ASCO Guidelines

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

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

Dr. Cris Bergerot and Dr. Enrique Soto join the podcast to discuss the new global guideline on geriatric assessment. This guideline provides evidence-based, resource-stratified recommendations across the basic, limited, and enhanced settings. Dr. Bergerot and Dr. Soto discuss who should receive a geriatric assessment, the role of geriatric assessment, which elements of geriatric assessment can help predict adverse outcomes, and how a geriatric assessment is used to guide care and make treatment decisions. They comment on the importance of this guideline worldwide, and the impact of this guideline for a wide range of clinicians, patients, researchers, policymakers, and health administrators. Read the full guideline, "Geriatric Assessment: ASCO Global Guideline" at www.asco.org/global-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/global-guidelines. Read the full text of the guideline, view clinical tools and resources, and review authors' disclosures of potential conflicts of interest in the JCO Global Oncology, https://ascopubs.org/doi/10.1200/GO-25-00276 Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Cris Bergerot from OncoClínicas & Co and Dr. Enrique Soto from the University of Colorado, co-chairs on "Geriatric Assessment: ASCO Global Guideline". Thank you for being here today, Dr. Bergerot and Dr. Soto. Dr. Cris Bergerot: Thank you. Dr. Enrique Soto: Thanks for the invitation, Brittany. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bergerot and Dr. Soto who have joined us here today, are available online with the publication of the guideline in JCO Global Oncology, which is linked in the show notes. So then to jump into the guideline here, Dr. Soto, could you start by providing an overview of the scope and the purpose of this global guideline on geriatric assessment? Dr. Enrique Soto: Of course, Brittany. So, this guideline comes from a request from the global oncology community and from the geriatric oncology community, who is very interested in making sure that geriatric oncology recommendations that are used in the United States can be adopted and used globally. So, this was a very highly rated topic when we had our call for proposals for guidelines, and that's why we decided to do this. The idea of this guideline is to provide resource-stratified recommendations for the use of geriatric assessments and interventions in older adults with cancer across different settings, right? And that these guidelines can be applied by clinicians working in low- and middle-income countries, but also, in a way, by clinicians working in community settings where the availability of resources may be limited. And the idea of these recommendations is to help clinicians evaluate older people with cancer better and also understand which interventions can be implemented with the resources they have and which interventions have a bigger bang for the buck, so to speak. And as all evidence-based, stratified guidelines that ASCO conducts, we stratified resources as basic, limited, or enhanced. And that means resources that go from those that provide the greatest benefits for patients in terms of outcomes to those that are evidence-based but provide additional additive benefits. And those resource-stratified recommendations can be found in the ASCO website as to how these guidelines are developed, and that's pretty standard for most resource-stratified guidelines. Brittany Harvey: Great. I appreciate that background and the impetus for this guideline, and thank you for providing that resource-stratified framework of basic, limited, and enhanced. I think that helps provide context for the guideline recommendations here. So then, Dr. Bergerot, I'd like to next review the key recommendations of this guideline across the four clinical questions that the guideline addresses. So, across those settings, the basic, limited, and enhanced settings, what is the role of geriatric assessment in older adults with cancer to inform specific interventions? Dr. Cris Bergerot: I think this is one of the most important points, so let's break it down. First off, who should actually receive the geriatric assessment? And the recommendation is clear. All patients aged 65 and older who are being considered for systemic cancer therapy should undergo a geriatric assessment. Now, depending on the available resources, for example, in basic setting, a quick screening may be enough, but in enhanced setting, a comprehensive geriatric assessment is encouraged. And for our next question, in which elements of the geriatric assessment can help predict poor outcomes, the core domains to focus on include things like physical function, comorbidities, polypharmacy, cognition, nutrition, social support, and psychological health. And there are also validate tools like the G8, the CGA, and the CARG that can be used depending on the setting and resources available. Now, talking about how we actually use the geriatric assessment to guide care, the assessment results can guide interventions to reduce treatment-related toxicities and maintain the patient functions. So, even in basic settings, the result can help guide those adjustments or identify the need for supportive care. And in more resource settings, we can implement more tailored intervention based on those findings. And finally, for our fourth question: How can geriatric assessment help guide treatment decisions? So, GA can influence decisions about how aggressive treatment should be, help clarify goals of care, and determine whether a curative or palliative approach makes the most sense. And again, even in settings with limited resources, a simplified GA can still provide meaningful guidance. Brittany Harvey: Great. Thank you, Dr. Bergerot, for that high-level overview of the recommendations of this guideline. So then, following that, Dr. Soto, which geriatric assessment tools and elements should clinicians use to predict adverse outcomes for older patients receiving systemic therapy across the basic, limited, and enhanced settings? Dr. Enrique Soto: Yeah, so that is an excellent question because it's something that people want to know, right? When people start developing a geriatric oncology clinic, one of the first things they want to know is which tools should I use. And we hope that this guideline will provide some clarity regarding this. So, our overarching recommendation is that every patient, regardless of the level of resources, should receive some sort of geriatric assessment. And that geriatric assessment can go from a simple screening tool, such as the G8 tool, which is available online and very easy to do, and that can be done in basic settings, to a more sophisticated geriatric assessment. The important thing, and what we emphasize in the guideline, is that regardless of the tool you use, it should include those high-priority domains that are associated with outcomes in older adults with cancer. And those include an assessment of physical function, of cognition, emotional health, comorbidities, polypharmacy, nutrition, and social support. In addition to that, an important thing that the guideline does is endorse the recommendation from our parent guideline, the guideline from high-income settings, the practical geriatric assessment, which is a tool that was actually developed by the ASCO Geriatric Oncology Group, which is a self-administered tool that people can use to evaluate their patients in a prompt and fast manner. And what we actually did for this guideline is include the validation of the various tools included in the practical geriatric assessment in the five most widely spoken languages in the world, including Hindi, Chinese, Spanish, and French, and Portuguese. And so, most of these tools are validated