the type of radiation, and, of course, the timing of radiation. All of that is important to be considered, and all of those specific features are mentioned within the recommendations.

BRITTANY HARVEY: Great. And then in addition to those radiotherapy recommendations, what's the role of systemic therapy for patients with salivary gland malignancy?

DR. JESSICA GEIGER: Well, unlike the radiation section, where I said we have 10 specific recommendations, we're limited with the evidence for the use of systemic therapy in the curative setting of these diseases. So one point that I will make is, again, we're very limited based on evidence, and this is what is driving such a guideline-- is evidence, evidence, evidence. And we just don't have it.

There are several large studies that are ongoing, but until those results flesh out, we were limited. And so our recommendations are based on the lack thereof, and often are considered low quality or moderate strength of recommendation at best, based on our expert panel.

Basically, outside of a clinical trial, we're not recommending the addition of radiosensitizing chemotherapy with post-op radiotherapy. Again, that can be contentious, especially in the clinical realm, where there's a wide variety of biologic behavior. So some of the more aggressive diseases, we know that oncologists are advocating for the use of chemotherapy. But again, the evidence is not there yet, and so we weren't able to make that informative within this guideline.

And then we also addressed tumors that are expressing different markers, like androgen receptor, HER2, and make a recommendation for the use of targeted therapy, again noting a lack of evidence for it outside of a clinical trial currently.

BRITTANY HARVEY: OK, thank you for explaining the reasoning and the evidence behind those particular recommendations. So then for patients who have then completed treatment for salivary gland malignancy, Dr. Ha, what are the timelines and recommendations for follow up for these patients?

DR. PATRICK HA: Well, so again, this is where the data are really not strong. And so you'll notice that pretty much all of these recommendations were informal in consensus. But similar to the NCCN guidelines for general cancer follow up was believed by the panel that early follow up more frequently and just sort of spaced out over time was important.

And then there was an emphasis on some form of imaging often, whether that be CT or MRI, it's sort of up to the practitioner. And then perhaps for a couple of years after treatment, that might be important.

It was also felt that, as everyone probably knows, that one of the areas where this may spread to distantly is in the lung. So getting some sort of chest imaging between years 2 and 5 would be important as well, just in case one can detect an asymptomatic yet potentially treatable metastasis.

So again, a lot of informal consensus. The idea is that we feel it's important to continue to follow these patients to look for signs of recurrence, whether that's with imaging or physical exam. We thought that either would be an option.

BRITTANY HARVEY: Definitely. And the last section of recommendations for this guideline is on recurrent or metastatic salivary gland malignancies. So what are those treatment options, Dr. Geiger?

DR. JESSICA GEIGER: Well like before, when we're talking about systemic therapy, again, informal consensus is sort of driving the majority of these recommendations, again highlighting lack of strong evidence. That said, there are several different clinical situations that we address within these recommendations.

So whether a patient presents with diffusely metastatic disease with a large tumor burden or oligometastatic disease, where maybe just one or two local or regional areas have recurred. And so in that latter case, you could discuss with the patient is it worthwhile to do some locally ablative therapy, such as SBRT, or possibly a resection versus, for more widely metastatic disease, starting systemic therapy.

Now, there's also a recommendation specifically for the histology adenoid cystic carcinoma. And that is based on studies that have been done with tyrosine kinase inhibitors. And so there's some evidence for that outside of cytotoxic chemotherapy.

And then we also make a mention, which is very important, again on checkpoint inhibitors, but also on some of the targeted therapies-- doing next generation sequencing, looking for molecular markers that drive the progression of these diseases, and then in subsequent targeted therapies for this.

So we really try to encompass any and all particular situations that an oncologist may encounter with these diseases and offer some guidelines and recommendations regarding the appropriate management.

BRITTANY HARVEY: Great. Thank you both for reviewing those key points of the recommendations. This guideline goes through a lot of content, and so it's interesting to hear more about what kind of those details are for each section. So Dr. Ha, in your view, what is the importance of this guideline, and how will it impact clinicians?

DR. PATRICK HA: Well, I think that we realized we had a lot to cover in just a short amount of time. And I think that we felt that while the data may not be as strong with-- full of randomized clinical trials as perhaps other disease subgroups, we felt it was important to organize what the current state of the data are, because these are rare cancers, and there are some nuances between some of the histologies even that it may be difficult to keep up to date all the time. So organizing it into one document where it we have clearly delineated what areas we feel are common practice amongst experts and what areas actually do have some studies and perhaps some deeper level of understanding and depth of studies would be important, so that clinicians understood where it was that they have to be a little more creative and areas where they felt like hey, we feel like this is important to do.

So I think that that would be useful for clinicians. And I think also it provides a framework for future studies, meaning that we hope that whenever these get updated and 5 or 10 years that there will be more studies. But it also does, I think, help for those of us who are in the field to organize where those gaps are so you can look at the guidelines and really understand OK, these are the areas that we need better understanding of how to treat patients.

BRITTANY HARVEY: Definitely. It's helpful to understand both where there is evidence and where there is no evidence and where informal consensus takes rule. So then finally, Dr. Geiger, how will these guideline recommendations affect patients?

DR. JESSICA GEIGER: Well, when it comes to cancer treatment, there is a lot of fear in the unknown. And I feel that patients are always asking am I doing the right things? Am I looking to make sure that I'm getting the best of care? And I think with any guideline-- this one included-- patients can rest assured that they don't have to make the trip and travel to a large academic center necessarily-- that they can feel comfortable knowing that their providers are following the data and following such guidelines that have been brought forth in one single document. Even though the patients aren't going to necessarily have this document at hand, they can have confidence within their oncology team.

And then I think they'll also benefit from, as Dr. Ha was saying, as medical professionals being able to identify gaps and bring forth clinical trials. That's the only way that we're going to be able to move this field forward, particularly in such a rare disease that many histologies as salivary gland malignancies. And so while being treated in a regional oncology office or a community oncology office, maybe their provider will then recommend clinical trials that are open and have that additional opportunity for patients, if they so desire. So knowing that they're getting great standard of care based on evidence, but then also the opportunity to create new evidence for us to better treat patients in the future.

BRITTANY HARVEY: Definitely. Well, I want to thank you both so much for your work on developing these evidence-based guidelines and for taking the time to speak with me today on the podcast, Dr. Geiger and Dr. Ha.

DR. JESSICA GEIGER: Thanks.

DR. PATRICK HA: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. David Hui from MD Anderson Cancer Center and Dr. Margaret L. Campbell from Wayne State University, co-chairs on “Management of Dyspnea in Advanced Cancer: ASCO Guideline.” This guideline outlines a hierarchical approach to dyspnea management, beginning with identifying and managing potentially reversible causes, followed by the use of non-pharmacologic interventions, and then pharmacologic interventions. Read the full guideline at www.asco.org/supportive-care-guidelines

TRANSCRIPT

My name is Brittany Harvey, and today I'm interviewing Dr. David Hui from MD Anderson Cancer Center in Houston, Texas, and Dr. Margaret Campbell from Wayne State University in Detroit, Michigan, co-chairs on "Management of Dyspnea in Advanced Cancer: ASCO Guideline." Thank you for being here, Dr. Hui and Dr. Campbell.

DR. DAVID HUI: Thank you. It's wonderful to be here.

DR. MARGARET CAMPBELL: Yeah, it's my pleasure.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Hui, do you have any relevant disclosures that are directly related to this guideline topic?

DR. DAVID HUI: I have no relevant disclosures.

BRITTANY HARVEY: Thank you. And Dr. Campbell, do you have any relevant disclosures that are related to this guideline topic?

DR. MARGARET CAMPBELL: No, I do not have any relevant disclosures.

BRITTANY HARVEY: Thank you. Then let's get into some of the guideline content. So first, Dr. Hui, can you give us a general overview of the purpose of this clinical practice guideline?

DR. DAVID HUI: Yeah. This clinical practice guideline is on dyspnea in patients with advanced cancer. And this symptom of shortness of breath, or dyspnea, is very common in our patients and extremely distressing. And the evidence base is rapidly evolving, so the purpose of this guideline is then to summarize the up-to-date information and provide some recommendations for clinical practice to help alleviate this very challenging symptom.

BRITTANY HARVEY: Great. Then let's review some of those key recommendations of this guideline. So Dr. Campbell, what is recommended for screening and assessment of dyspnea in patients with advanced cancer?

DR. MARGARET CAMPBELL: Well, as David mentioned, this is a highly prevalent symptom. But we know that in clinical practice, sometimes patients won't disclose their symptom unless they're asked. And it gives us an opportunity to be certain that we don't overlook the symptom, particularly when it's in the early stages, mild or moderate stages, where we can intervene rapidly.

So in order to treat a symptom, we have to know that the symptom exists. So in the guideline, we recommend at every clinical encounter that there be an assessment for dyspnea. So every clinical encounter could be every time the patient presents in the outpatient clinic, or it could be every day if the patient is an inpatient. Every day on rounds, or every time vital signs are obtained, there would be an assessment of the patient's dyspnea.

BRITTANY HARVEY: Great. Then, reading through this guideline, it takes a hierarchical approach to the management of dyspnea, addressing first potentially reversible causes, then the use of non-pharmacologic interventions, and finally pharmacologic interventions. So first, what does the guideline state regarding addressing those potentially reversible causes of dyspnea?

DR. DAVID HUI: Yeah, well, this is a very important aspect that you highlighted is that we really want clinicians to remember that it's not just about treating this symptom. It's ideally identifying what are the causes of shortness of breath that we could reverse. And in many patients, there may be multiple factors contributing to the shortness of breath.

Some patients may have some effusion, perifusion contributing to it. They may also have underlying emphysema. And other times they may have some complications, such as blood clots. And so it's important to kind of identify the issues that may be at stake. And some of them are very treatable, and patients may have significant improvement in their shortness of breath right away.

So I think it's a combination of identifying the complications and comorbidities in those patients. And of course that along with treating the cancer if the cancer is the cause of the dyspnea as well.

BRITTANY HARVEY: Great. Then so after addressing those potentially reversible causes, Dr. Campbell, what are the recommended non-pharmacologic interventions?

DR. MARGARET CAMPBELL: Well, in the case of a patient whose dyspnea is not severe but is a difficult to tolerate symptom, we propose that the clinician begin with a hierarchical approach from the easiest, simplest interventions that are non-pharmacologic that may actually help improve the symptom experience. So that might be as simple as changing the patient's position.

And depending on where their cancer is located, they may find that they are more comfortable sitting up straight propped with pillows, for example. In addition, circulating air around the face has a fairly strong evidence base. And that can be accomplished, weather permitting, by putting the patient's chair near an open window. Or it can be accomplished with a small handheld fan blowing on the face.

For some patients whose blood oxygen levels are low, then the application of supplemental oxygen may be helpful to correct the low blood oxygen. Those are the major interventions that we would suggest, but there could be others. If the patient is still ambulatory, then perhaps a walking aid, avoiding stairs. And some of that comes back to our comprehensive assessment. If we could determine what triggers the patient's shortness of breath, then perhaps we can suggest interventions to minimize that, like pacing activity.

So similarly, if the patient's in the hospital but has dyspnea, we would want to pace their clinical activity. We wouldn't want them to have their bed, bath, their breakfast, their linen change, their physical therapy all in the same short period of time. We would want to see those interventions staggered through the day.

BRITTANY HARVEY: Definitely. That makes a lot of sense. So then, Dr. Hui, what pharmacologic interventions are recommended for patients with advanced cancer and dyspnea?

DR. DAVID HUI: Yeah, and so building on Dr. Campbell's discussion of the non-pharmacologic interventions, sometimes patients will continue to have quite a bit of shortness of breath. Or it's a very acute or severe presentation, such as in the hospital setting, then we do recommend some pharmacologic interventions.

So the front line measure for that would be systemic opioids. And I recognize that, nowadays, opioids, there's still a lot of stigma around the use of it and concerns. But it is after careful review by the committee and based on the existing evidence that we do recommend this as the main pharmacologic agent. For patients, of course, the use of opioids need to be carefully monitored, and patients should be educated very carefully on how to use them properly for shortness of breath.

There are a number of other pharmacologic agents that may be considered for selected populations, other than opioids. So if patients have a higher level of anxiety, then a short-acting benzodiazepine may be considered for those individuals. And for patients with more structural causes of shortness of breath, such as airway obstruction, systemic corticosteroids may be considered. And for patients with airway obstruction, then bronchodilators may be helpful as well, although the evidence around that is still on the weaker side.

And there are some patients who, despite very active intervention with many of these non-pharmacologic and pharmacologic measures, who continue to have very severe shortness of breath. And for those who are, let's say, in a palliative care unit setting and have refractory dyspnea, palliative sedation is mentioned as an option for patients as a last resort.

BRITTANY HARVEY: OK, thank you both for reviewing those interventions for patients. So Dr. Campbell, in your view, why is this guideline important? And how will it change practice?

DR. MARGARET CAMPBELL: Well, for a busy oncologic clinician who may not have a lot of time to search the literature because of a busy practice, what this puts in one place is an opportunity to do a quick guideline that could suggest a treatment course. For a palliative care provider, who may have more experience with non-cancer diagnoses, this guideline focuses on the patient with advanced cancer.

So I think there's an opportunity for clinicians in both of those fields who would be taking care of advanced cancer patients to find a benefit.

BRITTANY HARVEY: Definitely. And then finally, Dr. Hui, how will these guideline recommendations impact patients with advanced cancer?

DR. DAVID HUI: Yeah, well, I'd like to echo what Dr. Campbell said. I would also say that perhaps one of the strongest recommendations of this guideline is actually for patients with dyspnea and advanced cancer to be referred to palliative care. Because dyspnea is such a multi-dimensional symptom and often just the tip of the iceberg in terms of what patients are going through.

So just the very presence of it really highlights that there is likely a high supportive care burden, and it would be a good idea for a team specializing in relieving of this symptom to be there to work with the oncology team to help patients. So we hope that with this guideline, that there will be more patients who will have access to palliative care teams. And I think that will be one important impact. And there is a lot of evidence that palliative care can help our patients.

And other, maybe, impacts, I think, down the road for maybe future patients would be that we highlighted that more research is really needed in this field. The guideline clearly highlighted some areas we need to work on for further research. And it is not easy to do research in dyspnea and cancer patients because these patients are so sick. And yet these are the very patients who need to have better interventions.

And so with this guideline, we hope that it can stimulate further research and to support some patients in the future as well.

BRITTANY HARVEY: Great. Well, it definitely sounds like these will have a positive impact for both researchers and for patients with advanced cancer. So I want to thank you both for your work on these guidelines. And thank you for taking the time to talk with me today, Dr. Campbell, and Dr. Hui.

DR. DAVID HUI: It's my pleasure.

DR. MARGARET CAMPBELL: Mine also.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Natasha Leighl, Dr. Andrew Robinson, and Dr. Gregory Riely on “Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO and OH (CCO) Guideline Update.” This guideline provides recommendations on systemic therapy for patients with stage IV NSCLC whose cancer has driver alterations, focusing on seven targets - EGFR, ALK, ROS-1, BRAF V600e, RET, MET exon 14 skipping mutations, and NTRK. Read the full guideline at asco.org.

TRANSCRIPT

PRESENTER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

My name is Brittany Harvey, and today, I'm interviewing Dr. Natasha Leighl from Princess Margaret Cancer Center in Toronto, Ontario, Dr. Andrew Robinson from Queen's University in Kingston, Ontario, and Dr. Gregory Riely from Memorial Sloan Kettering Cancer Center in New York, New York, authors on Therapy for Stage IV Non-Small-Cell Lung Cancer with Driver Alterations: American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) Guideline Update. Thank you for joining me today, Drs. Leighl, Robinson, Riely.

DR. ANDREW ROBINSON: Thank you for having us.

DR. NATASHA LEIGHL: Thanks for having us, Brittany.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Leighl, do you have any relevant disclosures that are related to this guideline topic?

DR. NATASHA LEIGHL: I don't have relevant disclosures, but I do have institutional research funding from a number of companies, including Amgen, ARRAY, AstraZeneca, EMD Serono, Guardant Health, Eli Lilly, Merck, Pfizer, Roche, and Takeda, and personal fees from Bristol-Myers and MSD, which are unrelated. Thanks.

BRITTANY HARVEY: Thank you. And Dr. Robinson, do you have any relevant disclosures that are related to this guideline?

DR. ANDREW ROBINSON: I do not have any relevant disclosures related to this guideline. My institutional list of research funding is not as extensive as Dr. Leighl's, but is still fairly extensive and includes many of those companies.

BRITTANY HARVEY: And Dr. Riely, do you have any relevant disclosures?

DR. GREGORY RIELY: I receive institutional research funding from Novartis, Roche, Genentech, GlaxoSmithKline, Pfizer, Moradi, Merck, and Takeda. But those are my only disclosures.

BRITTANY HARVEY: Thank you all. Then let's get into some of the content of this guideline update. So this guideline is an update of an earlier ASCO guideline on the systemic treatment of patients with stage IV non-small cell lung cancer, which was then divided into two companion guidelines, one on systemic therapy treatment options for patients without driver alterations, which was published in 2020, and then this one for patients whose cancer has driver alterations.

So Dr. Robinson, can you give us a general overview of what this particular guideline covers?

DR. ANDREW ROBINSON: Thank you, Brittany. It was a great experience to be part of this important guideline and an honor. As you mentioned, this guideline is on treatment of stage IV non-small cell lung cancer patients with driver mutations. And it's a companion guideline to the earlier guideline published on treatment of stage IV non-small-cell lung cancer without driver mutations. The guideline followed a robust evidence gathering and evaluation process as a standard for ASCO-Ontario Health guidelines. In this case, we ended up reviewing several phase III trials, as well as many earlier phase studies and specific driver mutation groups.

If we look back to 2017, there were four driver mutation group recommendations included in the guideline. We now have recommendations for seven different oncogenes, as well as some recommendations that are specific not only for the oncogene involved, but also the specific mutation within that gene. The non-driver mutation guideline is referenced as well frequently in this guideline, as many of the treatment options that are recommended in that guideline are also appropriate for patients with driver mutations, with the exception of a couple of key mutation groups such as EGFR.

Recommendations in the guideline are qualified as weak, moderate, or strong, and the level of evidence for each recommendation is given. For many of these novel agents, the evidence is relatively low in comparison to what we are used to with recommendations based on phase II trials without comparator arms, and with surrogate endpoints for patient benefits such as response rates and duration of response, as opposed to quality of life and overall survival. Nonetheless, it was felt appropriate to include many of these agents in the recommendations, with the caveat that the level of evidence is weak or non-evidence-based.

One of the recommendations in the introduction to these guidelines is to continue with studies such as phase III clinical trials in many of these settings, in order to move from an informal consensus-based recommendation, to a recommendation based on moderate to high quality evidence. We hope oncologists and their patients will find these guidelines useful.

BRITTANY HARVEY: Great. Then, as you just mentioned, this guideline focuses on seven targets, EGFR, ALK, ROS1, BRAF, RET, MET, and NTRK. I'd like to review those key recommendations for each of those targets. So first, Dr. Robinson, what is recommended for patients with stage IV non-small-cell lung cancer and an epidermal growth factor receptor mutation?

DR. ANDREW ROBINSON: Thank you. In terms of stage IV EGFR mutation positive lung cancer, the recommendations in the 2017 guidelines were to use tyrosine kinase inhibitors upfront, such as gefitinib, afatinib, or erlotinib, and to follow that with osimertinib if a mutation was found in T790M, or chemotherapy depending on what was available. In the current treatment guideline, we have recommendations not only for first and second line treatment, but also some acknowledgment and recommendations for treatment of patients with EGFR mutations other than the classical exon 19 deletion mutation or LA58R.

For patients with a classical EGFR mutation, several strategies have been shown to be superior to first generation tyrosine kinase inhibitors in the first line setting. And the panel strongly recommended osimertinib to be used as first line therapy with a high level of evidence, based on the FLAURA clinical trial. This demonstrated not only an overall survival benefit, but a quality-of-life benefit.

Other strategies that have been shown to benefit include dacomitinib as first line therapy, gefitinib plus chemotherapy as first line therapy. Erlotinib/bevacizumab and erlotinib/ramucirumab are also options with a lower level of evidence, as they have not been shown yet to be associated with improved overall survival. But they are associated with improved progression-free survival.

Most of the recommendations, other than osimertinib, are really recommendations for what to pursue if osimertinib is not available. If we move to patients with sensitizing but non-classical EGFR mutations, the evidence is certainly much more sparse, as are these patients. And the recommendation was for afatinib first line or osimertinib was also considered an option based on phase II data.

For patients with EGFR exon 20 insertion mutations, recommendation at this time was not to use a targeted agent first line, but to default to the non-driver mutation guidelines. For second line therapy, after tyrosine kinase inhibition stops benefiting, the recommendation was to use doublet platinum chemotherapy with or without bevacizumab.

The atezolizumab/bevacizumab/carboplatin/paclitaxel combination was acknowledged as an option based on an exploratory analysis of the phase III EMPOWER trial, but this was considered exploratory and this regimen was not strongly recommended until further evidence accrues.

BRITTANY HARVEY: OK, thank you. Then Dr. Leighl, what is recommended for patients with stage IV non-small-cell lung cancer and ALK rearrangement?

DR. NATASHA LEIGHL: So for patients with ALK rearranged stage IV lung cancer, in the first line setting, next generation ALK inhibitors alectinib or brigatinib should be offered to patients. This is based on randomized trials comparing these to first generation inhibitors, crizotinib specifically, demonstrating better outcomes including progression-free survival and better intracranial activity.

If you live in a region where alectinib and brigatinib are not available, earlier inhibitors like crizotinib or ceritinib should be offered again based on high quality evidence randomized trials demonstrating that these are better than chemotherapy. In the second line setting, if your patient has received alectinib or brigatinib first line, lorlatinib may be offered. If your patient received an earlier generation inhibitor crizotinib, they should be offered alectinib, brigatinib, or ceritinib, again based on randomized trials. And later, lorlatinib third line may be offered.

It's also important to remember that in this group of patients, chemotherapy, especially pemetrexed-based chemotherapy, is very active. And we would refer you to the ASCO-Ontario Health non-driver mutation guidelines for chemotherapy recommendations when targeted therapy is no longer an option. I should also note that when we drafted these guidelines, we did not yet have results of the first line lorlatinib study, the CROWN study, where we found that lorlatinib was also superior to crizotinib, the first generation inhibitor. This is currently under review by the US FDA. So while it's not recommended in our guideline, we may see this added to future guidelines in our next guideline update.

BRITTANY HARVEY: Great. Thank you. And then, what is recommended for patients with ROS1 rearrangement?

DR. NATASHA LEIGHL: So for patients with ROS1 rearranged stage IV lung cancer, in the first line setting, specific ROS1 inhibitors, crizotinib or entrectinib may be offered. Because this is based on very impressive response rates and prolonged duration of response and patient benefit, in single arm studies, we have to recognize that alternatives may also include standard treatment based on the ASCO non-driver mutation guidelines, as well as other target agents, such as ceritinib or lorlatinib, that may be offered.

If, though, your patient has progressive disease and previously received non-targeted therapy, targeted therapy with crizotinib, ceritinib, or entrectinib, can certainly be offered. Also, if your patient has received ROS1 targeted therapy in the first line setting, standard treatment based on the ASCO non-driver mutation guidelines should be offered also with consideration of clinical trials.

BRITTANY HARVEY: And then additionally, what is recommended for patients with stage IV non-small-cell lung cancer and an NTRK fusion?

DR. NATASHA LEIGHL: Thanks, Brittany. For patients with stage IV disease and an activating NTRK fusion, entrectinib or larotrectinib may be offered in the first line setting based on single arm studies, including patients with lung cancer and very dramatic response rates and prolonged duration of response. However, standard treatment based on the non-driver mutation guideline chemotherapy-based may also be offered in the second line setting. If NTRK targeted therapy was given first line, standard treatment with chemotherapy-based options may be offered second line based on the non-driver mutation guideline. If NTRK targeted therapy, though, was not given in the first line setting, entrectinib or larotrectinib may be offered to your patient.

And I think at this point, we really don't know what the optimal sequence is for these patients. But I think it's very clear from the data that we do have, that we want to try and identify this target and get patients on targeted therapy as soon as possible in the course of their disease.

BRITTANY HARVEY: Great. Then Dr. Riely, can you review what the guideline recommends for patients with stage IV non-small cell lung cancer and a BRAF mutation?

DR. GREGORY RIELY: Thank you, Brittany. I'll highlight that the BRAF mutation guideline pertains specifically to those patients with BRAF V600E mutations. The other BRAF mutations that we observed, we don't have sufficient data to make recommendations. But for those patients with BRAF V600E alterations, again, based on the quality of the data and the type of data available, the guidelines recommend consideration of first line use of dabrafenib with trametinib. This is a consideration rather than a should recommendation, given the absence of randomized clinical trial evidence.

But nonetheless, we recommend that they be considered in the first line setting. If, in fact, you choose to use a non-targeted approach in the first line setting, then the guidelines do recommend consideration of dabrafenib with trametinib in the second line setting. So it's, again, the first line setting, dabrafenib/trametinib combination. Or, if not used in the first line setting, then recommendation dabrafenib/trametinib in the second line setting.

BRITTANY HARVEY: OK, then, what is recommended for patients with stage IV non-small-cell lung cancer and a MET mutation?

DR. GREGORY RIELY: Again, specific for MET, we're talking about MET exon 14 alterations rather than MET amplification with other mutations, which we might call emerging targets. So for patients with metastatic exon 14 altered non-small cell lung cancer, the recommendation is for the use of capmatinib or tepotinib. These are newer MET inhibitors that have recently been approved. And again, the guidelines recommend that they should be considered in the first line setting. If, however, you choose to use non-targeted therapies in the first line setting, then MET directed therapy such as capmatinib or tepotinib should be considered in the second line setting.

BRITTANY HARVEY: And then the final target addressed in this guideline, what is recommended for patients with stage IV non-small cell lung cancer and RET rearrangement?

DR. GREGORY RIELY: RET rearrangements are relatively uncommon, but important in a subset of patients with non-small cell lung cancer. And we have MET targeted agents that are available. The current guidelines recommend that in the first line setting, we consider the use of selpercatinib. And in the second line setting, if patients have not previously received a RET inhibitor, one should consider selpercatinib in that context.

Patients who have received a targeted therapy in the first line then conventional chemotherapy with or without immunotherapy or bevacizumab should be considered. I will note that the guidelines were finalized prior to the approval of pralsetinib, and pralsetinib is another RET inhibitor with similar data in this context.

BRITTANY HARVEY: Great. Thank you all for reviewing those recommendations. So Dr. Robinson alluded to this earlier, but Dr. Riely, could you describe what emerging targets the panel reviewed but were unable to make recommendations for at this time?

DR. GREGORY RIELY: The development of treatments in patients with non-small cell lung cancer has really proceeded at a breakneck pace over the past 10 years. We've seen newer alterations identified, new drugs tested in those populations, and new drugs approved in relatively rapid succession. We have a number of targets that are currently being studied with new drugs, but we don't quite have enough data yet and the drugs aren't yet approved, so they can't be included in the guidelines.

Some of these targets include KRAS G12C, recently seen a number of direct KRAS inhibitors that have been developed and seem to have activity in that group of patients. And that's a hot area to look forward to. We've also seen that patients with EGFR exon 20 insertions don't seem to benefit from currently available EGFR TKIs at the standard recommended dose. And so we don't have recommendations for their utilization here, but there are new drugs that are being developed to target this group of patients.

Similarly, patients with HER2 mutations seem to not benefit from available therapies, but there are drugs that are being developed, and we look forward to seeing more data in that context. Finally, patients with NRG1 fusions are another emerging target, but we don't have good recommendations yet or good drugs yet.

BRITTANY HARVEY: Great. Understood. So then, Dr. Robinson, in your view, why is this guideline important, and how will it impact clinical practice?

DR. ANDREW ROBINSON: Well, this guideline is important because it's taking a problem that we see in the real world, which is patients with lung cancer with an ever-expanding number of driver mutations, and trying to give recommendations for the integration of new therapies with standard clinical practice.

It's important that I've highlighted that for most of these mutations, without phase III evidence, the recommendations were to consider the targeted agent as first line therapy. But also, if it's not given first line, to use it in subsequent lines. And I think we need to recognize that these targeted agents, it's most important that patients get these drugs at some point in their care, even if we don't know exactly what the optimal point in their care is.

The guideline was sort of the first one in lung cancer, where we've taken a number of these rare mutations and examined the phase II data, and will likely be the template for what is going forward with an ever-expanding number of medications. So hopefully, we get a bit of standardization out of it. Hopefully, we've highlighted some of the areas that are still unclear and can be a template for the next round of targeted therapy guidelines.

BRITTANY HARVEY: Definitely, it's an ever-changing landscape. So finally, Dr. Leighl, what do these updated guideline recommendations mean for patients with stage IV non-small-cell lung cancer?

DR. NATASHA LEIGHL: So this is really great news. And as Dr. Riely and Dr. Robinson have highlighted, in just a very short number of years since 2017, we've made tremendous progress. We have at least three new targets, many new treatments for almost every class of targeted therapy indication in lung cancer. And most of these new targets are their oral therapies or pills. And many of them should now be offered to patients as first or second line treatment instead of chemotherapy.

So for patients, this really means many more will be able to enjoy a chemotherapy-free world, or at least a chemotherapy-free period for a time. I think it's really important for patients and the oncology team to remember that genomic testing is essential. And it's an essential part of the stage IV non-squamous, non-small-cell lung cancer diagnostic process, and in some places, you know, any non-small-cell lung cancer. And this may be a very important part of the process. And it really doesn't depend on clinical factors like smoking. It's really about your pathologic diagnosis or in your tumor sample.

So it's really key that we make sure that patients get their samples tested as soon as possible in their lung cancer journey, preferably with comprehensive profiling so we can identify any of these targets, if our patients have them, and then get them onto the right treatment as fast as possible. If there isn't enough tissue for testing, liquid biopsy has emerged as a potential alternative. And I think it's so important for patients and oncology professionals to remember that PD-L1 expression, which is an important marker for immune therapy, is not enough.

At least a quarter of our patients with PD-L1 expression that suggests immunotherapy should be an option, in fact, have these actionable genomic targets. And we do know that in these patients, targeted therapy should come first. So again, tremendous progress, many exciting opportunities for our patients to be chemo-free for much longer. And again, important to get the right test as soon as possible so we can get you onto the right treatment as soon as possible.

BRITTANY HARVEY: Great. Well, thank you all for reviewing the extensive literature associated with this guideline and developing these recommendations, and for taking the time to speak with me today, Dr. Leighl, Dr. Riely, and Dr. Robinson.

DR. GREGORY RIELY: Thank you.

DR. ANDREW ROBINSON: You're welcome, and thanks a lot to the ASCO staff for doing all of the work in sort of herding the cats that are oncologists, as well as getting all the references and the deep literature searches for us.

DR. NATASHA LEIGHL: Agreed. Thanks so much.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview from Dr. Larissa A. Korde from the National Cancer Institute and Dr. Dawn L. Hershman from Columbia University on “Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline.” This guideline covers the optimal use of neoadjuvant therapy for women with invasive, non-metastatic breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

My name is Brittany Harvey, and today I am joined by Dr. Larissa Korde from the clinical investigations Branch of the Cancer Therapy Evaluation Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute in Bethesda, Maryland, and Dr. Dawn Hershman from the Herbert Irving Comprehensive Cancer Center at Columbia University in New York, New York, co-chairs on Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline. Thank you for being here Dr. Korde and Dr. Hershman.

DR. LARISSA KORDE: Thank you for having us.

DR. DAWN HERSHMAN: Yes, thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available on-line with the publication of the guideline in the Journal of Clinical Oncology. Dr. Korde, do you have any relevant disclosures that are related to this guideline topic?

DR. LARISSA KORDE: I do not.

BRITTANY HARVEY: And Dr. Hershman, do you have any relevant disclosures that are related to this guideline topic?

DR. DAWN HERSHMAN: No, I do not.

BRITTANY HARVEY: Great, thank you both. Then, Dr. Hershman, to kick off the content of the guideline, first, can you give us a general overview of the scope and the purpose of this guideline?

DR. DAWN HERSHMAN: Yeah, sure. In breast cancer, we have seen a plethora of studies looking at neoadjuvant therapy for breast cancer. And as we've learned over time, that neoadjuvant therapy has focused on the role of, really, response as a predictive marker and whether or not the improvement in a pathologic complete response rate translates into benefit in terms of long-term outcome. And the fact that several studies have shown that has really increased our interest in looking at pathologic complete response rate and its predictive value.

So part of the guideline is really to help us really elucidate as the understanding of biology of breast cancer has evolved over time, what scenarios where neoadjuvant therapy is the best choice for patients, and what the real purpose of neoadjuvant therapy is. So the guidelines' purpose is really to help us develop recommendations concerning the optimal use of neoadjuvant therapy, whether it be chemotherapy, endocrine therapy, or targeted therapy for a variety of different biologic subtypes. And I think the overarching principle is that the expert panel strongly advocated for a multidisciplinary team in the management of these patients. Specific guidelines really go into details about each of the scenarios where we would use this therapy.

BRITTANY HARVEY: Great. Then I'd like to review some of those key recommendations that you just mentioned for our listeners. So Dr. Korde, which patients with breast cancer are appropriate candidates for neoadjuvant systemic therapy?

DR. LARISSA KORDE: So when we sat down to write this guideline, we thought through this question in many different ways. But we basically ended up sort of dividing patients by breast cancer subtype and then coming up with recommendations separately for each subtype. So broadly speaking for triple negative breast cancer patients and for HER2-positive breast cancer patients, we felt that the kind of most important triage point is that in both those diseases, there are effective treatments that can be used in the adjuvant setting in patients who do not have a pathologic complete response to neoadjuvant therapy. And so broadly speaking, it's those patients where there would be an adjuvant therapy decision point, or recommendation in whom the neoadjuvant response is important. Those would be the patients in whom we would most strongly recommend neoadjuvant chemotherapy.

In ER-positive disease, we looked at both chemotherapy and endocrine therapy in the neoadjuvant setting. And we know that both of these can improve response. Pathologic complete response is less common in patients with ER-positive disease. But there are also benefits to neoadjuvant treatment in those patients in terms of being able to reduce the size of the surgery, reduce potentially morbidity from surgery, and then also in terms of being able to convert patients who were not lumpectomy candidates from mastectomy to lumpectomy. And so in the guideline we outline the scenarios for ER-positive patients in which neoadjuvant therapy would be recommended as well.

BRITTANY HARVEY: Great, got it. Then Dr. Hershman, what do the guidelines say about how clinicians should measure response in patients receiving neoadjuvant chemotherapy?

DR. DAWN HERSHMAN: Yes, so patients undergoing neoadjuvant therapy should really be monitored by their provider at each visit with a clinical examination at regular intervals. And we really felt that the role of breast imaging was really for patients where there was some clinical suspicion of progression during that therapy to ensure that patients were not progressing during treatment. And ultimately, the best modality for imaging was the modality that was most effective at the point of diagnosis, whether it be mammogram, ultrasound, or MRI, that should be the imaging modality used at follow up.

We did not feel that there were any specific blood markers or tissue based markers at this time that should be used for monitoring patients undergoing neoadjuvant therapy. Much of that is done for clinical trial purposes, but not so much in the clinic. And that when patients had completed their treatment, pathologic complete response rate is the most important outcome and would be really assessed at the time of surgery as the absence of any invasive disease in either the breast or the lymph nodes.

But in order for that to be good for clinical decision making, it's really imperative that the clinician and the surgeons make sure that the tissue is removed that is suspect to begin with, so to make sure that the clips that defined where the tumor was evaluated and that the tumor bed is clear of any evidence of disease.

BRITTANY HARVEY: Great, that's helpful information. So then, Dr. Korde, you mentioned that the recommendations are divided up by biologic subtypes. So what are those neoadjuvant systemic therapy regimens recommended for the following patient population-- so first, those with triple negative breast cancer, second, those with HER2-negative hormone receptor positive breast cancer, and then finally, for those with HER2-positive disease?

DR. LARISSA KORDE: So maybe we can divide this up a little. Let's start with the triple negatives. For triple negative breast cancer patients who are embarking on neoadjuvant chemotherapy, and that would be patients with clinically node positive disease, and/or at least T1C disease, and again, with the thought that the goal is really to think about whether adjuvant therapy recommendations would be altered based on PAP CR. But in that setting, we recommended that patients be offered an anthracyclines and taxane containing regimen.

We also found data supporting the use of carboplatin with neoadjuvant therapy for the purpose of increasing the likelihood of PCR. So we noted that while there is good data showing that PCRs increase with carboplatin, there is more conflicting data regarding the effect of carboplatin on long-term outcomes. Although, hopefully, new clinical trials that are ongoing now or that are in follow up may clarify this question a little bit more.

We felt at the time that we wrote the guideline, and certainly, this is potentially an evolving topic. But at this point, we felt that there was insufficient evidence to recommend routinely adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early stage breast cancer. And again, there may be more data on this upcoming in the next few years. So maybe Dawn can take the next category, the HER2-negative hormone receptor positive patients.

BRITTANY HARVEY: Yeah, that would be great.

DR. DAWN HERSHMAN: Absolutely. So we felt for this population of patients that neoadjuvant chemotherapy could be used instead of adjuvant chemotherapy in any patient where the chemotherapy decision could be made without the benefit of having the results from the surgical pathology data, or any results from the specific genomic testing. So if the decision was made that the patient was going to need chemotherapy regardless, that would be a patient that could get it neoadjuvantly.

We felt that for postmenopausal patients with hormone receptor positive HER2 negative breast cancer that neoadjuvant endocrine therapy with an aromatase inhibitor could be offered to either increase local regional treatment options, if there was no intent for surgery, endocrine therapy could be used for Disease Control. So in a patient where they really were not a good surgical candidate, we could offer this therapy to try to control their disease. For premenopausal patients with hormone receptor positive HER2-negative disease, we did really not feel that neoadjuvant endocrine therapy should be routinely offered outside of a clinical trial. Because in this scenario, there really wasn't enough evidence to offer this approach.

BRITTANY HARVEY: And then Dr. Korde, do want to finally address those patients with HER2-positive disease?

DR. LARISSA KORDE: Absolutely. So in patients with HER2-positive disease that is either node positive or high risk node negative, we felt it would be appropriate to offer neoadjuvant therapy with either an anthracycline and taxane containing regimen, or a non-anthracycline-based regimen in combination with targeted therapy. And we did feel that targeted therapy should include trastuzumab and may also include pertuzumab. For patients with smaller tumors, really those in whom it's unclear whether the more aggressive for on-chemotherapy regimens or even any chemotherapy at all is needed, for example, those with very small tumors, T1A and T1B, we did not feel that neoadjuvant should be routinely offered. And we did note that in those patients with smaller tumors, an alternative regimen, the APT regimen of paclitaxel and Trastuzumab is something that has been studied in the adjuvant setting. But again those patients with these very small node negative tumors, in general, would not be routinely offered neoadjuvant chemotherapy.

BRITTANY HARVEY: Great, thank you both for reviewing those neoadjuvant systemic therapy approaches for those specific patient populations. So Dr. Hershman, in your view, what is the importance of this guideline? And how will it impact clinical practice?

DR. DAWN HERSHMAN: Yeah, that's an excellent question. I think as our data has shown more and more studies where there's a benefit to giving adjuvant treatment based on the response of patients in the neoadjuvant setting to get additional benefit long-term amongst patients with residual disease, I think that these guidelines really can help clinicians to understand those scenarios where we know we can maximize treatment.

I think ultimately the goal of neoadjuvant therapy is that it gives us opportunities to both escalate treatment in patients that are at high risk that don't have great responses, and de-escalate therapy in patients that have outstanding responses. And so I think this will help clinicians understand what those benefits are.

BRITTANY HARVEY: Definitely. It seems like it will provide some clarity for those scenarios. So finally, Dr. Korde, how do you envision that these guideline recommendations will affect patients with non-metastatic breast cancer?

DR. LARISSA KORDE: Well, I think building on Dr. Hershman's answer to the previous question, really, the key here is to be able to personalize or tailor the therapy for individual patients. So in those patients whose disease is very high risk, or did not respond to initial therapy, patients can be given appropriate escalation of treatment. And for patients who have an excellent response to treatment in the neoadjuvant setting can potentially be spared other treatments. And so I think that the main use of neoadjuvant treatment and the use of this guideline in terms of how it affects patients is being able to offer the most appropriate therapy for each patient.

BRITTANY HARVEY: Great, well, thank you both for your work on this guideline on neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer. Appreciate your leadership on this guideline. And I want to thank you also for taking the time to speak with me today, Dr. Korde and Dr. Hershman.

DR. DAWN HERSHMAN: Thank you.

DR. LARISSA KORDE: Happy to be here. Thanks so much.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Megan E. Daly from the University of California, Davis on “Radiation Therapy for Small Cell Lung Cancer: ASCO Guideline Endorsement of an ASTRO Guideline.” An ASCO Expert Panel reviewed an ASTRO guideline on radiation therapy for SCLC and determined it was clear, thorough, and evidence based. ASCO endorsed the ASTRO guideline with a few discussion points, which Dr. Daly reviews in this podcast. Read the full guideline endorsement at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

PRESENTER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today, I'm interviewing Dr. Megan Daly from the University of California Davis, Co-Chair and lead author on "Radiation Therapy for Small Cell Lung Cancer: ASCO Guideline Endorsement of an ASTRO Guideline."

Thank you for being here, Dr. Daly.

DR. MEGAN DALY: Thank you. Glad to be here.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Daly, do you have any relevant disclosures that are directly related to this guideline topic?

DR. MEGAN DALY: I do not.

BRITTANY HARVEY: Great. Thanks so much. So generally, can you give us an overview of what this guideline endorsement addresses and how the ASCO guideline endorsement process works?

DR. MEGAN DALY: This guideline was designed to provide an endorsement of a very comprehensive guideline provided by the American Society of Radiation Oncology addressing the use of radiation therapy for small cell lung cancer. The guideline endorsement process involved us developing a team of physicians, both medical oncologists and radiation oncologists, to review and assess the ASTRO guideline and make recommendations and clarifications for the ASCO audience.

So our guideline panel met several times by teleconference. We carefully reviewed the guidelines with assistance from the ASCO staff. We reviewed each individual recommendation within the ASTRO guideline, including the supporting evidence and the final recommendations, and provided clarifying comments, when necessary.

The entire guideline panel had to vote and reach a consensus on each individual recommendation from the ASTRO guideline to form a final consensus. And ultimately in the case of this guideline, we largely agreed with the excellent ASTRO guideline that had already been produced. So this was largely a process of confirming and endorsing ASTRO's guideline product. We also, then, provided a written paper that provides some additional clarification in context for ASCO's audience.

BRITTANY HARVEY: Great. So you just touched on some of the recommendations of the guidelines. So what were those key recommendations of this guideline?

DR. MEGAN DALY: So this guideline was specifically addressing the use of radiation therapy for small cell lung cancer, both limited-stage and extensive-stage small cell lung cancer. So the key recommendations that came out of both the ASTRO guideline and ASCO's recommendation of ASTRO's guidelines were first that radiation therapy should be used for most patients with limited-stage small cell lung cancer, confirming standard practice, and that doses of 45 gray in twice daily fractionation remain the standard of care, but alternative schedules delivering 60 to 70 gray over a single fraction are also reasonable.

The guideline also addressed that stereotactic radiation is an appropriate consideration for early-stage node-negative limited-stage small cell lung cancer. The guideline also addresses the use of prophylactic cranial irradiation and continues to recommend the use of prophylactic cranial irradiation for fit patients with limited-stage small cell lung cancer while recommending shared decision making for other patients, including those with extensive-stage disease or patients who might have contraindications to PCI for limited-stage small cell lung cancer. And finally, the guideline also addressed the use of consolidated thoracic radiation in extensive-stage small cell lung cancer, providing a recommendation that it be considered for well-selected patients with extensive-stage disease.

BRITTANY HARVEY: OK, and then you mentioned earlier that there were select scenarios in which the panel offered clarifying comments. So in which sections did the ASCO expert panel decide to offer those clarifying comments?

DR. MEGAN DALY: Our clarifying comments were largely simply to provide clarification in several of the recommendations. For example, in recommendation 1.2, where ASTRO recommends that it's important to maintain the dosage and timing of chemotherapy with radiation and that timing is more critical for accelerated dose intensive radiation, we clarified that dose intensive radiation would be referring to twice daily hyper-fractionated regimens.

