Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck Guideline

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

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.23.02744.   

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. 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.  

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.

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

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.23.02746.   

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.  

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.

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.  

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.

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.

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

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 disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02128 

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.

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 

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. 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.  

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.

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. 

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.

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

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

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. 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-A*02:01-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-A*02:01-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.  

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.

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.  

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.