in these languages. So, we believe that the practical geriatric assessment is a tool that can be utilized across settings and that doesn't require a lot of resources. I think an important future step is making sure that we get the practical geriatric assessment translated into various languages, and we're working with the ASCO team in getting that done. Brittany Harvey: That's an excellent point. And yes, we'll hope to have the practical geriatric assessment translated into more languages. And that tool is available linked in the guideline itself, and we'll also provide a link for listeners in the show notes of this episode (Practical Geriatric Assessment). So then, following that, Dr. Bergerot, in resource-constrained settings, what general life expectancy data should clinicians use to estimate mortality and inform treatment decision-making? Dr. Cris Bergerot: So, in basic and limited resource environments, you might not have access to every tool or specialist, but you can still make informed and thoughtful decisions. So, what the guideline recommends is to start with population-level life expectancy tables. These are available through the WHO Global Health Observatory, and they offer useful starting points. And if available, clinicians should also look for country-specific or regional survival data. That kind of local information can be even more relevant to your patient population. The clinical judgment is also key here, and it becomes even more powerful when it's guided by the patient's geriatric assessment results. And when possible, use age- and comorbidity-adjusted models, like the Lee index or tools from the ePrognosis. This can help refine estimates of mortality risk and also inform how aggressive treatment should be. Brittany Harvey: Absolutely. I appreciate you providing those specifics as well. So then, following that, Dr. Bergerot mentioned this a little bit earlier, but Dr. Soto, how should geriatric assessment be used to guide management of older patients with cancer across the basic, limited, and enhanced settings? Dr. Enrique Soto: Yeah, and again, that's another important focus, right? Because if we assess things and then don't do anything about them, then why even assess them, right? And in many settings, people say, "Well, I don't have the tools to provide the interventions that these patients actually need." And a very significant part of building this guideline was coming up with a resource-stratified and evidence-based way in which to prioritize which interventions provide most benefits for older adults with cancer. And so, for each level and each domain, we have a series of interventions that have been stratified according to importance and evidence base, and that is actually one of the coolest features of the guideline. We included a table, and then we have for each of the domains, including falls, functional status, weight loss, et cetera, what are the interventions that oncologists can do in their clinical visit without needing a lot of resources, including providing some specific information, giving some recommendations to patients, to more high-level things that can be done when the healthcare system allows it, such as working with a nutritionist, providing supplements, testing for particular cognitive impairments, et cetera. So, I encourage people to take a look at that table. It was really a lot of work putting that table together, and that table has specific recommendations for each setting, and I think people will find it very useful. Brittany Harvey: Absolutely. That table certainly contains a lot of information that's very helpful for clinicians. I think it's important to call out those tailored interventions to improve care and quality of life for every patient. So then, we've just reviewed all of the recommendations in this guideline. So, I'd like to ask you, Dr. Bergerot, in your opinion, what should clinicians know as they implement these recommendations across resource levels? Dr. Cris Bergerot: I would say that clinicians should remember that even a brief geriatric assessment can make a meaningful difference. You don't need a full suite of tools to improve quality of care, but clinicians should tailor all the tools that are available in their local context and always keeping in mind the core geriatric domains that we have mentioned in the very beginning of our podcast. And let's be clear, the goal of the assessment isn't just to gather data, as Enrique mentioned; it's to use this information to guide treatment decision and also to improve outcomes. And whenever possible, clinicians should engage interdisciplinary teams that might include nurse, psychologist, social workers, community health workers, or anyone who can help address the patient's broader needs. And flexibility really matters. So, especially in settings with limited access to specialists or diagnostics, we should prioritize what is feasible and what will truly help our patients during their journey. And above all, we should keep this in mind that equity in care delivery is essential. Just because resources are limited doesn't mean we can't deliver age-sensitive and even patient-centered care. Brittany Harvey: Definitely. That multidisciplinary care that you mentioned is key, and also thinking about what is feasible across every resource level to provide optimal care for every single patient. So then, to expand on that just a little bit and to wrap us up, Dr. Soto, what is the impact of this guideline for older adults with cancer globally? Dr. Enrique Soto: Well, what we hope this guideline will lead to is to a boom in geriatric oncology worldwide, right? That is our final goal. And what we want is for clinicians interested in starting a geriatric oncology program or setting up a geriatric oncology clinic to use these guidelines in order to justify the interventions that they're going to do, to pick the important partners they need for their multidisciplinary team, to choose the tools that they're going to implement. And then, with that, to present this to leaders in their hospitals, leaders in their healthcare system so that they can start these clinics that will ultimately lead to better outcomes for older adults with cancer. So, I encourage people to view this as high-quality, evidence-based recommendations that are done by a group of experts and with a thorough review of the literature and also based on our parent guidelines. The fact that these guidelines are resource-stratified does not by any mean signify that they're of less quality or that the recommendations that are included in those are not proven to improve outcomes, cancer-specific and also general outcomes, in older adults with cancer. Another thing that I think these guidelines could do in the future is motivate researchers in low- and middle-income countries to fill in the gaps that we have identified in these guidelines. We've made it very clear across the guidelines where evidence is lacking. And I think that this should prompt researchers across the globe to start trying to fill in these gaps with high-quality research. And finally, I also think that this is a call for policymakers, health administrators, and people interested in public health to start scaling up resources so that places with basic resources can eventually become places with more sophisticated resources. And I think this does not only apply to low- and middle-income countries, but also to community oncologists in the US who may be facing resource constraints. And I think that these guidelines can help them stratify and understand what things should be implemented first and how to scale up. So yeah, that's the dream that with this guideline, more people will start implementing geriatric oncology around the globe and that ASCO will continue to be a leader in setting the stage for what should be done in geriatric oncology and for improving care to older adults with cancer, regardless of where they live. Brittany Harvey: Absolutely. This guideline is wide-reaching and has important impacts worldwide. So, I want to thank you both so much for the huge amount of work you took to develop this evidence-based guideline, and thank you for joining me on the podcast today, Dr. Bergerot and Dr. Soto. Dr. Cris Bergerot: Thank you so much. Dr. Enrique Soto: Thank you for the invitation. It was a pleasure. Brittany Harvey: And finally, thank you to our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/global-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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. Joshua Reuss joints that podcast to discuss the latest changes to the living guideline on stage IV NSCLC with driver alterations. He discusses the new evidence for NSCLC with EGFR mutations and NRG1 fusions and how this impacts the latest recommendations from the panel. He shares ongoing research that the panel will review in the future for further updates to this living guideline, and puts the updated recommendations into context for clinicians treating patients with stage IV NSCLC. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2025.1" at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-01061 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. Joshua Reuss from Georgetown University, co-chair on "Therapy for Stage IV Non–Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2025.1." It's great to have you here today, Dr. Reuss. Dr. Joshua Reuss: Thank you. Happy to be here. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Reuss, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So to dive into what we're here today to talk about, Dr. Reuss, this living clinical practice guideline for systemic therapy for patients with stage IV non–small cell lung cancer with driver alterations is updated on an ongoing basis. So what prompted this latest update to the recommendations? Dr. Joshua Reuss: Yes, thank you. It's very important that we have living guidelines that are continuously updated. We obviously don't live in a static environment where things are non-changing, and we really need to apply the most up-to-date and current evidence to treat our patients with the most effective strategies, the most groundbreaking strategies. And so to have guidelines that can be disseminated, particularly these ASCO guidelines, to treating providers is incredibly important. So, with any of these updates, we review ongoing studies, published work, for the quality of evidence to see if it's something that warrants making adjustments to our guidelines or at least incorporating the information so that providers can review it and incorporate this into their own personal decision-making. So in this particular update, we reviewed evidence particularly pertaining to EGFR-mutated non–small cell lung cancer and non–small cell lung cancer harboring an NRG1 fusion. Brittany Harvey: Yes, certainly there's a lot of new evidence in the advanced non–small cell lung cancer field, and so we appreciate the panel's continuous review of this evidence. So then you just mentioned two separate areas where the panel reviewed new evidence. So starting with that first one, what updated evidence did the panel review on first-line treatment options for patients with EGFR alterations, and how did this impact the recommendations? Dr. Joshua Reuss: Yes, so advanced EGFR-mutated non–small cell lung cancer, at least with classical activating alterations - that is our exon 19 deletions and our exon 21 L858R mutations - is something that's really evolved rapidly in the last few years. You know, for many years, we basically, for the frontline treatment setting, were saying, "Okay, we have a targeted therapy, osimertinib. We're going to give that, and we're going to see what effect we can get out of that," with, you know, a median time of duration of treatment response averaging around 18 months, knowing that there are some that that's a lot longer and some that are a lot shorter. But recently, we've seen a lot of data emerging on combination strategies. The guideline has already been updated to incorporate two of these combinations: osimertinib with chemotherapy based off of the FLAURA2 trial, and then the combination of amivantamab with lazertinib based off of the MARIPOSA trial. And that was data on progression-free survival that was published and led to those particular recommendations. Now, more recently, we've seen data come out in smaller, randomized studies for other combinations. And more recently, we reviewed the RAMOSE study. So this was a phase II, open-label, randomized trial for patients with tyrosine kinase inhibitor–naive and really, treatment-naive advanced EGFR-mutated non–small cell lung cancer harboring one of these two classical EGFR alterations, randomized to either osimertinib alone or osimertinib with the combination of ramucirumab, which is an anti-VEGF agent. There's been a lot of data, preclinical and clinical, for the role of VEGF blockade, particularly in EGFR-mutated non–small cell lung cancer, so exploring the combination of this for synergy in the frontline setting really made a lot of sense. So again, this was a phase II trial that randomized patients prospectively to one of these two regimens. The population here is really what we typically see with EGFR-mutated non–small cell lung cancer, predominantly a younger population - median age on this study was 65 - predominantly female - 71% female - and predominantly nonsmokers. Now, what this study showed was that at a median follow-up of 16.6 months, the progression-free survival favored the combination arm with a median progression-free survival of 24.8 months with the combination of osimertinib plus ramucirumab versus 15.6 months for osimertinib alone, for a hazard ratio of benefit of 0.55. The landmark one- and two-year endpoints for progression-free survival also favored the combination arm, and response rates were relatively comparable between groups, with overall adverse events being more frequent in the combination group, specifically high blood pressure, proteinuria, and epistaxis, which are our common adverse events related to VEGF-blocking agents. So, it's good to see data in this space. Now, of note, though, this was a phase II study, so not a phase III level of evidence. In addition, when looking at the population, this was a randomized, multicenter study, but it was a US-only population. There was also some imbalance in the number of visits between arms, so the combination arm was seen more frequently than the arm that got osimertinib alone. Now, the imaging assessments were no different, but obviously this could lead to potential confounding, at least in timing of awareness of potential side effects and and things being brought to the attention of investigators. So very promising data here, but because, you know, of this being a phase II study, this actually led to no changes in the guideline at this time. Brittany Harvey: Understood. Yes, as you mentioned prior, it's important to understand the full body of evidence and to review the trials even when it doesn't impact the recommendations. Dr. Joshua Reuss: And I will say that, you know, there is an ongoing phase III study looking at a very similar combination. It's the phase III ECOG-ACRIN trial of the combination of osimertinib plus bevacizumab versus osimertinib alone in this specific population. So, you know, I think we will see phase III–level data for a combination of VEGF with osimertinib, but again, promising phase II data that did not lead to a change in the recommendation at this time. Brittany Harvey: Absolutely. We'll look forward to that ongoing trial to learn more about combination in this patient population. So then moving to that second patient population that