We also provided clarification that ultracentral tumors refer to those where a planning target volume is overlapping or touching the proximal bronchial tree, the esophagus, and trachea within the recommendation that those tumors, even when early stage might better be addressed by fractionated, rather than a stereotactic radiation.

And finally, for recommendation 4.4, it states for patients with extensive-stage small cell with a response to chemotherapy and immunotherapy and residual disease in the thorax, thoracic radiation to 30 gray and 10 fractions within six to eight weeks can be considered. And we provided clarification that that would be six to eight weeks of completion of the chemotherapy and prior to maintenance immunotherapy.

BRITTANY HARVEY: Great. Then it sounds like those notes will be key for the ASCO audience in interpreting and implementing these recommendations. So in your view, what is the importance of this guideline endorsement? And how will it affect ASCO members?

DR. MEGAN DALY: So I believe this guideline endorsement and the initial ASTRO guideline are both very important in providing guidance to both radiation oncologists and medical oncologists who routinely treat small cell lung cancer patients in their practice. The small cell lung cancer space is constantly changing, and there have been some major developments in small cell lung cancer within the last 5 to 10 years, most notably surrounding the use of prophylactic cranial irradiation and extensive-stage disease.

There's also a number of interesting ongoing clinical trials looking at the use of consolidated thoracic radiation in extensive-stage disease. And many practitioners have questions about how to use radiation in the landscape of changing systemic therapies, for example, the integration of immunotherapy into extensive-stage disease, as well as how to integrate newer irradiation technologies like stereotactic radiation into the treatment of small cell lung cancer. So I believe that this guideline endorsement, as well as the original guidelines, can provide valuable guidance to the ASCO community in how to treat these patients in their daily practice.

BRITTANY HARVEY: Great. And then finally, how do these guideline recommendations impact patients with small cell lung cancer?

DR. MEGAN DALY: Hopefully, these guideline recommendations will help patients with small cell lung cancer receive standard of care latest treatments incorporating radiation. And there's a number of areas where radiation has been shown to improve survival in small cell lung cancer. So we absolutely want to make sure that our patients are receiving the best possible care that incorporates all available treatment modalities and incorporates all the latest data.

BRITTANY HARVEY: Great. Well, thank you so much for your work on this guideline endorsement, and thank you for taking the time to speak with me today, Dr. Daly.

DR. MEGAN DALY: Yeah, Brittany, thank you so much. Glad to be here.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Katherine S. Virgo from Emory University in Atlanta, GA on “Initial Management of Non-Castrate Advanced, Recurrent or Metastatic Prostate Cancer: ASCO Guideline Update.” This guideline updates recommendations for initial hormonal management of non-castrate advanced, recurrent, or metastatic prostate cancer. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Katherine Virgo from Emory University, lead author and co-chair on initial management of non-castrate advanced, recurrent, or metastatic prostate cancer, ASCO guideline update. Thank you for being here, Dr. Virgo.

DR. KATHERINE VIRGO: Thank you, Brittany.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Virgo, do you have any relevant disclosures that are directly related to this guideline topic?

DR. KATHERINE VIRGO: No, I do not.

BRITTANY HARVEY: OK, thanks. Then let's delve into some of the guideline content. What prompted this update of the initial management of non-castrate advanced, recurrent, or metastatic prostate cancer guideline, and what is the scope of the update?

DR. KATHERINE VIRGO: Well, the update of the 2007 version of the guideline was largely prompted by the many Phase III randomized clinical trials that had been completed or were nearly complete in the non-castrate space. It was believed that the results of these trials might permit revisiting previous recommendations regarding intermittent versus continuous androgen deprivation therapy and early or immediate versus deferred androgen deprivation therapy.

As you might imagine, it took quite some time to gather and review 13 years of literature for each of the study questions from the original 2007 guideline. So in the interim, a sufficient number of randomized clinical trials reached completion to also inform recommendations regarding the use of newer therapies in combination with androgen deprivation therapy as initial therapy for men with metastatic disease, such as docetaxel, abiraterone, enzalutamide, and apalutamide, and thereby also update another existing ASCO guideline authored by Morris et al in 2018, which previously only provided guidance on the use of docetaxel and abiraterone for men with metastatic disease.

BRITTANY HARVEY: Great, yeah, definitely a large volume of literature to review there. So then you talked about the recommendations. So I'd like to go through some of those. For men with metastatic non-castrate prostate cancer, what are the recommended standard initial treatment options?

DR. KATHERINE VIRGO: So docetaxel, abiraterone, enzalutamide, and apalutamide, each when administered with androgen deprivation therapy, represent four separate standards of care for non-castrate metastatic prostate cancer. The use of any of these agents in any particular combination or in any particular series cannot yet be recommended. That said, we were able to make a recommendation for each agent individually. So I'll go through those recommendations now, first for docetaxel.

So for men with metastatic non-castrate prostate cancer with high-volume disease who are candidates for treatment with chemotherapy, the addition of docetaxel to androgen deprivation therapy should be offered. Here, high-volume disease is defined per the charted trial as four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or the presence of any visceral disease.

Second, for abiraterone, for men with high-risk de novo metastatic non-castrate prostate cancer, the addition of abiraterone to androgen deprivation therapy should be offered per the latitude trial. For men who are considered low-risk, androgen deprivation therapy plus abiraterone may be offered for the STAMPEDE trial.

Third, for enzalutamide, androgen deprivation therapy plus enzalutamide should be offered to men with metastatic non-castrate prostate cancer, including those with de novo metastatic disease and those who have received prior therapies, such as radical prostatectomy or radiation therapy for localized disease. Enzalutamide plus ADT has demonstrated short-term survival benefits, such as PSA progression-free, clinical progression free, and overall survival when compared to androgen deprivation therapy alone for men with metastatic non-castrate prostate cancer per the ENZAMET trial.

And finally, fourth, androgen deprivation therapy plus apalutamide should be offered to men with metastatic non-castrate prostate cancer, including those with de novo metastatic disease or those who have received prior therapy, such as radical prostatectomy or radiation therapy for localized disease, per the TITAN trial. Thus in summary, to your initial question, all of the recommendations were phrased as "should be offered" except in the case of androgen deprivation therapy plus abiraterone for men with low-risk de novo metastatic non-castrate prostate cancer, for which the recommendation was phrased as "may be offered," as the evidence was not as strong as for the other recommendations.

BRITTANY HARVEY: Great, thank you for reviewing those standard initial treatment options for men with metastatic non-castrate prostate cancer. So then what does the guideline say regarding combination therapy for men with non-castrate locally advanced non metastatic prostate cancer?

DR. KATHERINE VIRGO: So here, androgen deprivation therapy plus abiraterone and prednisolone should be considered for men with non-castrate locally advanced non-metastatic prostate cancer, rather than castration monotherapy, due to the failure-free survival benefit for the STAMPEDE trial. We were unable to make a recommendation for men with high-risk non-metastatic prostate cancer progressing after radical prostatectomy or radiotherapy or both, as it's currently unclear whether enzalutamide in the 160-milligram dose plus leuprolide improved metastasis-free survival compared to enzalutamide monotherapy or placebo. The recruitment is complete for the ongoing Phase III EMBARK trial, which is designed to answer this question. The results are not available yet.

BRITTANY HARVEY: Great. Then how does the guideline address early or immediate androgen deprivation therapy versus deferred therapy for men with non-castrate locally advanced non-metastatic prostate cancer?

DR. KATHERINE VIRGO: So here, early or immediate androgen deprivation therapy may be offered to men who initially present with non-castrate locally advanced non-metastatic disease who have not undergone previous local treatment, and are either unwilling or unable to undergo radiotherapy, based on evidence in one meta-analysis of a modest but statistically significant benefit in terms of both overall survival and cancer-specific survival among the larger population of men with locally advanced non-metastatic disease. Unfortunately, we were unable to make a recommendation for men with PSA relapse after local treatment. Though existing studies suggest a potential overall survival benefit, additional research is needed, as such studies were underpowered.

BRITTANY HARVEY: And then finally, for men with biochemically recurrent non-metastatic disease, what are the recommendations for intermittent androgen deprivation therapy versus continuous androgen deprivation therapy?

DR. KATHERINE VIRGO: So intermittent therapy may be offered to men with high-risk, biochemically recurrent non-metastatic prostate cancer after radical prostatectomy and/or radiotherapy, based on evidence and meta-analyses of the non-inferiority of intermittent androgen deprivation therapy when compared to continuous androgen deprivation therapy, with respect to overall survival. This is further supported by evidence from four meta-analyses testing superiority. And here, high-risk biochemical recurrence after radical prostatectomy is defined as a PSA doubling time less than one year or a pathologic Gleason score of 8 to 10. High-risk biochemical recurrence after radiation therapy has a different definition, here defined as an interval to biochemical recurrence of less than 18 months or a clinical Gleason score of 8 to 10.

BRITTANY HARVEY: Thank you for reviewing all those recommendations and the evidence supporting them. It's very interesting to hear where you were able to make recommendations and where you weren't. So in your view, what is the importance of this guideline, and how will it change practice?

DR. KATHERINE VIRGO: As mentioned earlier, the previous version of the guideline was 13 years old. And practice, as you might imagine, has changed considerably in the interim. Though consensus documents have been issued by other organizations since that time, it was important, given ASCO's global audience, to provide up-to-date, evidence-based guidance for the organization's worldwide membership.

Practice patterns of most clinicians based at large university medical centers likely approximate the guidance provided in the ASCO guideline update, at least with respect to the treatment of men with de novo metastatic high-risk or high-volume disease. Some may be surprised by the current lack of evidence for the use of docetaxel among patients with de novo metastatic low-volume disease. The new guidelines should be particularly useful for community-based clinicians, who may not be as actively involved in clinical trial enrollment.

BRITTANY HARVEY: Definitely. And then finally, how will these guideline recommendations impact patients with prostate cancer?

DR. KATHERINE VIRGO: So patients will be impacted in three ways. First, the guidelines should be helpful to patients in understanding the various treatment options available to them, depending on the extent of their disease and any previous treatment they may have already received. The guidelines also highlight treatment options that should not be offered to patients who have certain characteristics and hopefully assist patients with adjusting their treatment expectations.

Second, the cost table in the guidelines should also be helpful to patients, as it provides some idea of how costs vary by the type of treatment received, while also indicating when a less costly generic equivalent is available. And finally, third, the guidelines suggest that patients be counseled about the potential side effects associated with androgen deprivation therapy, such as depression, dementia, stroke, myocardial infarction, deep venous thrombosis, hot flush, fatigue, and nausea. Side effects vary by type of androgen deprivation therapy, as well as by age and patient comorbidities. Knowing up-front that such side effects are possible can assist patients in having more informed conversations with their physician when treatment discussions are underway.

BRITTANY HARVEY: Great. Then it sounds like these guidelines have a real impact for both community oncologists and for patients. So I want to thank you for your leadership on the development of these evidence-based guidelines, and thank you for taking the time to speak with me today, Dr. Virgo.

DR. KATHERINE VIRGO: Thank you, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

A preview of the interview by ASCO in Action podcast host ASCO CEO Dr. Clifford A. Hudis with retiring ASCO Chief Medical Officer Dr. Richard L. Schilsky examining Dr. Schilsky’s trailblazing medical career, his leadership in ASCO and indelible mark on its research enterprise, and what he sees for the future of oncology. Dr. Hudis also shares what Dr. Schilsky’s friendship and mentorship has meant to him and suggests that he will still be supporting ASCO on critical priorities. Find all nine of ASCO's podcasts and subscribe at podcast.asco.org.

TRANSCRIPT

Dr. Clifford Hudis: Hello, I’m Dr. Clifford Hudis, CEO of ASCO, dropping into your feed to let you know about a special episode of the ASCO in Action podcast featuring the extraordinary career of Dr. Richard Schilsky, ASCO’s Chief Medical Officer. Rich and I discuss the advances that have revolutionized cancer care over the last 50 years and much, much more. Here’s a preview of the episode.

Dr. Richard Schilsky: The 1980s in many respects were the doldrums of progress in clinical oncology. There really was not a lot of innovation in the clinic. But what was happening and what was invisible to many of us, of course, was that was the decade of discovery of the fundamental biology of cancer. That's when oncogenes were discovered, when tumor suppressor genes were discovered, when it became clear that cancer was really a genetic disease. And that is what transformed the field and put us on the path to targeted therapy and precision medicine as we think of it today.

Dr. Clifford Hudis: You can find the ASCO in Action Podcast on Apple Podcasts or wherever you are listening to this show. And you can find all nine of ASCO’s podcasts which cover a wide range of educational and scientific content and offer enriching insight of the world of cancer care at podcast.asco.org.

View Details

An interview with Dr. Jun Ma from Sun Yat-sen University Cancer Center in Guangzhou and the Chinese Society of Clinical Oncology on “Chemotherapy in Combination with Radiotherapy for Definitive-intent Treatment of Stage II to IVA Nasopharyngeal Carcinoma: Chinese Society of Clinical Oncology and American Society of Clinical Oncology Guideline.” Read the full guideline at www.asco.org/head-neck-cancer-guidelines.

Transcript

Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm interviewing Dr. Jun Ma from Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy in Guangzhou, and the Chinese Society of Clinical Oncology, author on Chemotherapy in Combination with Radiotherapy for Definitive-intent Treatment of Stage II to IVA Nasopharyngeal Carcinoma, Chinese Society of Clinical Oncology and American Society of Clinical Oncology Guideline. Thank you for being here today, Dr. Ma.

JUN MA: Yes.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict-of-interest policy is followed for each guideline. The full conflict-of-interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Ma, do you have any relevant disclosures that are directly related to this guideline topic?

JUN MA: Thank you, Brittany. Hi, everyone. I'm Dr. Jun Ma from the Sun Yat-sen University Cancer Center in China. And I don't have any potential conflicts of interest related to this guideline topic.

BRITTANY HARVEY: Great. Thank you. Then can you give us a general overview of what this guideline covers?

JUN MA: Yes. This guideline aims to highlight significant clinical questions about the chemotherapy in combination with the radiotherapy for the definitive treatment of stage II to stage IVA NPC, nasopharyngeal carcinoma, It will clarify the fundamental principles of the radiotherapy planning and how to combine chemo with radiotherapy for a patient's success.

BRITTANY HARVEY: Great. Then this guideline covers five clinical questions. I'd like to review those key recommendations for our listeners. First, what does the guideline state regarding radiotherapy for patients with stage II to IVA nasopharyngeal carcinoma?

JUN MA: Yes. For all nasopharyngeal carcinoma patients, we support the use of IMRT summarized in the current evidence. We don't recommend the use of other techniques, such as 2D or even 3D radiotherapy. If IMRT is not available at that spot, patients should be transferred to the institution that could that could implement IMRT whenever possible.

For all NPC patients, a prescribed dose of 70 Gy in 33 or 35 fractions delivered over seven weeks should be offered. It should be noted that the radiation dose may be adjusted according to the tumor volume and its response to the chemoradiotherapy. In terms of the target delineation, we recommend you to follow several existing consensus guidelines. Thank you.

BRITTANY HARVEY: OK. Then what is recommended regarding chemotherapy sequence in addition to radiotherapy?

JUN MA: OK, generally speaking, patients with low disease burden, such as the lower end category of clinical stage, could receive lower intensity of chemotherapy. For T2, and if not negative of patients, chemotherapy is not routinely recommended, while for T1 or 2, N1 patients concurrent chemotherapy may be offered, particularly for T2 N1 patients.

For locoregional advanced disease, except the T3 lymph node negative patients, we recommend the use after concurrent chemotherapy with induction or adjuvant chemotherapy. It should be noted that there is a lack of head-to-head trials comparing induction chemo plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy plus adjuvant chemo. Thus, which sequence performs better in the contemporary era remains uncertain.

Finally, for T3 lymph node-negative patients, concurrent chemoradiotherapy should be offered. Adjuvant or induction chemotherapy may also be offered if there are adverse features, such as the bulky tumor volumes or high EBV DNA copy numbers.

BRITTANY HARVEY: Great. Then you just mentioned some chemoradiotherapy regimens. So for patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy, what are the recommended chemotherapy options?

JUN MA: OK, for all NPC patient without contraindications, concurrent cisplatin should be offered along with radiotherapy. Weekly use after suspending with 48 milligrams per square meter or three weekly with eight or 200 milligram per square meter is acceptable. We recommended the cisplatin dose should be attempted to achieve a cumulative dose of at least 200 milligrams per square meter.

For patients with contraindications to cisplatin, nedaplatin, carboplatin, or oxaliplatin may be alternative choice. For patients with contraindications to cisplatin-based chemotherapy, Fluoropyrimidines such as 5FU with concurrent chemotherapy also may be offered. Thank you.

BRITTANY HARVEY: Great. And then for patients with nasopharyngeal carcinoma receiving induction chemotherapy, what are those recommended options?

JUN MA: Yes. For all patients receiving induction or adjuvant chemotherapy, platinum-based induction regimens should be offered in terms of induction chemo, such as GP, TPF, TP, PF, and the PX regimens are recommended. So induction regimens should be administered every three weeks for a total of three cycles, or at least the minimum two cycles. If the patients receive induction chemotherapy, chemoradiotherapy should be commenced within 21 to 28 days from the first day of the last cycle of induction chemotherapy.

BRITTANY HARVEY: Great. And then for the final set of recommendations for patients with nasopharyngeal carcinoma receiving adjuvant chemotherapy, what are those recommended chemotherapy options?

JUN MA: Considering that adjuvant chemotherapy is a choice of adjuvant regimens were much fewer than those of induction chemotherapy, according to current evidence. PF regimen administered every four weeks for a total of three cycles is recommended. If with contraindication to cisplatin, carboplatin may be combined with 5-FU.

It should be noted that for all patients receiving adjuvant chemotherapy and with contraindications to platinum-containing chemotherapy, the use of non-platinum based regimens remain experimental at this time and should not be offered routinely outside of the context of a clinical trial. The main difference between the recommendation for the induction and adjuvant chemotherapy are primarily due to the number of the randomized trials in which there are few studies regarding the adjuvant chemotherapy in nasopharyngeal carcinoma. Thank you.

BRITTANY HARVEY: Thank you for reviewing each of those recommendations. So then, what is the importance of this guideline? And how will it impact clinical practice in patients with nasopharyngeal carcinoma?

JUN MA: For nasopharyngeal carcinoma, it has extremely uneven geographically global distribution. More than 70 percent of this new diagnosis worldwide in the 2018 year, occurred in the East and Southeast Asia. Therefore, nasopharyngeal carcinoma remains a significant public health problem in these regions, which emphasize the significance of this guideline for providers and patients from the endemic area.

From my point of view, one of the novel features of this joint deadline is that it was developed through the international collaboration with the regional groups. Experts from the CSCO and ASCO shared interpretation of the evidence while accounting for the organizing national or cultural diversity of different regions. In brief, the guideline provides the guidelines on how to plan radiotherapy and when and how to add chemotherapy. Through the interpretation protecting the guideline, care providers can avoid over or under-treatment. And providing the most suitable chemoradiotherapy for NPC patients.

Besides, for the patients, they could receive the most suitable treatment, which is the balance of the efficiency as a quantity of the life. Thank you.

BRITTANY HARVEY: Great. Definitely, we appreciate the collaboration between the American Society of Clinical Oncology and the Chinese Society of Clinical Oncology. So thank you so much for your work on these guidelines. And thank you for your time today, Dr. Ma.

JUN MA: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. John D. Gordan from the University of California, San Francisco, and Dr. Michal G. Rose from Yale Cancer Center and VA Connecticut Healthcare System on "Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline." This guideline addresses first-line and subsequent systemic therapy options for patients with unresectable hepatocellular carcinoma that is not amenable to local therapies. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.

Transcript

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network. A collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org

My name is Brittany Harvey, and today I'm interviewing Dr. John D. Gordon from the University of California, San Francisco, and Dr. Michal G. Rose from Yale Cancer Center, and VA Connecticut Health Care System, co-chairs on "Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline." Thank you for being here Dr. Gordon and Dr. Rose.

DR. MICHAL G. ROSE: Thank you.

DR. JOHN D. GORDON: Thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Gordon, do you have any relevant disclosures that are related to this guideline topic?

DR. JOHN D. GORDON: I do not.

BRITTANY HARVEY: Thank you. And Dr. Rose, do you have any relevant disclosures that are related to this guideline topic?

DR. MICHAL G. ROSE: I do not, either.

BRITTANY HARVEY: OK, then thank you. Then Dr. Rose, can you first explain the general purpose and the scope of this guideline?

DR. MICHAL G. ROSE: Of course. Thank you for this opportunity. As people know, the incidence of liver cancer, hepatocellular carcinoma, is rising rapidly in the United States and worldwide. And although there are multiple local and potentially curable treatments for early stage disease, the medical oncologist does get involved when these fail or if the patient presents with metastatic disease. And over the last three years, or bit more than three years, we've gone from having only one agent for advanced disease, which is sorafenib, to having nine agents approved for either first or subsequent lines of treatment. So this has created a really good problem for medical oncologists, how to choose between these multiple options. So the purpose of our guideline is to help us select the best treatment for the individual patient based on the best current evidence.

BRITTANY HARVEY: Great. Then this guideline covers both first line and subsequent systemic therapy options for patients with advanced hepatocellular carcinoma. Dr. Gordon, what are the key recommendations for first line therapy?

DR. JOHN D. GORDON: Thanks, and it's also a great pleasure for me to be on this podcast and I appreciate the entire process of putting together this guideline. In the front line setting, a lot of what motivates the completion of this guideline is the approval of the first front line combination for advanced HCC, which is the combination of bevacizumab and atezolizumab. So this was approved based on a report in the New England Journal of Medicine back in May that specifically studied a first line population of patients with advanced HCC and relatively preserved liver function. And the key recommendation of this guideline is that the combination of atezolizumab and bevacizumab be adopted for patients that meet this description. Particular caution is recommended for patients who are at risk of specific side effects or adverse events with these agents.

So for patients receiving bevacizumab, there is a particular risk of bleeding complications and MI or other ischemic complications. And so for patients with a recent MI or with uncontrolled esophageal varices, we recommend either management of these or not using this combination. Similarly, there are a range of contraindications to use of PD1, PDL1 inhibitors, such as atezolizumab, including history of various autoimmune diseases. And so we do not recommend this combination for patients with those co-morbidities. For patients with either more advanced liver failure or the specific risks that I just outlined, we're recommending continuation when safe and appropriate, of what was the previous standard of care. Which is front line treatment with either the oral TKI lenvatinib or the oral TKI sorafenib.

BRITTANY HARVEY: Great. Thank you for that overview of the first line recommendations. And Dr. Rose, what are the recommendations for second line therapy?

DR. MICHAL G. ROSE: So our team had a harder time with second line recommendations. And mainly because there's a lack, currently, of published data on treatment outcomes in patients who've received atezolizumab plus bevacizumab front line or lenvatinib front line. So we debated a lot in our group, which was a very multidisciplinary and collaborative group. And we did agree that patients who are well enough to receive second line therapy, that is their Child-Pugh was still A, and they had a good performance status, they should be considered for sorafenib, oral lenvatinib, if they had received atezolizumab plus bevacizumab in the front line setting. But of course other options for the second line would be cabozantinib or regorafinib, are reasonable in the evidence based options.

In patients who received sorafenib oral lenvatinib front line, we also discussed that it was reasonable to treat them with atezo bev because we presume that these patients did not have access to that combination in the front line. Of course if they meet the criteria that John outlined in the discussion of front line treatment. In patients who received sorafenib or lenvatinib front line, of course that we have data on using other tyrosine kinase inhibitors, such as cabozantinib or regorafinib. We also have data on using ramucirumab in patients who have an alpha fetoprotein greater than 400. And those were the recommendations that we made.

The other discussion that we had in these guidelines was the use of the immune checkpoint inhibitors second line. And we made the recommendation that they should be considered for patients who received sorafenib or lenvatinib in the front line setting, especially if they have contraindications to the use of further tyrosine kinase inhibitors. Or if they could not tolerate tyrosine kinase inhibitors.

BRITTANY HARVEY: Got it. Thank you for reviewing those second line systemic therapy options. Then Dr. Gordon finally, what is the importance of this guideline and how will it impact clinical practice and affect patients with advanced hepatocellular carcinoma?

DR. JOHN D. GORDON: Thanks. And so I think this very much follows on Michal's initial introduction about the purpose of this guideline, which was to address the dramatic proliferation of approved agents for advanced HCC. And what we were attempting to do, and I think achieved to the best that the evidence would support, was provide some degree of guidance on how providers could select both their first line agent and then later lines of therapy to the extent that patients are able to receive it. We think that the availability of these multiple agents for HCC, as Michal alluded to, is really an embarrassment of riches and now we need to think about how to use them wisely.

And we hope that actually as these new combinations and just a greater set of options enter clinical practice, it will be possible to actually do some of the studies that would address the questions that right now remain unanswered around treatments sequencing and the like. I think that there remain some interesting questions in the management of HCC, both for patients with more impaired liver function and for patients at the threshold between localized HCC who are still candidates for local regional therapies such as TACE or selective internal radiotherapy, and requiring systemic therapy as the outcomes from systemic therapy are becoming more positive. But in aggregate we think that these guidelines now provide something of a sequence for the treatment of patients who do require systemic therapy and hopefully an outline for further development.

BRITTANY HARVEY: Great. Thanks. It sounds like this will be important for both practitioners, and patients. So I want to thank you both for joining me on the podcast today and for your leadership on the development of these guidelines, Dr. Rose and Dr. Gordon.

DR. MICHAL G. ROSE: Thank you. And thank you for the opportunity to discuss them.

DR. JOHN D. GORDON: Yeah, thanks as well. And thanks to the amazing team at ASCO and to the entire expert panel, which put in quite a bit of time over the several years that we developed this guideline as more and more data became available.

BRITTANY HARVEY: Great. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Neelima Denduluri from Virginia Cancer Specialists, U.S. Oncology in Arlington, VA and Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, TX on "Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update." This update addresses the use of adjuvant trastuzumab emtansine and the use of biosimilar forms of trastuzumab. Read the full guideline at www.asco.org/breast-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Neelima Denduluri from Virginia Cancer Specialists, US Oncology in Arlington, Virginia, and Dr. Sharon Giordano from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, co-chairs on "Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update."

Thank you for being here, Dr. Denduluri and Dr. Giordano.

Dr. Neelima Denduluri: Thanks for having us.

Dr. Sharon Giordano: Yeah, we're delighted to be here. Thank you.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Denduluri, do you have any relevant disclosures that are related to this guideline topic?

Dr. Neelima Denduluri: Our institution has received research funding from companies including Genentech.

Brittany Harvey: Thank you. And Dr. Giordano, do you have any relevant disclosures that are related to this guideline topic?

Dr. Sharon Giordano: No, I don't have any relevant disclosures. Thank you.

Brittany Harvey: Thank you. Then let's get into the guideline content. Dr. Denduluri, what prompted this focused update of the selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer guideline?

Dr. Neelima Denduluri: There was an FDA meta analysis and several other studies that showed that patients that did not receive a pathologic complete response after preoperative therapy in the HER2-positive setting had a worse prognosis. In the past, we didn't have actionable findings to improve their outcome.

But there was a trial, the KATHERINE trial, that randomized patients that received chemotherapy and trastuzumab, plus or minus pertuzumab, that did not achieve a pathologic complete response to receive standard of care trastuzumab or 14 cycles of trastuzumab emtansine. And the patients that received trastuzumab emtansine had a significantly improved outcome over those that received standard of care trastuzumab. These were very impactful findings that changed care for women with early breast cancer. Therefore, we wanted to update the guideline.

Brittany Harvey: So Dr. Giordano, there are two new recommendations in this guideline update. First, what does the guideline say regarding the use of adjuvant trastuzumab emtansine following standard preoperative chemotherapy and HER2-targeted therapy for patients with HER2-positive breast cancer with residual invasive cancer in the breast or lymph nodes at surgery?

Dr. Sharon Giordano: So the first recommendation was based on the data from the KATHERINE trial that Dr. Denduluri just mentioned. And so their recommendation is that patients with HER2-positive breast cancer who have pathologic invasive residual disease at surgery to either in the breast or the lymph node after standard pre-op chemo with HER2-targeted therapy should be offered 14 cycles of adjuvant trastuzumab emtansine unless there's a recurrence or unworkable toxicity. So basically stating, based on the data from KATHERINE, that if patients have residual disease after their chemotherapy for HER2-positive breast cancer, they should get adjuvant trastuzumab emtansine. And the panel overall felt that the evidence behind this-- the quality of the evidence was very high, and it had a strong recommendation for this treatment.

Brittany Harvey: And then second, Dr. Denduluri, how does this guideline address the use of biosimilar forms of trastuzumab?

Dr. Neelima Denduluri: So biosimilars are increasingly being incorporated into clinical practice, and the guidance that we have from the FDA is that the efficacy of biosimilars compares well with standard trastuzumab. So, we said that patients that would receive trastuzumab are allowed to receive trastuzumab biosimilar without what we think will negatively impact their outcome.

Dr. Sharon Giordano: For that recommendation, we also had input from the Breast Cancer Guideline Advisory Group that helped us decide to expand the update to include the biosimilars. We think that at least five biosimilars have been approved by the FDA, and based on similar efficacy and similar safety data felt that it was appropriate to use them or trastuzumab in a setting where previously we had just used trastuzumab.

Brittany Harvey: Great. And then how will this guideline update impact clinical practice?

Dr. Sharon Giordano: I think that many practitioners have already adapted clinical practice to start to use adjuvant trastuzumab emtansine based on the KATHERINE data, but we certainly hope that this guideline update will reinforce the practice of providing adjuvant trastuzumab emtansine for patients with HER2-positive breast cancer with residual disease after preoperative treatment. The improvement in outcomes was really clinically meaningful for patients, so this does seem to be a significant step forward in the treatment of HER2-positive breast cancer.

Dr. Neelima Denduluri: Additionally, I think that it's important to remember, as clinicians, that we should think about preoperative therapy in those patients with higher-risk HER2-positive disease, because we know that we can impact their outcomes if they don't achieve a pathologic complete response. And hopefully this guideline will heighten the awareness that we need to do that. The other question that we commonly are asked is, even if there is a small amount of residual invasive carcinoma, should we switch to trastuzumab emtansine instead of trastuzumab plus or minus pertuzumab. And what the KATHERINE data did show is that patients that-- even if they had a small amount of residual cancer burden, they still derived benefit.

Obviously, we have to think about the safety, and we also wanted to outline that in this guideline that trastuzumab emtansine is associated with a higher risk of neuropathy and thrombocytopenia and liver function abnormalities. So we certainly need to worry about that. And those patients that do have poor tolerance, we can go back to their HER2-targeted backbone they received in the preoperative setting.

Dr. Sharon Giordano: Yeah, those are great additional points.

Brittany Harvey: Definitely. And you've both already touched on a bit of how adjuvant therapy impacts patients, but how will these guideline recommendations affect patients?

Dr. Neelima Denduluri: I think that really, as Dr. Giordano stated, this is an overwhelming benefit that we don't normally see in terms of impacting outcomes. So the addition of trastuzumab emtansine potentially has good efficacy for them and improves their outcomes.

Dr. Sharon Giordano: Yeah, I agree. I think this trial was associated with a really meaningful reduction in risk of recurrence and better outcomes. So this really is a step forward for treating HER2-positive breast cancer.

Dr. Neelima Denduluri: The other interesting thing about this trial is that it did not delay their local therapy. They allowed concurrent trastuzumab emtansine with radiation therapy. And they also, in terms of systemic therapy, allowed endocrine therapy with trastuzumab emtansine, similar to what we do with trastuzumab plus or minus pertuzumab in the adjuvant setting. So as Dr. Giordano stated, really impactful in terms of efficacy, well-tolerated in most situations, and pragmatic in terms of not holding up the local therapy and the systemic therapy that they may need additionally.

Brittany Harvey: Great, thank you so much for sharing that information about how it impacts patients. I appreciate you both coming on the podcast today and for all your work that you put into updating these guidelines. And thank you for your time today Dr. Giordano and Dr. Denduluri.

Dr. Sharon Giordano: Thank you so much. It was a pleasure.

Dr. Neelima Denduluri: Thank you both, and thank you Brittany for always working so hard to make sure that these guidelines help our patients.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Felasfa Wodajo from Virginia Cancer Specialists on "The Treatment of Metastatic Carcinoma and Myeloma of the Femur: Joint MSTS/ASTRO/ASCO Guideline." This guideline covers medical oncology, radiation oncology, and surgical recommendations regarding the management of patients with metastatic or myelomatous lesions of the femur. Read the full guideline at www.asco.org/supportive-care-guidelines.

Transcript

Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world's cancer care. You can find all the shows, including this one, at podcast.asco.org

My name is Brittany Harvey and today I'm interviewing Dr. Felasfa Wodajo from Virginia Cancer Specialists in Fairfax, Virginia, co-chair on the treatment of metastatic carcinoma and myeloma of the femur, joint Musculoskeletal Tumor Society, American Society for Radiation Oncology, and American Society of Clinical Oncology Guideline. Thank you for being here Dr. Wodajo.

Dr. Felasfa Wodajo: Thank you so much Brittany, I really appreciate the opportunity to talk about our joint guideline that is being published as we speak. It's a great opportunity to share the information with your members as well as hopefully patients and members of other societies.

Brittany Harvey: Great. Then first I'd like to note that ASCO takes care in the development of its guidelines in ensuring that the conflicts of interest are managed for each guideline. This guideline expert panel was assembled in accordance with the American Association of Orthopedic Surgeons conflict of interest policy implementation for clinical practice guidelines. And the full conflict of interest information for this guideline panel is available online in the full text of the joint guideline on the MSTS website.

Dr. Wodajo, do you have any relevant disclosures that are related to this guideline topic?

Dr. Felasfa Wodajo: There's one relevant, but not directly conflicting. I'm a consultant for ONKOS Surgical. That's a maker of implants, but mostly for patients who need sarcoma surgery, and they don't make implants for the types of conditions that are in the guideline.

Brittany Harvey: OK, well thanks for letting us know. First, can you give us a general overview of what this guideline covers?

Dr. Felasfa Wodajo: Sure. The guideline is focused on the effects of metastatic carcinoma or myeloma on the femur. And, as all medical oncologists are aware, metastatic disease to the bone and myeloma are often associated with skeletal pain and sometimes skeletal fractures. Those fractures can occur in any part of the body, spine, of course long bones, and ribs, and so on.

But in our world of orthopedic surgery-- I'm a representative from the Musculoskeletal Tumor Society-- the bones and then added complication are not all equal, and some areas have greater morbidity and effect on patient's outcome than others, the femur being a very important one. And we wanted to focus our efforts on discussing the causes and potential treatments of metastatic disease to the femur.

Brittany Harvey: And then what are the key recommendations of this guideline?

Dr. Felasfa Wodajo: Sure, I'm looking forward to discussing those. I do want to, of course, take a second to acknowledge the hard work that was done by my co-chairs, Dr. Patrick Getty, also from the MSTS, Dr. John Charlson, who was an ASCO co-chair, and Dr. Josh Petit, who is the ASTRO co-chair. And also this gives me a chance to say that this guideline was a joint effort between those three organizations which you already mentioned.

The initiative was led by our organization-- the Musculoskeletal Tumor Society, MSTS-- which is a mostly North American, but also international, society of musculoskeletal tumor surgeons, also known as orthopedic oncologists. And therefore, in almost every place that members of our group work, they're working in close association with medical oncologists and radiation oncologists.

So we wanted to make sure that the guideline reflects the input of all three specialties since all three specialists are often treating the same patients. And in developing the PICO questions-- which are the underlying questions in developing a guideline-- we made sure that we had co-chairs-- one from each of the societies-- agree on which PICO questions to include in the final literature search.

And then finally, the guideline as written, roughly breaks the recommendations down by specialty. It starts off with medical oncology topics, then radiation oncology topics, and then surgical topics. So that's a little bit of background that might be helpful.

I also wanted to mention that one of the meta level findings was the paucity or the dirth of literature that directly addressed the question at hand which is, what kinds of treatments can prevent femur fractures, and then which therapies are best for patients with disease in the femur that may or may not lead to fractures. And we started off with a fairly broad net. But as we focused down on the questions, our initial literature search-- which resulted in over 4,000 journal articles-- was winnowed down to a total of 23 papers which had the high enough level of evidence to be included in our guideline production. And therefore, that inevitably a good number of our questions-- not having strong enough evidence to make a strong evidence based recommendation-- and therefore more than half of our recommendations in the end had to be consensus or expert opinion.

So let me continue with your original question which is, what are the key recommendations. Well, questions that we were interested in were number one, to what extent can non-surgical treatments of metastatic disease to the femur, or myeloma in the femur, will reduce the risk of fracture.

So almost everybody listening to this podcast will know well that bone targeted agents such as the bisphosphonates and denosumab have a strong effect validated in multiple high level randomized and prospective studies in reducing Skeletal Related Events, SREs. As you know, as the listeners also know, Skeletal Related Events is a fairly broad umbrella term, and it includes fracture of any bone as well as hypercalcemia and need for surgery.

But like I said earlier on, a compression fracture of a vertebral body which causes back pain but is treated conservatively, and a fracture of the rib, which also causes pain, treated conservatively or nonoperatively, is a very different matter from a femur fracture which always requires surgery in order to allow the patient to ambulate and regain function.

Having said that, we were disappointed to find that in much of the literature around bone targeted agents-- of which there is plenty-- there's really very little of it that you can find where they stratify, or at least retort, which bones were fractured. So even though there is a strong literature base supporting reduction skeletal events, we can't really say for sure that the risk of a fracture of a femoral lesion is diminished by both targeted agents.

That came out as a consensus statement because this seems to reduce fractures overall, so we left this as a consensus and agreed that BMAs may assist in reducing the incidence of femur fractures.

The next item, number three, in our final report recommended that clinicians consider decreasing the frequency of zoledronic acid dosing to 12 weeks instead of the usual, and most common, four week interval.

There's actually a fair amount of literature supporting quarterly injections as equally efficacious. That's mostly focused on zoledronic acid. It may be true for [INAUDIBLE]. It may also even be true for denosumab, but the literature didn't support that as yet.

But we did make this strong recommendation on our part that clinicians consider reducing the frequency of dosing. If nothing else, because in addition to reducing costs to the patient and time of the patient, we think there may be-- and we put this in our rationale-- there's some chance that some of the unintended side effects of long-term treatment with these bisphosphonate and bismuth therapies such as aseptic necrosis of the jaw and atypical fractures, or brittle bone fractures, of the femur may be reduced with decreased frequency.

Extrapolating from the finding that the longer patients are treated, the higher the incidence of these conditions are, especially atypical fractures. So it could be that less frequent dosing is analogous to less length of treatment. So that was an evidence based and strong recommendation.

We also then looked at the effect of radiation on bone lesions and whether or not it does reduce risk of fracture. We found, not surprisingly, that the radiation oncology literature really focuses on pain. And it's been proven many times and in multiple studies across many decades that radiation therapy does reduce pain at 80% to 90%. And even re-treatment will reduce pain in up to 50% to 70% of patients. But surprisingly, there's actually very little data out there whether it reduces the risk of fracture.

Now we would presume that fracture risk is correlated to bone loss, and that would be radiolucency or loss of calcification on the X-ray. And there are some studies out there which attempt to measure density of bone before and after radiation therapy. And there seems to be some validation, or at least some measurement out there that radiodensity does increase with radiation therapy, and again, we went from that and extrapolated that fracture risk would best be reduced.

But that ended up being a consensus statement. And it's actually a fairly important topic. And hope that more studies would be forthcoming on this, because it would be very helpful for us to predict ahead of time whether this patient can avoid a fracture with radiation alone or do they need to go to surgery.

Next we talked about how effective or beneficial is radiation after somebody's had surgery. So whether or not they've had a fracture, is there a further benefit to radiation. And here the amount of data was even more disappointing.

There's really only two studies that attempt to address this question-- is there a benefit to additional radiation following surgery-- neither one of which was well controlled. They're way out of date and the criteria themselves used in measuring the benefit were not validated.

Now we felt, as a work group-- again consisting of medical oncologists, radiation oncologists, and surgical oncologists, in this case orthopedic oncologists-- that the additional morbidity from radiation after surgery is fairly low. So we left that recommendation as that it has some benefit, but that was the consensus only.

One item that we elevated from consensus to a moderate strength was the benefit of using multifraction radiotherapy to reduce the risk. There is some data-- again, it may be biased-- that patients who undergo single dose radiotherapy as opposed to multifraction radiotherapy for metastatic lesions have an increased risk of fracture. And it may be associated and it may be that those patients getting single dose radiation were at higher risk or had more rapidly progressing disease. But there may be some signal in that noise, and after evaluating the papers and with the help of our experts in radiation oncology, we elevated that to a moderate strength of recommendation.

Then there was a series of questions we tried to address, various surgical techniques and the management of pathology of fractures in the femur and prevention of, and those questions are really more about surgical technique. And these were addressed to our surgical colleagues in large part. I don't know, and I would suspect that the audience of this podcast probably won't be as interested in these questions as the ones we just discussed, so I'll leave those for another time. But I will say a large number of these ended up being also consensus driven evidence.

Brittany Harvey: Got it. Well, thank you so much for reviewing those highlights from the multidisciplinary group and the supporting level of evidence. That's very helpful. So in your view, why is this guideline so important and how will it impact clinical practice?

Dr. Felasfa Wodajo: So, thank you for the question. I'll answer that in two ways. I think the two items that might be of immediate clinical relevance, and therefore of help to patients and their physicians, is number one, further promulgation of the idea of less frequent dosing of bone targeted agents is equally efficacious.

We felt that, if based on our common experiences in our various practices and institutions, that still was not widespread practice. In other words, most patients were still receiving monthly injections of these medications. So we do believe that there is some net patient benefit available to us if those are reduced to quarterly injections for the reasons I mentioned above. So that's one potential immediate release and early improvement that we can expect for patients.

I think the other one, to some extent, may be that what I discussed a little while ago about and multifraction versus single fraction therapy. Again, we don't have nationwide survey data to tell us how often those techniques are used. Again, based on this sort of experience of the workup we thought that that may not be widely understood. So those are two immediate clinical benefits that may be there for patients.

The other way I would look at is at a meta level. Number one was that this is a cooperative venture in which the design and implementation of the guideline was across three organizations. And many times guidelines do incorporate the viewpoints of people of multiple specialties, and sometimes even patient representatives. But it's also, I think, further valuable to have multiple organizations involved because there's some cross-fertilization opportunities there, other products may arise from that, and then also you get what we hope is promulgation of that information to people of different specialties. In other words, these recommendations don't stay inside the ecosphere of one association.

Now when you have multiple organizations working on one project, necessarily it gets more complicated. And there is certainly a heavier administrative burden in getting this project initiated and completed. But hopefully the benefits of that will accrue.

The other thing which I'd like to mention is that I think the paucity of high level evidence for the questions we ask-- which we believe are important questions for physicians and patients-- I think hopefully should stimulate the researchers in these fields to accrue more data so that future researchers and clinicians have access to these information.

For example, I suspect that in future prospective studies of bone targeted agents-- those studies are ongoing-- new agents will be coming out. Pharma will be looking at how those work for their patients in the future. And we would like to ask that those future researchers include, at a minimum, anatomic data for fractures. In other words, they should unbundle Skeletal Related Events and tabulate fractures as occurring in which part of the bone, and if that resulted in surgery.

Those data are there in the records, but if they don't collate them as they go forward, they will not be available to us, and so therefore won't be as efficacious in helping our patients in the future.

Brittany Harvey: Definitely. Those are some important points and I like that you touched on the collaboration of the societies. We find that very important at ASCO to one, reduce the duplication of efforts, and then also to improve the clarity of the recommendations. So, I guess then, finally-- and you've addressed this a bit in terms of dosing of bone modifying agents-- what do these guideline recommendations mean for patients?

Dr. Felasfa Wodajo: Well, for the bone targeting agents, as I said, that might mean fewer doctors visits and maybe less expense, hopefully fewer side effects. For the hyperfractionated radiation, it may not be immediately apparent. I mean a lot of times when a patient's getting single fraction radiation they are fairly advanced in their cancer. But of course they'll get more fractions which means more time in the machine. But hopefully maybe some benefit If they survive longer, which of course, patients are now doing. So those are two potential patient benefits.

Brittany Harvey: Great. Well thank you for your work on these guidelines and for joining me on the podcast today Dr. Wodajo.

Dr. Felasfa Wodajo: I very much appreciate your invitation, and thank you.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store.

If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. William P. Tew from Memorial Sloan Kettering Cancer Center on “PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline.” This guideline provides recommendations on the use of poly (ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer. Read the full guideline at www.asco.org/gynecologic-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Brittany Harvey: Hello, and welcome to the ASCO guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today, I'm interviewing Dr. William P. Tew from Memorial Sloan Kettering Cancer Center in New York, New York, lead author on PARP inhibitors and the management of ovarian cancer. Thank you for being here, Dr. Tew.

Dr. William Tew: Thank you, Brittany, for having me.

Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Tew, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. William Tew: No, I do not.

Brittany Harvey: OK, thank you. Then, can you give us a general overview of what this guideline covers?

Dr. William Tew: Sure. So my co-chair, Elise Kohn, and panel members, and ASCO staff put together a very comprehensive guideline on the use of PARP inhibitors in the management of women with ovarian cancer. And as many of your listeners may know, there has been a rapid speed of phase 3 practice changing trials that have been published and FDA approvals within the last year, and what we wanted to do was to put that all in one document and give guidance on how and when and which PARP inhibitor to use in your specific patient and at what point during the lifecycle of ovarian cancer of when to use it.

So we broke up the guideline into five sections. One is the use of PARP inhibitors as maintenance therapy after first line platinum based treatment in women with stage 3 and 4 ovarian cancer. Second, we looked at maintenance therapy after a second or higher platinum based treatment. Three, the use of PARP inhibitors as treatment for patients with recurrent epithelial ovarian cancer.

We then looked at different combinations of PARP inhibitors, whether it's with chemotherapy or biologics and the data that we have presently on those combinations. And then lastly, we looked at common side effects with PARP inhibitors and offering guidance on how to manage those toxicities.

Brittany Harvey: Great. Then you just mentioned that this covers several different sections, so I'd like to go through each of those sections and review those recommendations for our listeners. So first, what are the recommendations for PARP inhibitors for patients with newly diagnosed epithelial ovarian cancer?

Dr. William Tew: So for women with newly diagnosed ovarian cancer, there's been several studies that have been published in the last year and a half, and we broke this up into the different studies and the different patient populations. First and foremost, we wanted to stress that PARP inhibitors are not recommended for the use in the initial treatment of patients with early stage, meaning stage 1 or 2 ovarian cancer, because there really isn't sufficient evidence to support the use in this population. All of the trials looked at patients with stage 3 or 4 epithelial ovarian cancer and used primarily in the main setting, and what that basically means is that women that have had a complete or partial response to first line platinum based chemotherapy and have response by CT scan or CM 125, when do you use a PARP inhibitor?

Which are the women that you would say PARP inhibitor is going to benefit you with long-term outcome? So our first recommendation is based on a trial-- looking at a drug called olaparib. Olaparib was the first PARP inhibitor published in this population, and in that study, they included women with both germline or somatic pathogenic or likely pathogenic variants in the BRCA1 or BRCA2 gene. And so this is a group of women that you could offer olaparib for.

And generally, that is given at a dosage of 300 milligrams once every 12 hours for up to two years. The second study looked at a drug called niraparib, and in this trial, they included population of all women, regardless of BRCA status. And they offered it to women with high-grade serous or endometrial ovarian cancer. And the FDA has given approval for the use of niraparib for all patients, and that is at a dosage of 200 to 300 milligrams oral daily for three years, with the lower dose given for patients who have a low platelet count or low body weight to prevent the common toxicity of thrombocytopenia.

Then you could consider longer durations in select individuals, but generally, these drugs are given for a limited period of time and continued unless a patient has significant toxicity or progression. The other two studies in the newly diagnosed ovarian cancer population was a study that looked at olaparib with bevacizumab maintenance. This was a study that included patients with germline or somatic mutations and BRCA 1 or 2 and/or genomic instability or homologous repair deficiency, as determined by the myriad my choice test.

And again, this population, a partial or complete response to chemotherapy and their first line therapy should have included bevacizumab. And so if one is on bevacizumab with their platinum based therapy, they should have a response to treatment, one could continue bevacizumab and add the addition of olaparib as a PARP inhibitor. And then the final study that we addressed was called switch therapy, and that we don't really have enough data to support its use, specifically that's with the drug called veliparib, and veliparib was given in addition to the chemotherapy and then continued as a maintenance therapy.

We don't really have sufficient data to suggest this was superior, equal, or less toxic than the approaches discussed above, which is single agent PARP inhibitor or bevacizumab with PARP inhibitor. And it should be noted, also, veliparib is not yet an FDA approved drug and not commercially available.

Brittany Harvey: OK, then what are the recommendations for PARP inhibitors for patients with recurrent epithelial ovarian cancer?

Dr. William Tew: Yeah, and this data has been around a little bit longer, and I think any oncologists that treat them with ovarian cancer are more comfortable with the evidence with these studies. So what we're talking about here is that patients who were in clinical remission and then their ovarian cancer recurs. And the first group of women that we look at is patients that are then retreated with platinum based therapy. Those women that have platinum sensitive disease, and then whether to offer PARP maintenance in the second line or more remission settings.

And there is very good data to support the use of PARP monotherapy in second or greater maintenance. This has been shown with all three commercially available PARP inhibitors, olaparib, rucaparib, and niraparib. We do know that women who have a germline or somatic pathogenic or likely pathogenic variant in the BRCA 1 or 2 genes have the highest benefit of maintenance PARP inhibition, and those patients have the strongest evidence to receive those drug.

So the only other point I wanted to make with current ovarian cancer is if a patient has received a PARP inhibitor in the past, there is no evidence to give a second exposure to PARP inhibitor. Those studies are being developed now, but PARP inhibitor use once in the life cycle is what's recommended. And then there's also evidence to use PARP inhibitor as an actual treatment. So not in the maintenance setting, and the drug most commonly used as one called niraparib or olaparib, and these are patients that have measurable disease or generally have platinum sensitive disease, and those women that have homologous repair deficiency, as determined by the Myriad myChoice test, and again, have platinum sensitive to disease do have benefit for treatment with PARP inhibitors.

Brittany Harvey: OK, then, so you just mentioned this, but is it correct that PARPi therapy for epithelial ovarian cancer should not be repeated over the course of treatment?

Dr. William Tew: Right now, that is what we recommend. All of the studies that looked at the use of PARP inhibitors disqualified women who have had prior PARP inhibitors. So as of now, we don't have any evidence to support the use of repeated PARP inhibition.

Brittany Harvey: And what does the guidelines say about using PARP inhibitors in combination with chemotherapy or other targeted agents?

Dr. William Tew: There are many studies going on currently looking at the use of PARP inhibitors in combination with immunotherapy, chemotherapy, and other targeted agents, but currently, at least in the recurrent setting, there is no data to support its use in combination with another anti-cancer treatment. Now, of course, in the context of a clinical trial, this would be very reasonable, and we encourage clinical trial participation.

The only studies that looked at PARP in combination with other anti-cancer treatments are in the first line setting, as I discussed earlier, including PARP inhibitors with bevacizumab, as in the case with olaparib or PARP inhibitors with chemotherapy, as is often the case with veliparib.

Brittany Harvey: OK, thank you. And then how should clinicians manage the adverse effects associated with PARP inhibitors?

Dr. William Tew: I think the first and foremost thing is to be aware of the specific side effect profile of each PARP inhibitor, because they can vary slightly between parts. The most common side effects include fatigue, nausea, change in appetite, and effects on the blood counts, and we gave guidance on each of those specific side effects. As far as the effects on the blood counts, anemia, I'd say, is one of the more common side effects across all PARPi's, and the use of blood transfusions is generally recommended if patients are symptomatic and their hemoglobin is below 8 to 7.

And then for neutropenia, usually, this requires hold of dosing, and we did not encourage the use of growth support, although it may be used in certain settings when the drugs on hold. And then the final cytopenia issue is the issue with platelets, and this is unfortunately very common side effect with niraparib. And we discussed earlier about starting at a lower dose, 200 milligrams of niraparib based on a weight and platelet count to help temper the degree of thrombocytopenia. But with thrombocytopenia, clearly, the drugs sometimes need to be held or discontinued if it's significant.

And with cytopenias, we do recommend close observation of laboratory blood work, particularly in the first month of use of PARP inhibitors, and then always being mindful if patients are on PARP inhibitors for prolonged periods of time that there has been reports of treatment related myelodysplastic syndromes and leukemias and that should be further worked up if there is any evidence of dysplasia.

Brittany Harvey: So then, what is the importance of this guideline in your view, and how will its implementation affect clinical practice?

Dr. William Tew: Well, I think this is the most up-to-date and comprehensive guideline on PARP inhibitors and will help, both clinicians and patients, understand all the practice changing studies, the populations, and the settings they will use, and all these studies that were published over the last five years. I think this last year we've seen such a rapid growth of clinical trial results and FDA approvals that this manuscript, I think, successfully puts them all together in table form and brief recommendations to better treat and provide proper management to your patients with ovarian cancer.

Brittany Harvey: And then finally, how will these guideline recommendations impact patients with ovarian cancer?

Dr. William Tew: We were very fortunate to have two patient advocates as part of our panel, and what they told us was that these recommendations will help them understand the scientific trials, will put in context when to use PARP inhibitors, and also to prepare them for those conversations that they have with their clinicians in discussing if they're a good candidate for a PARP inhibitor now or in the future. So we're really proud of that, that we were able to get our patients perspective in developing these guidelines.

Brittany Harvey: Definitely. Well, thank you for your work on these important and timely guidelines and for taking the time to join me on the podcast today, Dr. Tew.

Dr. William Tew: My pleasure. Thank you so much, Brittany, for having me.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Davendra Sohal from the University of Cincinnati, and Dr. Daniel Laheru from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins on “Metastatic Pancreatic Cancer: ASCO Guideline Update." This update covers new information on targeted therapies for metastatic pancreatic cancer. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines

Transcript

My name is Brittany Harvey, and today I'm interviewing Dr. Davendra Sohal from the University of Cincinnati, and Dr. Daniel Laheru from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, co-chairs on Metastatic Pancreatic Cancer, ASCO Guideline update. Thank you for being here, Dr. Sohal and Dr. Laheru.

Hi, Brittany. Thank you for inviting us.

Happy to be here. Thanks.

First, I'd like to note that ASCO takes great care in development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. But Doctor Sohal, do you have any relevant disclosures that are directly related to this guideline topic?

No, I do not have anything directly in conflict. Thank you.

And Dr. Laheru, do you have any relevant disclosures that are related to this guideline topic?

Thank you, Brittany. I do not either.

Great. Than delving into the guideline content, Dr. Laheru, can you tell us what prompted an update to this guideline?

Yeah, sure. So what has been seen in almost every cancer is that with careful understanding of the molecular alterations of individual cancers, that targeted therapies have been developed for almost every cancer. And so for pancreas cancer, we have not had an opportunity in the past to use targeted therapies. Because for pancreas cancer, many of the genetic alterations that are found in other cancers are not seen in pancreas cancer. And so the guidelines were updated based on new evidence of the use of certain targeted therapies for pancreas cancer.

Then Dr. Sohal, what are the key updates that were made to the recommendations in this guideline iteration?

So the key updates relate to the so-called targeted therapies, the genomic-driven therapies that have now come up with evidence that pertains to pancreatic cancer as well. The overarching update is that every patient with metastatic pancreatic cancer who is a candidate for treatment should have tumor or somatic, the so-called somatic genomic profiling, as well as germline genomic testing, because these can lead to treatment recommendations.

And those treatment recommendations include PD-1 checkpoint inhibitor therapies for microsat light instability high tumors, track the TRK fusion inhibitors, such as larotrectinib and entrectinib for track fusions in tumors. And PARP inhibitors, such as olaparib for germline BRCA1 or BRCA2 mutations to be used as maintenance therapy after stable disease on platinum-based therapy.

Then Dr. Laheru, can you speak to the importance of this guideline and how it will drive changes to clinical practice?

Yes. So as Dr. Sohal said, these specific genetic alterations, the mismatch repair deficiency, the use of PARP inhibitors for BRCA1, BRCA2 germline mutations or somatic mutations that are pathologically significant, and for the NTRK fusion transcripts, even though these mutations for pancreas cancer are quite unusual, less than 5%, for example, for NTRK fusion transcripts, 5% to 10% for BRCA1, BRCA2 germline mutations, and probably 1% or 2% for a mismatch repair deficient pancreas cancer, the committee felt that we should inform the larger cancer community that even though these mutations are uncommon, if they are found, they could be very important for individual treatment for pancreas cancer.

And so this is why we really felt that it was time to provide an update, because of the recent information with the olaparib maintenance and with the NTRK inhibitors for the NTRK fusion transcripts.

Great. And then finally, Dr. Sohal, how do you envision that this guideline update will affect patients?

I think it expands our armamentarium for pancreas cancer patient management. It affords opportunities for better treatments, targeted therapies, which have hopefully higher efficacy and lower toxicity than standard chemotherapy, even though, as Dr. Laheru said, the proportion of patients being eligible for these therapies may be only around 5%. Still, in a disease where there are not many options, every 1 in 20 patients can get these therapies based on tumor genomic profiling and/or germline testing.

And the other slightly different but associated topic is that if germline testing finds something in the patient, a bad gene, then obviously, that patient's blood relatives can be tested for that germline finding, and there may be implications for further testing and surveillance of family members.

Well, thank you both for your work on this metastatic pancreatic cancer guideline update. And thanks for taking the time to speak with me today, Dr. Sohal and Dr. Laheru.

It's our pleasure, Brittany. Thank you very much.

Certainly. Thank you so much.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Jessica Hwang from MD Anderson Cancer Center and Dr. Andrew Artz from City of Hope Cancer Center on “Hepatitis B Virus Screening and Management for Patients with Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update.” This update presents a clinically pragmatic approach to HBV screening and management that calls for universal HBV serological testing of patients at the onset of anticancer therapy. Read the full PCO at www.asco.org/supportive-care-guidelines

Transcript

Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at podcast.asco.org.

My name is Brittany Harvey. And today, I'm interviewing Dr. Jessica Hwang from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, and Dr. Andrew Artz from the City of Hope Comprehensive Cancer Center in Duarte, California, co-chairs on hepatitis B screening and management for patients with cancer prior to therapy, ASCO provisional clinical opinion update. Thank you for being here, Dr. Hwang and Dr. Artz.

Thank you for inviting us.

Thank you so much.

First, I'd like to note that ASCO takes great care in the development of its guideline products and ensuring that the ASCO conflict of interest policy is followed. The full conflict of interest information for this provisional clinical opinion panel is available online with the publication in the Journal of Clinical Oncology. Dr. Hwang, do you have any relevant disclosures that are related to this topic?

Well, I have received some research funding from Gilead, a maker of a hepatitis drug in the past.

And, Dr. Artz, do you have any relevant disclosures?

I have no relevant disclosures.

OK, then so, Dr. Artz, so this provisional clinical opinion, or PCO, on hepatitis B screening and management for patients with cancer prior to therapy was first published in 2010 and then last updated in 2015. What prompted this update to the PCO?

This PCO guidance, more broadly, is necessary because the hepatitis B status for most patients is actually unknown at the time they're starting cancer therapy. In 2015, the PCO though suggested that we limit hepatitis B screening to patients who were at most risk for hepatitis B reactivation, if they were hepatitis B carriers, so those receiving anti-CD20 antibodies, such as rituximab or stem cell transplant. But for the remaining patients, most patients receiving cancer therapy, the guidance was to survey patients about their close contacts or exposures to hepatitis B and determine if formal hepatitis testing should ensue.

This 2020 PCO represents an evolution in our understanding of hepatitis B screening and the dangers of hepatitis B after anticancer therapy. We've learned from studies, including those done by my colleague, Dr. Hwang, that questionnaires to detect hepatitis B are not very effective or practical. We also have accumulating information that many of our anticancer therapies pose a significant danger for hepatitis B related complications in hepatitis B infected patients. We believe appropriate monitoring and treatment, as outlined in the PCO, will reduce these dangers.

So given that new information, I'd like to discuss the updated statements for the PCO. So first, Dr. Hwang, for patients who will receive systemic anticancer therapy, who should be tested for HBV and how should they be tested?

That's a great question, Brittany. Thanks. I think that the data is really clear now that all patients with cancer anticipating systemic anticancer therapy should be tested for hepatitis B virus. That includes all solid tumor patients, as well as hematologic malignancy patients.

And they can be tested with a simple blood test. The hepatitis B virus can be tested by three blood tests for hepatitis. It's the hepatitis B surface antigen, HBsAG, or the hepatitis B core antibody. There are two types of this. It's either the IgG or the total IG, which shows, if positive, could indicate a patient has past infection. There is a IgM version of that core antibody test. And that tells, if positive, tells whether a patient has acute infection. So for our purposes, it's recommended that the IgG or total IG is used and not the IgM, because we are interested in whether a patient has past infection.

So the third test is a hepatitis B surface antibody. And this is a protective antibody. So if positive, it shows that a patient has had some exposure in the past or perhaps a vaccination in the past. And so this is a good test to have positive.

So then what does the PCO state for patients with chronic HBV infection?

Patients with chronic HBV infection, that is those patients with a positive hepatitis B surface antigen test, these patients really should have very close monitoring during as well as after anticancer therapy. These patients will need antiviral therapy prophylactically prior to enduring as well as after the cancer treatment. They should also see a clinician experienced in the management of hepatitis B, whether it's a hepatologist, a gastroenterologist, an infectious disease specialist, or maybe a primary care doctor who's experienced in treating and caring and monitoring for patients with hepatitis B. That's really important for these patients with a chronic hepatitis B, because they are at high risk of developing complications during and as well as perhaps even shortly thereafter of receiving systemic anticancer therapy.

And then what does the PCO state for patients with past HBV infection?

This is a really good question. The patients with past HBV infection are those who have a negative hepatitis B surface antigen and a positive hepatitis B core antibody. This represents maybe some 6% at least of the US population. It could be much higher. So this is a sizable group of patients. And it's really important to know that it is sort of a tailored approach.

So patients with past HBV infection who are anticipated to receive one of the high risk anticancer therapies that Dr. Artz mentioned just a few moments ago, namely stem cell transplantation or maybe one of the anti-CD20 monoclonal antibodies, these patients are at really high risk of reactivation. So these patients would need a very close monitoring plan. They would need their hepatitis B and liver test monitored during their anticancer therapy. And most often they would need antiviral prophylaxis before, during, and even after their immunosuppressive therapy ends.

So there are patients, of course, who don't receive these high-risk therapies. So that is patients with past HBV infection who are receiving anticancer therapy that's not a stem cell transplant and not an anti-CD20 monoclonal antibody. These patients could be monitored carefully. They could have hepatitis B and/or liver testing monitoring during anticancer therapy. And if they have any elevations in their surface antigen or their ALT, then they could have further hepatitis B testing to see if they have any evidence of complications from their hepatitis B. So that's in general what the PCO recommends for these two groups.

Well, thank you for reviewing those highlights from the PCO. So Dr. Artz, what is the importance of this PCO and how will its implementation impact practice?

Thank you for the question. This PCO I feel dramatically simplifies the challenge of hepatitis B screening by proposing universal hepatitis B testing, as Dr. Hwang outlined, at a defined point in time. That is at the initiation of therapy.

And clinicians have really struggled with hepatitis B testing for lots of different reasons. They're difficulties in knowing who to screen, how to screen, in part because the data have started to emerge that many of the therapies may pose some risks and the prior suggestion that we use questionnaires, but there wasn't a standard set of questionnaires that we could use if we wanted to identify people based on risk factors of acquiring hepatitis B. So this led to a lot of confusion on testing.

I think by standardizing this makes it considerably easier. And also, the guidance from the PCO is better harmonized with other organizations, such as the Centers for Disease Control and our Liver Society colleagues who actually participated in the panel. And so now the guidance clinicians receive are more consistent across organizations. So I think this will allow doctors and health care systems overall to now invest in the implementation of hepatitis B screening, rather than the question about who should we do it and can we do it and when should we do it, but rather more on the implementation to help patients.

Great. And then finally, what is the impact of this updated PCO for patients?

Well, I'll take the first part of that. I believe that the implementation should permit safer systemic anticancer therapy by reducing hepatitis B related complications. Whenever patients have complications or there's even uncertainty about whether hepatitis might be contributing, this also can lead to delays in our treatments. If we know in advance and we appropriately manage and monitor this, we should have fewer treatment delays as well. Dr. Hwang, I know, might also have some comments on this.

Thanks. I do have a few general comments beyond the cancer care implications. And I'd like to say I think that hepatitis B testing and then the results of that and sharing that information with patients is really important. Letting patients know their hepatitis B status, especially if they're positive, empowers them to seek further care, get connected with a hepatitis B specialist person who's experienced in managing hepatitis B, and also to look around the local environment to their household and close contacts because hepatitis B is a virus that is transmitted from person to person through blood-borne sexual transmission and close family or household contact.

So I think it's important for patients to know their status to protect themselves during cancer therapy, as Dr. Artz mentioned, but just in general for good health care for themselves and for those around them. And in addition, I think that it's important for the family members and those close contacts to then get screened and perhaps even consider getting vaccinated if they haven't been vaccinated.

Well, thank you both for your hard work on updating this PTO and for taking the time to speak with me today, Dr. Hwang and Dr. Artz.

Thank you, Brittany.

And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full provisional clinical opinion go to www.asco.org/supportive-care-guidelines. This PCO also has a companion cancer.net podcast episode. Cancer.net is the patient information website of ASCO. And we encourage you to learn more by tuning into their episode. You can find their podcast and all ASCO podcasts at podcast.asco.org.

You can also find many of our guidelines, PCOs, and interactive resources in the free ASCO Guidelines app, available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Charles Loprinzi from Mayo Clinic in Rochester, MN on “Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update.” This update incorporates new evidence into recommendations for the prevention and treatment of chemotherapy-induced peripheral neuropathy in adults with a history of cancer. Read the full guideline at www.asco.org/survivorship-guidelines

TRANSCRIPT

Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm interviewing Dr. Charles Loprinzi from the Mayo Clinic in Rochester, Minnesota, lead author on prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers, ASCO guideline update. Thank you for being here, Dr. Loprinzi.

It's my pleasure to participate.

First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each of our guidelines. The full conflict of interest information for this guideline panel is available online with the publication in the Journal of Clinical Oncology. Dr. Loprinzi, do you have any relevant disclosures that are related to this guideline topic?

Well, that's always the perception, I think. Let me mention a couple of things. I've been intimately involved with research with chemotherapy-induced neuropathy for about 20 years or so, and have looked at a lot of the different drugs and treatments that we considered in this guideline.

I consulted for companies that have interest in neuropathy, including Asahi Kasei Pharma, Disarm Therapeutics, Metis Pharmaceuticals, PledPharma, and NKMax America. But other than that, I do not have anything else to note there.

Great, thanks. So first, what prompted an update to this guideline on the prevention of management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers?

Well, it's been about five years since we did the initial guideline. It is a very prominent problem-- I think probably one of the most prominent chronic problems we get associate with chemotherapy. You get acute problems like nausea and vomiting, but those go away. But this can be a prominent problem that can last for years.

There have been about 40 new trials for looking at prevention of neuropathy while you're giving chemotherapy, or treatment of neuropathy after you receive the chemotherapy and looking at ways to try to treat that. About 40 new trials have been published since we did the last guideline. So it was decided that it's time to look at this again to see what's new, what's not new, and sort things out.

So with that new information that the guideline panel looked at, what are the recommendations for prevention of chemotherapy-induced peripheral neuropathy?

OK. So for prevention-- and we're talking about you're about to give chemotherapy that has neurotoxic properties, if you will. Not all chemotherapies cause neurotoxicity. And by neurotoxicity, I'm talking about numbness, tingling, pain, usually in distal extremities. Hands and feet is where it usually starts. But that's what we're talking about here.

And the bottom line answer, which is similar to what it was five years ago, is that there is no proven means for being able to prevent this problem other than not giving the chemotherapy that can cause the problem. And we usually want to give the chemotherapy to try to kill the cancer process. So there is no proven means.

There is, however, suggestive evidence for a few things. And each of these need more research to really clarify the risks of doing them and that benefits from. One of these things is something called cryotherapy or cold therapy. And you put cold therapy on hands and feet, causes less blood flow, and slows the metabolism somewhat while the person is getting chemotherapy. And there's suggestive evidence that helps, although not proof.

There is another thing that's somewhat related to that, and it's called compression therapy, where if you put tight surgical gloves on a hand while you're getting the chemotherapy, decreasing blood flow when there's a lot of chemotherapy in the blood-- again, suggestive evidence. But there is things where they've actually combined these things with both doing cryotherapy and some compression.

And the third thing is exercise. There are data suggestion that exercise can decrease the amount of neuropathy that patients get. Again, no proof for any of those three things, but more research is needed in that area.

Thanks for reviewing those recommendations for prevention. What are the recommendations for treatment approaches for chemotherapy-induced peripheral neuropathy?

So I think we have two things in here. One of them is what about when you're giving chemotherapy to a patient-- neurotoxic chemotherapy-- and you're planning to give, let's say, 12 cycles of paclitaxel, a common drug that we give for 12 cycles once a week-- one-week cycles, so dose once a week for 12 weeks, and it causes neurotoxicity. And you might be six or seven or eight doses in, and the patient's getting fairly significant neuropathy. And you're worried about giving more of that chemotherapy because it might cause more neuropathy, which may not go away for months or years after it is finished.

So in that setting, the decision, the recommendation, is for the doctor to think about how much additional benefit are we going to get from continuing onto the 12 cycles from the 8 cycles or 6 cycles wherever we are, and decide how much, if this is given in the adjuvant setting where you're trying to cure a person.

They've had surgery. They've had-- the cancer has been removed, and you can see that there's a risk of recurrence, and you're giving chemotherapy to try to decrease the risk of recurrence, what percentage benefit will it get if you go on to 12 cycles? Is that 1% additional benefit that the patient wouldn't get recurrence? Or is it 10%? Is it 5%? Is a 15%? So helping to sort that through, and then talking to the patient about that, and then making a decision. Do I continue on with the planned full dose of their chemotherapy?

The other aspect is what about treatment of a patient who is finished with their chemotherapy, and now they have the neuropathy? And, again, for some types of chemotherapy drugs, their neuropathy continues to get worse for about three months after you've did the last dose of chemotherapy. It's not because you stop the chemotherapy that it makes the neuropathy get worse. But it's rather, in my mind, that it takes three months to get full manifestations of the neuropathy for drugs such as oxaliplatin.

So in that setting, there is one drug that is a winner, if you will, called duloxetine. It does improve things statistically significantly. It doesn't improve them a whole lot. But it does work, and it's been shown in repetitive studies for that. So that's the one recommended approach there.

There are three things where there is suggestive evidence of benefit. And, again, exercise fits in that category. There is some suggestion that patients who exercise will get benefit and get improvement. There are some data that acupuncture will cause some improvement. And there are some data that something called scrambler therapy, a type of cutaneous neuro stimulation process will help decrease neuropathy in those situations. Again, for all three of them, the committee was unable to say yes, we-- was unable to say that we have scientific proof that these work. But there's suggestive evidence that they might provide some benefit.

So with these updated recommendations, in your view, what is the importance of this guideline and its relevance for practicing clinicians?

I think it's-- again, it's a big problem in practice for patients-- oncologists as they're seeing patients, and for the patients themselves, and to find what we do know works, and what we know doesn't work, and what we think might be helpful is helpful for patients. It's helpful for patients to hear this and know this.

It's helpful for physicians to be able to say, yes, we looked at all the data. There were 42 more studies, and most of them didn't show benefit, unfortunately. Here's the ones that did show benefit, and here's the ones that are suggestive evidence, or some things like exercise is probably a reasonable thing to go with. Even though it needs more study, it's probably a reasonable thing for people to do, because we don't exercise enough in this country.

And then finally, you've touched on this a bit, but how will these guideline recommendations impact patients?

I think that just kind of as we said. You know, whatever the doctors can understand better about it, the clinicians there, and then relate that back to the patients themselves is the best way. Is it possible for the patients, and there are some very bright patients out there who could read the medical literature and take a look at this and read it on their own? Yes. Sure. Why not? But that's how I think. Understanding-- getting the physicians to-- scientists to understand what we do know, and then getting that word on to the patients and their families in this setting.

Great. Well thank you for your work on this important guideline update and for taking the time to speak with me today, Dr. Loprinzi.

You're welcome.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/survivorship-guidelines. This guideline also has a companion cancer.net podcast episode. Cancer.net is a patient information website of ASCO, and we encourage you to learn more by tuning into their episode.

You can find their podcast and all ASCO podcasts at podcast.asco.org. You can also find more ASCO guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Paul J. Hesketh from Lahey Hospital and Medical Center in Burlington, MA on “Antiemetics: ASCO Guideline Update.” This update addresses antiemetic prophylaxis in patients treated with checkpoint inhibitors and incorporates new data since the last guideline publication. Read the full guideline at www.asco.org/supportive-care-guidelines

TRANSCRIPT

Hello, and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey. And today, I'm interviewing Dr. Paul Hesketh from Lahey Hospital and Medical Center in Burlington, Massachusetts, co-chair of antiemetics, ASCO Guideline update. Thanks for joining me, Dr. Kesketh.

Hello, Brittany. I'm very happy to have the opportunity to join in today's podcast.

First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Hesketh, do you have any relevant disclosures directly related to this guideline topic?

No, I do not have any relevant disclosures.

So, Dr. Hesketh, what prompted an update to this an antiemetics guideline, which was last published in 2017?

Well, as you know, Brittany, each guideline panel is instructed by ASCO to regularly review the evolving literature and other information, looking for any significant developments that are relevant to that specific guideline. And since our last update in 2017, there has been a tremendous expansion in the use of checkpoint inhibitors for a variety of different neoplastic diseases. Although they're often used alone, increasingly, the checkpoint inhibitors were being added to a variety of chemotherapy regimens. And as this was occurring, concerns were being expressed by some oncologists that corticosteroids, a critical component of many antiemetic regimens, might be contraindicated when checkpoint inhibitors were being added to chemotherapy regimens given the potential immunosuppressive possibility for corticosteroids. So the panel felt that an update was indicated to try to address this issue as well as providing information on new antiemetics, antiemetic regimens, and to try to categorize the medic potential of the many new anticancer agents that have been approved since our last update.

Great. So you touched on a couple things there. So first, how does the guideline address antiemetic prophylaxis in patients treated with checkpoint inhibitors?

Well, the search that we conducted for this guideline found 10 relevant publication on checkpoint inhibitors. The search reaffirmed the panel's conclusion that all currently available checkpoint inhibitors really have minimal emetic potential when used as monotherapy. And really, no prophylactic antiemetics are required when an individual checkpoint inhibitor is used.

When used in combination with chemotherapy, two phase III trials were particularly instructive in helping to formulate our guidelines. Both trials were conducted in adult patients with non-small cell lung cancers treated with a platinum based doublet with or without the Program Death 1, PD-1 inhibitor pembrolizumab. And they recommended in both those studies that all patients receive dexamethasone as a component of the prophylactic antiemetic regiment. And of note, in both studies, superior efficacy outcomes were noted in the PD-1 inhibitor containing harms. Therefore, the panel feels that there is really no clinical evidence at present to warrant emission of dexamethasone from guideline compliant prophylactic antiemetic regiments when checkpoint inhibitors are administered to adults in combination with chemotherapy.

And then you touched on also antiemetic regimens that were updated. Given the new information about olanzapine, what recommendations were updated?

Well, olanzapine is a very interesting drug. It's a second generation antipsychotic which, very interestingly, has significant antiemetic properties. And the updated guidelines reaffirms the role of olanzapine as part of antiemetic prophylaxis when one administers highly emetogenic chemotherapy regimens. And it also can be very useful as a rescue agent in patients developing emesis despite appropriate prophylaxis.

So the new studies that were published since our last update have demonstrated the value of adding olanzapine to a 5-HT3 receptor antagonist, dexamethasone, and an NK-1 receptor antagonist used in the setting of high dose chemotherapy when used with hematopoietic stem cell transplantation. In addition, the prior recommendations only specified a 10 milligram dose of olanzapine as the only option. We now have data from an updated study that a 5 milligram dose is an acceptable alternative to the 10 milligram dose when used in the setting of highly emetogenic chemotherapy.

Great. Thanks for reviewing that information. So what in your view is the importance of this guideline for clinical practice?

Well, we have made really enormous progress in developing effective means to prevent treatment induced nausea and vomiting in patients with cancer. Each update of the guidelines, the current version included, have provided additional valuable insight for clinicians to help further limit the frequency of this potential side effect of cancer treatment. The most important aspect of the current update will be providing reassurance to clinicians that effective antiemetic prophylactic regimens do not need to be compromised when the new checkpoint inhibitors are administered in combination with emetogenic chemotherapy regiments. In addition to the new information on olanzapine, the update also notes the addition of useful new IV formulations of aprepitant and the combination agent netupitant and palonosetron. In addition, we have information on the use of fosaprepitant and as an option when an NK-1 receptor antagonist is indicated in the pediatric setting.

And then finally, how do you view that these recommendations will impact patients?

Well, we know from many patient surveys that treatment induced nausea and vomiting are among the most dreaded potential side effects that patients worry about when they think about starting cancer treatment, especially if they're going to be receiving chemotherapy. So fortunately, we now have extremely effective and well tolerated antiemetic regiments for all treatment settings. However, patients will only benefit if these evidence-based regimens are utilized in a manner consistent with the ASCO guidelines. So we hope that this guideline update will provide useful information for ecology providers to really optimize the prevention of nausea and vomiting in patients receiving various emetogenic type of treatment regimens.

Well, thank you so much for your work on this ASCO guideline update on antiemetics and for taking the time to speak with me today, Dr. Hesketh.

Thanks very much, Brittany. Happy to do so.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available in iTunes or the Google Play store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Manish Shah from New York Hospital Weill Cornell Medical Center on “Treatment of Locally Advanced Esophageal Carcinoma: ASCO Guideline.” This guideline provides evidence-based recommendations on treatment options for patients with locally advanced esophageal adenocarcinoma and squamous cell carcinoma. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines

Transcript

Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey. And today, I'm interviewing Dr. Manish Shah from New York Hospital Weill Cornell Medical Center, lead author on "Treatment of Locally Advanced Esophageal Carcinoma," ASCO guideline. Thank you for being here, Dr. Shah.

I'm so pleased to be here on this podcast for ASCO with you, Brittany. I'm very pleased to talk about this guideline and its significance to the oncologic community and to our patients.

First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. But Dr. Shah, do you have any relevant disclosures that are directly related to this guideline topic?

No, I have no conflicts as it relates to this topic. I do have research funding from Merck, Boston Biomedical, Oncolys, BMS, and Acelis, and no other conflicts and nothing specific to locally advanced esophageal cancer.

Thank you. Then let's dive into this guideline. First, can you give us an overview of what this guideline covers?

Sure. This guideline covers the management of locally advanced esophageal cancer, both adenocarcinoma and squamous cell cancer, because management of these diseases is very complicated, primarily as the epidemiology of this disease has shifted over the past several decades. About 20 to 30 years ago, squamous cell cancers of the esophagus was the predominant disease subtype. About 90% of patients that we would see with esophageal cancer were of squamous cell histology.

However, with the rise in Barrett's esophagus and adenocarcinoma of the distal esophagus and GE junction, now, about 50% of esophageal cancers are adenocarcinoma histology. This distinction is important because, while the two diseases have significant overlap and treatment options, there are differences in sensitivity to various therapies. The guideline attempts to tease out these distinctions to provide the best evidence-based practice recommendations for the community.

Great. So you mentioned that this covers both adenocarcinoma and squamous cell carcinoma. So what are the key recommendations of this guideline for patients with locally advanced esophageal adenocarcinoma?

Sure. So for both squamous cell cancer and adenocarcinoma of the esophagus, locally advanced disease, the first and key recommendation is that multimodality therapy is considered and offered to both disease histologies. It's very important that these patients are treated through a multidisciplinary approach that involves a surgeon, typically a thoracic surgeon, but sometimes a general surgical oncologist as well, as well as a radiation oncologist and a medical oncologist.

For adenocarcinoma of the esophagus, which is really becoming the most common type, the primary recommendation is that patients with locally advanced esophageal adenocarcinoma receive either preoperative chemotherapy with radiation or perioperative chemotherapy. Because there is no comparative study for these two options, we also provide a clinical vignette to help readers understand some of the key features that may sway one to one treatment versus another.

For example, large bulky tumors where an R1 resection is more likely may be better suited for chemoradiotherapy, followed by surgery. An R1 resection, of course, is where the microscopic margin might still be positive. Additionally, patients who may not have a three-hole or a thoracic surgery as part of their surgical plan may not have an adequate lymph node dissection. That might be another reason to consider chemoradiotherapy, followed by surgery.

And what is recommended for patients diagnosed with locally advanced esophageal squamous cell carcinoma?

Yes. For squamous cell cancer, we recognize that these tumors are much more sensitive to radiotherapy. So the options that are recommended here, based on the evidence available, is that patients who receive preoperative chemotherapy and radiation or definitive chemotherapy and radiation, meaning chemotherapy and radiation with or without surgery. These are the recommendations for squamous cell cancer.

So why is this guideline important, and how will it change practice?

So we hope that our guideline will provide some clarity on a very murky field. The study suggests that there are several options available for patients with locally advanced esophageal squamous cell cancer and adenocarcinoma. And the guideline helps us frame the question and frame how we think about these options in offering patients the best practice that we can with regard to the available data. Additionally, the guideline may help define future research questions as well, as the gaps in knowledge are clear based on the guideline.

For example, there are patients, a significant number of patients, who have a complete response to chemotherapy and radiation. Should all of these patients have immediate surgery, or can surgery safely be delayed? That's an ongoing question that is being examined in rectal cancers. And also, there is some data in esophageal cancer as well. And that might be an important question to ask, moving forward, for example.

Great. And then finally, how will these guideline recommendations affect patients?

We hope that through the guideline process and understanding the nuances of how to treat patients with locally advanced esophageal cancer, that based on histology, based on the size and bulk of the tumor, based on the likelihood of an R1 resection, or based on even the surgical approach, that patients will receive more uniform therapy and therapy that is more tailored to their particular condition and situation. In the end, we hope that patients will receive the right care and ultimately have better outcomes because their care is more uniform.

It sounds like these guidelines could have a real impact for patients. So thank you for your work on these treatment of locally advanced esophageal carcinoma guidelines and for taking the time today to speak with me, Dr. Shah.

Thank you. It's a pleasure to be here.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Eric Roeland from Massachusetts General Hospital Cancer Center on “Management of Cancer Cachexia: ASCO Guideline.” This guideline provides evidence-based recommendations on the clinical management of cancer cachexia in adult patients with advanced cancer. Recommendations are made on both pharmacologic and nutritional interventions. Read the full guideline at www.asco.org/supportive-care-guidelines

My name is Brittany Harvey, and today I'm speaking with Dr. Eric Roland from Massachusetts General Hospital Cancer Center. Lead author on Management of Cancer Cachexia, ASCO Guideline. Thank you for being here, Dr. Roland.

Well thank you very much.

Before we get into the content of this guideline, I want to note that all conflict of interest disclosure information for the expert panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Roland, do you have any conflicts of interest to disclose?

Yes, within the last two years, I've served as a consultant for Asahi Kasei Pharmaceuticals, DIG Consulting, Napo Pharmaceuticals, American Imaging Management, Immuneering Corporation, and Prime Oncology. I've also served on advisory boards for Herron Pharmaceuticals and Vector Oncology. And I serve as a member on the Data Safety Monitoring Boards for Oragenics, Kalyra Pharmaceuticals, and [INAUDIBLE] Life Sciences Pharmaceutical Company.

Thank you. Then first, can you give us a general overview of what this guideline covers?

Sure. We performed a systematic review of the literature regarding available evidence for nutritional and pharmacologic interventions for cancer cachexia. Specifically, we searched PubMed and the Cochrane Library for randomized controlled trials and systematic reviews published between 1966 in 2019. We focused our review on adult patients with advanced or incurable cancer. And given the highly variable nature of cancer cachexia, we specifically evaluated the endpoints of loss of appetite or anorexia, body weight, and lean body mass, or skeletal muscle. Our targeted audience included clinicians as well as patients and caregivers.

Can you provide us with a little background on cancer cachexia?

Yes, first I think it's incredibly important for us to define cancer cachexia, especially given its prevalence in cancer care. Traditionally, cancer cachexia has been defined as a certain amount of weight loss over a defined time period. However, cachexia is much more complicated than weight loss alone. It is a multifactorial syndrome characterized by loss of appetite, weight, and skeletal muscle, which leads to fatigue, functional impairment, increased treatment related toxicity, poor quality of life, and even reduced survival. And as clinicians, we need to try to identify any reversible causes contributing to cachexia and treat them. This of course, includes treating the underlying cancer when possible.

Additionally, it's essential for patients to receive optimal palliation of all symptoms that may be interfering with the intake of calories, such as pain, nausea, vomiting, constipation, diarrhea, and depression. Therefore, as clinicians, we need to work in teams of experts that might include expertise in pain, palliative care, nutrition, physical occupational therapy, and mental health where available.

We also need to introduce and discuss the term, cachexia, with our patients and their caregivers, who often have never heard of it before. They may not understand that this term is unique and very different from weight loss alone. I personally have found that describing the unique nature of cachexia and providing the information to patients and caregivers can be very helpful.

Additionally, we need to recognize that food is a very complicated issue. And when we engage patients and caregivers around issues of food, we need to recognize that there are informational needs, but there are also emotional needs. And as clinicians, we help patients and caregivers gain access to evidence based information and interventions, but we equally need to ensure that they receive emotional support. Food represents hope and control in an uncontrollable situation. And not being able to eat or feed a loved one can cause severe distress.

Therefore, we need to engage patients and caregivers regarding these emotional issues and make sure they feel heard. We can also reach out to our mental health colleagues, such as social workers and psychologists, who may help us support patients and caregivers in this difficult issue.

Then, what are the key recommendations covered in this guideline?

With regard to our systematic review, we identified 20 systematic reviews and 13 additional randomized controlled trials. And from this data, we made the following recommendations. First, we found limited data supporting the integration of dietary counseling with or without oral nutritional supplements. However, given the lack of harm and the critical role of educating patients and caregivers, we felt it was important to support referring patients with incurable cancer and loss of appetite and/or body weight to registered dietitian for assessment and counseling.

It's critical for patients and caregivers to learn about practical and safe approaches to feeding. Specifically, registered dietitians may help develop strategies, such as shifting away from three larger meals per day towards frequent high protein, high calorie, nutrient dense snacks. Dietitians can also address questions regarding specific diets, including fad diets and unproven or extreme diets.

Moreover, clinicians should not routinely offer enteral tube feeding or parenteral nutrition to manage cachexia in patients with incurable cancer. A short term trial of parenteral nutrition may be offered to a very select group of patients, such as patients with a reversible bowel obstruction, or short gut, or issues with malabsorption, but otherwise reasonably fit. We also can consider discontinuing previously initiated enteral parenteral nutrition near the end of life, as it is associated with net harm at that time.

With regard to pharmacologic interventions, there are no FDA approved drugs to treat cancer cachexia. Yet there is sufficient data to support two pharmacologic interventions associated with improvements in appetite and/or body weight. And these include progesterone analogs, such as megestrol acetate and corticosteroids. The optimal dose and timing of each drug remains unknown.

Regarding megestrol acetate, data support its role in improving appetite, modest weight gain, and improvement in quality of life. However, the weight gain associated with megestrol acetate is primarily fat and not skeletal muscle. We also need to be aware of side effects of megestrol acetate, including an increased risk of thromboembolic events, edema, adrenal insufficiency, and even an increased risk of death.

As for corticosteroids, the first published double-blind randomized study dates back all the way to 1974, which showed an improvement in appetite and sense of well-being. However, clinicians are aware of the multiple side effects associated with corticosteroid use, that often limit initiation and timing of their use. Additionally, the weight gain associated with corticosteroids is not skeletal muscle.