you mentioned earlier where the panel reviewed evidence, what is the updated evidence and recommendation for patients with NRG1 fusions? Dr. Joshua Reuss: Yeah, so this was an exciting update that we made more recently with this unique iteration of the living guidelines. So, NRG1 fusions, this is perhaps a newer kid on the block in terms of driver alterations that has been known to be identified in non–small cell lung cancer among other solid tumors. It is very rare, occurring in less than 1% of solid tumors, but something that we know is a unique oncogenic pathway that can lead to oncogenesis and cancer development, including in non–small cell lung cancer. So up until now, unfortunately, there have not been targeted therapies that target this unique alteration. It's somewhat different than other driver alterations where there's a top-level signaling change in a protein. This is more of a ligand alteration that then alters, that then enables activation of more classical pathways, but again, through upregulation of a unique ligand. So a slightly different pathway but something that we know should be able to be targeted to promote patient survival for those with NRG1 fusions. So the therapy here is a therapy called zenocutuzumab. It's an IgG1 bispecific antibody against HER2 and HER3. So it prevents the downstream dimerization and signaling that occurs as a result of this NRG1 fusion and upregulation of the NRG1 signal. This was, as you can imagine with a rare alteration, a large phase II registrational study that examined this in advanced solid tumors containing the NRG1 fusion. This is the NRG1 registrational trial. And this study enrolled patients with advanced solid tumors who had progressed on prior therapy. Patients were treated with zenocutuzumab 750 milligrams IV every two weeks. Among 158 response-evaluable solid tumor patients, the response rate was 30%, median duration of response of 11.1 months, and a median progression-free survival of 6.8 months. Now, in those with non–small cell lung cancer, that made up 93 response-evaluable patients, very similar outcomes there: a response rate of 29%, median duration of response of 12.7 months, and a median progression-free survival of 6.8 months. This therapy did appear to be well tolerated. The most common higher-grade emergent side effects - grade 3 or higher - were anemia occurring in 5% and elevated liver numbers occurring in 3%. So this is a subsequent-line study, so this led to the updated recommendation that clinicians may offer zenocutuzumab in the subsequent-line setting for patients with advanced non–small cell lung cancer who harbor NRG1 fusions. So I think this does speak toward the incredible importance of next-generation sequencing and molecular testing for patients, particularly to include testing that looks at the RNA. These large fusions can sometimes be very challenging to detect on DNA sequencing platforms alone, so it's important to, if you have a high level of suspicion for an alteration like this, perhaps some of the mucinous adenocarcinomas where it's been challenging to find a driver alteration, and it's someone who is a never-smoker, really would want to include molecular testing that assesses the RNA level and not just the DNA. Brittany Harvey: Absolutely. It's important to have all the biomarkers available so that clinicians are able to use that to inform their decision-making. So then, given these changes in the guideline, what should clinicians know as they implement this latest living guideline update? And how do these changes impact patients? Dr. Joshua Reuss: Yeah, I think talking in reverse order of what we just discussed here, there is a new guideline update for NRG1 fusions. So I think making sure that that's being evaluated, that clinicians are testing for that and really looking for that result that should be incorporated in in most next-generation large sequencing assays to get that result, but it's very important that that is not overlooked now that we do have a therapy that's available in the subsequent-line setting, though it is important to note that patients with NRG1 fusions, at least the limited data that there is suggests that the efficacy to standard chemoimmunotherapy regimens is overall poor. So physicians unfortunately might be facing this question for second-line therapy in patients with NRG1 fusions sooner rather than later. For the former, for EGFR-altered non–small cell lung cancer and how do we incorporate VEGF-containing regimens into these patients? Our guideline top-level update did not change based off of review of this new study, but it's important for clinicians to know what other combinations may exist. You know, there are phase III studies looking at this combination in the frontline setting. And of course, there is data on other bispecific molecules that incorporate VEGF in the subsequent-line setting, particularly a combination that includes the VEGF/PD-1 bispecific antibody ivonescimab that's being studied in the HARMONi-A trial for patients with EGFR-mutated advanced non–small cell lung cancer, for which we hope to get some more definitive data in the coming months. Brittany Harvey: Definitely. And then you've just mentioned a few ongoing trials where we're looking for evidence to inform future updates. But thinking beyond that, into the future, what is the panel examining for future updates to this living guideline? Dr. Joshua Reuss: It's a very exciting time to be in the world of treating advanced non–small cell lung cancer, particularly patients with driver alterations, because there is so much evolving data that's changing our practice in real time, again highlighting the importance of these living guideline updates. I'd say there's many things that we're excited to see. You know, a lot of the combination regimens in EGFR-mutated non–small cell lung cancer for which there are approvals and current recommendations in our guideline, particularly osimertinib plus chemotherapy and amivantamab plus lazertinib - those are the two approved combination strategies in the front line - we are now seeing the emergence of overall survival data for those combinations. So obviously that is something that's going to be very important for the committee to review and incorporate into guideline updates. There are several new therapies coming down the road for other driver populations. We recently saw an approval for taletrectinib for ROS1 fusion–positive non–small cell lung cancer, so it's going to be important that the committee reviews the data and the publications regarding that therapy. And then there are other novel therapies that we're looking to see updated data on. There are multiple antibody-drug conjugates, which take the potent power of a chemotherapy molecule and attempt to make that targeted with an antibody targeting to a unique feature on the cancer cell. And there are several antibody-drug conjugates that are in development at various levels of promise in this space, particularly in EGFR-mutated non–small cell lung cancer, and I anticipate seeing some emerging data for that coming up in the near future as well. So really, lots to be excited in the space and lots for our committee to review to give guidance on so that these patients can really receive the top-level care wherever they are being treated in the country and throughout the world. Brittany Harvey: Yes, we'll await this new data to continue to provide optimal options for patients with stage IV non–small cell lung cancer with driver alterations. So, Dr. Reuss, I want to thank you so much for your work to rapidly and continuously update and review the evidence for this guideline and thank you for your time today. Dr. Joshua Reuss: Thank you so much. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available on the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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. Luis Raez and Michael Reff share the newest update to the medically integrated dispensing pharmacy standards from NCODA and ASCO. They review updates to domain one, on key patient-centered quality standards on health equity and social determinants of health, drug access, patient safety, education, and adherence to maximize treatment outcomes and domain two, on key operational quality standards on logistics, care coordination, and waste prevention. We also cover the impact of these updated standards for clinicians, oncology practices, and people receiving oral anti-cancer medications. Read the complete standards, "Medically Integrated Dispensing Pharmacy: ASCO-NCODA Standards." Transcript These standards, clinical tools, and resources are available on ASCO.org. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the JCO Oncology Practice. Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Michael Reff from the Network of Collaborative Oncology Development and Advancement and Dr. Luis Raez from Memorial Cancer Institute and Florida Atlantic University, co-chairs on "Medically Integrated Dispensing Pharmacy: American Society of Clinical Oncology – Network of Collaborative Oncology Development and Advancement Association Standards Update." Thank you for being here, Michael and Dr. Raez. Dr. Luis Raez: Thanks for inviting us. Michael Reff: Thank you for having us. Brittany Harvey: Then, before we discuss these standards, I'd like to note that ASCO takes great care in the development of its standards and ensuring that the ASCO Conflict of Interest policy is followed for each guidance product. The disclosures of potential conflicts of interest for the expert panel, including Michael and Dr. Luis Raez who have joined us here today, are available online with the publication of the standards in JCO Oncology Practice, which is linked in the show notes. So then, to dive into the content here, Michael, I'd like to start with what prompted an update to these ASCO-NCODA standards and what is the scope of this update? Michael Reff: Thank you, Brittany. What led NCODA and ASCO to endeavor in this, and it started back in 2019 as the amount of oral anticancer medications became more and more prevalent in cancer treatment, we saw the need providing a blueprint for excellence in care for patients prescribed oral anticancer medications, specifically in the outpatient setting. And the update was driven by the rapid growth of these oral oncolytics starting back in the mid to late 2015 through 2019 or so, and then continued on into the 2020s where we are today. We saw the increase in the complexity of the management of these patients with these therapies basically outside the traditional clinical settings. And we wanted to make sure that with more cancer treatments that are taken at home than just at the clinic, like in the oral setting, new challenges had emerged around patient safety, access, adherence, and overall treatment success. The updates now address patient-centered and operational interventions designed to improve access, safety, quality, accountability, and outcomes of oral anticancer and other supportive care medications prescribed for the cancer patient. Dr. Luis Raez: As Mike said, these guidelines help improve patient care tremendously, but also help us a lot as an oncologist, you know, community oncologists that- now that we have opportunity to dispense these oral oncolytics, we need help to create our medical integrated pharmacies, and NCODA is providing here a way that, how to do this safely, efficaciously, good quality, you know? So that's why I think we always do everything for the patients, but also this helps a lot to the doctors. And there are a lot of what we call specialty pharmacies or medical integrated pharmacies now nationwide. Michael Reff: I'll build on what Dr. Raez had mentioned. This is the impetus. If you looked at the innovation that was coming from the pharmaceutical companies, many of it coming in the oral form for anticancer medications, and based on that, taking a look at the infrastructure that is in place in these practices, whether it's in the community or the IDN or health system settings, this amount of innovation that was coming needed to be addressed by taking a look at the medically integrated oncology team. And these standards address not just the pharmacy component, but also the whole continuum of care, starting with a medical oncologist or the hematologist, with the pharmacists, nurses, the pharmacy technicians, others that are involved in the care of the patient. And there were no standards involved. And when we approached ASCO back in 2018 to eventually publish the first version of these standards, the need was identified, and we worked collaboratively with ASCO to create the first set and then the revisions as we talked about. One thing to note regarding the revision plus the original standards, we had a cross-section of the care team on the committee, and we did that very purposefully. So, the ASCO-NCODA team curated a committee to help develop these original standards and the revision of these standards with medical oncologists both from community and health systems, pharmacists from both community and health systems, and also nurses. And we also included a patient that currently has and currently receives oral anticancer medication. And so NCODA and ASCO are very proud of the committee that we put together because of the experts in their field, but also extended the invitation to a current patient. And we embedded everybody's expertise in the curation of these standards. Brittany Harvey: Absolutely. I appreciate that background and context and how it's critical to improve patient care. And these standards really help oncologists, and we're looking across the continuum of care to provide optimal care for our patients. So then next, Dr. Raez, I'd like to review the key points of the revised standards for our listeners. So for Domain 1, what are the key patient-centered quality standards on health equity and social determinants of health, drug access, patient safety, education, and adherence to maximize treatment outcomes? Dr. Luis Raez: Yeah, this was a great effort, you know, at the multidisciplinary team. And as you can read in the standard, there were more than 240 publications reviewed; more than 55 of them are quoted here. And the standards are in two groups, as you said. With the group one, I'll briefly mention some of them. For example, SDOH, social determinants of health, is very important because as doctors, we prescribe, and sometimes patients don't get the medication, you know? And we prescribe assuming that 100% of the patients will get the medication. But something simple like the patient doesn't have insurance, the patient is underinsured. I have a patient that we didn't have an address to send the medication because he's homeless. Something that as a doctor you say, "Oh, oh my God, this is outside my realm," but it's not outside reality. So that's why, even if we don't think that this is part of our expertise dealing with social determinants of health, the fact that the patients have food insecurity, they don't have transportation, they don't have insurance, they don't have a caregiver, impact tremendously in the outcomes of the therapy. So that's why, basically, in this standard, we want to call attention that SDOH, social determinants of health, needs to be identified. There are in the literature countless examples of why this is important. For example, in the guidelines, we quote two or three examples of prostate cancer studies that, for example, we quote a study of 27,000 people with prostate cancer that were taking oral oncolytics, and how come the fact that the elderly, seniors, the fact that they have high prescription costs, and how all of this affected the adherence to