As important as it is to know what drugs are evidence based, it is also important to note what pharmacologic approaches are not supported by evidence. There are many agents that have been evaluated in clinical trials without any evidence to support an improvement in cancer cachexia outcomes.

One such drug that frequently is asked about is dronabinol or the general class of cannabinoids. Insufficient data was available to recommend dronabinol or medical cannabis, and they have notable side effects, including altered mental status and a higher risk of falls. Especially in the elderly.

Why is this guideline important? And how will it impact practice?

Cachexia is a very common clinical entity and causes lots of distress for patients and caregivers. Oftentimes, the issues regarding nutrition and weight loss can be the central focus of clinical appointments and conversations with oncologists. We need to ensure that patients and caregivers have access to evidence based information and recognize that some interventions may be associated with more harm than benefit.

And finally, you've just spoken to this a bit, but how will these guideline recommendations affect patients?

Primarily, I think these cancer cachexia guidelines will serve as a great educational resource. They will also allow patients to better understand the risks associated with some of the pharmacologic interventions. I also think it's critical to define the current state of evidence in cancer cachexia, as we have many new exciting clinical trials evaluating novel agents in the setting.

Furthermore, as a cancer community, we need to ensure that interventional trials are focused on clinically meaningful endpoints, such as improvements in appetite, muscle mass, and quality of life. We also need to encourage a rigorous but expedited approval of these agents, given the lack of any FDA approved drugs in this setting.

Lastly, we need to recognize this is a multi-modal syndrome that requires the help and expertise of our interdisciplinary colleagues. Supporting our patients and their caregivers with this very difficult syndrome requires as much help as possible.

Great. Thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Roland.

Thank you so much, Brittany. I would also like to recognize and thank ASCO for its support of these guidelines, the talented ASCO staff, and the experts who contributed. Most of all, I'd like to recognize our patients and their caregivers.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/supportive-care-cancer-guidelines.

This guideline also has a companion, cancer.net podcast episode. Cancer.net is the patient information website of ASCO. And we encourage you to learn more by tuning into their episode. You can find their podcast and all ASCO podcasts at podcast.asco.org. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe, so you never miss an episode.

View Details

An interview with Dr. Benjamin Levy from Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital on “Lung Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline.” This guideline provides recommendations to clinicians on radiographic imaging and biomarker surveillance strategies after definitive curative-intent therapy in patients with stage I-III non–small-cell lung cancer and small-cell lung cancer. Read the full guideline at www.asco.org/thoracic-cancer-guidelines

Transcript

Hi. My name is Clifford Hudis, and I am the CEO of the American Society of Clinical Oncology, as well as the host of the ASCO in Action podcast. About twice a month, I interview thought leaders in health care and experts in oncology, and we provide analysis and commentary on a wide range of cancer policy and practice issues. You can find the ASCO in Action podcast on Apple Podcasts or wherever you are listening to this show, and you can find all nine of ASCO's podcasts which cover a wide range of educational and scientific content, and offer enriching insight into the world of cancer care at podcast.asco.org.

Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Benjamin Levy from Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, author on "Lung Surveillance After Definitive Curative Intent Therapy ASCO Guideline." Thank you for being here, Dr. Levy.

Thanks for having me.

So first, can you give us a general overview of what this guideline covers?

Yeah, I think that the general broad stroke intent of this consensus paper was to provide evidence-based guidelines and recommendations for practicing clinicians on what the optimal radiographic imaging and biomarker surveillance strategy should be for patients who received definitive curative intent therapy, and specifically for patients with stage I through III non-small-cell lung cancer, or patients who have received curative intent therapy for a limited-stage small-cell lung cancer.

And importantly, this expert panel comprised a multidisciplinary team, and this included not only medical oncologists, but surgical oncologists, pulmonologists, radiologists, a general internist, a patient representative. So we had, I think, the relevant stakeholders to make the best recommendations we could based on the evidence. And we really framed our recommendations by answering five questions, and I think we can get to the five questions at a later time during this cast, but we try to answer these five questions in a systematic way. And really looked at the type-- was an evidence-based or was it informal consensus? What was the evidence quality? Was it low, was it intermediate, or was it high? And then finally, the strength of the recommendation.

And importantly, we tried to answer these questions based on the evidence. We did a literature search, which culminated in a systematic review of more than-- close to 1,200 studies of which 14 studies were identified, and these 14 studies included meta-analysis, randomized control trials, case-controlled trials, and retrospective studies, and really by doing this, we wanted to come up with important guidelines. I think these guidelines are coming on the heels of a lot of confusion about what is the optimal surveillance strategies post-curative intent therapy for our lung cancer patients? So we recognize this confusion and tried our best to create guidelines that were reasonable to follow, and hopefully it can change practice.

Great. So you just mentioned that there were five key questions that you looked at for this guideline.

Yeah.

Could you elaborate on what those questions are and the key recommendations of the guideline?

Sure. So the crux of our recommendations, again, come on these five questions, and just a summary of these questions. One, what should be the frequency of surveillance imaging post-curative intent therapy? Two, what is the optimal imaging modality? Three, are there any patient factors such as performance status or age limits that would preclude surveillance? Four, is there a role for circulating biomarkers and surveillance? And then five, is there-- or what is the role of brain MRI imaging for surveillance of curative intent patients both non-small cell and small-cell?

And just briefly in terms of-- I'll maybe go over briefly just the answers to these questions that we tried to hash out in this consensus work-- for the question, what should be the frequency of surveillance imaging? We recommended that patients should undergo surveillance imaging for recurrence every six months for two years. We then recommend that patients should undergo surveillance imaging for detection of new primary lung cancers annually after the first two years.

And in question 2, what is the optimal imaging modality? We recommended a diagnostic chest CT that included the adrenals with contrast, that's preferred, or without contrast when conducting surveillance for recurrence during the first two years post-treatment. We did state that there was no evidence of any added benefit for CT of the abdomen and pelvis over a chest CT through the adrenals, that surveillance. We then, again, similar answer to recommendation 1, we do recommend a low dose screening for chest CT when conducting surveillance for new lung primaries after those first two years. And then I think importantly, we take a hard stand on PET scans as part of the answer to question 2, where we really should not be using PET scans as a surveillance tool in the surveillance starting post-curative intent therapy.

Question 3, are there any patient factors such as performance status or age limits that would preclude surveillance? And for us, we make the recommendation that surveillance imaging may be permitted in some patients who are clinically unsuitable, have multiple medical comorbidities, or unwilling to undergo further treatment. Doesn't make a lot of sense to offer surveillance imaging if patients are stating that they're not going to undergo any further treatment. We also state that age should not preclude surveillance imaging, but there needs to be a consideration for overall health status and chronic medical conditions and patient preferences.

Question 4 was, is there a role for circulating biomarkers in surveillance? And this is probably one of the more confusing parts of surveillance. Many physicians are still using CEA to monitor for a recurrence, and we really take a hard stand and say that clinicians should not be using circulating biomarkers as surveillance strategy for the detection of recurrence in patients who've undergone curative intent treatment, but we also do state that there is emerging data looking at ctDNA that may change this over the next four or five years, but we're certainly not there yet. So standard of care should not be-- to be using anything like that.

And then question 5 is, are there-- or what is the role for brain MRI for surveillance in patients with both non-small-cell and small-cell? And our recommendations are a little nuanced here. We did say for patients with stage I through III non-small-cell lung cancer, clinicians should not be using a brain MRI for routine surveillance after curative intent therapy, and patients who have undergone curative intent treatment for small-cell and did not receive prophylactic cranial radiation, this is where we do say clinicians should offer a brain MRI every three months for the first year and then every six months for the second year for surveillance. So a little bit different surveillance strategies for patients whether you're small-cell or non-small-cell.

So those are the broad stroke overviews of the recommendations that we put together in this consensus statement.

And then can you speak to the importance of this guideline and these recommendations and how they will impact practice?

I think that ASCO recognized how much confusion there was post-curative intent therapy. So I think this is the reason why these guidelines are so important. We need to keep in mind that health care resources that are utilized and be mindful of that. There's no real role for routine imaging less than the intervals that we're describing as they may obviously not be in touch with health care utilization and cost.

The other thing is this idea that patients are getting scans so frequently that we're picking up on a lot of false positive information that can't be used, and so we recognize that as well. So I think that on the heels of the confusion coupled with cost considerations, as well as what we're picking up on frequent scans, we do have to make recommendations that will hopefully unify and harmonize practice across the country to better suit patients and also evidence-based practice. I think that's really important.

And finally, how will these guideline recommendations affect patients?

Yeah, I think patients hopefully, if physicians follow these guidelines, will be receiving the appropriate interval. I mean, look, we understand that two-thirds of patients with lung cancer who relapse will present with metastatic disease and that there have been limited data thus far on what should be the optimal interval for scans. But we understand also that patients who do relapse could present with potentially curable lung cancer, and in addition, there's been recent data to suggest that even patients with limited metastatic disease who was detected on recurrence may be cured or may have improved survival with certain strategies like local ablative therapy.

So we hope that these guidelines can be firmly cemented into the practice for clinicians so that the appropriate interval is selected, but that also patients can benefit from these appropriately timed-out scans to improve outcomes for them.

Great. Thank you for your work on these guidelines, and thank you for taking the time today to give an overview to our listeners, Dr. Levy.

Thank you so much.

And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Jessica Geiger from Cleveland Clinic on “Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline.” This guideline provides evidence-based recommendations addressing diagnosis, surgery, radiation therapy, and systemic therapy for patients with squamous cell carcinoma of unknown primary in the head and neck. Read the full guideline at www.asco.org/head-neck-cancer-guidelines.

Transcript

[MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at podcasts.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Jessica Geiger from Cleveland Clinic, author on Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck ASCO guideline. Thank you for being here, Dr. Geiger.
Thanks, Brittany, for the invitation and the opportunity.

First, can you tell our listeners what is squamous cell carcinoma of unknown primary in the head and neck and what this guideline generally covers?

Sure. So cancer of unknown primary or carcinoma of unknown primary in the head and neck is metastatic squamous cell carcinoma found in cervical lymph nodes. And importantly, there's a lack of a primary mucosal tumor that's identified. So these patients comprise about 5% of all head and neck cancers. And it poses a challenge for all members of the treatment team, both from a diagnostic perspective but as well as treatment management; what is the best way to proceed for treatment with these patients? Now this guideline provides an up-to-date and evidence-based management for recommendations. And these recommendations are based on published literature. But where the data is lacking in the literature, expert panel consensus was utilized to provide recommendations.
I'd like to discuss some of the key recommendations of this guideline. First, with regard to diagnosis of squamous cell carcinoma of unknown primary in the head and neck, what are the challenges, and what are the recommendations from the guideline?

The diagnostic challenges come about when a patient presents with a neck mass. They often have imaging, a clinical exam. But again, about 3 to 5 percent of patients, we will be unable to locate where this tumor started. Squamous cells don't show up in the lymph nodes by themselves. They came from somewhere else. And part of the reason that this makes a diagnostic challenge if we're not able to readily see where the primary tumor is, oftentimes, it's very small in size. And so it's not picked up by imaging or by a physical exam. Also, these are sometimes difficult anatomic locations to evaluate. So all of this can pose a challenge to coming up with the right diagnosis. Now some of the recommendations for diagnosing these patients, obviously, we need to have a complete history and physical exam. And this physical exam should include a fiberoptic laryngoscopy, so a good lab endoscopy exam looking at all of the mucosal tissues, trying to find abnormalities, trying to see where exactly this cancer started.
Now in order to make the diagnosis of squamous cell carcinoma, obviously, a biopsy needs to be done, and that is in the neck, where these suspicious nodes are. Either a fine needle aspiration or a core needle biopsy is recommended within these guidelines. The guidelines also indicate when to do additional pathologic testing. So this is for high-risk HPV, especially in neck nodes that are in level two or three. If high risk HPV testing is negative, then we give recommendations regarding Epstein-Barr virus testing, so looking to find is this nasopharynx primary cancer and then, of course, imaging guidelines. So the image modality of choice is a contrast enhanced CT of the neck, not just to elucidate and better evaluate the nodal burden of disease, which the patient presents with, but also to investigate for evidence of a mucosal primary. Now if that fails to produce a primary then we give recommendations regarding PET scans.

And then what are the recommendations for surgery for a squamous cell carcinoma of unknown primary in the head and neck?

There are many recommendations that we go into to address the surgical approach to a cancer with unknown primary. Now the previous question asked about diagnosis included in the surgical recommendations in our guidelines for diagnostic surgical interventions. So we can sort of branch point or divide recommendations for surgery, whether it's a diagnostic or a therapeutic procedure. And then in the therapeutic procedures, we can look more in detail at what surgery is recommended for a primary or the mucosal, and then how to how do we address the neck? So first, as part of diagnosis with surgery, all patients need a complete operative evaluation of the upper aerodigestive path. And this includes directed biopsies. So the surgeon goes in the operating room, gets a good look around. Any suspicion for any possible cancer is biopsied, as opposed to blind biopsies or random biopsies, which are not recommended.

Now the recommendations for surgery also include when to do tonsillectomies and what tonsillectomies to do. So are these palatine tonsillectomies or lingual tonsillectomies? Do we perform them or recommend them on the ipsilateral side, or what is the role for a contralateral or even bilateral tonsillectomy? And I won't go into the specifics because they're all-- all the different scenarios are laid out within the guidelines, but the recommendations are based on the patient's nodal burden. So do they have bilateral lymph nodes; do they have lymph nodes just on one side; how big they are, that all plays a role into the recommendations regarding surgical intervention. Now if mucosal primary tumor is identified, there are clear recommendations and guidelines that every effort to clear the disease with negative margin is of paramount importance. So we're talking about a definitive oncologic surgery in this case. And the reason we want to stress that negative margins are the goal is because we're trying to avoid trimodal therapy. So we're trying to get to a good surgical resection. A positive margin left behind is likely going to lead to recommendations for postoperative radiation with the addition of radiosensitizing chemotherapy, which is what we do not want. We want to try to avoid toxicities with trimodal therapy.

That brings me to then surgical management of the neck and the guidelines set forth in this document. So recommendations for neck surgical management are broken into whether the patient has what we consider small volume disease versus large volume disease. So for small volume disease, small lymph nodes on one side of the neck, we recommend a multidisciplinary discussion whether or not the patient should be best served with a definitive surgery involving a neck dissection or if they should have definitive radiotherapy. Again, our goal is to avoid trimodal therapy. So if there's obvious gross extranodal extension seen on imaging, then they would be best served with a primary radiation approach, as opposed to surgical. Similarly, any large volume disease, obviously, gross extranodal or extracapsular extension, definitive chemo radiotherapy is favored. Now a comment on management of the neck, if you're suspecting an oropharynx primary, which is the majority of cancer of unknown primaries of the head and neck, we give specific recommendations regarding what levels to routinely surgically dissect, levels IIa, III, and IV in that instance.

In your discussion of the surgical recommendations, you began to touch on the radiation recommendations. Could you elaborate on those recommendations from ASCO on radiation therapy for this patient population?
Of course. And again, when you refer back to the guideline and the recommendations, there are even more specific recommendations regarding when and how to use primary radiotherapy or adjuvant radiotherapy in this setting. So I'm not going to go into great detail for every single recommendation that is provided, but a nice overview is, basically, if a patient is receiving radiotherapy as the primary definitive management of cancer of unknown primary, obviously, we recommend treatment should be given to gross nodal disease but also to neck regions and mucosal anatomic regions, which are considered at risk for containing microscopic disease. So it's not just good enough to radiate what we see on imaging but also to consider the areas around it, the nodal echelons and other mucosal areas where there could be cancer. So for example, an HPV-related disease where it's likely oropharynx unilateral disease, there are specific locations to include. And this is also the same for HPV-negative disease. Now if we're worried about a possible nasopharynx cancer in the setting of E-Barr or EBV-positive disease, the mucosal radiotherapy can be limited to just the nasopharynx, but you want to radiate bilateral necks, level II through IV, and include the retropharyngeal lymph nodes.

There are specific recommendations where unilateral versus bilateral neck irradiation is recommended. And again, I just encourage the listeners to refer back to the guideline itself for these specific instances. Also included within the radiotherapy guidelines and recommendations are specific doses. What doses do you use? Where do you use these doses? And these doses are extrapolated from known and well established evidence for traditional head and neck squamous cell carcinoma in which we know where the primary is, also, when to give post neck dissection kind of in the adjuvant setting, again, all extrapolated from known head and neck squamous cell carcinoma but very specific and laid out within the guidelines.

And what does the expert panel recommend for systemic therapy for squamous cell carcinoma of unknown primary in the head and neck?

Similarly, when we devised the recommendations for radiotherapy for this disease, the use of systemic therapy, when to use it, when to add it to radiation is also extrapolated from the head and neck guidelines and evidence for known head and neck cancer. So we recommend adding chemotherapy to definitive radiotherapy in advanced nodal disease, and we've defined what advanced nodal disease is based on the AJCC 8th Edition. So in HPV-negative disease, this is N2 or N3, in HPV-positive disease, multiple ipsilateral lymph nodes. If a lymph node is greater than three centimeters, we recommend adding chemotherapy to radiation in the definitive setting. Now, specifically, the chemotherapy that we recommend is cisplatin. Again, this is based on well-established studies and evidence in head and neck cancer. So patients who are medically fit and able to receive cisplatin, that is the treatment of choice. There are also recommendations regarding resected cancer of unknown primary. So with evidence of extranodal capsular extension, we recommend the addition of, again, cisplatin chemotherapy to postoperative radiotherapy, again, extrapolated from well-established head and neck studies. And then, again, if you are concerned that this is an Epstein-Barr-related nasopharynx cancer, stages II through IVA, again, AJCC 8th Edition, we recommend the addition of chemotherapy to radiation in those settings as well.

Great. This guideline covers a lot of ground and many recommendations. Can you speak to why this guideline is important and how you envision it will impact practice?
So this guideline is important because a fair amount of patients will be presenting with cancer of unknown primary. We stress through this guideline that this is very evidence-based recommendations and guidelines with a focus on a multidisciplinary approach to how to treat these patients.

And finally, how will these guideline recommendations affect patients?

Well, hopefully, this guideline will provide reassurance to patients that no matter where they are receiving treatment, they are receiving quality standard of care management, again, largely driven by evidence. And it doesn't matter whether they're treated by locally practicing experts and specialists or at a large institution, they're being treated by the standard of care that is accepted across the board.

Well, thank you for your time today, Dr. Geiger, and for working on these comprehensive guidelines.
You're very welcome. Thanks, Brittany.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available and iTunes or the Google Play Store. If you have enjoyed what you've heard today, please write and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Nadine Tung from Beth Israel Deaconess Medical Center in Boston, MA on “Management of Hereditary Breast Cancer: ASCO, ASTRO, and SSO Guideline.” This guideline covers recommendations for the management of patients with breast cancer with germline mutations in breast cancer susceptibility genes. Read the full guideline at www.asco.org/breast-cancer-guidelines

View Details

An interview with Dr. Pauline Funchain from Cleveland Clinic in Cleveland, OH on "Systemic Therapy for Melanoma: ASCO Guideline." This guideline provides recommendations on systemic therapy options for adult patients with cutaneous and noncutaneous melanoma. Read the full guideline at www.asco.org/melanoma-guidelines

View Details

An interview with Dr. Gabriela Chiorean from the University of Washington, Fred Hutchinson Cancer Research Center, Dr. Mary Chamberlin from Dartmouth-Hitchcock Medical Center, and Dr. Pritesh Lohar from the HCG Cancer Center, on “Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline.” This guideline provides guidance for resource-constrained settings on the management of late-stage CRC. Read the full guideline at www.asco.org/resource-stratified-guidelines.

View Details

An interview with Dr. Sharon Giordano from MD Anderson Cancer Center and Dr. Michael Hassett from Dana-Farber Cancer Institute on "Management of Male Breast Cancer: ASCO Guideline". This guideline provides recommendations concerning the management of male breast cancer; addressing five main areas where treatment for men differs from the approach used for women with breast cancer: adjuvant endocrine therapy, endocrine therapy for advanced/metastatic cancer, adverse effects of endocrine therapy, germline genetic testing, and survivorship. Read the full guideline at www.asco.org/breast-cancer-guidelines.

View Details

An interview with Dr. Nasser Hanna from Indiana University Simon Cancer Center and Dr. Gregory Masters from Helen F. Graham Cancer Center and Research Institute on "Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update." This guideline provides recommendations on systemic therapy treatment options for patients with stage IV non-small-cell lung cancer (NSCLC) without driver alterations in epidermal growth factor receptor or ALK, based on histology, PD-L1 status, and/or the presence or absence of contraindications. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.

Transcript

[MUSIC PLAYING]

Hello, and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at podcasts.asco.org.

My name is Brittany Harvey. And today, I'm interviewing Dr. Nasser Hanna from Indiana University's Simon Cancer Center and Dr. Gregory Masters from Helen F. Graham Cancer Center and Research Institute, co-chairs on therapy for stage IV, non-small cell lung cancer without driver alterations, ASCO and CCO Joint Guideline Update. Thank you for being here today Dr. Hanna and Dr. Masters.

Thank you. Glad to be with you.

My pleasure. Thanks.

First, Dr. Hanna, can you give us a general overview of what this guideline covers?

Sure. So the ASCO guidelines for the treatment of patients with stage IV, non-small cell lung cancer were last updated in 2017. And since that time, there has been a tremendous amount of change that has taken place. The 2017 guidelines included recommendations for basically three subgroups-- those patients with non-small cell lung cancer who have certain targetable DNA mutations and those who do not have those mutations but have a PD-L1 score of 50% or higher and then everyone else.

But because of the rapid and vast changes that have taken place, we decided to make a separate guideline for those with targetable DNA mutations and to focus this current guideline on those without the targetable mutations. So within that context, this guideline categorizes patients by whether their tumors have a PD-L1 score of 0% to 49% or those who have a PD-L1 score or 50% or greater.

And within those categories, recommendations are characterized based upon whether the patient has squamous cell histology or non-squamous cell histology. And we also consider whether patients are candidates for chemotherapy or perhaps even those that decline chemotherapy and whether they have any contraindications for immunotherapy.

So what distinguishes these guidelines from other guidelines is our attempt to adhere to the strongest available evidence-based medicine. And while not every iteration of clinical management can be covered, these guidelines provide oncologists with a strong, evidence-based roadmap to treat the vast majority of patients with non-small cell lung cancer.

So as a result of this collective effort by ASCO staff and the guideline writing committee, this report offers a substantial amount of change to the recommendations from the clinical practices guidelines provided in 2017. In 2017, the only recommendations for the use of immunotherapy were in the first line setting for patients who had a PD-L1 score of greater than 50% and in the second line setting of patients progressing after first line chemo.

But these updated guidelines include the incorporation of immunotherapy in all subgroups of patients regardless of histology and PD-L1 score. So as a result, there are about three times the number of options to consider in the first line setting with these new guidelines compared to the 2017 guidelines. However, the 2020 guidelines provides a preferred treatment regimen for each situation to simplify the decision making process for most patients.

And what are those key recommendations of this guideline update for patients without driver alterations?

So the key changes for 2020 is the incorporation of immunotherapy into nearly all settings in the first line setting, regardless of tumor histology and regardless of PD-L1 score. For those patients who have a PD-L1 score of 50% or higher, single agent pembrolizumab remains the preferred treatment for most patients.

But new evidence does provide a rationale for giving select patients chemotherapy, either carbo and pemetrexed if they have non-squamous, or carbo plus paclitaxel or nab-paclitaxel for squamous plus the addition of pembrolizumab in this subgroup of patients. For those patients with PD-L1 scores of 0% to 49% who are eligible and willing to take chemotherapy, these new guidelines recommend chemotherapy plus pembrolizumab.

For those who have a PD-L1 score of 1% to 49% are not appropriate for chemo or decline chemotherapy, these guidelines suggest single agent pembrolizumab as a reasonable option. The guidelines also provide the option of alternative chemo immunotherapy regimens to be used in patients with non-squamous, non small-cell that were not included in the prior guidelines.

And while these are not necessarily preferred for most patients, select patients can be considered for these regimens, which include the immunotherapy drug, atezolizumab, and combination chemo with atezolizumab and bevacizumab. And the guidelines provide some commentary on potential scenarios in which these options should be considered.

Dr. Masters, why is this guideline important, and how will it change practice?

Well, the new ASCO CCO joint non-small cell lung cancer guideline update is important in that it clarifies recommendations for an international audience and is co-sponsored by the American Society for Clinical Oncology and Cancer Care Ontario. These guidelines were developed through a rigorous, evidence-based process with a broad range of experts, including a multidisciplinary team of clinicians, researchers, data specialists, and patient representatives.

The new guideline update provides a comprehensive review and analysis of the current literature on the treatment of advanced non-small cell lung cancer. The current update also includes a data supplement with evidence tables, slide sets, and links to patient information through cancer.net, ASCO's patient information website.

In an increasingly complicated environment for oncologists, managing patients with advanced cancer, we're learning how to incorporate molecular testing and other biomarkers. And this guideline will help change day-to-day practice for clinicians as they implement these recommendations. This guideline will help clarify the optimal treatment strategies for non-small cell lung cancer patients without driver gene mutations and allow individualization based on tumor histology and immunotherapy biomarkers, such as PD-L1 testing.

At the same time, the update allows clinicians to use their individual judgment and experience to incorporate unique, intangible characteristics of patients. It also emphasizes the importance of patient preferences in deciding the optimal care for an individual affected by advanced non-small cell lung cancer.

And finally, how will these guideline recommendations impact patients?

The broad range of experts who've contributed to these guidelines includes a multidisciplinary team, including clinicians, researchers, data specialists, and patient representatives. This assures patients of a consensus opinion based on the available clinical research on treating advanced non-small cell lung cancer. It provides clinicians with the best up-to-date distillation of the many complicated trials of chemotherapy and immune checkpoint inhibitor therapy in an area where patient-centered, precision medicine dictates the optimal treatment strategies.

We incorporate molecular testing in these guidelines, although this particular guideline is directed at patients without driver gene mutations. We include recommendations on implementation of chemotherapy and immunotherapy based on the best available data on biomarker testing for PD-L1.

We recognize, however, that new research continues into treatment strategies and molecular analysis to help guide incorporation of targeted therapy and immunotherapy. We recognize that new treatment options and combinations will become available, and new testing techniques will help guide the decision process in the future. We plan to continue to analyze the available research and update these guidelines as clinically indicated to provide the best options for our patients.

Most of our patients will still be treated with palliative intent. But a growing number of patients have sustained control of their cancer with recent studies and updates suggesting that up to 25% of patients may have control of their disease for five years or longer. Now that more patients can maintain their quality of life with prolonged survival, with the current therapy, it is also critical that we continue to look to patient reported outcomes as an important way of defining the best options for our patients.

Thank you both for your work on this ASCO CCO guideline update for therapy for stage IV, non-small cell lung cancer without driver alterations and for coming on the podcast today to provide an interview, Dr. Hanna and Dr. Masters.

Thanks for having us on the program. And we have enjoyed being part of the process.

Thank you.

And thank you to all our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available and iTunes or the Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Philip Saylor from Massachusetts General Hospital on "Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline." This guideline includes recommendations for management of osteoporotic fracture risk in nonmetastatic disease and interventions for men with castration-resistant prostate cancer metastatic to bone. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.

Transcript

[MUSIC PLAYING]

My name is Brittany Harvey, and today I'm interviewing Dr. Philip Saylor from Massachusetts General Hospital, lead author on "Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline." Thank you for being here today, Dr. Saylor.

Oh, it's my pleasure.

First, can you give us a general overview of what this guideline covers and about the endorsement process?

Yes. So the Cancer Care Ontario has a program in evidence-based medicine, and they periodically put out clinical practice guidelines for management of a whole variety of topics. And they relatively recently put out a publication on bone health and bone-targeted therapies in prostate cancer.

And so that's a really big topic because bone health is such a big part of prostate cancer care across the entire range of scenarios that patients can face. And their guideline addresses topics all the way from osteoporosis and fragility fractures and that risk as it relates to GnRH agonist, androgen deprivation therapy that men can get for really any prostate cancer scenario, goes all the way from that to improving quality of life in patients who have bone metastases that have progressed despite systemic therapy. So it's really a very broad series of topics that they addressed.

And so when they put out that guideline, ASCO identifies it as something that's very relevant to the ASCO community and goes through, then, a formal process of reviewing the methodology of those guidelines and then having an expert panel discuss the quality and evidence of the guidelines and really provide, if appropriate, an endorsement and some additional discussion of those topics.

So what are the key recommendations of this guideline?

They really have four sort of subtopics within this bone-themed guideline that are addressed and discussed in a fair amount of detail. And each one of those four topics deserves some of its own discussion. The first topic is osteoporosis and risk for just fragility fractures, like hip fracture and vertebral body compression fractures. That's one.

The second is potential prevention of bone metastases in a patient that does not yet have bone metastases. The third one is management of castration-resistant prostate cancer metastatic to bone. And the fourth one is symptomatic management of men with CRPC metastatic to bone. So it is probably worth discussing each one of those, in some detail, one by one.

So for the osteoporosis fracture risk question, Cancer Care Ontario, their recommendation really is that men with non-metastatic prostate cancer at high risk for fracture who are receiving ADT should be considered for the osteoporosis dosing of denosumab. And in situations or places where denosumab is not available, then patients can consider a bisphosphonate as an alternative.

So we had a fair amount of discussion of that recommendation. We endorsed that recommendation. And I guess my personal emphasis would be that osteoporotic fracture risk is really the biggest challenge to that is not forgetting about it.

So you can often have men who are in a good prostate cancer scenario, likely to be cured by their therapy. They're going to get some duration of ADT. And they look healthy as they sit there in clinic with you. They're likely to do well from a prostate cancer standpoint.

And it just would be so easy not to adequately screen for osteoporotic fracture risk, and just not to remember that because so many of our discussions together in clinic are focused on the prostate cancer more than the broader health questions. And so, I mean, to me, I think not forgetting about this issue is really one of the most important things to emphasize in any discussion of osteoporosis.

And so really, it's a fairly simple problem to screen for and manage. Most men should be, if they're going to be on any duration of ADT, should be tested with a bone density test, a DEXA scan. It's really a fairly inexpensive and easy test for getting a sense for where their bone health is as they begin.

And I usually tell my patients in clinic that most men don't need any new prescription medicines to manage that risk, but we'll never figure out the ones who need it unless we go through the very disciplined systematic work of doing that screening. And then among those who really do deserve treatment, it's really denosumab at the osteoporosis dosing or a bisphosphonate. Really, any of those choices really works well for improving bone mineral density.

One of the big ASCO discussion points is that denosumab is the only medicine that's been shown definitively to improve fracture risk in this setting. But that's really a product of denosumab being studied in a really large prospective randomized controlled trial. And so that's one where they required more than 1,000 patients in order to assess that fracture endpoint.

So the reason, perhaps-- probably the most important reason that bisphosphonates have not been shown to improve fractures is that none of them have been studied in such a big study. The bone mineral density trials that have studied bisphosphonates are all on the order of maybe 30 to 100 patients rather than 1,000. So really, in many clinical settings, cost and convenience are important considerations. And when those are factored in, it's often very reasonable to use a bisphosphonate rather than denosumab, though either one really could be considered a gold standard. So that's point number one from the guidelines.

Number two really discusses the issue of prevention of bone metastases. And so there are a couple of sub-recommendations from Cancer Care Ontario. But really, the most important point from that is that there is no bone-targeted drug that has been shown to prevent or delay the development of the first bone metastasis. So a number of different studies have tried to address this question in slightly different clinical scenarios.

But the bottom line is, we don't use bone-targeted medicines to prevent the first bone metastasis. And so there's always been sort of an attractive potential effectiveness there because you think if your bone-targeted therapy changes the bone microenvironment, could the natural history of prostate cancer play out differently? But the answer is that we really don't have any convincing evidence of effectiveness on that front using any drug, in any situation. So that's a pretty easy one to summarize.

For the third category of situation that's addressed in the guideline really relates to castration-resistant prostate cancer metastatic to bone. And so there are three sub-recommendations there. In that situation, either zoledronic acid or denosumab in monthly dosing at the skeletal event preventing dosing is a gold standard and reasonable to pursue. So that's one thing.

In men with symptomatic disease, radium-223 can be considered, both to prevent skeletal events and to improve health-related quality of life. And then, finally, all radiopharmaceuticals can be considered in that situation for palliation of bone pain. And so we endorsed those recommendations as well.

And we added a fair amount of discussion about how to optimally support men's health in those situations. For one thing, it's important to note that monthly zoledronic acid or monthly denosumab, whichever is pursued, is a fairly intensive osteoclast-targeted therapy. And so the studies that formally establish those as gold standards in that setting, they really only treated for about two years, plus or minus. So we don't know a lot about the safety of that intensity of therapy beyond two years.

And so that's an important consideration, because there are many men who do well, thankfully, for a lot longer than two years in the castration-resistant setting with bone metastases. And so we really do, as clinicians, need to respect the possibility of toxicities, especially osteonecrosis of the jaw seems to be a much, much more common phenomenon with longer durations of treatment and with these more intensive regimens. So that's one thing that deserves a lot of attention by clinicians.

The other thing is that dental evaluation and proactive dental care before and during any of these bone-targeted therapies is really an important issue not to miss. So the highest risk for having osteonecrosis of the jaw is in patients who are on one of these intensive regimens and then need to have invasive dental work when they're already been started on one of those regimens. Those are the jaws and mandibles that seem not to heal as well.

And so ideally, every patient that is going to go on intensive osteoclast-targeted therapy really should be evaluated by a dentist with the question of whether there's any dental work that really needs to be done proactively before the start of one of those medicines. And so I always say I have to be humble as a medical oncologist to say I really know little to nothing about teeth. And so I have to reach out to my colleagues in the dental field to tell me which are the patients that need to do something ahead of time and heal before they start one of these medicines. So those are a couple of important points.

And then the other thing that's really not a new piece of information but is important to emphasize is that it's really monthly therapy with denosumab or zoledronic acid should really be used only for patients with castration-resistant prostate cancer metastatic to bone. So the patients who are responding to their systemic therapy really seem not to benefit from the bone-targeted therapy. And that's likely because any systemic therapy that's controlling the prostate cancer, in general, that's active against the cancer, in general, is going to prevent skeletal complications. We just have a lot fewer of those events, thankfully, when the disease is under control.

And then, finally, the fourth category of recommendation addresses symptomatic castration-resistant prostate cancer metastatic to bone. And that's a situation where the radium-223 given in the typical once per month times six series of treatments is a gold standard, improves health-related quality of life and overall survival.

I think one of the important discussion points on that front relates to recent clinical trial data that examines the use of other secondary systemic therapies in addition to the radium. So we have a prospective randomized study that looked at abiraterone with or without radium. And what it really showed was that the combination of abiraterone and prednisone with radium resulted at a very high rate of fractures and worsened overall survival. So that's really a combination that should absolutely not be pursued outside of a clinical trial.

And so that's an important thing to know, but it's also sort of a cautionary tale that if we're tempted to combine other secondary medicines with our radium treatment, we really don't have a lot of evidence for the safety or efficacy of doing that. So that's the sort of thing that really should be reserved for clinical trials. And those are probably the most important-- those are the four main topics addressed by the guidelines. As you can tell, it really includes situations that are relevant to just about every man who receives systemic therapy for prostate cancer.

Absolutely. And thank you for that comprehensive overview and those considerations of the guideline endorsement panel. Why if this guideline important? And how will it impact practice?

So I think there's really sort of two main ways that it's important to the reader in 2020. I'd say, first of all, as a reminder and sort of educational promotion of awareness of the things that we already know but are easy to overlook. And I think the things that are really there are that it is easy to focus on the cancer therapy and easy to overlook the bone-targeted therapy.

So as we have an increasing number of systemic therapies that are active against the cancer itself, and as we have sort of, in the best possible way, more options and more molecular considerations for our prostate cancer patients, we really can't forget to do the fundamentals, like doing monthly zoledronic acid or monthly denosumab in men with castration-resistant disease that's metastatic to bone. So I think that's the kind of thing that would be easy to forget, but that we shouldn't.

And the second subtopic there would be screening for osteoporosis in any man who receives ADT. And again, that's something that-- osteoporosis or someone at high risk for fragility fracture, that's an asymptomatic situation until the fracture occurs. And then at that moment, you're really thinking back and saying, man, I wish I'd done something three years ago, or five years ago, or 10 years ago to improve bone health so that this wouldn't have happened in the first place.

So it really is up to us as the clinicians caring for these prostate cancer patients to advocate for their general health in a way that includes their bone health. We just have to really not forget to screen for osteoporotic fracture risk. So I think those reminders of things that we already know but are really easy to miss, I think that's one aspect of this.

And I think the other is just discussion of the data. It really adds some richness to the topics. And we do have these updates in an emerging field, particularly when it relates to radium-223. It seems like a drug really on, like, a drug strategy that could easily be paired with other drug strategies because it's reasonably well-tolerated.

But we learned, really especially from that clinical trial experience of radium with abiraterone, we really learned that freewheeling combinations are not necessarily safe and not necessarily effective. And so we have to just be mindful of recently emerging data and have an ear to the ground about ongoing clinical trials, sort of how to best combine and sequence all the different medicines that are sort of in our back pocket.

And finally, how will these guideline recommendations affect patients?

Yeah. I mean, I think bone health is really just so important to every patient with prostate cancer. And it's almost, for clinicians, it's almost an educational issue where we have to help our patients understand how important bone health is. When we talk in clinic about a DEXA scan to look at bone density, a lot of men really look at me a little bit blankly. They think of osteoporosis more as this sort of issue that women deal with more so than men.

But I always talk about, if you imagine having a hip fracture and needing hip surgery, or if you think about the pain and the postural changes that happen with vertebral body compression fractures, we really have to do something before any of those things occur. And most men agree with me if you put it in those practical terms. It's just the kind of thing that you have to take a couple of minutes out of your clinic visit to make sure that you address.

And the other thing really is, in men who have more challenging prostate cancer metastatic to bone, even life-threatening prostate cancer, all the complications that can happen later in the course of disease, we really need to do the best possible job not only to keep men living longer, but also to make sure their quality of life is the best it can possibly be.

And that's really-- and most of the time when prostate cancer starts to become a physical burden as it progresses, it's really a physical burden that's centered on bones and skeletal health. And that can have an effect on comfort. That can have an effect on mobility. And these things are hugely central to quality of life. So the impact on patients, all the way from osteoporosis to bone metastases, really, it's just such a central theme within the management of everybody who has to face prostate cancer.

Thank you for your work on this important guideline, and thank you for your time today Dr. Saylor.

Oh, it's my pleasure. We got to keep working to get the word out there and have the optimal management for all of our patients.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.ASCO.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Christina Annunziata from the National Cancer Institute on "Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline". This guideline provides recommendations for women diagnosed with epithelial ovarian cancer and their families on which individuals should receive risk evaluation, counseling, and genomic testing, and when they should be tested. Read the full guideline at www.asco.org/gynecologic-cancer-guidelines.

Transcript

[MUSIC PLAYING]

Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at podcast.asco.org.

My name is Brittany Harvey. And today, I am interviewing Dr. Christina Annunziata from the National Cancer Institute, co-chair on Germline and Somatic Tumor Testing and Epithelial Ovarian Cancer: ASCO Guideline. Thank you for being here Dr. Annunziata.

Oh, it's my pleasure. Thank you.

First, can you give us a general overview of what this guideline covers?

Sure. So this guideline is covering the use of molecular testing in women diagnosed with ovarian cancer. And that's specifically what tests should be done and when to do them.

And what are the key recommendations of this guideline?

The key recommendations really are that all women diagnosed with ovarian cancer should be tested for certain gene mutations that are responsible for predisposing people to ovarian cancer and also that a genetic counselor should be involved in discussing the results of these tests with the person involved and with her family. In the guidelines, we go into specifics of which genes should be tested at what point in the course of the disease. And the guidelines mainly focus on the BRCA genes and mismatch repair genes because these are the ones with approved treatments for cancers with these mutations.

What are the clinical questions that you addressed in this guideline?

So we have three main questions when we started out. We wanted to know, first, in which individuals should risk evaluation counseling genomic testing for germline and somatic tumor alterations be performed. We also wanted to know, number two, which genomic alterations had actually demonstrated clinical utility to direct therapy for women with ovarian cancer. And third, what is the most appropriate sequence and timing of testing, meaning specifically at what point in the course of the diagnosis and the treatment of the women should we be performing this testing?

So we came up with specific answers to each of these questions. And just to briefly summarize, for the first questions in which individuals should we test, we did find evidence that all women diagnosed with ovarian cancer should be offered germline testing for, specifically, BRCA1 and BRCA2 cancer susceptibility genes, irrespective of whether or not they had a family history of the disease.

Also within that question, we found evidence that women who have non-high grade serous ovarian cancer, specifically clear cell endometrioid or mucinous ovarian cancer, should have somatic tumor testing for mismatch repair deficiency. And both of these recommendations are because there are FDA approved therapies for women with cancers with these particular genetic makeups.

In the second question, we asked, which genomic alterations have demonstrated clinical utility? This goes specifically into, which specific genes should be tested in the germline and the somatic setting? And in that recommendation, specifically, we focused on, again, the BRCA1 and 2 genes and the mismatch repair deficiency genes.

We did not make specific recommendations for the homologous recombination deficiency assays at this time. Those are still undergoing evaluation. And it's likely in the near future that we will amend this recommendation to specifically discuss those.

In the third question, what is the most appropriate sequence and timing of the testing? That goes into, when should we be doing this in the course of the disease? And we did want to emphasize that women with ovarian cancer should be tested at the time of diagnosis because of the specific implications for therapies. If they have not had testing at the time of initial diagnosis-- let's say they were diagnosed several years ago-- then they should be tested at the time of their first recurrence or subsequent recurrences if those have already happened. And again, these have implications for treatment.

Why is this guideline important, and how will it impact practice?

So one of the most important recommendations is that all women should be tested at the time of the initial diagnosis. In practice today, we estimate that only about 1/3 of women are actually being tested at the time of diagnosis. This testing is important, especially for the BRCA genes, because this has implications for the choice of treatment because of recent FDA approvals for PARP inhibitors in this setting.

And how will these guideline recommendations affect patients?

Our goal is to ensure that all women have access to the best treatments for their ovarian cancer. In order to achieve this goal, doctors need to be aware of best practices, and patients need to understand the results in the context of their disease.

This is why we recommend that the results of the gene testing be delivered to the patient in conjunction with a genetic counselor because this has been shown to increase understanding of the tests and follow through on the recommended treatments. In some settings, we know it may be difficult to arrange these discussions with a genetic counselor, so we hope that these guidelines will emphasize the importance of this step.

Well, thank you for your overview of these and for your work on these guidelines. And thank you for taking the time today to come on the show, Dr. Annunziata.

Oh, you're very welcome. And thank you for the opportunity to highlight these guidelines.

And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available and iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

[MUSIC PLAYING]

View Details

An interview with Dr. Edouard Trabulsi from the Sidney Kimmel Medical College at Thomas Jefferson University on "Optimum Imaging Strategies for Advanced Prostate Cancer: ASCO Guideline." This guideline outlines techniques available and provides recommendations on appropriate use of imaging for specified patient subgroups. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org.

My name is Shannon McKernin, and today I'm interviewing Dr. Ed Trabulsi from the Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania, lead author on "Optimum Imaging Strategies for Advanced Prostate Cancer: ASCO Guideline." Thank you for being here today, Dr. Trabulsi.

Thanks, Shannon. Thanks for inviting me.

So first, can you give us a general overview of what this guideline covers?

Sure. So the purpose of this guideline, and it's fairly broad, is to try to come up with some recommendations and strategies for appropriate imaging for patients with advanced prostate cancer. Also, that includes patients that are newly diagnosed that are high or very high risk for having micrometastatic disease.

Also, patients that have been treated and are suffering recurrence of disease as indicated by rising PSA. And then also, patients with metastatic disease, either on initial diagnosis, or on treatment and who are contemplating changing treatments.

Also, it has a wide range of different patient populations that all fit in the category of advanced prostate cancer. And the idea is to try to figure out or make some recommendations on strategies for what imaging is appropriate for each of those groups of men.

So what are the key recommendations for this guideline?

Well, the big impetus for this guideline is the awareness of what we would consider next-generation imaging, meaning that there's a large group of new or novel imaging studies available and on the horizon. And we're trying to figure out the best way to fit them in in the context of traditional imaging in what we would call conventional imaging.

So that would be-- conventional imaging would be imaging tests like CAT scan, radionuclide bone scan, prostate MRI, that sort of thing. Next-generation imaging would include some of the newer PET imaging scans, using different tracers and isotopes, and some of the new SPECT imaging scans, as well as full body MRI.

And so how to interweave those different imaging tests is really what's proving to be not as straightforward as we'd like. And so we realized that we need to really approach this based on a clinical disease state model. So not just one monolithic category of advanced prostate cancer, but looking at specific scenarios.

And we developed this guideline as a scenario-based algorithm. So the initial diagnosis of prostate cancer of men that are at high risk, what images we think about there; for men that have been treated and their PSA is rising, and so forth.

And so we shouldn't jump to next-generation imaging across the board. We really should look very specifically at circumstances where these new, novel, and unfortunately, expensive imaging tests could have real clinical impact.

So patients that are newly diagnosed that are high risk who have suspicious or equivocal conventional imaging, so they have a CAT scan or a bone scan or something that we're really not sure if something that we're seeing there might be an indication of disease, that's a good spot where next-generation imaging might be very helpful.

For patients that have been treated and their PSA is rising, say, after surgery or, say, after radiation, and they get traditional, what we would call conventional imaging, and we don't see a source for the PSA, well, that is another scenario where a patient-- or a category where next-generation imaging should be considered.

In that specific space, there actually are two PET imaging studies that have been approved by FDA in the US with C-11 choline, as well as the fluorine-18 fluciclovine scans.

And then also overseas, or not yet approved in the US, there are other PET-based agents that are being used in that specific space.

Another important aspect of this is that it should have real clinical impact. So if you have a man who unfortunately may be suffering, or evidence of recurrence of disease after surgery or radiation, but because of their comorbidities or age or patient preference, they're not necessarily going to be aggressive with additional therapy, then we probably don't need to chase some of these next-generation imaging studies in that man.

In the confirmed metastatic patient population, that is a little more unclear in terms of what the benefit of next-generation imaging would be outside of the setting of a clinical trial. And in those patients, if it is thought that there would be a change in clinical treatment based on the results of the scan and of next-generation imaging, then that would be a scenario where those might be considered. But we wouldn't necessarily recommend them across the board.

And so why is this guideline so important? And how will it change practice?

Well, it's important and timely because of the tidal wave that we are expecting of novel, next-generation imaging that is going to become closer and closer to clinical practice. Patients are aware of these studies, and they're asking for them, even if they're not currently available or approved by an FDA or covered by a third-party insurance.

There's been a plethora of research studies and new imaging tracers in Europe, Southeast Asia, and Australia. And so trying to get ahead of where they might fit in, and which patients might benefit now and in the future, was really one of the main drivers to come out with a strong position statement on the appropriate use of imaging.

There's a lot of controversy about some of the implications of the next-generation imaging, such as the potential for false positives and the attendant prognostic tests, that that might trigger false negatives, and potentially offering clinicians or patients a more optimistic outlook than may be really present.

And so figuring out specific scenarios and specific patient populations that would benefit from next-generation imaging is the real goal of this guideline.

And so finally, how will these guideline recommendations affect patients?

Well, the ultimate goal is to improve patient care and improve patient outcomes. And so by coming up with some reasonable templates and framework of where some of the next-generation imaging will fit in on a patient's disease spectrum and disease course will help them both to potentially indicate when treatment changes may be necessary, or to isolate areas of disease, and to importantly and accurately give their correct stage. And then that will translate, or we hope and expect, with more information and more accuracy in diagnosis, in better treatment plans and better patient outcomes.

Great. Thank you for your work on this important guideline on Optimum Imaging Strategies for Advanced Prostate Cancer. And thank you so much for your time today, Dr. Trabulsi.

Thank you so much. Thanks for having me.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline and find additional resources, such as the guideline pocket card, go to www.asco.org/genitourinary-cancer-guidelines.

And you can find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. And if you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Kimberly Allison from Stanford University School of Medicine and Dr. Antonio Wolff from Johns Hopkins University on "Estrogen and Progesterone Receptor Testing in Breast Cancer Guideline: ASCO/CAP Guideline Update." This guideline updates key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen and progesterone receptor testing in breast cancer guideline, and focuses on low estrogen receptor expression cases. Read the full guideline at www.asco.org/breast-cancer-guidelines.

View Details

An interview with Dr. Scott Eggener of University of Chicago Medicine on "Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline." This guideline provides recommendations for available tissue-based prostate cancer biomarkers geared toward patient selection for active surveillance, identification of clinically significant disease, choice of postprostatectomy adjuvant versus salvage radiotherapy, and to address emerging questions such as the relative value of tissue biomarkers compared with MRI.

Read the full guideline at www.asco.org/genitourinary-cancer-guidelines

TRANSCRIPT

If you like what you hear from the ASCO podcast, please let us know. Take our listener survey and help shape the future of the ASCO Podcast Network. Visit podcast.asco.org, and click on the survey link. Once again, that's podcast.asco.org. The survey will just take a few minutes to complete and will help us get to know you better. Thank you so much for listening.

Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at podcast.asco.org. My name is Shannon McKernin. And today I'm interviewing Dr. Scott Eggener from the University of Chicago Medicine, lead author on molecular biomarkers in localized prostate cancer ASCO Guideline. Thank you for being here today, Dr. Eggener.

Thanks for having me, Shannon, and covering the guideline.

So first, can you give us a general overview of what this guideline covers?

Yeah, this guideline has been two years in the making and is an overview of the available molecular biomarkers to help clinicians and patients make smart decisions for men with localized prostate cancer. And that's in the newly diagnosed setting, as well as for certain patients that have undergone surgery and are considering adjuvant radiation therapy.

And so what are the key recommendations for this guideline?

So there was a lot of data that the team looked through with the help of the ASCO home office, and a Herculean amount of work went into it. There's a lot of commercially available tests out there. Most of them are quite expensive. And we are trying to make sense of the available literature and provide a guide to clinicians on what these tests are, which patients they might be relevant for, and how to interpret them.

The key takeaways that the data that's been published for most of these biomarkers are purely prognostic. And there is good science and good data supporting them. But they have not been embedded in a rigorous fashion or within trials or validated to have the highest level of evidence. However, they can be used in certain situations to add additional info for the patient and clinician to try to make smart decisions based on prognostic information.

Another key recommendation is that there are select patients that these can be helpful for. And we dive into a lot of the details on who these patients may be. Number one is a patient newly diagnosed with prostate cancer who is trying to determine whether to do treatment of the prostate cancer or embark on active surveillance. And some of those decisions are relatively easy and straightforward.

But when the clinician and the patient are looking for all pieces of information to influence one way or the other, genomic or molecular biomarkers can be useful at that critical fork in the road. However, we made it very clear multiple times throughout the guideline that our group's recommendation is that the biomarkers should not be reflexively ordered for every individual newly diagnosed with prostate cancer. It seems wasteful and not an appropriate use of resources.

The other situation clinically where these can be used are for men that have had previous surgery and are considering secondary radiation therapy, which can be given in an adjuvant or salvage manner. And there are some data suggesting that a specific test by Decipher, a genomic classifier, can be used to help inform whether adjuvant radiation would be appropriate or not.

So that was a good overview. And this guideline also includes some special commentary sections with additional research questions that the expert panel wanted to address. So can you tell the listeners a little more about these important considerations?

Yeah, it's critically important to know that these tests are not black and white. And they don't always clarify a data-based path forward. But we tried to emphasize in many different areas that integrating genomic or molecular information can be integrated into optimizing decisions.

And the special commentary really dives into a lot of those details on working with the pathologists on selecting the appropriate biopsy sample to send to one of these laboratories. It gets into some of the specifics on interpreting the data, as well as the role of CLIA-approved labs and non-CLIA-approved labs for certain staining that's done internally within organizations or with biomarker panels.

And so would you be able to expand a little more about which patients may benefit from having molecular biomarkers?

Yeah, the sweet spot for some of these biomarkers include a couple different patient groups. The first one is what I alluded to earlier-- the man newly diagnosed with prostate cancer deciding whether to do active surveillance, which is a monitoring program, or to have treatment of the prostate typically by either surgery or radiation therapy.

Again, worth emphasizing-- these tests are not appropriate for every newly diagnosed patient. And I would argue even for the man deciding between surveillance and treatment, there are specific men, perhaps those with higher volume low risk prostate cancer or lower volume favorable intermediate risk prostate cancer, that provides the ideal patient that may benefit from some of these tests.

The second clinical scenario that was discussed amongst the group were patients where treatment intensification might be valuable. Again, these biomarkers are purely prognostic, and there's no high level evidence suggesting that treatment intensification leads to better outcomes. Although intuitively, the higher risk profile a patient has, either by clinical factors or biomarkers, there is a conceptual rationale that treatment intensification might prove beneficial.

And the third category of patients that may benefit are those who have had prostatectomy where the pathology shows some adverse features, and there's a high likelihood of recurrence, and the clinician's decision is to guide the man on whether pure adjuvant radiation in the setting of an undetectable PSA or early salvage therapy at the time of biochemical recurrence would be more valuable. And there is one test that is commercially available that can help inform that decision.

Great, so finally, what do you envision as the future of molecular biomarkers for localized disease?

As we took an overview of the landscape in 2018 and 2019 of these molecular biomarkers, much of the group thought this was version 1.0 or 2.0 in this space.

And it is our hope and likely scenario that not only will we have better data on some of the currently available biomarkers with higher levels of evidence from either correlative science from randomized trials or formally embedded into randomized trials, but also that there's a large amount of work being done to improve the quality of biomarkers and that, in the future, we'll see improvements on the currently available ones or newer biomarkers coming around that will be valuable for these men as they make decisions along their prostate cancer course.

Great. Thank you for your work on this important guideline. And thank you for your time today, Dr. Eggener.

Thank you, Shannon.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline and find additional resources such as the guideline's pocket card, go to www.asco.org/genitourinary-cancer-guidelines. And you can find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or in the Google Play Store. And if you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

View Details

An interview with Dr. Melissa Dillmon on the Patient-Centered Standards for Medically Integrated Dispensing: ASCO/NCODA Standards. The interview covers the findings of the systematic review, which were consistent with the NCODA patient-centered standards for patient relationships and education, adherence, safety, collection of data, documentation and other areas. NCODA standards were adopted and used as basis for these ASCO/NCODA standards. Additional information is available at www.asco.org/mid-standards.

View Details

An interview with Dr. Charles Shapiro from Mount Sinai Hospital in New York and Dr. Joan Neuner from Medical College of Wisconsin, co-chairs of "Management of Osteoporosis in Survivors of Adult Cancers with Nonmetastatic Disease: ASCO Clinical Practice Guideline." This guideline includes recommendations on assessing risk factors and interventions, including pharmacologic and nonpharmacologic options. Read the full guideline at www.asco.org/survivorship-guidelines

TRANSCRIPT

Hi. My name is Clifford Hudis, and I am the CEO of the American Society of Clinical Oncology as well as the host of the ASCO in Action podcast. About twice a month, I interview thought leaders in healthcare care and experts in oncology, and we provide analysis and commentary on a wide range of cancer policy and practice issues.
You can find the ASCO in Action podcast on Apple podcasts or wherever you are listening to this show, and you can find all nine of ASCO's podcasts, which cover a wide range of educational and scientific content, and offer enriching insight into the world of cancer care at podcast.asco.org.

Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org.
My name is Shannon McKernin and today on the ASCO Guidelines Podcast, I'm interviewing Dr. Charles Shapiro from Mount Sinai Hospital in New York, and Dr. Joan Neuner from the Medical College of Wisconsin, Milwaukee, co-chairs of management of osteoporosis in survivors of adult cancers with non-metastatic disease ASCO clinical practice guideline. Thank you for being here, Dr. Shapiro and Dr. Neuner.

Thanks a lot.

Pleasure to be here.

So first, can you give us a general overview of what this guideline does cover?

This guideline covers very important topics, that of osteoporosis and that of cancer survivorship. It's the coalescence of these two common problems that is the impetus for this guideline. It covers risk factors and what you can do as a cancer survivor to mitigate your risk.
It covers screening and identification of the best test to use to measure your bone density, and it covers how to treat or pull the trigger for anti-osteoporosis drugs based on the guidelines that are contained within the document.

And what are the key recommendations for this guideline?

So we developed this guideline with three key guideline questions in mind. And they really required a fairly extensive search of the literature to address them. And we did that by looking to some of the literature outside of cancer in osteoporosis screening in other patients as well. So I'll sort of talk about it in terms of the three key questions.
So the first question we had was, which patients with non-metastatic cancer are at increased risk for developing osteoporotic fractures? So that first question was, which patients are we really addressing in this guideline? And how do we assess whether they're at potentially increased risk?
So in response to that, we strongly recommend that oncologists teaming with other physicians, including primary care doctors like myself, evaluate their patients to determine whether they're high risk. And so we provide a lot of details in an extensive document. But in our bottom line, we have a summary of the most common and the most severe risk factors. And those include things like advanced age, current smoking, excessive alcohol consumption, and a history of prior fractures, so already showing that they're at high risk for fractures.
So we recommend you look to that list. And then add in your own clinical judgment, particularly about patients who have added risks from their cancer treatments. And so we do also talk about those patients. And in particular, we call out patients with specific anticancer therapies, for example, aromatase inhibitors given to breast cancer patients, antiandrogens or GnRH agonists given to breast cancer and prostate cancer patients and call out how they're at particular risk.
And finally, in response to this question, we also recommend that you consider using a risk assessment tool. And here, I mention that we had to look to the non-cancer literature. So here, the WHO actually developed something called the Fracture Risk Assessment Tool, or FRAX. And we do recommend that you use this tool or something like it to help you to assess whether your patient is at high risk. And those are readily available on the web. Search FRAX-- F-R-A-X-- to use it. And, of course, we have links in the guideline.
So that addresses the first question, which again was, which patients are at increased risk? And we have a list of risk factors that you should be considering and some references, particularly FRAX, to help you with thinking about those risk factors and how important any specific risk factor is.
Our second question really dovetailed right on that. And that was, how should patients who are at increased risk, you've identified as part of that first question, to be at increased risk for osteoporotic fractures be screened? And here again, we look to the standard recommendations for patients who don't have cancer as well.
And there are two ways that you could move towards, should you screen your patient or not? One could be your patient had one of those risk factors that we talked about and are listed in the document. The other is you use that FRAX tool and patients are more than average risk. And then we recommend patients be screened using one of the standard screening tools. The most common one, is called dual X-ray absorptiometry.
And I want to specifically mention central dual X-ray absorptiometry, which means that the test is done on the hip and the lumbar spine. Those are readily available. All major medical centers have them, and many clinics have them as well. And so we do recommend that for screening. And then we offer some specifics about how frequently you might screen, because that's another question that often comes up.
And so then our final question is once you determine that your patient is at high risk because their bone density test and/or their FRAX test shows that patients are at high risk, we do encourage talking to them about treatment options. And the first thing I want to say is essentially everyone that our guideline addresses, which is all patients who currently have or who are survivors of non-metastatic cancer, that they should consume a diet with adequate calcium and vitamin D. And so that's generally considered to be 1,000 to 1,200 milligrams of calcium and at least 800 to 1,000 IUs, international units, of vitamin D.
We also strongly recommend exercises and call out some specifics. That you want to work on balance, flexibility, and resistance, if possible. And that you quit smoking and limit alcohol consumption. All very good things for the body generally, but also very good for the bones.
Obviously, the meat of this guideline is also about pharmacologic intervention specifically. And since Dr. Shapiro treats so many patients with this, I'm going to ask him if he wants to comment further on specifics about pharmacologic treatments, when you think patients should get them.

So thanks, Joan. So pharmacologic interventions include RANK ligand inhibitors, like Denosumab or IV or oral bisphosphonates. So clearly, if your patients are at risk, that means a hip fracture predicted at 3% or more or a non-hip vertebral fracture at 20% or more-- and you get these numbers from the FRAX calculator and other calculators in common usage-- then you pull the trigger and use one of these agents.
Now we couldn't distinguish between the agents in terms of what's one was preferred. It depends on patient preference, comfort with the doctor in terms of how comfortable the doctor is using the agent, and other factors that go into the decision about which biphosphonate to use. Generally, the IV Zoledronic Acid and sub-cu Denosumab are used in the cancer populations. But oral biphosphonates can be used as well.

And why is this guideline so important? And how will it change practice?

Well, this guideline is so important because we know from survey studies that osteoporosis and preventing osteoporosis and treating osteoporosis in the cancer survivor population is underutilized. And this is an important point, because many people, especially with breast and prostate cancer and colorectal cancer and bone marrow transplants, will be long-term survivors. And we don't want to cure a patient just to have them fracture 10 or 20 years later. So that's the importance of the guideline.
So it's the recognition that osteoporosis is treated the same, whether you're a cancer survivor or not. But the cancer treatments we use in routine practice can cause osteoporosis and bone loss. And that's the importance of this recommendation, as well as the particulars of who's at risk, the risk factors, screening, and pulling the trigger for treatment.
So that's basically in a nutshell, why this guideline is so important and how it will change practice, because we hope that the guideline stimulates us, as health practitioners, to screen our patients for osteoporosis, recognize risk factors, and how to pull the trigger on treatment to prevent or treat osteoporosis in this population. It doesn't matter who follows patient, but the patient has to know who's going to follow the bone density and treatment for osteoporosis, whether it's comfort that an oncologist has with the whole process of screening and risk factors and pulling the trigger for bisphosphonates or Denosumab or endocrinologists, the rheumatologist, the primary care physician. The patient's got to know who's going to be responsible for what aspects of care, survivorship care. And this is a big part of survivorship care.
So the treatment summary, which is a document that the patients get and is given to the primary care provider, should specify who will take responsibility for what aspects of survivorship care. And this is a big aspect of survivorship care, osteoporosis screening and treatment, if necessary. So it doesn't matter who does it, as long as it gets done.

I would jumped in if I could, Charlie.

Yes, so please jump in.

So I guess the only other point that I wanted to make about how it might change practice is osteoporosis guidelines have been out since the late '90s, early 2000s. And so many patients probably have thought about osteoporosis and their risk in the past. But I did want to note that there have been a number of studies in the last five years showing that in primary care-- so family medicine and general internal medicine, like I practice-- that we're actually ordering fewer bone densities than we did in the past.
And all the reasons for that aren't clear. Perhaps it's because of some concerns about the rare side effects of some of these medicines. Perhaps it's because the guidelines aren't clear because the data is not clear about how often we should test people who don't seem to be at high risk once they've had a first test. But nonetheless, there seems to already be some effects of this that the hip fractures, which had been decreasing are starting to look like they're rising again.

So it really is important then if we're not going to screen very frequently everybody, that we are screening the people who really need it. And so then this guideline it calls that out that these are patients who because either their cancer treatment and the debilitating nature of that in some cases or the specific medications puts them at particular risk. Those are the ones that we can't omit this.

Great. Finally, how will these guideline recommendations affect patients?

You know, I think we're hoping that this will help in the care of cancer survivors and spark people to use things like survivorship care plans. Or if those don't work in your institution, other ways to make clear what the patients who are survivors are at risk for, both related to their cancer and outside their cancer, so that we can all work as teams of health care providers to make sure all of the things on those lists addressed.
So we're hoping that with some very clear recommendations about how to address bone health that we can help those teams serve patients that they can. Obviously, it can also provide some really essential information for patients who are wondering what the things that need to be wondering about in this new phase of survivorship after cancer that they're dealing with.

Dr. Shapiro, did you have anything to add to that question?

Hopefully, we can prevent fractures in our cancer survivors by following these guidelines. It's really important that we prevent osteoporosis and hip fractures and vertebral fractures, because we don't want to cure the patient just that saddle them with osteoporosis and breaking a hip or breaking vertebral body 10 or 20 years down the line. So this will hopefully affect patients positively.
And we intended the guideline to be for patients in terms of risk factors. And if you need a biphosphonate or anti-osteoporosis drug, then it's clear indications in the document who gets it and who doesn't. So I think that the effect we hope would be great on patients, that part of general health is osteoporosis screening. And just because you're a cancer patient doesn't absolve you from participating in all the health recommendations, including osteoporosis screening.

As with all ASCO Survivorship Guidelines, we do hope that this one informs many conversations between patients, survivors, and providers. Thanks to your overview here today and your work on this guideline, more clinicians will be informed of the risk factors and possible interventions for osteoporosis and survivors of non-metastatic cancers.
So I want to thank you both for coming on the podcast to discuss this guideline with me today.

Thanks for having us.

Yes, thank you.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/survivorship-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe, so you never miss an episode.

View Details

An interview with Dr. Kala Visvanathan from Sidney Kimmel Comprehensive Cancer Center, and Johns Hopkins Bloomberg School of Public Health on the guideline update. This update adds anastrozole to the options of pharmacologic interventions for breast cancer risk reduction based on recent practice changing data. Read the full guideline at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Hi. My name is Clifford Hudis, and I am the CEO of the American Society of Clinical Oncology as well as the host of the ASCO in Action podcast. About twice a month, I interview thought leaders in health care and experts in oncology. And we provide analysis and commentary on a wide range of cancer policy and practice issues.
You can find the ASCO in Action podcast on Apple Podcasts or wherever you are listening to this show. And you can find all nine of ASCO's podcasts, which cover a wide range of educational and scientific content and offer enriching insight into the world of cancer care at podcast.asco.org.

Hello, and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin, and today I'm interviewing Kala Visvanathan from the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, and Johns Hopkins Bloomberg School of Public Health, co-first author on "Use of Endocrine Therapy For Breast Cancer Risk Reduction: ASCO Clinical Practice Guidelines Update." Thank you for being here, Dr. Visvanathan.

Thank you as well for having me.

So can you tell us about the phase III randomized trial, which provided the signal for this update?

Yes. This was the IBIS-II trial that was reported out by Cuzick, et al in 2014. It was a double-blind, randomized placebo-controlled trial that assessed the safety and efficacy of Anastrozole, the aromatase inhibitor Anastrozole, at 1 milligram per day for five years. And the primary endpoint was the reduction of the incidence of breast cancer in postmenopausal women at increased risk of developing breast cancer.
The trial itself was reported out with a median follow up of five years and the intention-to-treat analysis actually revealed that 85 women in the placebo group and 40 women in the Anastrozole group had developed both invasive and noninvasive breast cancer. What it showed was that there was a reduction in the incidence of breast cancer of 53% overall. It included both invasive and non-invasive breast cancer after a seven-year followup.
And importantly, in subgroup analysis, similar to the other hormone endocrine therapy prevention trials, it also showed that the reduction in breast cancer risk among invasive cancers was limited to those individuals with ER-positive and PR-positive tumors. And the reduction in breast cancer incidence was among hormone-positive breast cancers.
Another interesting point to mention here was that the five-year adherence was only slightly less in the Anastrozole arm compared to placebo. So it was well tolerated. And that was 68% in the Anastrozole group compared to 72% in the placebo group.
And in all the subgroup analysis, there was no significant difference, except when they stratified by hormone replacement, women who had no prior hormone replacement, they saw a clear risk reduction. And this was not seen in women with prior hormone replacement therapy.

And so what are the key recommendations for the update of this guideline?

So based on these results, the update really adds Anastrozole as another option for endocrine prevention in women at increased risk. So specifically, we say that Anastrozole 1 milligram per day orally for five years should be discussed as an alternate to tamoxifen, raloxifene or exemestane in postmenopausal women for the reduction of breast cancer in women at increased risk.
We also clarify further who are the women most likely to benefit from Anastrozole or the other endocrine prevention drugs. And these are women diagnosed with atypical hyperplasia, either ductal or lobular, or lobular carcinoma in situ or women with an estimated five-year risk of at least 3% based on the NCI Breast Cancer Risk Assessment tool or a 10-year risk of at least 5% based on the IBIS Tyrer-Cusick Risk Calculator.
But we also give parameters for other risk models, and that is a relative risk of at least four times the population risk for women in the age group 40 to 45 and two times that of the population age group from 45 to 69.
I think this is an important part of the recommendations, because up till now, the recommendations for women at increased risk have really followed the eligibility criteria for these trials, which were often a five-year risk, for example, of 1.7% in the NSABP trials. And here, we're trying to really highlight the importance of considering this women at higher risk where there is a clear benefit when you look at benefit-risk ratios.
We also talk about the fact that Anastrozole should not be prescribed in women who are premenopausal and that it is really important that both patients and health care providers discuss the benefits and risks of Anastrozole along with the other risk-reduction agents when they are considering prescribing this.
And then lastly, the importance of talking about specific adverse effects of Anastrozole, because here we're talking about a population of women at increased risk who are cancer free. And that includes baseline fracture risk, a measurement of bone mineral density as well as other adverse effects like joint stiffness, arthralgias, vasomotor symptoms, hypertension, dry eyes and vaginal dryness. So we think it's important that they have this discussion with women before the study.

So what are some of the clinical considerations for the use of endocrine prevention pharmaceutical agents for breast cancer risk reduction?

So in this guideline, we have introduced this section called Clinical Considerations to try to tackle some of the challenging questions that providers have when considering prescribing endocrine prevention.
So I urge people to have a look at this section, because it's really a question-answer format. So one of the things we talk about first is what I just alluded to, how do you identify women at risk, where the benefit of endocrine prevention outweighs the risks? And we go through different risk calculations, and we give examples of clinical patients who fit into these risk categories.
The second thing, which I think is an important thing, is we talk about a new study that came out while we were preparing this guideline update. And this was by De Censi, et al. And it's been published in the JCO on low-dose tamoxifen.
This was a randomized trial in women with intra-epithelial neoplasia. So this includes women with atypical hyperplasia, lobular carcinoma, or ductal carcinoma in situ. So slightly different population. And the women were randomized to tamoxifen at 5 milligrams a day-- so this is 1/4 of the standard 20-milligram dose-- or placebo for three years.
So remember-- or endocrine prevention trials were for five years. So this was a shorter duration. And then a median followup of five years, they reported out the results, and they saw half the number of neoplastic events, so DCIS or invasive cancer, compared to placebo. So the results were very comparable to the original NSABP-P1 trial and very promising.
So the further I think, what has been a sometimes prevented uptake of these agents, has been the adverse effects of tamoxifen, for example, equal to uterine cancer. And in this study, they did not see an increase in the number of serious adverse effects, including deep venous thrombosis and endometrial cancer.
They still saw an increase in hot flashes. So I think this is very promising data and could be an alternate option for some patients, where side effects are a problem or they're reticent to take prevention given the side effects.
Another thing we tackle is the question of age when you start recommending hormone prevention. And here, this relates to we talk about at 70, not so much that you would stop it at 70, but at that age or 70 or above, you would actually make sure you're taking into consideration their life expectancy. So they should have a life expectancy of 10 years or greater. And you're also taking into consideration their breast cancer risk.
So the question there was, is there an upper age limit for endocrine risk reduction therapy? And we think that, at least the panel thought that, in women 70 years of age or older, you should actually consider both the short-term risk. It should be at least in the range of 1% or more per year. So that would be women with atypical hyperplasia, a family history, or some with carcinoma in situ. We want to make sure they're active and that they have a life expectancy of 10 or more years.
Another question we tackled here was, what is the duration of endocrine therapy in this setting for breast cancer risk reduction? And this comes in the context that now, in the treatment setting, a subset of women are given, for example, tamoxifen for more than five years.
In terms of data, with the exception of raloxifene, where we do have longer-term data that is greater than five years, in women at increased risk of breast cancer from the osteoporosis prevention trial, where we see that even with women taking raloxifene for more than five years still have a benefit in terms of the breast cancer risk reduction.
We don't really have data for any of the other agents in the preventive setting. So there is currently no data from randomized trials that any of these agents, except for raloxifene, should be given for longer than five years. And that is in the setting of women with osteoporosis.
And then the last question that we tackle is to look at how you decide between taking an aromatase inhibitor endocrine prevention therapy or a SERM. And this is really only in postmenopausal women, because we still only have one option for premenopausal women, and that is tamoxifen.
Here, we just go through step by step sort of the process of thinking about the side effects for each of these agents. And in the context of the woman who is considering endocrine therapy and tailoring it to their age, what symptoms they have, or other comorbidities.

Finally, how will these guideline recommendations affect conversations between providers and women at increased risk for breast cancer?

So I think, firstly, these guidelines, again, bring attention to breast cancer prevention and the need for us as a community, both providers and women, to move this field forward. And what do I mean by that is we need to be more systematic about identifying women who are truly at increased risk and then subsequently having these discussions with them about the options available.
And so I think this guideline adds another agent to the list of agents we now have that can be used to reduce breast cancer risk or breast cancer incidence and also provide the opportunity to-- we look at this and think about how we might incorporate discussions on breast cancer risk reduction into clinical practice.
We do also want to stress the importance of discussions on lifestyle factors or risk reduction in addition to these agents. So I think hopefully this guideline helps to, again, refocus attention on the issue and encourage both women to ask their providers about their breast cancer risk and then providers to re-look at this question about breast cancer prevention and how to identify those who are at risk and then discuss endocrine prevention in those at higher risk.
I think this is particularly important as we think about our aging population and the increase we are expecting in breast cancer over the next 10 to 20 years. And then also, as we think about breast cancer is now the number-one cancer diagnosed, well, the prevention becomes even more important.

Great. Thank you for your work on this guideline. It sounds like there may be many important conversations which happen between women and their providers based on the work and the research about breast cancer risk reduction. So thank you again for coming on the podcast to share with us today, Dr. Visvanathan.
Thank you. I would like to thank ASCO for having these podcasts and also shining a light on breast cancer prevention and getting this information out to its listeners.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Anna Falanga on "Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Clinical Practice Guideline Update." The guideline revises several previous recommendations. Most notably, direct oral anticoagulants (DOACs) have been added as options for VTE prophylaxis and treatment.

Read the full guideline at www.asco.org/supportive-care-guidelines

Find all of ASCO's podcasts at podcast.asco.org

TRANSCRIPT

Hi, my name is Clifford Hudis and I am the CEO of ASCO and the host of the ASCO in Action Podcast. About twice a month, I interview thought leaders in health care and experts in oncology, and we provide analysis and commentary on a wide range of cancer policy and practice issues.

You can find the ASCO in Action Podcast on Apple Podcasts or wherever you are listening to this show, and you can find all 9 of ASCO’s podcasts which cover a wide range of educational and scientific content and offer enriching insight into the world of cancer care at podcast.asco.org

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today I'm interviewing Dr. Anna Falanga from the hospital Papa Giovanni XXIII in Bergamo, Italy. Senior author on "Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Clinical Practice Guidelines Update."
Thank you for being here today, Dr. Falanga.

Yes, thank you. I am very happy to talk on the update of the ASCO VTE guidelines.

So this guideline was first published in 2007 with an update in 2013 and a reaffirmation in 2015. So what prompted this 2019 update?

Thanks for this first question. I think that an update was urgently needed at this time. You know, before, the ASCO guidelines were published in 2007. And then an update was made in 2013, and the second one in 2015.
But in 2015 was basically a confirmation of the previous 2013 update. Now the update was urgently needed, because in the very recent years there has been even more evidence of the relevance and impact of a venous thromboembolism in the cancer patients. But in addition, and very importantly, new data from prospective randomized clinical trials with the new drugs for the management of VT in the oncological patients have become available.
In particular, as you know, low molecular weight heparins were largely used in the setting of the treatment and trauma prophylaxis in the cancer patients. And actually, the low molecular weight tapering have been the standard of treatment for many years.
However, recently the results of prospective randomized clinical trials of direct oral anticoagulant, particularly, the anti-Xa inhibitors, Edoxaban and Rivaroxaban, for cancer associated with [INAUDIBLE] treatment support the role of this new oral agent in the VT management in this setting. And this is related to new politics in the VT management in these patients.

So what are the key recommendations for this guideline update?

The main changes to the previous recommendations are first that Rivaroxaban and Edoxiban, the two anti-Xa inhibitors oral anticoagulants have been added as an option for routine treatment in cancer patients in this update. Also, now we may offer thrombo prophylaxis with Apixaban, Rivaroxaban, or low molecular weight tapering to selected high-risk outpatients with cancer.
And about other changes of these new guidelines compared to the last one include that patients with brain metastases have been addressed in the VT type treatment sections, whereas before, only patients with the primary tumors were mentioned in the previous edition.
And finally, the recommendation regarding long-term postoperative thromboprophylaxis with low molecular weight heparin expanded to patients undergoing a major open or laparoscopic abdominal or pelvic surgery. These are the main changes that all I think are very, very important.

Why is this guideline so important? And how does it affect practice?

Well, I think that the question how these changes affect our practice is a very important question, because I believe that these guidelines reflect the new evidence that we have from the new data. And this data clearly expand our possibility to choose now between the different treatment options in the single patient in the cancer population.
For instance, the new data show that treatment with [INAUDIBLE] anticoagulants compared to low molecular weight heparin lower the risk of a recurrent thrombosis. But in some instances there's a higher risk of bleeding, particularly in the gastrointestinal and urinary tract cancer patients. So therefore it is evident that the patient selection and the individualization of a therapy based on the patient characteristics and the type of cancer-- all these become very important.
And we have the possibility now to choose between different treatments, or in the same patients we can change from one treatment to the other according to the face of the disease or complications if the patient is in a phase that is assuming chemotherapy with many side effects like nausea and vomiting. Of course, in these cases a parenteral injection is preferable for the management of a venous thromboembolism. Whereas in other instances, a long-term and oral intake is surely more convenient.
So it depends also from the level of risk. But now for the six months treatment we can offer different choice of the oral treatment and also for high-risk patients the primary prophylaxis with Apixaban Rivaroxoaban, and a low molecular weight tapering can be chosen.

And what should patients be aware of when it comes to VTE risks and treatments?

I think that patients should be educated about the risk of a cancer associated with VTE. You know, there is that evidence that they are educated about it. And they know a lot better about neutropenia, and the fever associated with this the neutropenic condition and the other side effect. But they know very little about the possibility that they can experience venous thromboembolism. s
So I think they should be taught on how to recognize the symptoms and alert their physician. You know, sometimes the symptoms are indistinguishable It can be just a little pain in the calf. And patients must know that these are to be considered important. They must alert their physician to undergo some test-- objective test-- to see if there is a real thrombosis in the leg or not. This is extremely important, because one important consequence of venous thromboembolism of the extremities is a pulmonary embolism that can be also fatal. So they must know about that.
Also, I think they should know about the risk of bleeding associated with the anticoagulant treatment, and also that this risk of bleeding can be different in the different type of tumors.
Finally, I think that also they must be told about the once they have, for instance, and episode of venous thromboembolism they have to receive a treatment for that, and these are usually six months to the minimum, and then we'll decide. So they must know what these are the efficacy and the safety profiles of the different drugs. They must know the differences in the route of administration and the other characteristics of the drug.
So I think that their shared decision with the patients of the type of treatment must be an integral part of the decision making and is certainly desirable.

Great. It sounds as though there's some important considerations for patients and important conversations which may be prompted by this guideline. So thank you for taking your time to discuss this with me today, Dr. Falanga.

I thank you very much for this interview and talk that our colleagues and also the patients will be happy with these new guidelines of ASCO. Thank you.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Noam Yarom, Dr. Charles Shapiro, Dr. Deborah Saunders and Dr. Doug Peterson on "Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline." This guideline addresses the prevention and management of MRONJ in patients with cancer. This guideline is intended for oncologists and other physicians, dentists, dental specialists, oncology nurses, clinical researchers, oncology pharmacists, advanced practitioners, and patients with cancer.
Read the full guideline at www.asco.org/supportive-care-guidelines

Find all of the ASCO podcasts at podcast.asco.org

TRANSCRIPT

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello, and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin. And today, I'm interviewing a panel of authors from "Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline." So could I have you each introduce yourselves for the listeners today?

Thank you, Shannon. I'm Dr. Deborah Saunders. I'm the president of the International Society of Oral Oncology and was the section head for the Systematic Review on "Medication-Related Osteonecrosis of the Jaw," with MASCC and ISOO. I was a proud part of the steering committee and one of the authors.

Thank you, Debbie. My name is Dr. Douglas Peterson. I am professor of oral medicine in the School of Dental Medicine at the University of Connecticut Health Center in Farmington, Connecticut. I am also a faculty member in the Head and Neck Cancer Oral Oncology Program at the university's Neag Comprehensive Cancer Center. I'm a member of the steering committee for this clinical practice guideline and one of the co-authors as well. In addition, and as of June 2019, I have been serving as chair elect during this next year for ASCO's Clinical Practice Guidelines committee.

Thank you, Doug. My name is Noam Yarom. I'm an all medicine specialist from the Sheba Medical Center in Tel Aviv University in Israel. I'm serving as a culture of this guideline, and it is a pleasure to be with you today.

Thanks, Noam. I am Dr. Charles Shapiro, professor of medicine at the Mt. Sinai Hospital in New York. And I'm co-chair of the guideline "Medical-Related Osteonecrosis of the Jaw." And I'm happy to be here.

Thank you all for being here today to discuss this guideline on the podcast. So first, can you give us a general overview of what this guideline covers.

Sure. So you know, ASCO and MASCC, as well as ISOO decided that it would be great to provide a practical evidence-based approach in a multidisciplinary type setting to address this important topic that impacts all of our professions, that being medication-related osteonecrosis of the jaw.
It's terminology and its definition and the path that's varied and even part of this publication identifies the need for us to move forward with a concise definition and similar terminology, that being medication-related osteonecrosis of the jaw.
Medication-related osteonecrosis of the jaw is defined as the presence of an exposed or bone that is probable by a probe in a patient that has a history or is undergoing present use of a bone-modifying agent. This being in the absence of any patients having received any radiation to the head and neck and the absence of metastatic lesions to the jaw.
The importance of us identifying this definition and agreeing on the terminology allows us to move forward in future publication to better compare outcome and provide better prevention and treatment for our patients moving forward.

And what are the key recommendations of this guideline?

There are six clinical questions associated with this clinical practice guideline as well as a series of recommendations built within each of the clinical questions. Clinical question one is directed to the preferred terminology and definition for osteonecrosis of the jaw, both of the maxilla and the mandible, as associated with pharmacologic therapies in oncology patients.
The panel recommends that the term medication-related osteonecrosis of the jaw, MROJ, be used when referring to bone necrosis associated with pharmacologic therapies. As Dr. Saunders has described, the definition contains three key elements-- current or previous treatment with a bone-modifying agent or angiogenic inhibitor, exposed bone, or bone that can be probed through an intra or extra-oral fistula in the maxillofacial region and that has persisted for longer than eight weeks. And third, no history of radiation therapy to the jaws and no history of metastatic disease to the jaws.
Clinical question two is directed to specific steps that should be taken to reduce the risk of MRONJ. The recommendation begins with emphasizing the absolute importance of interprofessional communication of the oncology team with the dental team in advance of initiating the bone-modifying agent.
For patients with cancer who are scheduled to receive a bone-modifying agent in a non-urgent setting, a comprehensive oral care assessment, including dental examination and periodontal examination and an oral radiographic exam when feasible to do so should be undertaken prior to initiating the BMA therapy.
Once the dental care plan has been developed, it should be discussed with the dental team, the patient, and the rest of the oncology team and then implemented based on medically necessary dental procedures. These procedures should be performed prior to the initiation of the bone-modifying agent.
Once the bone-modifying agent is implemented, there should be ongoing followup by the dentist on a routine schedule, for example, every six months following initiation of the BMA therapy. It's also important to realize that there are a series of modifiable risk factors which should be emphasized with the patient.
For example, poor oral health, invasive dental procedures, ill-fitting dentures, uncontrolled diabetes mellitus, and tobacco use are all factors that have been associated with development of a MRONJ. All of these modifiable risk factors should be addressed, where appropriate, with the patient in advance of the bone-modifying agent.
As far as elective dental alveolar surgery, these procedures, if they are not medically necessary, for example, extractions or alveoloplasties or implants, they should not be performed during active therapy with a bone-modifying agent being given at an oncologic dose.
Now, exceptions to this may be considered when a dental specialist with expertise in prevention and treatment of MROJ has reviewed the benefits and risks of the proposed invasive procedures with the patient and the oncology team. In general, however, elective dental alveolar surgical procedures should be deferred while the patient is undergoing active therapy with a bone-modifying agent.
If the dental alveolar surgery is performed, the patient should be evaluated by a dental specialist on a systematic and frequently scheduled basis, for example, every six to eight weeks until there is full mucosal coverage of the surgical site. And once again, communication between the dental team and the rest of the oncology team is absolutely paramount in assuring ongoing comprehensive care of the patient.
Interestingly, there are still questions in the literature relative to whether or not there should be temporary discontinuation of bone-modifying agents prior to dental alveolar surgery. Unfortunately, there remains insufficient evidence to support or refute the need for discontinuation of the bone-modifying agent prior to dental alveolar surgery.
And so the administration of the bone-modifying agent may be deferred at the discretion of the treating physician, in conjunction with discussion with the patient and the oral health provider. So it really becomes an individual judgment call by the treating physician relative to whether or not to temporarily discontinue the bone-modifying agent prior to dental alveolar surgery.
Clinical question three involves the staging of MROJ. There are a number of well-established staging systems in the literature addressing severity and extent of MROJ. For example, the 2014 American Academy of Oral and Maxillofacial Surgeons Staging System is one example.
Another example is the National Cancer Institute's Common Terminology Criteria For Adverse Events. And there is a 2017 International Task Force on O and J Staging System for MROJ that is available as well. So there are at least three well-established, widely utilized staging systems for MROJ.
Having said this, it's important in the view of the panel that the same staging system should be used throughout an individual patient's MROJ course of care. And optimally, the staging should be performed by a clinician experienced with the management of MROJ.
Clinical question four involves management of MROJ directly. Here, the recommendations talk in terms of initial treatment of MROJ, which is centered in conservative measures. Now, these conservative measures may include antimicrobial mouth rinses, antibiotics if clinically indicated, effective oral hygiene, and conservative surgical intervention such as a removal of a superficial bone spicule.
In cases, however, of refractory MROJ, more advanced MROJ, aggressive surgical interventions, for example, mucosal flap elevations, bloc resections of necrotic bone may be used if MROJ is persisting and severely affects function despite conservative initial treatment.
Clinical question five involves bone-modifying agents and whether they should be temporarily discontinued after a diagnosis of MROJ has been established. And once again, there is insufficient evidence to support or refute the discontinuation of the bone-modifying agents after a diagnosis of MROJ has been established. The bone-modifying agent may be deferred at the discretion of the treating physician, again in discussion with the patient and the oral health care provider.
And finally, clinical question six involves what outcome measures that should be utilized in clinical practice to describe the response of MROJ lesion to treatment. During the course of MROJ treatment, the dentist, dental specialist, should communicate with a medical oncologist in an ongoing way, both the objective and subjective status of the lesion. The guideline presents a scale that can be utilized to describe the trajectory of the MROJ-- resolved, improving, stable, or progressive.
The clinical course of MROJ may impact both local and systemic treatment decisions relative to the cessation or the recommencement of bone-modifying agents. So once again, it becomes very, very important that the ongoing interprofessional communication relative to the clinical course of MROJ-- resolved, improving, stable, or progressive-- be discussed with the oncology team.

Great. Thank you, Dr. Peterson. So on that last note, how can oncologists, dental specialists, and dentists all work together to manage medication-related osteonecrosis of the jaw?

Throughout these guidelines, we do emphasize the importance of collaboration among the cancer care team, dentist, and dental specialists in order to coordinate care and modify risk factors. It is very important that cancer care team and the dental care team speak the same language. Therefore, we spend time on clarifying the definitions, the diagnostic criteria, and staging of MROJ.
As been said earlier, we have developed a new system to evaluate the response to treatment, which is based both on objective findings and symptoms. By using this scale, oncologists and dentists would be able to communicate more easily for the benefit of the patients.
We emphasized the need for multidisciplinary discussion in a few critical points throughout the course of bone-modifying agent therapy. And it is most important in case of a planned oral surgery in a patient without MROJ or before aggressive surgical treatment of refractory MROJ.

And how will these guideline recommendations affect patients, and what should they talk to their doctors about?