the medication. And that's why it's important to identify the SDOH. And in other sections of the guidelines, we said how to address them, no? Another important thing in this domain is the cultural, you know, we need to be culturally sensitive and to take care of all of these social factors. For example, here in South Florida, we deal with the Haitian culture, Filipino culture, Latin culture, and American culture, and it's a blend, but it's not easy to go from one to the other. Another one is the fact that we have to include new technologies. A lot of patients, for example, we use EMR, EMR Epic, and now Epic has everything in the phone. The fact that we can have now the patient can see her prescription medication over the phone, the fact that they can use the phone to request from you a refill, and from your phone, you send the refill to the pharmacy, and you notify from your phone to the patient that the refill is sent, and the patient can check in his phone that the refill is ready. These things are amazing because that's why it's important that we incorporate these technologies to the patient care, and in this specific case, of dispensation of oral therapies, no? Another crucial point is education. You cannot be sending a patient a package of 300 pills without education. So that's why in our guidelines, mainly pharmacy, clinical pharmacies, or in some centers like mine, we have advanced practice providers, it's mandatory in our centers to have like a one hour of education before you send the prescription. So the patient is aware about side effects and contraindications, all of these things. They provide them also materials and also consent. You know, in the old times, you don't give chemo without a consent. Now, a lot of people say, "Oh, it's only a pill." There is a lot of benefits or side effects that can come from the pill, so you need to consent everybody, you know? So, another aspect is adherence. I already told about that, but we need to provide patients with a baseline assessment, no? So, you cannot send again the prescription and hope, "Oh, I'll figure it out what happened next month when the patient comes back." I tell you, the patient is homeless, where are you going to send it? If the patient is telling you, "I don't have insurance," what good is it for you to send a prescription? The patient will not get it. So that's why you need to do a baseline assessment of adherence. You need to do a calendar. You need to do electronic support, I mentioned already with the EMR and the phones. For example, my MIP, my specialty pharmacist, sends me a message in the EMR, "Dr. Raez, the insurance is not covering, the patient has a high copayment, we are going to delay the dispensation of the medication." So there needs to be a communication. Or sometimes there is a confusion with the insurance, and I cannot wait for the poor patient to call three, four weeks later, "Oh, I didn't get the medication," to know what happened, no? My MIP is very good. They send the clinical pharmacist a message, "Hey, you know, the insurance doesn't believe that the pill is adequate, or you need to provide more documentation. You need to prove the mutation, the genetic aberration." So if you provide us that, the insurance may approve. So that communication with the doctor is very important to improve adherence. And one important thing that we have in this one that we didn't have in the anterior is the tracking of outside medications. A lot of times you say, "Okay, the insurance allowed us to provide the medication it's 100% responsible." But then the insurance says, "Oh, no, no, don't worry. CVS will provide the medication." So it says, "Well, it's you know, it's not my responsibility. CVS will provide the medication, they have to take care." But we know that outside our specialty pharmacies or MIPs, the care is not very good. So that's why we are taking our ownership that, "Okay, the insurance said the patient will get the medication from some outside pharmacy." But our clinical pharmacists track that. What happened? Did the patient get it? The patient didn't get it. The copayment is still high. So even if you get the medication from somewhere else, if the copayment is high, we, our clinical pharmacists, help the patient to navigate and get the foundation or the copayment or finally the maker, the industry partner, provides the drug for free, but somebody needs to do the paperwork. And that's why this is very important. We cannot abort our responsibility because, "Oh, the insurance said somebody else will give it." I work for the public healthcare system, so my patients, some of them don't have insurance, they are underinsured. So we see these problems every day. And finally, the standards talk about the importance of safety, documentation, verification, monitoring, refills, you know, you need to keep track of refills. We already mentioned how important is the technology to facilitate the refills, and the quality. Brittany Harvey: Yes, thank you for touching on those highlights for Domain 1. It's important that all patients have access to care and these oral anticancer medications, and not only just access to care, but safe and effective care. It's really important, as you mentioned, Dr. Raez, to meet patients where they're at and incorporate technology. And I also want to note the coordination with external pharmacies that you mentioned in tracking outside medications as well. It's not only important for multidisciplinary care within the oncology practice itself, but also external to the oncology practice. That's why we put together this multidisciplinary panel to develop these standards. So then, expanding on that, Dr. Raez, for Domain 2, what are the key operational quality standards? Those on logistics, care coordination, and waste prevention. Dr. Luis Raez: Yeah, we have a lot of standards here, but maybe we can summarize in five or six points, no? For example, financial toxicity in cost and waste are very important because the patients, yeah, you put them on therapy, but as you can understand, if there is disease progression, the patient don't need the medications. And sometimes you get refills even if the patient has disease progression. If you do a dose reduction, the same problem. Or you discontinue medication and the patient keeps getting the drugs. So, you're talking about drugs that are between 20 and 30 thousand dollars per month. This is a lot of money. There are studies that we're quoting in the standards that the waste could be from 1 to 3 or 4 thousand per patient, no? Another aspect is dispensing. When you dispense the medication, this is not as easy as, "I'll ship to your house a bag of medications." You know, there needs to be a diagram, a decision tree. You need to train the staff to know what we're doing. There needs to be an auditing of the process. They need to be even packaging and shipping, you know? For example, I'm in Florida today and outside in summer it's going to be 95 degrees. So, everybody leaves the package outside your house, and sometimes you go the whole day until when you come at 6:00 p.m. There are medications that cannot be left outside there, you know? I don't know, it sounds like a joke, but I have a patient that the medication used to be stolen because people thought that that was something important, you know? And of course, it's important because it's a $20,000 medication. So, the poor patient, because he lives in an area that is not safe, has to come and pick up in person. All of these things sound very trivial, but that's real life that affects adherence. Another important thing is shortage. This is something that we just suffered two or three years ago, and we have to think about what happens in the next shortage. What happens if there's going to be a shortage? What do we do or how are we going to do that? Now we know it's something that is happening probably very soon again, and something that we have to consider. Another standard is the care coordination. You need to have probably, if it's possible, a coordinator. I know that for small practices it's very hard, but for big cancer centers, you should have a coordinator of this. I already mentioned before, the communication between the physicians and the doctors to coordinate the care, no? You need to write the prescription again, you need to provide more information, or to be notified, "Hey, you know, the patient is throwing up in the first week, you need to see the patient, please," no? So, this type of communication needs to exist so we can serve the patient better. It's also important, you know, we're improving quality and we're improving care. It's important to try to collect patient-reported outcomes. This is something that now we have the opportunity, if we do things well, to do it and show that we're providing a better care. The other thing is that we already mentioned SDOH in the other standard. In this standard, we mention mainly SDOH to partner. For example, we collect in my center SDOH, and I always get frustrated when the patient doesn't have transportation. But I didn't know that there are local institutions that provide free Uber rides, free Lyft rides. So that's why it's important to partner with these institutions. I have a local grocery chain that provides free food for the patients, and I didn't know that. It's important to be aware what the patient needs and what resources do you have to fulfill the SDOH. That's the part that we mention in here. So that's why, in summary, those are the six probably most important points here. I'll ask Mike for some comments. Michael Reff: Thank you, Dr. Raez. Brittany, to answer your question, and as was pointed out on logistics, care coordination, and prevention of waste, certainly that is an aspect that has changed in the revision that we're here to talk about. There's really two components to waste, and it's cost avoidance and then waste prevention. And as Dr. Raez mentioned several times, the importance of the medically integrated team and having the ability for that practice to fill that prescription internally and have robust documentation. Cost avoidance is a critical component that the medically integrated pharmacy, or the MIP, can help the total cost of care. And that is by preventing errant fills or waste that can occur by intervening in the care of the cancer patient, as we do every day. But when the practice has access to the medication and can fill that prescription in-house in the medically integrated pharmacy, that team, that care coordination that takes place, can prevent those errant fills or additional fills when there's dose reductions, there's holidays, there's things that happen in real time. And it's impossible for a mail-order pharmacy that's in another state that has lead times, when a prescription needs to be mailed 7 days or 10 days before the patient will run out of the medication, it's impossible for them to logistically coordinate that care like we can internally within the medically integrated pharmacy. So, we prevent waste and overall cost of care by cost avoidance and having that coordination or that continuity of care that we talk about. And we prevent waste from the mail-order pharmacies by taking that prescription internally and filling it, but also doing it in a way that's more sustainable and cost-effective for all stakeholders in the oncology ecosystem. Brittany Harvey: Absolutely. Thank you both for reviewing those key standards for Domain 2 and touching on the importance of distribution logistics and all the things that a medically integrated pharmacy needs to think through in getting oral anticancer agents to patients. Following that, Michael, we've touched on this a little bit earlier, but how will these updated standards impact clinicians and oncology practices? Michael Reff: Yes, and as Dr. Raez and I have discussed throughout this podcast, these additional standards are there to help support that continuity of care by educating the clinicians that are in the oral anticancer medication space to elevate their provision for these oral therapies. What I mean by that is the practice has to perform at a certain level in order for them to, as I call it, deserve the right to fill that prescription by having the processes and procedures in place. And these standards, these updated or revised standards, are the blueprint for better patient care and to help the practices execute on that journey of continuous improvement. Dr. Luis Raez: Yeah, I only want to add, we have practical examples in the guidelines. We quote a couple of studies that have been successful. And this year, for example, I am a lung cancer doctor, we are presenting in World Lung our standards of adherence to oral oncolytics for EGFR therapy, following the NCODA-ASCO standards. We're around 95% of adherence. We are a healthcare system that is public. We have people with no insurance and a lot of social determinants of health. We are trying to show that it's feasible, even in the most difficult circumstance, when you follow the standards, to be successful. Brittany Harvey: Definitely, these standards can help clinicians and oncology practices succeed in providing these medications. So then beyond that, and to wrap us up, Michael, what do these revised standards mean for patients who are receiving oral anticancer medications? Michael Reff: Yes, great point and question, Brittany, because we have covered the benefits to the clinicians and the practices themselves. But how is this going to support better patient care? And it does it in a whole host of ways. I'll cover just a few of them. What I'm about to share with you relates back to what we call at NCODA the "core claims." Like, what's the core claims of having a medically integrated pharmacy within the practice? And there are seven different core claims that we feel practices that are focused on the continuity of care can deliver better outcomes that are embedded in these standards. And it's talking about abandonment, adherence, access and affordability, speed to therapy or time to fill, as we call it, education, patient satisfaction, and cost avoidance that we covered earlier. So those are the core claims that a practice that follows these revised standards can help elevate. So, faster and more affordable access to the oral cancer medications; individualized support to address barriers like transportation, finance, language, or health literacy, and so on; clear, patient-friendly education; something that is near and dear to all clinicians' hearts, and of course, the patient that was on our panel or on our committee, to empower them to manage side effects and recognize when to seek help; and a stronger partnership with a care team, with regular follow-ups focused on their experience, challenges, and successes; and then, greater overall safety through proactive monitoring for medication errors or complications. So all of these aspects, or tenets, as I'll call them, are baked into these quality standards that are totally aligned with NCODA's core claims document that, again, talks about abandonment, adherence, access and affordability, speed to therapy, education, satisfaction for the patients, and also cost avoidance. Dr. Luis Raez: I only want to add and invite the community to adhere to these standards, to practice the standards. You will be providing the best patient care that we can nowadays. Brittany Harvey: Definitely. I think these standards are very important. And Michael, I thank you for touching on those key claims from NCODA. I think those, along with these updated standards, will improve outcomes for patients everywhere. So I want to thank you both so much for your work to update these standards and all the time you put into