There are a number of things that patients, providers, dental specialists, and medical oncologists can do to lessen the risk and prevent MROJ. Because the key to MROJ is prevention. Once MROJ is established, it's difficult to treat, impacting a patient's quality of life. So we want to prevent, reduce the risk of developing MROJ.
Patients can do a number of things-- pursue good oral hygiene, stop smoking, or reduce smoking, and control their diabetes, for example. Those things lessen the risk of MROJ. Providers, dental providers, dental specialists, who are specialized in the area or providers, dentists otherwise in the community, when they encounter a patient that's contemplating bone-modifying agents, they can do what's called a complete dental screening exam, which involves a complete examination of the mouth, Panorex X-rays and X-rays as clinically indicated.
We want to identify work in the mouth that needs to be repaired before initiating bone-modifying agents. That way, we don't have to deal with an emergent situation when it could be preventable prior to bone-modifying agents, because one of the single highest risk factors for MROJ is emergent dental work while you're on bisphosphonate or another anti-resorptive agent-- bone-modifying agents.
So a dental screening exam is critical to prevent or reduce the risk of MROJ. And medical oncologists have a role too in communication with the dental specialists and really think hard about the indications for bone-modifying agents, whether it be for osteoporosis, whether it be for metastatic disease, and whether it be for anti-cancer effects.

And finally, where can both patients and clinicians go to get more information on this topic or to find a dentist or a dental specialist?

Now, as far as websites, ASCO, MASCC, and ISSO all have websites you can go to to find out more information about MROJ.

Yeah, I think that's great advice. Our links for additional information are listed in the Clinical Practice Guideline as well. This is a really first step at a framework in trying to manage a side effect that affects our patients but is very multidisciplinary. And like Dr. Shapiro was saying, really the best way to prevent this is with proper communication between the dentist and the oncologist and making the patient aware of what is needed prior to commencement of these treatments.

Well, it certainly sounds as though there are some important considerations for clinicians and patients. And I really hope that this guideline is widely read and makes a real impact on the management of osteonecrosis and the communication between oncologists, dental specialists, and dentists. So from me and all of our listeners, thank you all for coming on the podcast today to discuss "Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline."

Thank you.
Thank you for having us.
Thank you very much for this opportunity to contribute to this important discussion.
Thank you for allowing me to participate in this important podcast.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go www.asco.org/supportive-care-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Lynn Henry from University of Utah Huntsman Cancer Institute on "Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision-Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of CCO Guideline." This guideline update includes data from the MINDACT and TAILORx trials to clarify the recommendations forpatients with hormone receptor-positive, HER2 not overexpressed, axillary node-negative early breast cancer.

Read the full guideline at www.asco.org/breast-cancer-guidelines

TRANSCRIPT

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Hello and welcome to the ASCO Guidelines Podcast Series. My name is Shannon McKernin. And today, I'm interviewing Dr. Lynn Henry from the University of Utah Huntsman Cancer Institute, lead author on "Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision-Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of CCO Guideline." Thank you for being here today, Dr. Henry.
Thank you very much for the invitation.
So this guideline was updated to incorporate new data from the TAILORx and the MINDACT trials. So can you give us an overview of these trials and their results?
Sure. So patients with hormone receptor-positive, HER2 negative breast cancer, are generally treated with anti-estrogen treatment and are sometimes also recommended to have chemotherapy. Since these tumors don't always respond well to chemotherapy, tests have been developed that provide more information about how much benefit, in terms of reduction of the likelihood of cancer coming back, an individual patient is likely to get from treatment with chemotherapy. It is important that the benefit of a treatment outweighs the risk of toxicity from the treatment.
Two of those tests are called Oncotype DX and MammaPrint. And they have recently been tested in large clinical trials. So TAILORx is a large prospective trial that tested the Oncotype DX assay. In the Oncotype DX assay, a tumor is tested to get more information about how likely a cancer is to return and how much benefit the patient is likely to get from chemotherapy. Scores on this assay can range from 0 to 100.
Previously, a study showed that patients whose tumors had scores of 10 or less, and who received five years of anti-estrogen treatment, were very unlikely to have their tumors return. So chemotherapy is not recommended for them. For patients with higher scores, above 30, we also already knew that chemotherapy is likely to decrease the chance of cancers in those patients, and, so, therefore, we generally recommend chemotherapy for women with higher scores.
In the TAILORx trial, the recently reported trial, more than 6,700 women with hormone receptor-positive, HER2 negative, lymph node-negative breast cancer had their tumors tested and were found to have Oncotype DX recurrent scores between 11 and 25, which is in that intermediate range or at the higher end of the low range. Before this trial was conducted, many people with tumors like these, in the intermediate range, were treated with both chemotherapy and endocrine therapy because we weren't sure how much benefit they would obtain from chemotherapy, and we didn't want to leave out a potentially helpful treatment.
In this trial, patients were randomized, or randomly assigned by a computer, to treatment with chemotherapy followed by endocrine therapy or to treatment with endocrine therapy alone. The trial was mainly looking at whether leaving out chemotherapy would increase the likelihood of invasive cancer returning. And, luckily, overall, the trial showed that the likelihood of cancer returning in those patients who got endocrine therapy alone, without chemotherapy, wasn't significantly different compared to those who were treated with chemotherapy followed by endocrine therapy.
They also looked, specifically, at the group of women who were 50 years of age or younger. So mostly premenopausal women. Now, this was an exploratory question, meaning it provides information that may be correct, but it hasn't been as fully tested as the main question about what do we do for all women? In these younger women, there appeared to be some benefit from chemotherapy in those whose tumors had scores from 21 to 25, and, also possibly, in those whose tumors had scores from 16 to 20. Therefore, we still consider giving chemotherapy to younger women with Oncotype DX scores in the middle range, from 16 to 25, but not to women over age 50.
So that was the TAILORx trial. The MINDACT trial was a bit different. It was testing the MammaPrint assay and the trial also included primarily women with hormone receptor-positive, HER2 negative breast cancer. But in this case, most women's sorry lymph nodes were negative, although a few women had up to three lymph nodes involved. In that trial, patient's risk of disease recurrence was assessed in two ways.
First, it was assessed based on clinical factors. So the size of the tumor, how many lymph nodes were involved, and the estrogen receptor, progesterone receptor, and HER2 receptors. Second, it was assessed based on genomic factors-- that was using the MammaPrint test. So if patients were low for both clinical factors and genomic factors, they only were treated with anti-estrogen therapy.
If they were high for both clinical factors and genomic factors, then they were treated with chemotherapy followed by anti-estrogen therapy. However, if they were high for one and low for the other, then they were randomized to either endocrine therapy alone or chemotherapy followed by endocrine therapy. So it was a little bit of a confusing trial.
In the MINDACT trial, those patients who were thought to be high risk based on their clinical risk, so the size of the tumor, the number of lymph nodes, but then found to be low risk on the MammaPrint assay. They found that there was no benefit to treatment with chemotherapy in terms of how likely a woman was to develop distant metastatic disease. And if they were low risk, based on the clinical assessment, then there didn't appear to be a benefit of actually doing the test, the assay, because chemotherapy wouldn't be recommended for the patient, regardless of the results. So that was the MINDACT trial.
So what are the new and updated recommendations for the guideline?
Yes, so in this guideline, we, based on the TAILORx trial, we made new recommendations for use of the Oncotype DX results. All of these results apply to women with hormone receptor-positive, HER2 negative, lymph node-negative breast cancer. So for women older than age 50, if they have an Oncotype score of 25 or lower, then clinicians may offer endocrine therapy and no chemotherapy.
However, for women age 50 or under, if they have an Oncotype score of 15 or lower, 15, then, clinicians may offer endocrine therapy and no chemotherapy. But if the score is 16 to 25, then chemotherapy can be considered in addition to endocrine therapy. So it made a difference in that gray area in the middle. For all women with score 26 to 30, chemotherapy may be considered. And for scores above 30, chemotherapy should definitely be considered.
The data from the MammaPrint trial actually aren't that new. Results from that trial were originally published in 2016. However, that was after the original guideline was published, so we wanted to add these results to these updated guidelines for completeness. For a patient with hormone receptor-positive, HER2 negative, node-negative breast cancer, who is thought to be at high clinical risk of breast cancer recurrence, if the MammaPrint assay shows low genomic risk, then treatment with chemotherapy can be avoided.
If a patient is thought to be at low clinical risk, the MammaPrint should not be used as chemotherapy can be avoided regardless. And for a patient with hormone receptor-positive, HER2 negative breast cancer, but who has one to three positive lymph nodes, who is thought to be at high clinical risk of breast cancer recurrence, if the MammaPrint assay shows low genomic risk, then it is possible that chemotherapy could be avoided, especially if only one lymph node is involved.
So I think the bottom line for this part is that both of these tests-- there are now women who previously would have been recommended to have chemotherapy that maybe now we can avoid chemotherapy based on using these assays on their tumors.
So why are these changes so important and how will they affect practice?
Yes, that's a good question. Before the publication of the TAILORx trial, we had good information about how to treat patients who had either very low or very high Oncotype scores. But we really weren't sure how best to treat those patients who scores fell in the middle. Now, we have important information to guide decisions about chemotherapy for patients with intermediate scores.
For many patients with scores in this range, these new results mean they will be able to avoid chemotherapy and just get endocrine therapy. While these results don't give us answers for every patient, they do provide more information that oncologists can use when having discussions with patients about the benefits and risks of chemotherapy.
And what does this mean for patients with early-stage invasive breast cancer? And what should they talk to their doctors about?
So as a result of both of these trials, we now have additional tools that can help oncologists provide more individualized treatment recommendations for patients and really assess whether or not chemotherapy, in addition to endocrine therapy, is likely to provide benefits. Knowing which patients' tumors will respond to chemotherapy can help some patients avoid unwanted side effects from a treatment that's not likely to actually give them much benefit.
Now, these tests aren't appropriate for everyone and don't provide all the answers, but they are an important step in the right direction for providing more personalized treatment for women newly-diagnosed with certain types of breast cancer. Patients should talk with their doctors about whether these tests are right for them when they're making important decisions about whether or not they should receive treatment with chemotherapy.
Great. Thank you, Dr. Henry, for this informative overview of the guideline. Keeping these clinical practice guidelines updated is really crucial and it takes a lot of careful thought to ensure these recommendations represent the evidence. So thank you for coming on the podcast to discuss the "Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision-Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of CCO Guideline."
Thank you very much for the opportunity to talk with you today.
And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. AloK Khorana from Cleveland Clinic on "Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update." This guideline update adds another treatment regimen to the options for patients with resected pancreatic adenocarcinoma who did not receive preoperative therapy.

Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines

See all of ASCO's podcasts at www.asco.org/podcasts

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Hello, and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Alok Khorana from The Cleveland Clinic, lead author on "Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update." Thank you for being here today, Dr. Khorana.
Thank you for having me.
So this guideline was first published in 2016. And then we saw an update in 2017. And now we've just updated it again. So can you tell the listeners what has prompted these updates?
In the world of pancreatic cancer, this has been an evolution in adjuvant treatment, which is sort of a surprise, because we've been treating pancreatic cancer in a very similar fashion over the past several decades. And between the 1990s and until just a few years ago, there hasn't really been much progress in terms of what to do with pancreatic cancer patients after they've had their cancer resected.
It's pretty clear that these patients should not have just the surgery, that they should have additional treatment after the surgery. And for decades, the standard treatment after surgery was either 5-fluorouracil or gemcitabine, but most oncologists are opting for gemcitabine. The two recent updates of the ASCO Guidelines reflect two large randomized trials that have been published in this area. The first changed-- added a new standard of care, which was a doublet adjuvant therapy with gemcitabine and capecitabine.
And the reason for this most recent update is the publication of a large randomized trial of adjuvant FOLFIRINOX for patients with pancreatic cancer that was published in December 2018 in "The New England." And we felt that the results were so compelling that we needed to update the guidelines so oncologists and practitioners would have the most current data to help them make decisions for patients.
So for our listeners who may not now, can you tell us what changes have been made to the recommendations in this newest version of the guideline?
So this is a guideline on a potentially curable pancreatic adenocarcinoma, which is we are saying these are resectable pancreatic cancer patients. And the guideline update changes primarily one recommendation, recommendation 4.1, which is a listing of additional adjuvant therapy options. As I mentioned earlier, the most common monotherapy option used to be the gemcitabine 5-fluorouracil. And that recently changed to doublet therapy.
And we've kept those recommendations, but we've added the modified combination regimen of 5-fluorouracil, oxaliplatin, and irinotecan, which is known as the FOLFIRINOX regimen. And we are making this the preferred regimen for patients in the absence of concerns for toxicity or tolerance. We are still keeping the recommendations for the doublet therapy with gemcitabine capecitabine as well as monotherapy with gemcitabine alone or fluorouracil with cholanic acid. But those are not the preferred regimens, because the data for FOLFIRINOX is much better than prior regimens.
Having said that, there are concerns about using such an aggressive regimen and in patients who have undergone a major surgery. So patients have not recovered from operation, then it's reasonable to consider one of the other regimens. But the update primarily focuses on adding adjuvant FOLFIRINOX as the preferred option in the adjuvant setting.
And how has this guideline and its updates affected care for patients with pancreatic adenocarcinoma?
I think since the results of this trial, the PRODIGY 24 trial came out of post-operative FOLFIRINOX. Almost every oncologist I know that focuses on treating patients with pancreatic cancer has suddenly added its use in patients that respected pancreatic cancer who are healthy enough to tolerate adjuvant FOLFIRINOX therapy. So it's definitely a practice-changing landmark paper.
The results of the study were really quite impressive. The use of adjuvant therapy with FOLFIRINOX led to much longer survival than we've seen in any trial of adjuvant therapy of pancreatic cancer, almost 54 months-- or actually just over 54 months, almost 55 months-- in patients who are randomized to the modified FOLFIRINOX group and about 35 months in the gemcitabine alone group.
The overall survival at three years was 63% in FOLFIRINOX and nearly 49% in the gemcitabine group. So that's a big difference at three-year survival as well. The one thing clinicians should be aware of is that this adjuvant therapy trial used a modified dose of FOLFIRINOX. They initially started off at the full those, which is 85 milligrams per meter squared of oxaliplatin, 400 mg per meter squared of leucovorin, and 180 milligrams per meter square of irinotecan.
But the dose of iriniotecan was reduced part way through the study to 150 milligrams per meter squared, along with, of course, the conventional 2.4 grams or 5-fluorouracil over 46 hours. This modification of the irinotecan dose from 180 down to 150 is what many patients on the study received and was the more tolerable regimen and allowed the study to be completed.
So the Guidelines Panel felt quite strongly that when using FOLFIRINOX in the adjuvant setting, we should stick with this modified dose, which is a lower dose of irinotecan at 150 milligrams per meter squared. And I think it's important that clinicians be aware of this distinction. And so taking this into account, many of us have made this recommendation to patients who are healthy enough to tolerate adjuvant FOLFIRINOX. And the hope is that this guideline will inform this ongoing practice as it changes in response to new data.
And finally, what trials or new research are you keeping an eye on that may prompt an update for this guideline in the future?
The results of another large adjuvant therapy trial are expected, hopefully at ASCO this year. This trial is the APAC trial that utilizes gemcitabine and nab-paclitaxel or Abraxane. This doublet combination is quite widely used in patients with metastatic pancreas cancer, particularly those patients for whom we feel FOLFIRINOX may not be appropriate because of their performance status or functional status. And the hope was that the doublet combination would also have good success in the adjuvant therapy setting and perhaps be a better option than the gem-cape doublet.
There has been a press release from the sponsor of that trial, and it looks like the trial was not successful, although the way the press release is worded is rather confusing. So we wait for the full results of that trial to be presented at ASCO before we have an understanding of whether that is an appropriate regimen to use or not in the adjuvant setting. So that's certainly one large trial that many of us have been looking forward to complete sort of the set of ongoing adjuvant therapy trials in this setting.
Great. It sounds like there's some really exciting things happening in pancreatic cancer right now. And I look forward to seeing this guideline evolve with the research. So Dr. Khorana, thank you so much for coming on the podcast today and summarizing the Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update.
Thank you, Shannon.
And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Fabrice Andre from Institute Gustave Roussy, Paris Sud University, in Paris, France on "Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update: Integration of Results from TAILORx." This update provides updated recommendations on chemoendocrine therapy for patients who present with a hormone receptor positive, HER2 not overexpressed, axillary node negative early breast cancer.

TRANSCRIPT

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Hello, and welcome to the ASCO Guidelines Podcast Series. My name is Shannon McKernin, and today I'm interviewing Dr. Fabrice André from the Institute Gustave Roussy in Paris, France, lead author on "Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Early Stage Invasive Breast Cancer. ASCO Clinical Practice Guideline Update: Integration of Results from TAILORx." Thank you for being here today, Dr. André.
Thank you.
So based on the title of this guideline, we know that this update was prompted by the results of the TAILORx trial. So can you tell us more about that trial and what its results were?
Yes. So the TAILORx trial was a trial that randomized two treatment modalities, endocrine therapy versus chemotherapy endocrine therapy in patients who presented what we call an intermediate recurrence cohort. So before moving to the results, maybe we can discuss a little bit the background. What we knew from the past is the fact that patients who present a recurrence score below 11 should be treated with endocrine therapy alone, because they have the good outcomes. And patients who present recurrence score that is high, 31 but also can be more on 25, should receive chemotherapy.
And we are talking about patients with hormone-receptor receptor positive, HER2-negative early breast cancer without lymph node involvement. And this is extremely important. So to summarize, it's a clinical trial that includes patients with hormone-receptor positive HER2-negative lymph node negative in early breast cancer, who present with recurrence score between 11 and 25. And the question is whether we can avoid adjuvant chemotherapy in these patients who present this intermediate score. So this is the general design and the question.
In terms of research, what we have learned. We have learned that for patients above 50 years old, there is no difference between endocrine therapy and chemotherapy followed by endocrine therapy. So it means that this patient or these patients, we would consider endocrine therapy alone. Then, for patients below 50 years old, there was some difference. And I think we go further into the detail. There was some difference favoring the use of chemotherapy in the group of patients who presented with recurrence score from 16 to 25.
And so what changes were made to the recommendations in this update of the guideline?
So first, what were [INAUDIBLE] the previous guidelines. The previous guidelines were telling the clinician which genetic tests they could use in patients with hormone-receptor positive, HER2-negative early breast cancer. Now, the big change is that we are making guideline to explain how to use the test. And what is new is that we have made three important decisions.
So first, for the patient is at the age above 50, now it is recommended clinician may recommend endocrine therapy alone for women older than 50 who present a recurrence score below 26. Before, the recommendation to use endocrine therapy alone was for patient's who present with low recurrence score.
So it means now we have broadened-- we have increased the number of patients who could receive endocrine therapy alone and not receive chemotherapy. Then, for patients who present a recurrence score between 16 to 25 and who are below 50 years old, the clinician may offer chemotherapy followed by endocrine therapy, meaning that we are moving from [INAUDIBLE]. This intermediate score between 11 to 25 was what we call a [INAUDIBLE].
There was no recommendation on how to use the recurrence score. So right now, the update from the ASCO guideline is to provide recommendation on which treatment to administer in case a patient presents with intermediate recurrence score, and there are two different situations above 50 years old and below 50 years old.
So why are these changes so important and how will they affect practice?
So they will affect practice because for many reasons, I will say. In the US, they would affect practice because they increase the number of patients who will not receive adjuvant chemotherapy, because right now, we have an answer from randomized trial that we can avoid chemotherapy in women above 50 and from 11 to 25 recurrence score. So the impact in terms of public health would be that we could have a decrease in the use of chemotherapy or at least a better precision about who should receive adjuvant chemotherapy.
Globally, this trial is going to provide an incentive and increase the level of evidence supporting the use of genetic tests. So it's important to remember that in a large number of countries, genetic tests are not reimbursed. But now, because lack of evidence, and here we have a randomized trial showing a level 1 evidence supporting the use of genetic tests.
So we have two direct impacts of this trial. The first, inside US, where [INAUDIBLE] colleagues already use genetic tests, it provides better precision on who will receive adjuvant chemotherapy. And it's going to broaden the number of patients who will not receive. And globally, it's prospective randomized trial that we hope is going to incite payers to reimburse the genetic test in patients with early breast cancer.
And so what does this all mean for patients with early stage invasive breast cancer? And what should they talk to their doctors about?
So for patients with early breast cancer, so what are the messages for the patient? I think for the patient, the key message is that we are moving to precision medicine. We need a medicine that is extremely precise in terms of who should receive which treatments. And now, thanks to this trial, we are going to decrease the number of patients who receive chemotherapy, but also for the ones who will receive adjuvant chemotherapy, the value of the treatment, we need what the treatment provides to the patient is going to be very, very high.
So what is important for patients is to understand that because of this trial, when we give them chemotherapy, we will know that the value of this treatment and the expected benefit is going to be higher than what we used to do in the past. So it's really fast forward and more precise medicine that consists in using molecular tests in order to provide or administer treatment with very high value.
Great. Thank you Dr. André for your overview of this guideline update. This has been very informative. It's really good to hear that the expert panel has incorporated the latest research into the guideline and has carefully considered the implications for the patients. So thank you for coming on the podcast to discuss the "Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update: Integration of Results from TAILORx"
Thank you. What people don't realize is we did hard work that ASCO doing with all these guidelines, and people are very committed, and they are [INAUDIBLE]. I mean, it's very reassuring for ASCO member to know that there are highly professional people who provide guidelines and it is also reassuring for the patients, for everyone.
And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast, and refer the show to a colleague.

View Details

An interview with Dr. David Adelstein of the Cleveland Clinic on the ASCO PCO which provides statements on the role of treatment deintensification in the management of p16+ oropharyngeal cancer. Read the full PCO at www.asco.org/head-neck-cancer-guidelines

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today I'm interviewing Dr. David Adelstein from the Cleveland Clinic Taussig Cancer Institute. Lead author on "Role of Treatment Deintensification in the Management of p16 Positive Oropharyngeal Cancer: ASCO Provisional Clinical Opinion."
Thank you for being here today, Dr. Adelstein.
Thank you, Shannon. Before we get started, I'd like to first note the contributions of my panel co-chair, Drew Ridge, and those of all of the other panel members. And I'd like to extend a special thank you to ASCO for their support in allowing us to put this together and specifically Nofisat Ismaila who did a tremendous amount of work in allowing us to complete this provisional clinical opinion.
First, can you give us an overview of the clinical issue for this PCO?
Sure. So this really came out of the implications of human papillomavirus mediated oropharynx cancer. I think as most of the listeners know, over the last several decades we've recognized the fact that oropharynx cancer has a second ideology, that not all of it is caused by tobacco use, but that the human papillomavirus is now the major ideologic factor in North American and northern Europe.
The importance of this is that the human papillomavirus-induced oropharynx cancer is a different disease. It has a number of different characteristics from the kinds of head and neck cancer we've seen in the past. It's a disease that tends to occur in younger patients, patients who are otherwise generally more healthy. It is unassociated with smoking, although it can occur in smokers. But it's much more frequent in nonsmokers.
And I think most importantly, it's a disease that has a dramatically better prognosis than the tobacco related disease. Now over the last several decades, our ability to treat advanced head and neck cancer has improved significantly, because we've begun to incorporate non-operative treatments-- chemotherapy and radiation-- and have been more aggressive in our utilization of chemotherapy and radiation with significantly greater success than we had in the past. The problem with this kind of treatment is that it is quite rigorous. And there's a good deal of acute and, more importantly, late toxicity that patients experience from these kinds of approaches.
Now as we became more familiar with the importance of HPV associated oropharynx cancer, we realized that there are subgroups of these patients who have cure rates that are in excess of 90%. And the question arose whether the kinds of rigorous chemotherapy and radiation therapy treatments that we were utilizing were really necessary. Was it necessary to cause this much acute and late toxicity in patients who in vast majority of cases were going to be cured of the disease.
And it's important, because these are younger patients. And the late toxicities are going to have a major impact on their quality of life for a number of years.
What came about was the notion of treatment deintensification, the idea that perhaps it would be possible to deintensify the kinds of treatments we were giving in select patients. It's a very compelling hypothesis for medical oncologists and radiation oncologists.
But there are a number of problems as we try to test this hypothesis. The first problem is how do we identify the good risk patients? There are patients with HPV-positive disease who do not do so well-- the heavy smokers and patients with very advanced tumors. And we need to be careful if we're going to be talking about giving less treatment that we don't give less treatment to the patients who have a worse prognosis. We pick the best prognosis patients.
There have been a number of what we call risk stratification schemes that have been developed looking at trying to identify the very good prognosis patients-- those patients who are HPV positive who don't smoke and who have relatively limited disease extent. There's not universal agreement on how best to define these patients. All we know is that they do exist, that you can look at patients with these characteristics and see very good outcomes.
One of the issues that has come up is how do we utilize the American Joint Committee staging system-- AJCC the 8th edition. One of the things that AJCC 8 did which is new is that it defined a separate staging system for patients with HPV-positive oropharynx cancer, a system which is entirely different than the staging system that we've used for head and neck cancers for many years.
This was based on the recognition that the prognosis of patients with HPV-positive disease is so good so that many patients who we would previously have considered to have stage 4 disease are now classified as having stage 1 tumors, because their prognosis is so good. And that can be confusing, because the typical thought process for an oncologist is that a patient with stage 1 disease should be treated with single modality therapy.
The reason that the HPV-positive patients have such a good prognosis, however, is that many of them have been treated with combined modality therapies. And to make the assumption that because now they're classified as stage 1 is incorrect. It is they shouldn't be treated with less intensive treatments and can be confusing. AJCC 8th edition is a prognostic robust staging system, but it really doesn't help us in defining treatment.
First problem is how best to define patients who are appropriate for deintensification. Second problem is, what do you do to deintensify? What constitutes meaningful deintensification?
Well, over the last 10 or 20 years there have been some significant advances in our standard treatments for all head and neck cancers that weren't developed the idea of deintensification. We now have tremendous experience using transoral surgical techniques, which are generally minimally morbid, much less morbid than the former open techniques that previously were used, which allows consideration of surgery for many of these patients where we wouldn't have considered it before.
Similarly, intensity modulated radiation therapy has been widely adopted, and d clearly an approach using radiation, which is far less difficult, far less toxic than the former 2D or 3D radiation planning techniques that used to be used.
But if we talk about intensification, what kinds of things can we do to deintensify our treatments? Well, one thought is to reduce the radiation dose. Then the question is, how much reduction is reasonable? And how much reduction is going to actually impact on this toxicity? And are our toxicity measuring tools adequate to even detect the difference in reduction of a radiation dose? Many of our toxicity tools are very crude. Perhaps we should be using some of the patient-reported outcome quality of life instruments that are available.
Other thoughts are, perhaps one can reduce the size of the radiation therapy field. Can we reduce the dose of the chemotherapy? Can we eliminate chemotherapy? Can we even use less intensive chemotherapy? Generally, the other treatments for this disease have employed high doses of cisplatin, which is a toxic agent.
And then there the question has been asked as to whether we can reincorporate minimally morbid transoral surgical techniques in an effort to better pathologically stage patients and define more appropriate adjuvant treatment. Perhaps not all patients need adjuvant radiation or chemotherapy and radiation.
All of these approaches are interesting. They're exciting. They're being tested. But all of the experiences is preliminary.
And that really brings us to the third and the biggest problem in any deintensification approach. And that's the need to be certain that if we deintensify our therapy, we're not going to compromise outcomes. It would not be acceptable to give less treatment or less intensive treatment if our survival were compromised. And we have to be certain that we don't do this.
So what has evolved over the past decade is a whole number of treatment approaches that have some very enthusiastic early results. But these are generally single arm phase 2 reports where there is no comparison to conventional treatment. And they become difficult to interpret, because the results in general are very good.
I think what really raised a red flag for us and that really caused us to take notice was the results of the RTOG 1016 trial that we reported last year. And at the same time, the European de-escalate trial, both of which had a similar design. These were studies that were designed in an effort to see if treatment deintensification would be possible by randomly comparing the standard treatment radiation and cisplatin with what was felt to be a less intensive approach-- radiation and concurrent cetuximab. And cetuximab is an accepted agent in the United States for treating head and neck cancer.
The assumption here is that the survival would be equivalent when these two arms were compared, but that the toxicity would be improved by giving the less intensive systemic agent-- the cetuximab. The surprise when the study was analyzed was that that assumption was incorrect, that the radiation and cetuximab arm-- the deintensified arm-- actually proved inferior in terms of survival.
And this was in both trials-- both the RTOG trial and the trial from Europe. And that was a big note of caution, because it was somewhat unexpected. I think we learned from that kind of a study, from a good randomized-- a large randomized trial-- that even though the outcomes may appear to be good, we need to be very careful about deintensifying our treatment until we're sure that the survival is equivalent.
So although it's tempting for the clinician to see these very exciting reports about administering less treatment with the idea of producing less toxicity, the guideline advisory committee for ASCO really thought it was important that we get the message out that this kind of approach is not a treatment standard. This remains an investigational approach, and that the treatment standards for this disease really haven't changed.
So what are the provisional clinical opinions that were made by the expert panel?
They made several statements. The first was to acknowledge that the idea of treatment deintensification is a very compelling hypothesis, and it does require careful and appropriate testing. The second was that even though we are now better at identifying good prognosis patients, and we've seen some very promising early results, and even though we're now reclassifying patients with previously advanced stage HPV-positive disease as stage 1 or stage 2 tumors, the treatment recommendations for this disease have not changed. And they're based on the results achieved using AJCC 6 and 7.
Standard of non-operated management to patients who are eligible to receive cisplatin remains high concurrent radiation and high dose cisplatin given every three weeks. If patients undergoing a surgical resection, then adjuvant chemotherapy and radiation with radiation and high dose cisplatin every three weeks is recommended in those patients with high risk factors of positive surgical margins or external tumor extension.
And most importantly, deintensification, though it's a compelling hypothesis, is something that should only be undertaken on a clinical trial.
Why is this guidance so important? And how will it affect practice?
Well, I think the important thing about this guideline is that it shouldn't affect practice. The practice shouldn't change. The standards of care are not altered. And that for the clinician, this remains something that is exciting, something that should encourage enrollment on a clinical trial, but that we haven't changed treatment standards.
And finally, how will this guidance affect patients?
So from a patient's point of view, I think there is continued reason for optimism. A patient with the diagnosis of an HPV-positive oropharynx cancer is a patient with a very good prognosis. Patients are increasingly sophisticated. They read about the potential for treatment deintensification, and recognize that this is not something which is an accepted standard. But it should encourage their participation in clinical trials if [INAUDIBLE] is offered.
I think ultimately it's a remarkable thing when oncologists can consider the possibility of reducing treatment intensity because the treatment results have been so good.
Great. Thank you for your overview of this PCO. And thank you for your time today, Dr. Adelstein.
And thank you, Shannon. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full PCO, go to www.asco.org/head-neck-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An intervew with Dr. Nancy Baxter on "Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline." The guideline makes recommendations based on the results of the IDEA collaboration. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines

Hello, and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today, I'm interviewing Dr. Nancy Baxter from St. Michael's Hospital in Toronto, senior author on "Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline." Thank you for being here today, Dr. Baxter.

Thanks very much, Shannon, for speaking with me. I'm happy to share our work developing this guideline.

So first, can you give us a general overview of what this guideline covers and the studies which provide the evidence?

Absolutely. So use of adjuvant therapy for patients with stage III colon cancer is common, and it's effective. We know that these patients are at substantial risk of recurrence of their disease and that adjuvant therapy can reduce that risk.
But we also know that comes with a cost. The most effective adjuvant therapy is FOLFOX or oxaliplatin-containing chemotherapy regimens. And we know that a really substantial number of people will end up with neurotoxicity, with peripheral sensory neurotoxicity, that can be long lasting and certainly affects their quality of life.
So the whole question was whether the duration of oxaliplatin-containing chemotherapeutic regimens could be shortened when they're used for adjuvant therapy, so if we could give three months instead of six months. Because we know that if we give three months of therapy, the risk of neurotoxicity is much lower. So if we had the same effectiveness with the shorter duration, then we could spare patients the negative consequences of the agent given for a longer period of time.
So in developing these guidelines, we looked at the results of international group of trials, the six trials from the IDEA collaboration. So these were six randomized trials in various jurisdictions that tried to look at this question, so three months of an oxaliplatin-based chemotherapeutic regimen for adjuvant therapy for stage III cancer versus six months duration of therapy. And so there was a planned analysis to bring all of these data together to develop the evidence base to make this recommendation.
So our guideline and our systematic review basically identified this is the key piece of literature to base our recommendations and guidelines on. That's essentially the main study, so the meta-analysis of these six randomized controlled trials that formed the basis of the IDEA collaboration.
So the IDEA collaboration studies-- there were six individual randomized trials that formed part of the IDEA collaboration. And they were conducted in Italy, Greece, Japan, North America, through CALGB/SWOG, the UK, Denmark, Spain, Australia, Sweden, and New Zealand, as well as France. So data came from, really, around the world.
The median age of people in the studies was 64 years of age. And these people had a really good performance status, so almost all of these patients had an ECOG performance status of 0 or 1. So they were healthy patients that were in the study.
And so some patients received CAPOX, and some received FOLFOX. That wasn't part of the randomization scheme. Other than the CALGB/SWOG study, this was up to the discretion of the investigator or patient. In the SWOG/CALGB study, only FOLFOX was given.
And the authors planned a prespecified subgroup analysis to look at differences between CAPOX and FOLFOX. There was also a prespecified analysis to look at differences based on stage.
What they found when they looked at the results was that, overall, the difference between groups in terms of the three months versus six months was that the hazard ratio between these two was 1.07, meaning a small difference between the groups in terms of recurrence or death between three months and six months overall. But because the prespecified confidence interval, noninferiority interval, for the difference in outcome was 1.12, the 95% confidence interval for the hazard ratio was above this. So it was 1.15, indicating that this prespecified noninferiority margin was exceeded.
And so the study did not prove noninferiority of the three-month regimen. So we're left with an inconclusive result. So that's why our guidelines don't have a strong recommendation for the three months, because we can't rule out a small but potentially important difference between the two groups in terms of recurrence or death.
Now, interestingly, when they looked at the prespecified subgroup analysis, which was looking at CAPOX versus FOLFOX, a difference was found. So they actually found that for FOLFOX chemotherapy, three months of therapy was inferior to six months of therapy, while for CAPOX, actually, three months and six months were the same. So it met the criteria of noninferiority. So these are kind of two different conclusions based on which type of chemotherapy was used.
This was surprising to the investigators and was not expected. And certainly, it was not consistent with the randomized trials that we have comparing these regimens. So we therefore did not make any conclusions in our recommendations about CAPOX versus FOLFOX. But this is certainly something that requires further investigation in the future.
In terms of stage, we did not find that there was an interaction between T stage or end stage when you looked at the differences between the three and the six month. And that was the prespecified analysis. But in non-prespecified analysis, which was the higher risk versus lower risk categories, you did find this difference where the patients with high-risk disease had inferior disease-free survival with three months versus six months of therapy, while those at low risk of disease, it seemed quite safe to give three months versus six months.
So that's a long story. But essentially, because the high risk versus low risk analysis was not prespecified, there's a limitation to how strong our recommendations can be to have three months of therapy. However, given that the hazard ratio associated with three months versus six months of therapy for this lower risk group was only 1.01, indicating they were the same, and the risk of neuropathy was substantially higher with six months, this has led to us making recommendations that the three months of therapy is adequate for patients with low-risk disease after discussion with patients about the possible pros and cons.

And what are the key recommendations of this guideline?

Well, so the recommendations of this guideline do depend on the pathology, so how high risk the patient is. So based on the evidence from the IDEA collaboration, the researchers found that patients who had a high risk of recurrence-- so had T4 disease or heavily node-positive disease, N2 disease-- the six-month duration of therapy was better than the three-month duration of therapy.
These studies and the meta-analysis were designed as noninferiority meta-analyses. But it was clear from the results that the three-month duration was inferior when compared to three months for these high-risk patients. So that seems clear, although we know that those patients will also be at more risk of neuropathy. And so that needs to be discussed with patients, as well.
So for the second group, which are patients who are at lower risk of recurrence, what we found was there was less of a clear benefit of six months of therapy. The recommendation was that patients who are in this low-risk category-- so T1, T2, or T3 cancers that are N1, so not heavily node-positive-- clinicians can offer three months versus six months of therapy after having a discussion with their patients about the pros and cons of that. So the clinicians can go ahead and offer that to patients and still be within the common guidelines based on evidence for treatment of stage III colon cancer.
So because there's some uncertainty after analysis of the IDEA collaboration, one of the really important recommendations that we make is about this shared decision-making approach. So the third recommendation that we make is that oncologists should discuss these factors with their patients who have stage III resected colon cancer and that the duration of therapy needs to take into account the tumor characteristics-- the surgical resection, the number of lymph nodes examined, the comorbidities, the patient functional status, all of these various things-- and there needs to be a discussion of the potential for benefit and the risk of harm based on the duration of therapy.
And oncologists definitely discuss these things with their patients. And this just emphasizes how this is yet another component of the discussion that needs to be included, particularly when speaking with low-risk patients who are at substantial risk of harm from neuropathy and are unlikely to benefit greatly by extending chemotherapy to six months.

So why is this guideline so important? And how will it change practice?

Well, I think, until now, the standard recommendation has been six months of FOLFOX or six months of oxaliplatin-based chemotherapy. And again, there are many patients who have quality of life-affecting neuropathy because of this. So for a substantial proportion of patients who present to us with stage III cancer-- so those that are low risk-- I think this provides some options to them.
So they can opt for a shorter duration of chemotherapy with a lower risk of toxicity. This saves time. This saves cost to the patient and to the system and potentially improves their quality of life without a great impact on outcome in terms of disease recurrence.
So that's a substantial number, a substantial proportion of our patients, who can be treated in this way. So I think that this is a real benefit. Again, oncologists need to have a conversation with their patients about the pros and cons. But this is an option for their patients, whereas from an evidence-based perspective, it wasn't before the publication of the IDEA collaboration.

Finally, how will these guideline recommendations affect patients?

So for patients who have heavily node-positive disease-- so high-risk patients with T4 or N2 disease-- it's not going to affect care. So the expectation would be those patients would be treated with six months of therapy, similar to previous recommendations.
So this will be for people who are at lower risk of disease recurrence, so patients with T1 to 3 tumors that are N1 positive, so not heavily node positive. So these patients will have the opportunity to opt for a shorter duration of therapy. So that's a major benefit to patients.
Again, it's important that there's a discussion and that patients understand the pros and cons. But this is now an option for them, which is excellent.

Thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, please go to www.asco.org/gastrointestinal-cancer-guidelines.
And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Alejandro Lazo-Langner on Management of Cancer-associated Anemia with Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update which provides recommendations on ESAs (and biosimilars) for patients with chemotherapy-associated anemia in the noncurative setting.

Hello and welcome to the ASCO Guidelines Podcast Series. My name is Shannon McKernin, and today I'm interviewing Dr. Alejandro Lazo-Langner from Western University in London, Ontario, senior author on Management of Cancer-Associated Anemia with Erythropoeiesis-stimulating Agents, ASCO/ASH Clinical Practice Guidelines Update. Thank you for being here today, Dr. Lazo-Langner.

Thank you very much for the invitation to present the new guidelines.

So this guideline has been updated now three times since its original publication in 2002. So how has this guideline changed over time?

Since initial publication in 2002, this guideline has undergone a number of different changes. If you look at the initial series of recommendations in the 2002 guideline, it was really limited and it was fairly upfront recommending the use of erythropoiesis-stimulating agents in this setting.
But during the last two updates in 2007 and 2010, that has changed significantly. And in the current guidelines, we have added some additional evidence that has been published in the last eight years. And now, in general, what we can tell is that the use of erythropoiesis-stimulating agents is now more restrictive than in the original guideline and is basically recommended for only one or two situations.
There has been some other updates in the last iteration of the guideline that I can certainly discuss in more detail later. But basically, in general, the guideline has now, in the last iterations, restricted the recommendations that were much more general during the first edition of this guideline, almost all of them based on available and emerging evidence regarding the onset of their side effects with these medications.
And can you give us a general overview of what this new guideline update covers, especially that new evidence that's emerged?
Yeah. So the new guideline has changed a few items. And indeed, we-- the committee did a little bit of an overhaul in the recommendations that are not in the same order as they were in the previous editions. We can say that there is a couple of important updates.
The first one would be addressing the use of biosimilars, which were not available in the previous guidelines. And we have addressed that in the current edition. The biosimilars have not been extensively studied in cancer, but they have. And so far, the committee considered that they were equivalent in terms of effectiveness and safety to the originator agents, both epoetin and erythropoietin.
And the second most important update on the guideline is the recommendation of the concurrent use of iron supplementation in patients who are receiving erythropoietin-stimulating agents. The previous versions of the guideline just recommended the use of iron supplementation in patients with documented iron deficiency. However, in the last eight years, there's been a number of studies that have suggested that the concurrent use of iron supplementation, irrespective of the baseline iron status, does increase the efficacy of the agents.
Third point is that, although this is not new, there's been more emerging evidence supporting the notion that all of the erythropoietin-stimluating agents increase the risk of thromboembolism. And this has been very consistent across all studies, and in particular derive from Julia Bohlius's systematic review and meta-analysis that was published a few years ago. And she's the lead author on these guidelines now. This has been confirmed, and I think that at this point this is probably the main limiting factor on the use of these medications.
And the final minor update was that regarding the use of erythropoietin in patients with myelodysplastic syndrome. This guideline now suggests baseline serum erythropoietin level cut-off that might actually increase the chances of the erythropoietin-stimluating agents of being effective. This has been updated from the previous guidelines based on recent research.

And what are the key takeaways of this guideline update?

Well, the key takeaways is that if a clinician is deciding to use erythropoietin-stimluating agents, in agreement with the previous guidelines, the first thing that you have to consider is that you should not use these agents in patients that are receiving chemotherapy with a curative intent.
And it should be reserved to patients in whom the chemotherapy is being given with a palliative intent. It should be only used to decrease the use of red blood cell transfusions. And if a clinician is to make a decision as to whether to use these agents or not, they should consider concurrent use of iron supplementation.
But basically, the other consideration that needs to be made is that because of the confirmed increase in the risk of thromboembolic complications, in the last eight years, there's been a myriad of new treatments that may potential increase the risk of these complications, specifically and most importantly in patients with myeloma in whom the use of immunomodulators such as lenalidomide or thalidomide does increase the risk of thromboembolic events per se.
And in those patients, if they were to be considered for treatment with erythropoietin-stimluating agents, that should be done in a very, very careful fashion. The risk of thrombosis is significantly high in these patients, and the concurrent use of erythropoietin-stimluating agents is probably not a very good idea.
So if one were to summarize the guidelines, I would say that, one, consider very carefully whether your patient actually needs these agents, and if they do need the agents, whether they should be receiving them, specifically if they are only being given chemotherapy with palliative intent with a short time life expectancy. Some patients would be considered to be in palliative.
However, in conditions such as myeloma, for instance, although they are not curable, the patients may go on living for many years. So that's probably not a very good idea to use these agents if they increase the risk of complications. And if one is going to be considering these, they should consider also the concurrent use of iron to improve the efficacy of these agents.

And finally, how will these guideline recommendations affect patients?

Well, the guideline recommendations won't have a particularly high impact on patients. The most important thing is that, if patients require ongoing transfusional support due to the palliative chemotherapy or the nature of the disease they have, the use of erythropoietin-stimluating agents might decrease the need for these transfusions at the cost of increasing the risk of complications.
The new updated guidelines are probably going to result in-- if they are considered when a clinician is using these agents, they are probably going to result in lower complications for patients due to the more restrictive nature of the recommendations.
And in general, the only other consideration would be that under special circumstances related to, for instance, access to transfusional support or other personal considerations from certain patients and groups, these guidelines might actually help to overcome those barriers for transfusional support. But those were the two major impact points that would be considered based on this updated guideline.

Great. Thank you for your work on this important guideline and thank you for your time today, Dr. Lazo-Langner.

Thank you for the invitation.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Joe Mikhael from the City of Hope Cancer Center and International Myeloma Foundation on the ASCO and CCO joint clinical practice guideline. The guideline makes recommendations for patients who are transplantation eligible and ineligible with relapsed or refractory disease.

View Details

An interview with Dr. Susan Chang from the University of California San Francisco on the ASCO and SNO Endorsement of the CNS Guidelines. Read the full guideline at www.asco.org/neurooncology-guidelines

Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Susan Chang from the University of California San Francisco, lead author on "Anticonvulsant Prophylaxis and Steroid Use in Adults with Metastatic Brain Tumors: ASCO and SNO Joint Endorsement of the CNS Guidelines." Thank you for being here today, Dr. Chang.

Thank you so much for this opportunity.

So first, can you give us the general overview of what this guideline covers and about the endorsement process?

Absolutely. So one of the things we've noticed, of course, is that the incidence of newly diagnosed adult patients with brain metastases is now estimated to be in the range of about 20,000 to 40,000 per year. And this has really been increasing because of several factors. This includes improved imaging tools, the fact that there's an increase in the number of cancers that are prone to spread to the brain, and the improved survival of patients with cancer.
And so the Congress of Neurological Surgeons have developed a series of guidelines on the treatment of adults with metastatic brain tumors. That includes systemic therapy, as well as supportive care. There are two guidelines that address the role of anti-convulsant abuse and steroids in the care of patients with brain tumors.
Specifically, the guideline questions were do prophylactic anti-epileptic drugs decrease the risk of seizures in both non-surgical and post-surgical patients, who are otherwise seizure free? So these are patients who have never had a seizure, does it make any sense to use these drugs? The second is do steroids, which are commonly used in patients when there is increased mass effect and cerebral edema, could that help to improve neurological functioning or quality of life, compared to supportive care or other treatments? And if they are used, what sort of dose should be used?
So the process of endorsing these guidelines included an initial assessment by content evaluators from ASCO and members of the Society of Neuro Oncology, or SNO guidelines committee. And subsequently, it was determined that a detailed review of the guidelines should be pursued.
So in this joint effort of both ASCO and SNO, a multidisciplinary expert panel of medical and radiation oncologists and neurosurgeons, neurologists, and others providing care for adults with metastatic brain tumors reviewed the content to determine the appropriateness for endorsement by the two professional societies.

So what are the key recommendations of this guideline?

The key recommendations of this guidelines include the fact that routine use of prophylactic anti-epileptic drugs is not recommended for patients who are seizure free, either in the non-surgical and post-surgical settings, and that steroids could be used when patients had mild, moderate, or severe symptoms that were related to mass effect in the brain.
This choice of steroids that was recommended was dexamethasone, and the doses was about 4 to 16 milligrams, depending on the severity of the symptoms. Now, what they found was that there was insufficient evidence to recommend steroid use in asymptomatic patients, when they didn't have any mass effect.
And one of the additional aspects that the panel provided was that the minimal effective dose should be used, and that nighttime doses should be avoided. And this is because of the known side effect of insomnia that a lot of our patients experience when taking this medication right before they go to sleep.

So why is this guideline so important, and how will it change practice?

Well, these guidelines provide a basis for oncologists to avoid the over prescription of anti-epileptics and steroids in patients with brain metastases, particularly in those who are asymptomatic and those without signs of mass effect. It also highlights that if steroids are going to be administered, that clinicians should be very familiar with both the short and long term sequelae of steroid therapy, and they should have a plan to taper the steroids as fast as can be clinically tolerated.

So finally, how will these guideline recommendations affect patients?

Well, both anti-epileptics and steroids have a wide range of toxicities that can adversely affect a patient's quality of life. And so the routine use of these drugs in patients with incidentally discovered or asymptomatic brain metastases is not supported by the available medical literature. For patients with symptoms related to mass effect, the best evidence supports the temporary use of steroids are the lowest effective dose with the intent to taper them off, and if tolerated, and after a definitive treatment of brain metastases has been initiated.
And because of the well known side effects of insomnia and agitation, nighttime doses of steroids should be avoided. So the hope is that this will have a direct effect on how we care for our patients.

Great. Thank you for your work on these important guidelines, and thank you for your time today, Dr. Chang.

You're very welcome. It's such a pleasure to be able to provide this for patients and families.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, please go to www.asco.org/neurooncology-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Rachna Shroff from the University of Arizona Cancer Center on the guideline which provides recommendations on the role of post-operative therapy in patients who undergo surgical resection for biliary tract cancers. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines

Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Rachna Shroff from the University of Arizona Cancer Center, lead author on "Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline." Thank you for being here today, Dr. Shroff.

Thank you so much for having me.

So what does this guideline recommend?

This is a guideline that is basically looking at the role of post-operative therapy in patients who undergo surgical resection for biliary tract cancers. Biliary tract cancers are a somewhat heterogeneous group of malignancies that include intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gall bladder cancer.
And so the question always in most cancers are, if you are able to undergo surgical and curative treatment, is there a role for post-operative chemotherapy or radiation therapy to help improve the chance of cure and decrease the risk of recurrence? So that is exactly what we investigated as an expert panel.
So our recommendations are actually twofold. The first one is that we are clearly recommending that patients with resected biliary tract cancer should be offered adjuvant chemotherapy with capecitabine for a total of six months. Within that recommendation, we do acknowledge that this is based on the BILCAP phase III randomized controlled trial and that there was a specific dosing and treatment schedule that was done in that study, but that we are allowing for institutional and regional variances that we've noted in terms of dosing of capecitabine. And so as a result, we're recommending adjuvant capecitabine, and we're allowing practitioners to determine what the best and safest dosing would be, based on their experience.
The second recommendation is more specifically for patients with extrahepatic cholangiocarcinoma or gallbladder cancer who undergo resection and have a microscopically positive surgical margin, which is an R1 resection. And in those patients, we are recommending that we could consider offering these patients chemoradiation therapy.
Now, again, this is not as strong of a recommendation, because we do not have prospective randomized phase III data to support it. This was based more on a prospective single-arm study out of the Southwest Oncology Group, as well as some other retrospective studies. And so we do go on to qualify that that recommendation should really be made in a shared decision-making approach, with a multidisciplinary conversation to decide the risks and benefits of radiation in these patients-- and that we acknowledge that a prospective study would really help clarify that question a little bit more.

So can you tell us about the research that informed these recommendations?

There have been a number of studies that have looked at the role of adjuvant therapy in biliary cancers. And up until very recently, a lot of these studies were small retrospective series, single-institution or multi-institution, but everything in retrospect-- no prospective or randomized data. And so I think a lot of the reasons that we decided to have these guidelines come out now is that in the last two to three years we do finally have prospective randomized data that helps guide the recommendations.
And the majority of the recommendations that we made are based on one randomized phase III, which is BILCAP study. This was a study that was done in the UK and was presented at ASCO in 2018 and is currently in press. And it is basically a randomized controlled trial that compares adjuvant capecitabine by itself versus surveillance alone in patients who undergo surgery for biliary tract cancers.
And so our recommendations, which include that study as well as a couple others, is primarily hinged on that, since that is the largest prospective data we have so far. And based on that study, we did in fact recommend that there was a role for adjuvant chemotherapy with capecitabine after complete resection for biliary tract cancers.
And based on that research that was done in that trial that was completed, we do believe that the role for capecitabine for six months is pretty strong and that the data supports that now.

So why is this guideline so important, and how will it change practice?

Well, I think it's going to be practice-changing because up until now there has not been a clear consensus on how we approach these patients. And I will say that even now, it's really just this one study that has helped guiding these recommendations. There were a number of other studies that we looked at as part of the expert panel. And these were all prospective studies as well that looked at things like gemcitabine and oxaliplatin in the adjuvant setting, or single-arm phase II studies that came out of the Southwest Oncology Group that also explored the role of radiation. But really, nothing was a positive study other than the BILCAP study.
And so up until now, I would say it was a little bit all over the place in terms of how medical oncologists approached resected biliary cancers. I think the majority of us felt that there was probably a role for adjuvant chemotherapy or perhaps chemoradiation. But there was no rules that we could follow, and there was no clear study that we could turn to that would tell us what we should give, how long we should give it for, and whether it should be a combination of chemotherapy or chemoradiation.
And so I think it will be practice-changing because now, as part of the expert panel, we are making a very clear recommendation that patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a total of six months, hopefully eliminating that kind of regional or specialist-based variation that has been happening up until this point.

And finally, how will these guideline recommendations affect patients?

Again, I think that the main way it's going to affect them is that there's going to be a little bit less gray area, in terms of medical oncologists having conversations with the patients and saying, well, you know, I think that there's probably a role for agent therapy here, but I can't show you the data that supports why I think that.
And as a result, I would hope that patients will have a little bit more faith and confidence in knowing that there is a large study that has looked at and proven the benefit of adjuvant capecitabine and that that decreases the chance of recurrence and improves overall survival. The improvement in overall survival was dramatic in this study. And we had not seen a survival of 51 months, which is what we saw in this study, in a very long time.
So for patients, not only does it make clear what they should be doing after surgery, but I would hope it also gives them additional hope that we have really changed the bar by doing this adjuvant capecitabine, and that the chance for cure is even higher when we can offer adjuvant chemotherapy.
I think the only other thing that may still be a gray area, and that is kind of what we allude to in our second recommendation, and that is in patients who undergo resection and have a microscopically positive margin or an R1 resection. And that's typically patients with extrahepatic cholangiocarcinoma or gall bladder cancer.
In those patients, we suggest that they could be offered chemoradiation therapy, but the evidence is not as strong there. Again, it's more retrospective studies that we looked at. There is no prospective study that answers the question of whether or not there's a role for radiation. And so as a result for patients, I think that is still the one area that's a little bit of a gray zone in terms of knowing whether chemoradiation would benefit them if they undergo surgery and have a microscopically positive resection.
But I do think that there is a definitive benefit to giving adjuvant chemotherapy, and that, hopefully, will clarify things not only from the physician perspective but also from the patient perspective.
Great.

Thank you for your work on these important guidelines, and thank you for your time today, Dr. Shroff.

Thank you.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

View Details

An interview with Dr. Shlomo Koyfman of the Cleveland Clinic on "Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline" which provides recommendations on topics such as neck dissections and postoperative treatment.

Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Shlomo Koyfman from the Cleveland Clinic, lead author on "Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline." Thank you for being here today, Dr. Koyfman.

It's a pleasure.

So first, can you give us a general overview of what this guideline covers?

Yeah, so this is an exciting guideline because it covers a topic that we don't usually think about in head and neck cancer in a formal way, and that is management of the neck in squamous cell cancer of the oral cavity and the oropharynx. So there's a lot of literature and guidelines out there on how to manage oropharynx cancer, which is becoming a more and more common cancer, especially in the HPV-positive era, less so on oral cavity. But a lot of times it's focused on people who don't get surgery, chemoradiation, or people who do get surgery and TORS, Transoral Robotic Surgery, and different approaches. But rarely do we have something focus on management of the neck per se, which is really, really important in these cancers and often overlooked in favor of the primary tumor itself. So these guidelines really take us through some salient questions in how to manage the neck in these two cancers.

And what are the key recommendations of this guideline?

The recommendations came off of six fundamental questions, three in oral cavity and three in oropharynx. There are some commonalities between the two and some differences. A lot of the fundamental questions revolve around surgical quality, and neck dissection is the standard surgical approach for management of the neck in these patients. And as we enter the quality era, how do we define benchmarks of surgical quality, which is one thing that it deals with.
The other is when to do adjuvant therapy like adjuvant radiation or chemoradiation. We also deal with when to do surgery for the neck or to do nonoperative approaches like radiation or chemoradiation. And then lastly, how do you follow patients after you've treated them? So those are kind of the salient issues that we dealt with.
And what we came out with was nothing earth shatteringly new, but I think the way it was organized and systematically put together, I think it's going to be really, really helpful for people. So some of the most important findings that this recommendation does, I think this is the first that incorporates surgical quality, as I mentioned before. So specifically neck dissection should have 18 or more nodes as multiple studies have shown that that's associated with better outcomes. And similarly we define for different diseases of oral cavity and oropharynx, and depending on what kind of tumor it is and where, what nodal levels should be dissected or treated, whether surgically or nonsurgically, and when to do just one side of the neck versus both sides of the neck. So I think there's a lot of good guidance there in terms of the surgical quality.
From a standpoint of adjuvant therapy, we define pretty clearly indications for when after surgery for oral cavity cancer, for example, when radiation should be added and when chemoradiation should be added, and I think that's very helpful. And especially for the neck itself, there's been confusion about what happens if I have 30 nodes taken out and they're all negative but I have a big, large primary tumor. What do I do with the neck? Do I radiate it? Do I not radiate it at one side, both sides? And this guideline gives some pretty clear guidance in different scenarios about how to think about that, which is pretty novel and really important, I think. I get questions about this all the time. It comes up in tumor boards all the time, and it's pretty practical.
And mostly what we say is if you have a primary tumor that's like a T3 or T4 oral cavity cancer or it approaches midline, either a contralateral neck dissection should be done or radiation should be done to the contralateral neck. And even if you have a lot of lymph nodes taken out and they're negative, if you have very high-risk primary tumor features like very large tumor or multifocal perineural invasion, those kinds of things, even with a negative neck dissection we still typically do treat the neck.
So the next recommendation that's really helpful is who can be observed after surgery? And specifically low-volume N1 you can consider observing in oral cavity cancer, whereas N2 or N3 patients all need radiation or chemoradiation in the setting of extranodal extension and positive margins. We did come out pretty firmly advocating for bolus cisplatin 100 milligrams per meter squared every three weeks as recent studies suggest that weekly cisplatin or other regimens are not as effective, and we were pretty clear about that. We were pretty synchronized with recent ASCO-endorsed guidelines in oropharynx cancer that say similar things.
In addition, one of the very important questions that comes up is a surgeon will say, well, I'm cutting out the neck tumor, and I know it comes to midline and he's got a bunch of nodes on the right side, but do I really need to do a left neck dissection? Aren't you going to radiate it anyway? And that comes up all the time. Is radiation adequate to manage a clinically negative neck in oral cavity cancer and oropharynx cancer?
I think in oropharynx cancer everybody feels pretty comfortably yes. I think in oral cavity cancer it's been somewhat controversial. We favor neck dissections when possible, but if radiation is known to be happening, especially to an elective contralateral neck, that that is adequate therapy. However, we're pretty strong in the fact that neck dissections are the tried and true way to treat oral cavity cancer and that in a T2 or above tumor where a neck dissection is indicated, just resecting the primary and leaving the neck to elective radiation is not something that we thought there was enough evidence for to advocate, and we still advocate classic neck dissection first followed by adjuvant radiotherapy as indicated.
One area of controversy that we did touch on is the issue of early stage tongue cancers and whether they need a neck dissection at all. And we came down pretty consistently with all of the co-authors on the guideline that we advocated for a neck dissection for all patients with oral cavity cancer unless it is a very small tumor that we define with very compliant patient who is amenable to very rigorous follow-up that has been done in Europe and in some other places with, specifically, people trained in careful neck ultrasound techniques. So all of those really help guide, both in early stage and more advanced stage, how to manage the neck and oral cavity cancer.
And in oropharynx cancer, again, many of the same quality metrics apply. We have some guidance about when doing transoral robotic surgery how to reduce bleeding risk by ligating feeding blood vessels, which is an important addition. We also discuss the fact that, as opposed to lateralized oral cavity patients where a unilateral either neck dissection of radiation is often indicated, in oropharynx cancer the group felt very strongly that bilateral neck should be treated. And typically if tumors extend to midline or involve the posterior oropharyngeal wall, which has bilateral drainage, that either bilateral neck dissection should be performed in those cases or a unilateral neck dissection can be done as long as adjuvant radiation is planned to both necks.
Finally, a couple of very important questions of who should not be treated surgically and who should be treated with a nonoperative chemoradiation based approach. In oral cavity cancer, as long as they were not metastatic, we felt people should be resected as long as they were surgically resectable and medically operable. In oropharynx cancer, however, anybody who had unequivocal extranodal extension of nodes into soft tissues or involvement to the carotid artery or extensive cranial-nerve involvement or skull-based involvement by extensive nodal disease are not good candidates for surgery and should be preferentially treated with chemoradiation. That was pretty strong.
And finally, the other thing we gave clarity on is when we treat oropharynx cancer with chemoradiation, how do we follow them and when do we decide to do a neck dissection or not? And essentially we recommended a PET CT scan at 12 weeks. And as long as that was negative, a neck dissection should not be done. If you don't have a PET scan and you just have high quality CT or MRI but all of the neck disease has resolved, similarly there should be no neck dissection.
And then most importantly, the situation we all face which is very complex is what happens when you have a PET CT done three to four months after treatment and you have small nodes that are still there? You have a little bit of uptake. The FDG avidity is much less than it was. There still is a lesion there, but it's much better and the patient is feeling well. And we felt pretty comfortable not doing a standard neck dissection on those patients but rather following them closely with a follow-up CT scan two to three months later and continual assessment and reserving surgery for obvious progressive disease.

So why is this guideline so important, and how will it change practice?

So this guideline is really important because head and neck cancer being not the most common cancer, and especially because head and neck cancer is not really one disease-- there's so many different diseases. Even oral cavity and oropharynx, there's quite a bit of variability in how we think about it. There's not a one size fits all recipe for how to manage people properly, and that leads to a lot of confusion and sometimes doubt as to what the best thing to do is in these patients. And that is a very common thing.
So I think the most important reason why these guidelines are helpful is they're really clear. They give really clear guidelines of if you're going to do surgery, here's the expectations of what nodal levels to take out and how many nodes to take out. Here's when you should do adjuvant radiation. Here's when you should do adjuvant chemoradiation. Here's when you should treat one side of the neck. Here's when you should treat both sides of the neck. If you're not going to do surgery, here's when you do radiation.
And for oropharynx cancer, here's when you can consider surgery. Here's where surgery is not the best idea. And when you treat them and if you do surgically, here's how you do it. If you do with radiation, here are the nodes that should be treated, the nodal levels. And finally, after you do that, how do you watch and act to make sure that people don't fail?
So I feel like all of those things lend a lot of clarity to some complicated decision-making processes for these patients, and this really lends clarity to that, which should help kind of lend consistency of practice. That's really our goal. Our goal was there a lot of great docs taking care of these patients out there, but patients are treated in very different ways depending on who they're seeing and where you go. Our goal was to try to increase the consistency of how people are treated no matter where they are. And if practitioners, surgeons, radiation oncologists, medical oncologists see this guideline and kind of follow it and, of course, reach out with any questions at any time, then what we'll be able to do is kind of harmonize the way patients are treated in this country, which should help, I think, the quality of care.

And finally, how will these guideline recommendations affect patients?

They're going to affect patients because right now a lot of patients get great care, but there are some patients that are not getting ideal care either because maybe they're in parts of the country that don't have the same access to resources or they're in places where the volume of these kind of very complicated and yet not so common diseases aren't seen as high and there's confusion about how to manage them or what the quality metrics are.
I think patients are going to be affected knowing, hey, if I'm going to have a neck dissection, here's what I should be asking to make sure my surgeon knows to do and does consistently to make sure it's of high quality. Here's where I think I should be treated with surgery, maybe I shouldn't be treated with surgery, and here's how to follow me. Because there is a lot of variability in how patients are treated, and sometimes there's too many surgeries being done, not enough surgeries being done. If they're being done, maybe they're not the best quality. Even if we don't treat with surgery and we do chemoradiation, we're watching them and we may not be following them as closely, and then people may be recurring and we're not picking it up closely enough.
So I think it's going to harmonize, for patients, the way they're ultimately treated. If everybody in the country is treated relatively compatible with this guideline, I think the standard of care will go up across the board.

Great. Thank you so much for your work on this important guideline, and thank you for your time today, Dr. Koyfman.

Thank you so much.

And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Manish Shah from New York Presbyterian Weill Cornell Medical Center on the ASCO Resource Stratified Guideline which covers treatment of patients with early-stage colorectal cancer. To read the full guideline go to www.asco.org/resource-stratified-guidelines

Hello, and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today, I'm interviewing Dr. Manish Shah from New York Presbyterian Weill Cornell Medical Center, senior author on "Treatment of Patients with Early-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline." Thank you for being here today, Dr. Shah.

Thank you, it's a pleasure and honor to be here.

So first, can you give us a general overview of what this guideline covers?

Yes, absolutely. So the "Treatment of Patients with Early-Stage Colorectal Cancer" is a resource-stratified guideline. And it focuses on the management of patients with early-stage colon cancer. It's different than the surveillance and screening guideline that was written simultaneously for ASCO as another resource-stratified guideline. We felt that this was a big enough topic that we should keep it separate.
So it really talks about the management of pre-malignant lesions, as well as early-stage colon cancers, as well as rectal cancers. And the other aspect of this is that we really focused on how the guideline may apply in settings where there-- they don't have maximal resources, so basic or limited settings as well. So I would like to talk a little bit about how the guideline was created, because I think that's an important aspect. And it distinguishes it from typical other ASCO Guidelines.
So the management of colon cancer or colorectal cancer, there's a lot of literature on this. And there are several guidelines that have been produced by colorectal cancer societies, or surgical societies, or from other countries like the EORTC, or Japan, or Korea, or even the UK. So in fact, there were, I think, 30 to 40 different guidelines that we reviewed.
And we felt that, instead of doing a new literature search to kind of rehash much of the same information, we reviewed all the guidelines for certain quality measures to then select a handful of guidelines that we would use as the reference for each of our key questions or key points. And this was done in a formal process, the first by ASCO and Sarah, who was the ASCO staff who wrote the guideline, along with the members of the guideline panel. And in this process, I think that we have a pretty comprehensive guideline that covers the questions with the best evidence available.

So what are the key recommendations of this guideline?

Yeah, so we addressed some several questions with regard to key recommendations. The first question, for example, was, what's the optimal treatment for patients with colon cancer that would be clinical stage 1 through 3c? And we distinguish that from a non-obstructing cancer to obstructing cancers as well, because the management would be very different.
And what we really sort of focused on is that these patients should have resection following oncologic principles. Then ideally, they should have an en bloc resection by a surgical oncologist to give the patients the best chance of care. But I think what's unique to resource-stratified guidelines, and what we have to do is sort of highlight the care that would be achieved in settings that have less resources. So a non-obstructing colon cancer in a basic setting should still have surgery and should still undergo an en bloc resection following standard oncologic principles. So that was, for example, one of the key points that was uniform across all the settings.
Other things were how to manage [INAUDIBLE] colon cancer. So in more enhanced and maximal settings, sometimes there might be opportunity to place a colonic stent, for example, by either a colorectal surgeon or by someone who has specialized training in the placement of these stents. And that would be a preferred approach in both the enhanced and maximal guidelines, whereas in a more basic setting, the recommendation was to perform a resection and possibly, if required, if a resection was not possible, a diversion to overcome the obstruction in that localized setting.
There were other recommendations that were also important. So for example, in early-stage rectal cancer, so clinical stage 1, T1 and 0 rectal cancer, in a maximal setting, these are sort of low-risk cancers without adverse features like high-grade or involvement of lymphovascular structures. The surgical oncologist and/or colorectal surgeon might consider a local excision such as the TEM procedure, which is a transendomucoscal resection. And in basic or limited settings, we would still recommend surgery in that setting following TME principles to achieve clear margins and a good surgical outcome, because we felt that, in basic-limited settings, the skill and the equipment necessary to do a local excision may not be available.
Another recommendation that might highlight the differences between basic and limited settings versus a more maximal setting is the optimal strategy for post-treatment surveillance. So this is after resection of the stage 1 to 3 colorectal cancer. What would be the best way to monitor and surveil patients? And this is the recognition that the purpose of surveillance is to identify recurrence early at a time point where the patient may still be amenable to having local regional resection or resection of the metastatic lesion to change the outcome.
So the current ASCO guidelines are to perform a medical history, and physical examination, and a CEA every six months for three to five years, have an abdominal and chest CT scan, in high-risk patients, every 6 to 12 months for three years, and a colonoscopy one year after the surgery, and then every five years or so after that, as indicated, up to age of 75. And that's what we recommended in the maximal and enhanced settings.
But in a more basic setting, the recommendation was similarly medical history and physical exam every six months for three years, a CEA every six months for three years, a chest X-ray and abdominal ultrasound twice in the first three years, and a colonoscopy once i the first two years. And then if a colonoscopy is not available, we recommended a double-contrast barium enema or, for left-side tumors, a sigmoidoscopy to try to surveil the local regional extent of the the disease. So I think what we're trying to highlight is that we think that we can help patients for the management of localized early-stage colon cancer, both for treatment as well as for surveillance, and that these recommendations may vary a little bit in more limited settings, but with these recommendations, we can provide the best care for patients overall.

And so why is this guideline so important? And how will it change practice?

I think that the guideline is really important, because we recognize that we're practicing medicine in the United States, or in Europe, or wherever you practice, but the levels of resources that are available to us are not uniform. And so we really are getting to the aspect that cancer care is a global proposition. And ASCO should reflect that.
And so the intention of these resource-stratified guidelines is to try to provide guidance into the best management for the indication across the spectrum of resources that are available. Interestingly, we've also heard from many people who practice in more resource-limited settings that they can use these guidelines to sort of advocate for their own area, to say that, based on our availability, we fit in a criteria that's basic or limited, but we really want to be an enhanced setting, and lobby their governments or their local officials to say, these are areas that we can improve on to take us to the next level, literally.

And finally, how will these guideline recommendations affect patients?

Yeah, at the end of the day, I think it's very important that we remind ourselves that we're doing this to improve patient care overall. I think, in maximal and enhanced settings, the guidelines kind of reiterate the best practices across [INAUDIBLE] of guidelines that were reviewed. So I think that's a very important thing. And they unify the treatment plan across different practices.
But I think most importantly, in basic and limited settings, it provides a benchmark for what should be done. I think, for me, one key thing was that, even in basic and limited settings, we don't want to compromise oncology principles for a surgical resection. You know, it's not appropriate to just resect the tumor but leave some tumor behind to relieve an obstruction. We still need to manage that appropriately. And that is the expectation in a basic setting, for example.
So I think that, overall, wherever you are, this guideline provides recommendations to help manage the patient across the resources that are available to you. I think that's very important, because we live in a heterogeneous environment where resources are not uniform across the world.

Great, thank you for your discussion of this important guideline. And thank you for your time today, Dr. Shah.

Oh, it's my pleasure. Thanks for having me.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Marcia Cruz-Correa from the University of Puerto Rico and MD Anderson Cancer Center on the ASCO Resource Stratified Guideline on early detection for colorectal cancer.

Hello, and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today, I'm interviewing Dr. Marcia Cruz-Correa from the University of Puerto Rico and MD Anderson Cancer Center, senior author on "Early Detection for Colorectal Cance: ASCO Resource-Stratified Guideline." Thank you for being here today, Dr. Cruz-Correa.

Well, thank you very much for the opportunity to speak with you today.

So first, can you give us a general overview of what this guideline covers?

Absolutely, Shannon. Well, we are very excited to review the content of the guideline. And we put together a summary of the current guidelines out there for patients that are undergoing colorectal cancer screening.
With these particular resource, a certified guideline takes, for the first time, into account the place where the colorectal cancer screening is being delivered, which is different from when you read any other colorectal cancer screening guidelines, where normally we assume that all available methodologies are equally distributed regardless of the country or the setting. So in our particular guideline, we really emphasize the fact that, depending on where our clinicians are, they might have differing technologies available. And that's why it's called resource-stratified-guidelines, to help our clinicians and our practicing physicians to understand what would be the best method to be able to implement screening in their own settings.

So what are the key recommendations of this guideline?

I think that the most important recommendation is that colorectal cancer is a prevalent disease, not only affecting very highly developed countries, but a disease that we're seeing more and more in low-to-middle-income countries. As ASCO is an organization that has members from around the world, being cognizant of the fact that colorectal cancer affects many individuals across different settings, and countries, and continents, for that matter, allows us to provide the most important information which is to consider colorectal cancer screening across the different settings, so not only in the industrialized well-developed first-world country, but also in the low-to-middle-income, or those that are becoming more and more industrialized.
So our main recommendation-- it's number one-- that we need consider colorectal cancer screening even in settings where, for many years, the burden of disease was really focused in infectious-driven diseases. Nowadays, we're seeing more and more low-to-middle-income countries where the number one cause of death, it's not an infectious-driven disease, but rather a cancer. And colorectal cancer, it's one of the top cancers that we're seeing in many of the settings. So our number one recommendation is to be cognizant about that so that different countries and different settings, the practitioners consider screening.
And our second and most important recommendation is that, the important thing is to consider what you have available in your setting, in your clinical practice. And depending on what you have available, then you can offer the method that could be given to your patient. So it's almost like thinking differently. It's not a one size fits all, but rather it's more or less of a personalized recommendation based on your setting, based on your clinical practice methods available to you.

So why is this guideline so important? And how will it change practice?

We believe that it's very important, because when you look at guidelines in any published article out there, we read it. And it looks as if everyone had every resource available. And when you're practicing in a low-to-middle-income country, or a place-- it could be a rural area where you have more basic settings or more limited settings-- you might not have that new machine or that new equipment.
So then, as a practitioner, you feel that you're not equipped to be able to provide the best care to your patients. So this guideline, it's mirrored after a previous guideline that was put together by the ASCO Clinical Practice Group, where we stratify the type of practice for our-- where our practitioners are providing care. There are four main practice settings.
The first one is what we call the basic setting, which is where you have the minimal necessary facilities to be able to evaluate patients and provide first primary care services. The second tier, it's called the limited setting, where you have more clinical facilities, but yet you don't have all the elements, like imaging, for instance, or the specialized surgeon, or the third- or fourth-level specialized technology.
Then you have something, the next level would be the enhanced, where you, again, you see more methods and more availability of more clinical instrumentation and facilities. And then final one, which is the fourth level, will be the maximal setting. So in a maximal setting is when you go to a city, a cancer center, for instance, where you have all the specialists, all the imaging, all the endoscopy, and experts that are able to use those equipments and provide the best care.
So using that four-level approach, from basic-- and think about, when you think about basic, it's in a rural community maybe in-a-low-to-middle income or developing country, places where you have a general surgeon. And you may have a primary physician. You may have nurse practitioners or nurses that actually provide that first care, first-level care. And then you keep going from there all the way to the maximal setting. So depending where you are, these resource-stratified guidelines will provide the physician and the clinical practitioner with methods that they can implement now.
So to give you an example, when you think about colorectal cancer screening, you think about individuals that come to see you because they have no symptoms or they might have some symptoms. Most of the time, they would be asymptomatic individuals that come for a general screening, general visit. So this resource-stratified allows the physician that is practicing at a basic or a limited setting to provide, for the case of colorectal cancer, screening to provide fecal or cold-blood testing. This is a test that has been shown to be effective, that when used in the adequate setting for a patient that is 50 years of age or older, will provide enough sensitivity to diagnose an individual that might have either colorectal cancer or advanced colonic polyps so that that patient can then undergo a confirmatory test such as a barium enema, if you are in a basic setting.
Very different, Shannon, when you are in a setting where you have all the instrumentation there-- you as a physician, you could either do a fecal immunological testing to look for, or cold blood. Or you could decide to refer a patient to a colonoscopy. And I think, when you practice in the US, I mean, large or industrialized places like Europe or Australia, you think that everyone has access to endoscopy.
And believe it or not, one of the things that we realized when we were looking at all these data, is that in basic settings, setups for colonoscopy for removal of polyps with polypectomy during a colonoscopy are not available. So we took all those factors of clinical facilities, and availability of equipment, and expert physicians to be able to provide adequate care for the patients that are receiving care by our practitioners in the different settings, from basic all the way to enhanced and maximal settings.

And finally, how will these guideline recommendations affect the patients?

You have asked the most important question. The reason that we put guidelines out there is to guide our physicians, our practitioners to provide the best care that they can regardless of where they are. By providing this information, the ultimate and most important beneficiary of these guidelines is the patients.
Right now, in many settings, especially in low-to-middle-income or developing countries, they are not receiving screening or preventive testing. In fact, there are many countries that do not have standardized or institutionalized programs for colorectal cancer screening. So if you don't have a program in place, you can imagine that then a patient would not even be considered for preventive care.
So the ultimate and most important beneficiary of this resource-stratified colorectal cancer screening guideline is the patients that we serve. So as countries continue to evolve, and even in a country that is industrialized but where you have limited resources, only access to a basic laboratory, there we can still provide screening.
And then the guidelines are written in a way that you can identify the type of practice where you're at. And you can choose between the different methods. And then it guides you as to decide when to refer a patient to a higher level with regards to clinical facilities.
So if you're in a basic setting and you get a positive screening test, what do you do with that patient? Are you able to refer to the second level, which will be the limited? Or do you have to refer it all the way to enhanced? So it's almost like it's a guideline, but it's very practical in nature.
So our hope is that this will allow our practitioners to feel empowered, to understand that this is a disease that will be affecting their population, the patients that they are taking care of, but furthermore, that they feel empowered to provide the best care, because that's why we practice medicine. And that's the bottom line, the most important reason why this was put together.

Great, thank you so much for your work on this important guideline. And thank you for your time today, Dr. Cruz-Correa.

Thank you very much for the opportunity, Shannon. And you know, hopefully we'll get many comments from across the different members of the organization across the globe.

View Details

An interview with Dr. Paul Celano from the Greater Baltimore Medical Center on the recently published ASCO Standards on safe handling of hazardous drugs.

Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin. And today I'm interviewing Dr. Paul Celano from the greater Baltimore Medical Center, lead author on "Safe Handling of Hazardous Drugs: ASCO Standards." Thank you for being here today, Dr. Celano.

Thank you for having me. I'm certainly glad to talk about these standards. They're very important to our employees and our patients.

So first I want to make the distinction that this publication is not a guideline like we usually cover on this podcast. So can you tell us what standards are and how they differ from guidelines?

Well, guidelines really are intended to guide practitioners around recommended care options. They give obviously a lot of latitude to clinical judgment and circumstances. Standards, on the other hand, are really meant primarily for the organization of care and are intended to have a higher level of obligation to help drive either practice or policy or even legislative efforts. So that's really the distinction.

And what are the standard statements that are made by ASCO in this publication?

The publication really is about safe handling of hazardous drugs. This all came about is because recently there have been a number of national guidelines or standards that have been offered by other organizations, but not specifically oncology or certainly ASCO or the ASCO organization. We felt a need to address the standards that have been put out on the basis of the evidence, so that best practices can be offered.

Initially, we did collaborate with other societies, such as the Oncology Nursing Society and the Hematology Oncology Pharmacy Association. That was really the impetus behind making sure that we are, in a sense, congruent with standards that are already being published and discussed, but also to also place in our interpretation of these standards so that they're based on the best evidence that's available.

And what qualifying statements are there to note about these standards?

Well, I think the best way to look at these standards is there has been recently published or offered what's been called the UST 800 standards, which really incorporate other previous standards by the Pharmacy Association as well as OSHA, the Occupational Safety and Health Association, as well as NIOSH, the American Society of Hospital Pharmacists, Oncology Nursing, etc. So there's a lot of standards that have been offered.

And in fact, the ASCO review of this really in a sense agrees with many of the standards that have already been published and offered-- types of exposures, the responsibilities of personnel handling the drugs, the personal protective equipment, how we communicate the hazardous drugs, the training of compounding personnel, how the drugs are dispensed and even transported. So there's lots of things that we really do agree with.

I think it's also important to understand that the objectives of this is really to protect personnel and the environment to make sure the standards apply to all personnel who compound hazardous drugs and preparations, all places where hazardous drugs are prepared and stored, transported and administered. So that's really a key part of this. These are a comprehensive program really to prevent worker environmental exposure and to provide the most practical safety environment for all involved.

So finally, why are these standards so important? And how will they affect practice?

Well, they effect practice in many ways. I mean, the key thing is making sure that our employees, meaning the nurses, pharmacy, the technicians, really everyone involved that they're not unduly exposed to these hazardous drugs. And so that's really the key thing that we're all trying to achieve by this.

Now, what really makes the sort of ASCO standards somewhat different or the things that we came into a contention with has to do with the differences that ASCO has come up with in contrast to some of the other standards. And these have to do with really four main areas within these standards. They have to do with medical surveillance, external ventilation, closed system transfer devices, and also proper assignment of our personnel while they may have either trying to conceive or pregnant or nursing.

So those areas that in our review, the ASCO review, have come under some question. As an example, medical surveillance, there in some of the standards offered-- not ASCO's-- that there's a number of medical surveillance procedures that have been elucidated, that really we find, number one, have really not any proven value for our employees and generate a lot of confusion in terms of how this process is supposed to be done. Obviously, if one of our employees has some undue exposure, such as a spill of chemotherapy or even just have flat out a concern, then obviously those things will be clearly investigated. But to have general medical surveillance of all employees, really we did not feel was of great value.

But also further, we really feel that this is an area where more research needs to be done to better elucidate really what should this process look like and what value are we providing to our employees.

Another aspect of this is the use of what are called closed system transfer devices. Currently, there are a number of these devices available that there is interestingly no standard way that these devices have been evaluated. And so it's hard to recommend one device over another, because there is no standards for which they're really being compared. And there certainly have been no studies looking at really any form of health outcome that really help us to direct this to how best to use these devices. And so really, a lot of these objections are more around let's do things in an evidence-based way so we can better know how to best direct our practices.

Another area of concern in terms of ASCO standards have been the implementation of external ventilation in either containment secondary engineering controls or other situations. And the challenges is that HEPA filters are probably appropriate for collecting solid or aerosolized particles, but don't capture vaporized drugs. But there's little data available on the ability of hazardous drugs to vaporize within the workplace environment and what those hazards really are. And so again, it's is a call for more research to have an optimal environment for preparing these drugs and without having to place undue burdens in terms of external ventilation.

Another area is options for alternative duties for workers who are actively trying to conceive or are pregnant or breastfeeding. And these we recognize can be special burdens to small practices looking to implement alternative duty programs. There is a lot of controversy regarding the potential level of risk that really these workers really have. And basically our stance has been that we should have a policy that identifies alternative work options for workers who are trying to conceive, are pregnant or are breastfeeding, and that this information needs to be conveyed to these employees at the time of their hire so they understand what their risks are and what their options are within the workplace.

Again, trying to make sure everyone is well informed and aware of what the work environment they're in and as their life circumstances change what they can do to change with this. I think the key is that we all feel that this is an area that we should have continued research on. And our standard, certainly ASCO's standards will continue to evolve as more and more research and evidence becomes available.

Thank you so much for taking the time to explain these standards to us today, Dr. Celano.

You're welcome.

View Details

An interview with Dr. Valerie de Haas from Princess Máxima Center for Pediatric Oncology in the Netherlands on "Initial Diagnostic Workup of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the CAP and ASH Guideline.” ASCO fully endorses the CAP-ASH guideline on initial diagnostic work-up of AL and includes some discussion points according to clinical practice and updated literature.

[MUSIC PLAYING]

Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Valerie de Haas from Princess Máxima Center for Pediatric Oncology in the Netherlands, lead author on "Initial Diagnostic Workup of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the CAP and ASH Guideline.”

Thank you for being here today, Dr. de Haas.

Thank you.

So first, can you give us a general overview of what this guideline covers?

Well, yes. The laboratory evaluation of patients who are suspected of having acute leukemia is very complex, and it has evolved significantly with the incorporation of advanced laboratory techniques. The traditional backbone of initial workup of AL, of acute leukemia, is composed of ctyomorphology, cytochemistry, immunophenotyping, and molecular cytogenetics.

These techniques are the backbone of the initial diagnostic workup of acute leukemia. This is leading to risk stratification and fine tuning of the therapy by molecular signatures. The advanced molecular diagnostics, such as next-generation sequencing, has become more important in the diagnosis and in the risk stratification of acute leukemia.

This guideline is meant for both pediatric and adult patients, and it was initially published in 2017. This year, we reviewed this guideline, and we have taken into account two important developments.

First, since 2017, we've seen that there are major advances in molecular techniques and also that we can identify and validate new molecular markers. And those two events have contribute to a better risk stratification. And the second development is the effect that the WHO classification was revised in 2017 which also has led to new risk recoveries and refined subclassifications.

So what are the key recommendations of this guideline?

Well, in total, we have reviewed 27 guideline statements by the ASCO endorsement expert panelists. And discussion points are used to summarize issues that were identified from the updated literature. The ASCO expert panel determined that the recommendations from the guideline as published in 2016 are clear, thorough, and they are based upon the most relevant scientific evidences.

We fully endorse the CAP-ASH guideline on initial diagnostic workup of acute leukemia. And we decided to include some discussion points according to clinical practice and according to the updated literature. In fact, we identified four categories of key recommendations. The first one is the initial diagnostics focusing on basic diagnostics and determination of risk parameters.

This concerns, in total, about 11 guideline recommendations, and they give an overview of the initial workup varying from the collection of the clinical history of the patient to initial basic diagnostics by cytomorphology, flow cytometry and molecular cytogenetic analysis of peripheral blood, bone marrow, and cerebrospinal fluids.

Secondly, the second category were molecular markers and MRD detection, and they were addressed by 10 of the recommendations. And these recommendations give a structural overview of the molecular and cytogenetic workup for acute lymphoblastic leukemia versus acute myeloid leukemia identifying different prognostic markers.

Also, the detection of MRD is taken into account in this recommendation. There is a major difference between children and adults, and this part is given most attention in the discussion part as the developments have been major during the past few years.

The third one is the context of referral to another institution with expertise in the management of acute leukemia. This is addressed by four recommendations, emphasizing the point that referral to an institution with specific expertise is of major importance for the central workup of acute leukemia.

And finally, the final reporting and report keeping is reflected in three recommendations, mainly supporting conclusions from 2017 which were describing the fact that the complete report with basic diagnostics in one central report should be available within 48 to 72 hours. And this should be followed by complete, final, comprehensive report in one or two weeks.

So can you tell us about those discussion points that were made and why the panel decided to include these?

The discussion points include mostly issues regarding diagnostics that involve flow cytometry and molecular techniques as addressed in part one and two of the guidelines. We think that the cytomorphologic assessment is essential for initial diagnosis of acute leukemia.

Multicolor flow cytometry using 8 to 10 colors has led to a better distinction between myeloids, lymphoid, and mixed lineage blast origin. Even when the number of cells are limited, for instance in CNS involvement, fine needle aspirate of extramedullary leukemic infiltration, or skin biopsy for leukemic cutis.

Also, it was suggested to better assess the central nervous system involved in leukemia. The expert panel recommends the immunophenotyping studies as an additional detection technique next to the cytomorphological examination of cytospins and particularly for those with a low level involvement of acute leukemia that cannot be well addressed by a morphologic examination only.

The TDT immunohistochemistry staining of cytospins has alternatively been used for detection of CNS disease in AML and evaluation of CSF by multicolor flow cytometry has been recently adopted in some centers. Flow cytometry, using at least six, but we now use in some laboratories, even 8 to 10 colors has led to a much more specific in tentative diagnosis. And this has improved the detection of CNS involvement.

The use of molecular tools, for instance, polymerase change reaction, PCR, NGS for low-level CSF involvement is still under study, and therefore, we did not recommend this in our discussion.

Regarding the molecular markers and MRD detection, the discussion here was mainly based upon the results of translational research supported by better molecular detection techniques. And those molecular diagnoses have been developing in the past few years with the inclusion of many more molecular markers. And they included one of the key diagnostic criteria in the revised WHO classification, which was revised in 2017. And we made substantial changes that have been made in the ASH-CAP guidelines concerning molecular diagnostics.

Those newly identified targets by advanced molecular techniques give possibilities for better risk stratification. Some examples of better molecular characterization of acute lymphoblastic leukemia are, for instance, additional testing for MLL translocations. Furthermore, we can look in patients with T-ALL for NOTCH1, and FBXW7 mutations.

The Ikaros family zinc finger gene, the IKZF1 gene is frequently deleted in adults as well in children with B-ALL. And it was shown to have an independent prognostic significance and was also associated with poor clinical outcome.

In the current text of the current risk that the protocols IKZF1 should be regularly included in the screening panels for all ALL patients.

If we look for examples for better characterization of AML, acute myeloid leukemia, we have found an increasing number of additional cytogenetic aberrations, like for instance FLT3 ITD which is associated with poor outcome.

Another example is appropriate mutational analysis for kids, which can be detected both in adult patient as pediatric patients with a confirmed core binding factor acute myeloid leukemia. So this is myeloid leukemia with a translocation A21, RUNX1, or inversion 16.

This recommendation is very strong in adults, whereas in children, this prognostic fact impact remains unclear. So there have been proven several publications which refer to a similar prognosis for children and others who refer to a poor prognosis in comparison to known mutated genes. So we suggest to test for this mutation in adults, especially, but also in children to learn from it.

Finally, emerging evidence supports molecular studies as principle test for monitoring minimal residual disease of acute leukemia. And there are several key molecular markers that are included in the initial workup, which will be carried on for monitoring MRD, for instance, PML- RAR-alpha, RUNX1-RUNXT1, CBFB-MYH11, and NPM1, CEBP-alpha and others.

Beside those aforementioned markers, it's very important to screen for other molecular markers that have predictive or prognostic value in the individual. And it is possible to use them for MRD. We have found a recent consensus from the European Leukemia Net MRD Working Group, who was proposing that for detection of molecular MRD, and they refer the RT PCR platform to NGS and digital PCR platforms.

Although all those molecular techniques have been developed very quickly and it is very tempting to use them for initial diagnostics, currently, not all laboratories will have all those techniques available. So the expert panel strongly advises understanding to make distinction between diagnostic that are needed in the first phase to start treatment and subsequently, treatment stratification, in contrast to the usual dose findings in a broader research.

For instance, available karyotyping, FISH, PCR techniques, if possible, NGS can be used in the initial start of treatment, whereas techniques like whole exome sequencing, whole genome sequencing, RNA sequencing, and epigenomic studies are meant for a broader research.

And finally, how will these guideline recommendations affect patients?

Well, in the end, the patients will receive better and especially, more personalized treatment. If we have results available within two weeks from diagnosis, it will be possible to better identify which basis will better benefit from more intensified and more personalized treatment, whereas others may need less intensive treatment with less toxicity.

If you use traditional techniques to do this supported by molecular techniques like karyotyping, FISH, and PCR techniques, and in the end, following MRD to see which patients are responding to treatment, MRD detection will help to identify these patients and stratify them finally to the best treatment.

Great. Thank you for your work on this important guideline, and thank you for your time today, Dr. de Haas.

OK. Thanks a lot.

And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

View Details

An interview with Dr. Elena Stoffel from University of Michigan on Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma.

Hello, and welcome to the ASCO Guidelines Podcast Series. Is my name Shannon McKernin and today, I'm interviewing Dr. Elena Stoffel from the University of Michigan, lead author of "Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion.” Thank you for being here today, Dr. Stoffel.

I'm delighted to join you.

So first, can you tell us what a professional clinical opinion is and why this topic is so important to ASCO?

Well, a provisional clinical opinion is a statement that ASCO puts out when we are seeing trends that are relevant to the care of our patients but that may not necessarily have the level of evidence needed to include in a true clinical guideline. This particular provisional clinical opinion that deals with the management of patients with pancreatic cancer and their families is based on some new data that has been published regarding the prevalence of inherited factors influencing pancreatic cancer risk.

So what are the key statements of this Provisional Clinical Opinion or also known as a PCO?

This particular provisional clinical opinion, which is about just the inherited susceptibility to pancreatic cancer, was prompted by several recent publications, which found that the prevalence of genetic predisposition among patients with pancreatic cancer was much higher than we had originally anticipated. And this is relevant because in talking about pancreatic cancer as one of the deadliest cancers in both in the United States and worldwide, we are very interested in finding ways to reduce the morbidity from this cancer to patients and their families. And this particular provisional clinical opinion addresses the role that genetic risk assessment should have in the care of pancreatic cancer patients and also the role for clinical genetic testing, as well as the risks and benefits of pancreatic cancer screening for at risk family members.

What considerations are there for having these conversations with patients and their families?

Well, many times when we see families affected with cancer, one of the questions they have is what is the likelihood that this will happen to other individuals in our family and what can we do to prevent cancers in other family members. And I think what's important here is that review of the data from multi-gene panel genetic testing in unselected individuals diagnosed with pancreatic cancer identified pathogenic germline variants in 1 out of every 10 individuals. And this is really important because when you think about it, if 1 out of every 10 patients with pancreatic cancer develop their cancer in the setting of a genetic predisposition syndrome, this has tremendous implications for management both for them as well as for their family members.

One of the most common inherited cancer syndromes identified in families affected with pancreatic cancer is hereditary breast ovarian cancer associated with mutations of BRCA1 and BRCA2. As you know, there are definite screening recommendations we make for individuals who carry these genetic alterations. And certainly if a family member is diagnosed with a genetic alteration, then that has an impact for cancer screening and management.

Furthermore, there are emerging data about the utility of pancreatic cancer screening in high risk individuals. And while there's still some controversy about how to screen individuals at risk for pancreatic cancer, certainly there are some emerging data suggesting that this may have a role for early detection.

And finally, the panel included a discussion section on the limitations of the research and future directions. So what are the key points of this section?

I think that what we're learning is with genetic testing, and particularly with multi-gene panel testing, we are we often find unexpected results. Certainly variants of uncertain significance are not uncommon when multi-gene panel tests are used. And being able to interpret the clinical significance of some of these genetic test results can pose some challenges, especially for clinicians who don't have specific expertise in genetics. Certainly being able to deal with the volumes of patients who need genetic testing who are also battling pancreatic cancer, we want to make sure that we have the resources to be able to offer genetic testing to everyone who needs it.

And finally, in talking about screening for pancreas cancer, while there are some studies that have demonstrated that screening with MRIs and/or endoscopic ultrasounds has led to early detection and down staging of cancers in some cases, larger studies are needed to be able to refine more specifically who and how to screen individuals at risk for pancreas cancer.

Great. Thank you so much for taking your time today to discuss this PCO with us, Dr. Stoffel.

Thank you very much for having me.

And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. If you've enjoyed what you heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Jennifer Griggs from University of MIchigan on Adjuvant Endocrine Therapy for Women with Hormone Receptor Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. This guideline provides recommendations on extended adjuvant therapy. on particular, use of aromatase inhibitors in women who had completed five years of adjuvant endocrine therapy.

Hello, and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Jennifer Griggs from the University of Michigan, senior author on "Adjuvant Endocrine Therapy for Women with Hormone Receptor Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update." Thank you for being here, Dr. Griggs.

And thank you for the opportunity to talk about this focused update to the guidelines on extended adjuvant therapy. I would, of course, like to thank all my co-authors in the ASCO guidelines team for their contribution to this effort.

So first, can you give us a general overview of what this guideline covers and their research which informed this focus update?

Yes. First of all, the goal of the guideline was to give an update to the previous guidelines on this topic. And we specifically focused on extended adjuvant therapy. In particular, the aromatase inhibitors in women who had completed five years of adjuvant endocrine therapy. And it goes without saying, but it's worth reminding our listeners that the guideline is restricted only to post-menopausal women with hormone receptor-positive breast cancer. And, of course, our guidelines are only as good as the data upon which we rely. So for this guideline, six phase III randomized controlled trials met the pre-specified eligibility criteria for the updated systematic review and provide the evidence base for the guideline recommendations on the duration of aromatase inhibitor therapy. Each of the trials used the standard doses of the drugs that we use in practice today. So I'm not going to say the doses of each of the medications. So I'm going to go briefly over those six trials and just describe them so everybody's up to date with how the studies were designed.

So briefly, the first trial I'll describe is MA17R, which compares letrozole to placebo for five years in over 1,900 women who had already received 4.5 to six years of adjuvant therapy with an AI, proceeded in most women by treatment with tamoxifen. The second study is NSABP B-42. And this also compares letrozole to placebo in nearly 4,000 women who'd completed five years of endocrine therapy with either five years of an aromatase inhibitor or up to three years of tamoxifen followed by an aromatase inhibitor, for a total of five years.

The third study that we looked at is the DATA trial, which stands for the Different Durations of Adjuvant Anastrozole Therapy. This trial compared six years of adjuvant anastrozole with three years of adjuvant anastrozole in over 1,600 women after two to three years of adjuvant tamoxifen. The fourth trial out of the six is the IDEAL trial, the Investigation on the Duration of Extended Adjuvant Letrozole. This study randomized over 1,800 women to either 2 and 1/2 or five years of letrazole after five years of tamoxifen, an AI, or a combination in sequence of tamoxifen and an AI. So very similar study designs.

The fifth study is the ABCSG-16 trial, the Austrian Breast Cancer Study Group Trial 16, which randomized nearly 3,500 women following four to six years of adjuvant therapy with tamoxifen and AI or a sequence of tamoxifen and then an AI, to either two or five years of anastrozole as extended therapy. And finally, the study of letrozole extension, or the SOLE trial, randomized over 4,800 women with node-positive breast cancer who had completed five years of adjuvant endocrine therapy to receive either continuous letrozole for five years or five years of an intermittent schedule of letrozole given nine months on and three months off in years one to four and on continuously for a year or five.

So I know that's a lot to take in, but I do think it was important for our audience to understand the six trials that were included. These were all large studies, randomized, and patients had completed five years of adjuvant endocrine therapy. And then, were randomized either to placebo or different durations of an aromatase inhibitor or a placebo. For all of these studies, it's important to know that the primary outcome was disease-free survival. Overall survival and adverse events where secondary outcome.

Great. So given that research and those trials, what are the key recommendations for this guideline update?

Five key recommendations are included in this focused update to the previous guidelines. And they are for women with node-negative breast cancer, extended adjuvant aromatase inhibitor therapy can be offered for up to a total of five years of adjuvant therapy. Recommendations are based on considerations of recurrence risk using our usual established prognostic factors. However, since the recurrence risk is lower, the benefits are likely narrower in node-negative patients.

The guidelines panel recommends that women with low-risk, node-negative tumors should not routinely be offered extended adjuvant therapy. Now, that might sound vague. We did not make recommendations using genomic profiling results because we don't have sound data to support such views that we felt were strong enough to integrate genomic testing results. Our second recommendation is that women with node-positive breast cancer should be offered extended AI therapy for up to a total of 10 years of adjuvant endocrine therapy. And that means combined tamoxifen and aromatase endocrine therapy. That's the total that we meant to recommend.

Third recommendation is that women receiving extended adjuvant endocrine therapy should receive no more than 10 years of total treatment. The fourth recommendation is when given as prevention of secondary or contralateral breast cancer, the risk of second breast cancers based on prior therapy should inform the decision to pursue extended therapy. So what this means is specifically, a woman who has had a bilateral mastectomy will not reap the benefit of preventative therapy with endocrine therapy.

The fifth recommendation is that extended therapy carries ongoing risks and side effects, and these should be weighed against the potential absolute benefits of longer treatment in a shared decision-making process between the clinical team and the patient. Specifically, to date, none of the studies have shown improvement in overall survival with longer duration aromatase inhibitor therapy. As such, the recommendations, therefore, an extended adjuvant AI therapy are based on benefits that include prevention of distant recurrence and prevention of second breast cancers.

So why is this guideline so important and how will it change practice?

The importance of this guideline rests in the fact that it supports what many clinicians and patients are already doing in practice. The second is it recommends against durations of endocrine therapy longer than 10 years in the absence of data supporting such a practice. So it's our thought that doctors and patients and other care providers, nurse practitioners, physician assistants, primary care doctors, are already practicing what we're recommending, and it supports doing so. And the second is that for those providers and patients who aren't sure that 10 years is enough, this guideline suggests that 10 years is sufficient. We don't have any data supporting giving more than 10 years.

And the third recommendation is that this guideline really supports the need for shared decision-making, given the absence of data supporting an improvement in overall survival.

So finally, since you did mention shared decision-making, how does this guideline recommendation affect patients?

Well, the panel strongly believes that the tailored decision-making process is key in the decision to recommend extended adjuvant therapy. So tailoring on disease factors plays a role in the recommended duration of therapy. Obviously, since we stratified by high-risk and low-risk and what treatment's been received specifically. And if a woman's had bilateral mastectomy, she's not going to benefit from the risk reduction that's achieved with giving somebody extended therapy.

But in addition to disease factors, patient preferences and tolerance of therapy should inform clinician and patient decision-making. Again, since none of the studies have shown improvement in overall survival with longer duration of AI therapy, patients and their medical providers need to make decisions based on an awareness that the benefits include, specifically prevention of distant recurrence and prevention of second breast cancers. And the importance of those benefits is going to vary according to a patient and how she views her life going forward and how bad her side effects have been, how well she tolerates the therapy.

From my own personal point of view, as a breast oncologist, I believe two things. Number one, we should provide aggressive support for managing symptoms in patients who are most likely to benefit from extended therapy. That is, we should not stop therapy early if she is very likely to benefit if we haven't maximized control of her symptoms. There are many things we can do to improve symptoms and we shouldn't just stop therapy because she's not tolerating treatment if we haven't done the most that we can to improve her quality of life and her symptoms.

Conversely, my hope is that we are not doggedly persisting in recommending prolonged therapy in a patient who has a fear of recurrence but who has little to gain from extended therapy. In the latter case, high quality information support is more therapeutic than extended therapy with a medication that's proven, in randomized controlled trials and in her own personal experience, to decrease her quality of life with marginal, if any, medical benefit.

Thank you so much for the overview of this guideline today and thank you for your time.

Thank you.

And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

View Details

An interview with Dr. Scott Morgan from the Ottawa Hospital and University of Ottawa on "Hypofractionated Radiation Therapy for Localized Prostate Cancer: an ASTRO, ASCO, and AUA Evidence-Based Guideline.” This guideline provides recommendations on hypofractionated external beam radiation therapy for localized prostate cancer.

Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Scott Morgan from the Ottawa Hospital and University of Ottawa, lead author on "Hypofractionated Radiation Therapy for Localized Prostate Cancer: an ASTRO, ASCO, and AUA Evidence-Based Guideline.” Thank you so much for being here today, Dr. Morgan.

It's my pleasure, Shannon. I'm happy to take part in the podcast and hopefully share the highlights of the guideline with your listeners.

So first, can you give us a general overview of what this guideline covers?

Yeah. So the guideline covers really hypofractionated external beam radiation therapy, which is a treatment for localized prostate cancer, and for the non-radiation oncology folks in your audience, I think it's important to begin by placing the guideline sort of in its context and going over some of the terminology that we use as radiation oncologists. So external beam radiotherapy, it's a standard treatment-- standard local treatment option for men with localized prostate cancer. It gives outcomes which are really equivalent to those of radical prostatectomy or brachytherapy, which are the other two standard local treatment options.

And traditionally, it's given in small daily fractions over several weeks and the usual daily fraction size is 1.8 to 2 Gray per day. And this is called conventional fractionation. And that really translates into a course of about seven and a half to nine weeks of treatment. And so that total dose which is delivered in those daily treatments, five days a week, is about 76 to 80 Gray. And that's what we call conventional or standard fractionation.

And there's a theoretical framework in radiation medicine and there's some evidence to accompany that that suggests that prostate cancer is quite sensitive to radiation fraction size. And just to give a brief primer, for any tissue, cancerous or non-cancerous, there's a sensitivity to fraction size and it's characterized by something called the alpha-beta ratio. And for prostate cancer, that's felt to be low compared to most other cancers, the alpha-beta ratio, and indeed, it's thought to be lower than the adjacent dose-limiting normal structure, which is the rectum.

And so an implication of that is that hypofractionation, and by that we mean daily fraction size of more than 2 Gray, might improve the therapeutic ratio of radiation therapy in localized prostate cancer. Now the guideline-- and I think it's important to emphasize this-- it draws a distinction between what we call moderate hypofractionation and ultra-hypofractionation. Clearly, fraction size is a continuous variable, so any subdivision that we might make is necessarily a bit arbitrary, but it turns out that at least in clinical practice, there's been really two distinct approaches to hypofractionation that have arisen.

And one of these is moderate hypofractionation and that's an approach where the fraction size is modestly higher than 2 Gray per fraction, and in the guideline, it's been defined as a fraction size between 2.4 and 3.4 Gray, whereas ultra-hypofractionation, this is defined in the guideline as a fraction size greater than 5 Gray. And it's also been referred to in the literature as extreme hypofractionation or Stereotactic Body Radiation Therapy, SBRT, or SABR, Stereotactic Ablative Radiation Therapy.

But in any case, we are talking here about, with ultra-hypofractionation, with radical courses of treatment that are often delivered over as few as five fractions, often on an alternate day approach over two or two and a half weeks. And so the guideline really was largely motivated by the publication of a number of randomized trials, including four large-scale trials in the past two years that have compared conventionally fractioned radiation therapy and moderately hypofractionated radiation therapy. So that is really what stimulated the guideline, which was the evidence concerning moderately hypofractionated radiation therapy.

But at the same time, there has been an increasing use in routine clinical practice that's been observed of ultra-hypofractionated radiotherapy, so the decision was made to make recommendations on it as well. So ASTRO, American Society for Radiation Oncology, in collaboration with ASCO and the AUA, convened a panel of radiation oncologists, medical physicists, urologists, radiation oncology resident, patient representative, and a systematic review of the literature was conducted and their recommendations have been made on the basis of this systematic review. So the aim was to provide recommendations on use of both moderate hypofractionation and ultra-hypofractionation, in particular with reference to oncologic outcomes, toxicity, and quality of life. So we didn't directly consider health economic endpoints, though clearly the very nature of hypofractionation is such that there are potential advantages in terms of cost and convenience for patients.

And what are the key recommendations of this guideline?

We separated the key recommendations into three main groups and the first set of recommendations pertains to moderate hypofractionation, and these are generally based on the highest-quality evidence. So they could be viewed as the strongest recommendations in the guideline. And the second set of recommendations concern ultra-hypofractionation. They're somewhat less strong given they're based on somewhat weaker evidence. And then the third set of recommendations relate to some of the technical aspects of the planning and delivery of hypofractionated radiation therapy.

So, dealing with the moderate hypofractionation recommendations first, arguably the most important recommendation of the guideline is that the panel has recommended that in patients with localized prostate cancer who are candidates for external beam radiation therapy, moderate hypofractionation should be offered. And this is graded as a strong recommendation. It's based on high-quality evidence and it applies to patients across all risk groups.

So it applies to patients with low-risk prostate cancer who require active treatment or who have declined active surveillance and it also applies to patients with intermediate-risk or high-risk localized prostate cancer. And why really does it apply to all these groups? It's essentially because these groups are well-represented in the trials of moderate hypofractionation. And the trials have shown that moderate hypofractionation really gives similar outcomes in terms of efficacy to conventional fractionation.

Now one caveat I guess that I should say is that the trials generally only looked at radiation therapy to the prostate rather than radiation therapy to the prostate as well as the pelvic lymph nodes. So the panel's recommendations regarding moderate hypofractionation don't apply to the scenario where the clinician has decided to include the pelvic lymph nodes in the radiation therapy volume. The panel also made recommendations with respect to toxicity and quality of life, and specifically, they did recommend that men should be counseled about a small increased risk of acute gastrointestinal toxicity, typically rectal toxicity, with moderately hypofractionated radiation therapy. And they should also be counseled that moderately hypofractionated radiation therapy has a similar risk of late GI toxicity and also has a similar risk of both acute and late GU toxicity compared to conventional fractionation. The only difference was seen in acute GI toxicity.

And I think it's probably worth dwelling on this a little bit more. Probably the most granular data on acute GI toxicity comes from the CHHiP trial. This was a trial from the UK. It was far and away the largest randomized trial of moderate hypofractionation versus conventional fractionation.

And they followed the amplitude of GI toxicity very carefully over the short and long term and what they did found was that in the early weeks, there was greater peak acute GI toxicity with moderate hypofractionation, but this difference had really disappeared by about 18 weeks after the start of radiotherapy. So within a few months, there was no difference, and afterwards, there was no consistent difference in long-term GU or GI toxicity across these trials. Now I guess I should mention that, at the current time, that the median follow-up of most of these trials is between five and six years, so arguably, the last word hasn't been written.

The panel also offered conditional recommendations on particular moderate hypofractionation regimens. There were multiple different regimens that were evaluated but most were not compared head-to-head. And the panel preferred two particular regimens-- 60 Gray and 20 fractions over four weeks or 70 Gray and 28 fractions over five and a half weeks, as these were the two regimens that were evaluated in the largest populations. And of these two, likely the strongest evidence supports 60 Gray and 20 fractions, given it was used in two different trials and it was used across all risk groups and with or without concomitant hormonal therapy. So those were the recommendations regarding moderate hypofractionation.

So moving to ultra-hypofractionation, again, this is talking about fraction size of at least 5 Gray, typically a course of as few as five fractions over perhaps two or two and a half weeks. I think it's important to say that, at the time we were preparing this guideline, there were no published efficacy or toxicity data from randomized trials comparing ultra-hypofractionation and conventional fractionation. So the strengths of the recommendations made by the panel is correspondingly lower than was the case for moderate hypofractionation.

But having said that, there are several prospective non-randomized studies that have been published and have documented safe delivery of ultra-hypofractionation for appropriately-selected patients and pretty good biochemical control and low toxicities have been observed in these studies. But again, relatively few have follow-up beyond five years.

So what the panel recommended was that in men with low-risk prostate cancer-- and the bulk of the data to date for ultra-hypofractionation has been in this group-- panel conditionally recommended that in those who decline active surveillance and choose active treatment with radiation therapy, that ultra-hypofractionation may be offered as an alternative to conventional fractionation. Again, this is a conditional recommendation.

In men with intermediate-risk prostate cancer, the panel has conditionally recommended that ultra-hypofractionation may be offered as an alternative to conventional fractionation but it's strongly recommended in this group that these patients be treated as a part of a clinical trial-- and there are several clinical trials ongoing-- or as part of the multi-institutional registry. And then finally, in patients with high-risk localized prostate cancer, there was really insufficient comparative evidence for the panel to suggest offering this outside of a clinical trial or outside of a registry.

Regarding particular regimens, that the panel again made a conditional recommendation that a schedule of 35 Gray to 36.25 Gray and five fractions delivered to the planning target volume could be offered and that it recommended against consecutive daily treatments for this schedule. So I think it's again important to note that compared to moderate hypofractionation, the ultra-hypofractionation literature is really substantially less mature and it is evolving rapidly. And therefore, a short-term update of this guideline to address new data pertaining specifically to ultra-hypofractionation is likely going to be necessary.

And then I mentioned there was a third set of recommendations and these pertain to the technical aspects of planning and delivering radiation therapy. And these probably are not of core interest to your audience, but briefly, the guideline recommends that in the planning of hypofractionated radiotherapy, that normal tissue constraints and target volumes derive from published reference standards the use and that image guidance and intensity modulation at one form or another are recommended in delivering hypofractionated radiotherapy.

Great. Thank you for the overview of those guideline recommendations. So why is this guideline so important and how will it change practice?

Yeah. I guess the first point to make is that the guideline potentially can inform the care of a very large number of patients. Across North America, about 200,000 patients a year are diagnosed with prostate cancer and its far and away that the most prevalent non-dermatologic cancer in men and it's the third-leading cause of cancer death in men, at least in North America. So the vast majority of those 200,000 men are diagnosed with localized disease at the time of presentation and therefore they're potentially treatable with radiation therapy and therefore the guideline is relevant to these patients.

Prior to the publication of the trials that motivated this guideline, the overwhelming majority of these men who chose external beam radiotherapy as their primary treatment have been treated with conventionally fractionated therapy. In other words, seven and a half to nine weeks of treatment. And already, since the publication of these trials-- the trials of moderate hypofractionation-- we're talking really about moderate hypofractionation because I think that is where the guideline will have its impact, at least in the short term. In the jurisdiction where I practice in Canada, practice has already substantially changed in light of these trials, and I think a large majority of patients with localized prostate cancer choosing external beam radiation therapy are now typically being treated with a moderately hypofractionated approach, typically a four-week schedule. So it will be interesting to see if a similar change is occurring or will occur over time in the United States, particularly informed or potentially informed in part by this guideline.

And then finally, with respect to ultra-hypofractionation, I think again I have to note that this is a very dynamic space in terms of evidence and there are a number of large-scale trials looking at ultra-hypofractionation and comparing it to either conventional fractionation or moderate hypofractionation that are in progress or near to reporting. And so again, an update of the guideline in the short-term as data emerges from these studies will likely be important and it may ultimately influence practice as well on a large scale.

And finally, how will these guideline recommendations affect patients?

So I think in the short term, that the recommendation that has the potential to impact patients in the greatest way is the recommendation regarding moderate hypofractionation. And the guideline really recommends that this is a management approach that substantially reduces the treatment burden without compromising treatment efficacy and without increasing the risk of long-term side effects. So in my view, the move to moderately hypofractionated radiation therapy is a win for patients with localized prostate cancer who choose radiation therapy as their primary treatment modality.

And so moderate hypofractionation really represents about a halving of the overall treatment time in some patients. And those who live, for example, in rural or remote areas and who need to travel considerable distance to have their treatment, a halving of treatment time is significant. But I think even more generally, halving of treatment time is significant for patients regardless of where they live. And clearly there are also benefits potentially in terms of cost and also benefits in terms of for the health care system but those really weren't specifically studied in the guideline.

Great. Thank you so much for your time today, Dr. Morgan, and thank you for your work on this important guideline.

My pleasure, Shannon, and thank you for having me.

View Details

An interview with Dr. Carole Fakhry from Johns Hopkins School of Medicine on the ASCO endorsement of the CAP guideline on human papillomavirus (HPV) testing in head and neck carcinomas. Read the full guideline at www.asco.org/head-neck-cancer-guidelines

Hello, and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Carole Fakhry from Johns Hopkins School of Medicine, lead author on Human Papillomavirus Testing in Head and Neck Carcinomas: ASCO Clinical Practice Guideline Endorsement of the CAP Guideline. Thank you for being here today, Dr. Fakhry.

Thanks for having me.

So first, can you give us a general overview of what this guideline covers?

Sure. This guideline serves to guide multi-disciplinary clinicians in the evaluation of head and neck cancers. And it really starts to clarify which HPV tests to order and when. Also discusses some of the imitations of using surrogate HPV testing in specific situations.

The College of American Pathology Guidelines were recently published and we are providing an endorsement with certain classifications and discussions of nuances that we as a committee felt were important and clinically significant, specifically, aspects that could alter clinical care.

So what are the key recommendations of this guideline?

So first and foremost, the key recommendation is that HPV tumor detection should be performed in oropharynx tumors and not for non-oropharynx tumors. An important aspect of that is that HPV tumor testing should not be altered based on sex, race, age, or smoking history. Another important recommendation is that the term "high-risk" only be used when HPV-specific testing is performed.

That would establish the tumor is ideologically related to the infection human papillomavirus. In the absence of HPV-specific testing, we recommend that the term HPV-related tumors be used, and that p16 deserving for oropharynx tumors only.

And can you tell us a little bit about the qualifying statements made on some of these recommendations, and why the expert panel decided to include these?

Sure. So one of the qualifying statements that we did make was a generalized one, and the one that I kind of just touched upon, that the term "high-risk HPV" should only be used in situations when HPV-specific testing was performed. And that's because sometimes things are p16 positive but not necessarily HPV-related or etiologically related to the infections.

So as a committee, we wanted to make sure that that was clear. In light of that, one of the recommendations from the CAP Guidelines was that for tissue specimens presenting with medistatic squamma cell carcinoma of unknown primary and cervical upper, or mid-jugular, chain lymph nodes, pathologists should perform p16 in situ hybridisation.

They also had added a note saying that additional high-risk HPV testing on p16-positive cases should be performed for tumors located outside of level two or three in the neck, and/or for tumors with keratinizing morphology. So in the qualifying statement, our committee felt that p16 immunohistochemistry alone was not sufficient in the scenario of an unknown primary cancer.

We can get false positives and tumors that are p16-positive but not related to HPV. Can arise in situations of metastasis from the skin cancers, salivary gland malignancies, or even lung primaries. Therefore, in the case of an unknown primary, we would recommend HPV-specific testing. What other important consideration that our committee felt was important to clarify was that in the unknown primary, whether or not a tumor is felt to have keratinizing or non-keratinizing morphology, that HPV-specific testing should be done.

And the reason for that is that the pathologists acknowledge that considering a tumor keratinizing or non-keratinizing may be a difficult distinction for most pathologists, and that discerning HPV status may actually be easier and may help hone in on the diagnosis. And as part of this, what we did was we created an algorithm which simplified the College of American Pathologists algorithm for HPV detection. So there are fewer nodes in terms of HPV detection.

And in general, for oropharynx tumors, we recommend starting a p16 immunohistochemistry. We endorse the 70% cutoff used on immunohistochemistry for p16. And if it's an oropharynx tumor with greater than 70% p16 staining, then that can be considered an HPV-related squama cell carcinoma. For non-oropharynx tumors, we don't ever recommend HPV tumor status evaluation. And then for unknown primary, whether or not it's a level 2 or 3, starting with p16 is adequate, but if it is p16-positive, that needs to be followed up with HPV-specific testing to be deemed HPV-related.

In the College of American Pathology algorithm, acknowledging that determining HPV status can be complex, there are more nodes and more decisions that could be made in terms of discerning what's HPV-related and what's not. And so our committee tried to distill it down and simplify the algorithm.

And finally, how will these guideline recommendations affect patients?

So it is recommended that patients with oropharynx cancer be tested for HPV. And so this really helps their clinicians determine how to best test their tumors. In cases that are not so clear that are not oropharynx tumors, it also helps to guide their clinicians in terms of the when and how to test their tumors.

Great. Thank you for your work on this important guideline, and thank you for your time today, Dr. Fakhry.

Thanks for having me.

And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

View Details

An interview with Dr. Justin Bekelman from University of Pennsylvania Perelman School of Medicine on the ASCO endorsement of the AUA/ASTRO/SUO Guideline on the management of localized prostate cancer. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines

Hello and welcome to the ASCO Guidelines Podcast Series. My name is Shannon McKernin, and today I'm interviewing Dr. Justin Bekelman from University of Pennsylvania Perelman School of Medicine, lead author on "Clinically Localized Prostate Cancer: ASCO Clinical Practice Guideline Endorsement of an AUA/ASTRO/SUO Guideline.” Thank you for being here today, Dr. Bekelman.

Thanks for having me.

First, can you give us a general overview of what this guideline covers?

Sure. So this guideline addresses the key question about what is the current best practice available for the management of localized prostate cancer. It's an endorsement guideline, which means it reinforces the recommendations offered by the American Urologic Association, ASTRO, SUO, which is the Society of Urologic Oncology.

In April of 2017, these three groups got together to release a joint evidence-based practice guideline on clinically localized prostate cancer. And then, now more recently, in 2018 ASCO assembled a panel to review those policies, update them, and endorse them as appropriate.

So this guideline has over 60 recommendations. So I'm not going to ask you to read through all of them. But can you talk about some of the key topics and discussion points that was added by the ASCO expert panel?

Yeah, absolutely. I'd like to highlight four areas. The first area-- panel endorsed guideline recommendations on active surveillance for men with low risk Gleason 6 prostate cancer, what's called grade 1 prostate cancer now. The panel also felt it reasonable to add that ASCO has also produced a guideline on active surveillance which provides more context and counsel for clinicians and patients.

It also includes a discussion of how surveillance might be considered for men with low volume Gleason 3+4, or what's called grade 2 cancers. And so I would reference that ASCO guideline on active surveillance for folks who are interested in that.

Second, panel updated the recommendation regarding the length of androgen deprivation therapy or hormone therapy for men with higher risk clinically localized prostate cancer. Prior recommendations considered 24 to 36 months to be appropriate. And that's what's captured in the 2017 guidelines from the AUA, ASTRO, and SUO.

But new evidence released after those guidelines were published from two trials-- one called RADAR and one called PCS IV trial-- shows that 18 months may be equivalent and permissible, and thus these trials should be followed really closely. But that's really interesting, provocative information for patients as they consider adjuvant hormone therapy for high risk cancers when they're receiving radiation.

Third, the panel describes two really high impact quality of life studies comparing surgery, external beam radiation, and brachytherapy that were published in JAMA in 2017, again, after the AUA guideline was published. These two studies are actually summarized in the discussion of the panel findings. And they are an excellent reference for both clinicians and patients as they consider the potential benefits and harms of the various treatments for prostate cancer.

The last one I'd want to highlight to the audience is the panel's recommendations regarding cryosurgery. And even though the original guidelines stated that selected patients are candidates for cryosurgery, the panel found that there was insufficient evidence to support the use of cryosurgery for clinically localized prostate cancer. So those are four highlights from the evidence based review.

And why is this guideline so important? And how will it change practice?

This guideline represents the most up to date consensus recommendations from the major professional societies that represent clinicians-- the surgeons, the radiation oncologists, the medical oncologists-- who counsel and treat men with prostate cancer. So it's a really important initial original guideline and then a really important endorsement. I think it will change practice by highlighting what the current best practice standards of care are for clinically localized prostate cancer.

And finally, how will these guideline recommendations affect patients?

I think this guideline will have an immediate impact on important questions that patients and their clinicians want answered. I think that's how the panel actually took its role, is thinking, how can we both endorse and provide further evidence that would be patient centered as we considered these guidelines.

So this endorsement and the guidelines, they ask questions like, how should we conduct shared decision making with our patients to offer the highest chance that treatment decisions will be concordant with our patient goals of care? That's number one and so crucial.

Who is appropriate for active surveillance? A top topic for men facing clinically localized prostate cancer. What are the differences and side effects among the major treatments for clinically localized prostate cancer, mostly focused on surgery and radiation?

The endorsement updates the latest data through 2017 and even in 2018 with really patient-centric information about what patients might expect with each of these treatments. Even what are the aspects of prostate cancer care that represent the highest quality? And how might patients assess that? What are the most important aspects of survivorship?

So the endorsement and recommendations from the original guidelines themselves hit on each of these. And I think that patients will find them very interesting and insightful.

Great. Thank you so much for your time today. And thank you for your work on this important guideline, Dr. Bekelman.

Oh, my pleasure.

And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

View Details

An interview with Dr. Randy Taplitz from UC San Diego Health on the guideline update which addresses antimicrobial prophylaxis for adult patients with immunosuppression associated with cancer and its treatment. Read the full guideline at www.asco.org/supportive-care-guidelines

Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Randy Taplitz from UC San Diego Health, lead author on Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update.

Thank you for being here, Dr. Taplitz.

Thank you.

So first, can you give us a general overview of what this guideline covers?

Yes. I mean, I think we're all aware that infection in the setting of neutropenia associated with cancer chemotherapy is really a major cause of morbidity in these patients. And it's also important to be aware that prevention and appropriate management of febrile neutropenia and infection should thus be a critical focus in cancer care. So the focus of this particular guideline was to evaluate the risk and benefits of antimicrobial prophylaxis in these patients and really to determine evidence-based best practices for prevention of infection and how to go about doing that. So

In this guideline, what we do is we identify the groups at risk for febrile neutropenia and really recommend settings for which prophylaxis with antibacterial, antifungal, antiviral medications are indicated. And then as well make recommendations for consideration of vaccination and other measures such as respiratory etiquette, and hand hygiene, and the like that will help reduce the risk of infection in these vulnerable patients.

So since this is an update of a 2013 guideline, what are the major changes? And can you tell us a little bit about the research that informed this update?

Yes. Really, when you update a guideline, one is informed by review of articles that encompass, in this setting, randomized clinical trials as well as meta analysis of interventions to prevent microbial infections in patients with neutropenia or other types of immunosuppression.

And one example of this-- I think one of the better examples-- is we reviewed a large meta analysis of antibiotic prophylaxis in neutropenic patients after chemotherapy that showed that for fluoroquinolone prophylaxis resulted in really significant reductions in all cause mortality and febrile episodes, particularly in patients who were high risk, meaning the hematologic malignancy population and stem cell transplant population. And in that particular population, in fact, the number needed to treat to prevent one death was 29. So therefore, in that high risk population, really as with prior guidelines, the fluoroquinolone prophylaxis is recommended.

However, we also reviewed other articles that include emerging data on some of the risks of fluoroquinolone prophylaxis. So for instance, the effect of fluoroquinolone on the intestinal microbiome and its association with selection of fluoroquinolone-resistant bacteria such as Gram-negative rods, as well as selection of organisms such as Clostridium difficile and enterococcus. And then we also reviewed fluoroquinolone toxicities.

So what is added to this guideline are some qualifying statements alerting clinicians to really be aware for these concerns and to consider what the clinical spectrum of things like Clostridium difficile infection, et cetera, look like.

In terms of antifungal prevention, including pneumocystis prevention, we really haven't made any major changes to this guideline with the exception that in this new guideline, the panel has also started looking at complications associated with immunotherapy and actually makes a suggestion that people consider pneumocystis prophylaxis in the setting of prolonged steroid use when it's used to treat immune-related adverse events that we've begun to see in increasing numbers associated with agents like checkpoint inhibitors and other immunotherapies.

In terms of viral infections, the updated guidelines recommend risk assessment for hepatitis B reactivation and then treatment in accordance with other ASCO guidelines and yearly influenza vaccine, as well as really endorsing other vaccines as described in the Infectious Disease Society of America Guideline for Vaccination in Immunocompromised Hosts.

So really, those are the main new events since 2013.

And what are the key recommendations of this guideline?

So the key recommendations-- the first thing is what we call a risk assessment. So after-- what one does is carefully assess, really, what the risk of febrile neutropenia is. And that includes assessment of patient, what the cancer is, and what the treatment-related factors are. And then after they're risk adjusted and risk assessed, then we take, in turn, different forms of prophylaxis that we consider.

And so the first one that we always consider is antibiotic prophylaxis against bacterial infections. And the recommendation is still with the fluoroquinolone. And that's recommended for most patients who are at high risk for febrile neutropenia or profound, really prolonged neutropenia, such as those getting therapy for AML, or myelodysplastic syndrome, or stem cell transplant recipients, particularly with myeloablative regimens. In the lower risk groups, such as those with most solid tumors, fluoroquinolone prophylaxis is not recommend.

In terms of antifungal prophylaxis, what is recommended is an oral triazole or Micafungin-- for patients, again, at risk for profound protracted neutropenia such as that AML, MDS, stem cell transplant group during that period of neutropenia.

When the risk of invasive aspergillus is high, such as in patients with AML or MDS during the neutropenia period while getting chemotherapy, then the consideration of a mold-active triazole is recommended and in addition should be considered in the context of stem cell transplant recipients with graft versus host disease.

In terms of PCP prophylaxis, PCP preventive therapies are recommended for those at high risk for PCP, which include those on greater than what we say 20 milligrams of prednisone equivalent a day for over a month, or based on purine analog use.

Viral prophylaxis for HSV is recommended for seropositive patients undergoing allogeneic stem cell transplant or leukemia induction.

And then as I mentioned before, patients at risk for hepatitis B reactivation are recommended treatment with a nucleoside reverse transcriptase inhibitor. And this is more carefully discussed in the ASCO Provisional Clinical Opinion on Hepatitis-B Virus Screening for Patients With Cancer Before Therapy.

It's also recommended that a yearly flu vaccine is given to patients as well as given to family, household contacts, and health care workers. Other vaccination recommendations are as per the Infectious Disease Society of America Guidelines for Vaccination of Immunocompromised Hosts.

And then the other things that are recommended are really review and repeat recommendation of adherence with hand hygiene, with respiratory etiquette, which is recommended and really required for all health care workers. And that out patients with neutropenia from cancer chemotherapy should avoid high risk activities, which include really contact with environments that have high concentration of fungal spores such as construction and demolition, high intensity gardening, et cetera.

So those are really a summary of the key recommendations of this guideline.

And finally, how will these guideline recommendations affect patients?

I think it's important to remember that to ensure best practices on infection prevention, the literature needs to be reviewed frequently and guidelines need to be updated. I don't think that these current guidelines will dramatically change the preventive strategies that are used for patients, with the exception of perhaps a few extra vaccines-- some newer indications for pneumocystis prevention, hepatitis B reactivation prevention, those kinds of things.

However, I think in reviewing the literature, it becomes clear what will we will need to be thinking about in the coming years, what we will need to be assessing. And a couple of those things are the dramatic increase in the use of immune-based therapies and how that will affect infection risk in patients with or without neutropenia. We need to be considering the effects of routine antibiotic prophylaxis on the microbiome and the risks that that might incur. And we need to really understand how new vaccines can be utilized.

So yeah, I think these areas are really ripe for research and need to be followed closely to ensure optimization of these preventive strategies for our patients in the future.

Thank you for your time today, Dr. Taplitz.

You're quite welcome.

And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you heard today, please rate and review the podcast and refer this show to a colleague.

View Details

An interview with Dr. Naren Ramakrishna from University of Florida Health Cancer Center at Orlando Health on the guideline update which addresses management of brain metastases for patients with human epidermal growth factor receptor 2–positive advanced breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines

View Details

An interview with Dr. Nancy E. Davidson from Fred Hutchinson Cancer Research Center and University of Washington on the guideline update which provides recommendations on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)–positive
advanced breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines

View Details

An interview with Dr. Gary Lyman from Fred Hutchinson Cancer Research Center and University of Washington and Dr. Lorenzo Cohen from the University of Texas MD Anderson Cancer Center on the ASCO endorsement of the SIO guideline on use of integrative therapies during and after breast cancer treatment. The guideline addresses the use of integrative therapies for the management of symptoms and adverse effects. Read the full guideline at www.asco.org/supportive-care-guidelines.

View Details

An interview with Dr. Hedy Kindler of the University of Chicago on the guideline which includes recommendations on diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Read the full guideline at www.asco.org/thoracic-cancer-guidelines

View Details

An interview with Dr. Antonio Wolff from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center on the ASCO/CAP guideline update which addresses IHC and ISH testing for HER2 in breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines

View Details

An interview with Dr. Davendra Sohal from the Cleveland Clinic on the guideline update regarding second-line therapy for patients with metastatic pancreatic cancer. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines

View Details

An interview with Dr. Neelima Denduluri from US Oncology, Virginia Cancer Specialists, on the key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Read the full guideline on www.asco.org/breast-cancer-guidelines

View Details

An interview with Dr. Supriya Mohile from University of Rochester on the guideline published in JCO which provides guidance regarding the practical assessment and management of vulnerabilities in older patients undergoing chemotherapy. To read the full guideline go to www.asco.org/supportive-care-guidelines.

View Details

An interview with Dr. Neelima Denduluri, Dr. Manish Shah, Dr. Mariana Chavez Mac Gregor, and Tom Oliver discussing the ASCO Clinical Practice Guidelines program, methodology, panel representation, and vision for the future. Read more at www.asco.org/guidelines

View Details

An interview with Dr. Nahla Gafer from Radiation & Isotope Center in Sudan on the Palliative Care in the Global Setting: ASCO Resource-Stratified Guideline.

The purpose of this new resource-stratified guideline is to provide expert guidance to clinicians and policymakers on implementing palliative care in resource-constrained settings and is intended to complement the Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology (ASCO) Clinical Practice Guideline Update of 2016. It is the view of the ASCO that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Read the full guideline at www.asco.org/resource-stratified-guidelines

View Details

An interview with Dr. Paul Hesketh from Lahey Hospital and Medical Center on the antiemetics guideline update published in 2017. The guideline update expands the recommendations to include olanzapine and neurokinin 1 receptor antagonists. Read the full guideline at www.asco.org/supportive-care-guidelines

View Details

An interview with Dr. Timothy Gilligan from Taussig Cancer Institute and Institute and the Center for Excellence in Healthcare Communication, Cleveland Clinic, Cleveland, OH on the guideline providing guidance to oncology clinicians on how to use effective communication to optimize the patient-clinician relationship, patient and clinician well-being, and family well-being. Read the full guideline at www.asco.org/supportive-care-guidelines

View Details

An interview with Dr. Betty R. Ferrell of City of Hope Medical Center on the guideline "Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update" which provides evidence-based recommendations to oncology clinicians, patients, family and friend caregivers, and palliative care specialists on the integration of palliative care into standard oncology care for all patients diagnosed with cancer.

A guideline on palliative care in the global setting is currently in press with the Journal of Global Oncology and there will be an episode on this topic when it publishes.

Read the full guideline at www.asco.org/supportive-care-guidelines

View Details

An interview with Dr. Alison W. Loren of Perelman School of Medicine of the University of Pennsylvania on the ASCO guideline update which provides current recommendations about fertility preservation for adults and children with cancer. Read the full guideline at www.asco.org/survivorship-guidelines

View Details

An interview with Dr. Michael J. Morris from Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine on the ASCO clinical practice guideline which addresses abiraterone or docetaxel with androgen-deprivation therapy (ADT) for metastatic prostate cancer that has not been treated (or has been minimally treated) with testosterone-lowering agents. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines

View Details

An interview with Dr. Christopher Flowers of Emory University School of Medicine on the ASCO/IDSA clinical practice guideline which provides updated recommendations on outpatient management of fever and neutropenia in patients with cancer. Read the full guideline at www.asco.org/supportive-care-guidelines

View Details

An interview with Dr. Bryan Schneider of the University of Michigan on the ASCO clinical practice guideline to increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Read the full guideline at www.asco.org/supportive-care-guidelines

ASCO Guidelines: Recent Episodes

American Society of Clinical Oncology (ASCO)