it. And thank you for your time today too, Michael and Dr. Raez. Michael Reff: I'd like to thank not only the committee, my esteemed committee that helped support the standards and the revision. Many of the original healthcare providers and patient that were on the first go of the standards were part of the second standards. We revised it, of course, and we got additional support from the new committee. And certainly ASCO and their partnership and collaboration with NCODA has been tremendous. And we look forward to the oncology community at large adopting these standards, again, to work together, we do become stronger, and it will improve cancer care for patients receiving oral anticancer medications. So thank you, Brittany. Dr. Luis Raez: I only want to say the same thing. Actually, there is probably more people in NCODA that is not in the publication that has helped. Same in ASCO. Also, we want to give thanks to Dr. Stephen Grubbs, our leader in quality. He's retiring. We're going to miss him, but he has been a key collaborator with Mike organizing these standards for the last five or six years. So, looking forward to these standards in practice. Brittany Harvey: Absolutely. A big thank you to the entire panel and everyone who contributed to this, and NCODA as well. And then finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the complete standards, go to www.asco.org/standards. I also encourage you to check out the companion episode on these standards on the PQI podcast by NCODA, which you can find on Apple Podcasts and Spotify. You can also find many of our standards and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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 shares the updated recommendations for the ASCO guideline on systemic therapy for patients with metastatic castration-resistant prostate cancer. He discusses the systemic therapy options for patients based on prior therapy received in the castration-sensitive and non-metastatic castration-resistant settings. He emphasizes personalizing treatment choices for each individual, considering patient-specific symptoms and signs, treatment-related toxicities, potential drug interactions, cost, and access. He also reviews recommendations on response assessment. The conversation wraps up with a discussion of potential future updates to this guideline, as the guideline transitions into a "living guideline" on mCRPC. Read the full guideline update, "Systemic Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Update". Transcript This guideline, clinical tools, and resources are available at www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology. 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 in Patients with Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Update." Thank you for being here today, Dr. Garje. Dr. Rohan Garje: Absolutely. Thank you so much for having me, Brittany. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Garje, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to start on the content of this guideline, first, could you provide us an overview of the purpose of this guideline update? Dr. Rohan Garje: Sure. So ASCO has guidelines for prostate cancer and the specific guideline which we have updated for metastatic castrate-resistant prostate cancer was originally published in 2014. It's almost a decade. It's been a long time due for an update. Over the last decade, we have seen a lot of advances in the treatment of prostate cancer, specifically with regards to genomic testing, newer imaging modalities, and also the treatment landscape. Now we have newer options based on genomic targets such as PARP inhibitors, we have radiopharmaceuticals, a newer variant of chemotherapy, and also some specific indications for immunotherapy which were not addressed previously. Because all these advances have been new, it was really important for us to make an update. In 2022, we did make a rapid update with lutetium-177, but these additional changes which we have seen made it an appropriate time frame for us to proceed with a newer guideline. Brittany Harvey: Absolutely. It's great to hear about all these advances in the field to provide new options. So I'd like to next review the key recommendations from this guideline. So let's start with the overarching principles of practice that the panel outlined. What are these key principles? Dr. Rohan Garje: As a group, all the panel members came up with some ground rules: What are necessary for all our patients who are being treated for metastatic CRPC? First, the founding aspect was a definition for what is metastatic CRPC. So we defined metastatic CRPC as castrate level of testosterone with evidence of either new or progressive metastatic disease on radiological assessments or patients who have two consecutive rising PSAs in the setting of existing metastatic disease. We also emphasized on the need for germline and somatic testing for patients with metastatic prostate cancer at an earliest available opportunity because it is critical to select appropriate treatment and also right treatment for patients at the right time. And we actually have a concurrent guideline which addresses what genes to be tested and the timing. The other principles are patients should continue to receive androgen deprivation therapy or undergo surgical castration to maintain castrate level of testosterone. Now the key aspect with these guidelines is personalizing treatment choices. As you can see the evolution of treatment options for prostate cancer, the drugs that were initially developed and approved for prostate cancer were primarily in castrate-resistant settings, but now most of these drugs are being utilized in castrate-sensitive. So, when these patients develop castration resistance, the challenges are there are no appropriate particular drug-specific guidelines they meet. So, it's very important for the clinicians to be aware of what treatments have been received so far prior to castration resistance so that they can tailor the treatment to patient specific situations. In addition, prior to choosing a therapy, it is important for the physicians to consider patient specific symptoms or signs, treatment-related toxicities, potential drug interactions, cost, and also access to the drugs. There may be multiple treatment options available for the patients, but for a patient specific scenario, there may be a drug that may be more promising than the others. So, it is important to tailor the drug choices based on patients' unique circumstances. The panel also recommends to early integrate palliative and supportive care teams for symptom management and also discuss goals of care with the patient as each patient may have unique needs and it's important for physicians to address those concerns upfront in the care. The panel also suggests patients to receive RANK ligand inhibitors such as denosumab or bisphosphonates such as zoledronic acid to maintain the bone strength to prevent skeletal-related events. Finally, I would like to also emphasize this point about the lack of randomized clinical trial data for optimal sequencing of therapies for patients with metastatic CRPC. As I previously alluded, we have taken into account all ongoing clinical trials, prior published data, and came up with a format of preferred drugs based on prior treatments and, I think, by following these several clinical principles which I just mentioned, we can optimally choose and utilize best treatments for patients with metastatic CRPC. Brittany Harvey: Absolutely. These principles that you just outlined are important for optimal patient care, and then I want to touch on one of those things. You talked importantly about the treatments received so far. So in the next set of recommendations, the role of systemic therapy was stratified by the prior therapy received in the castration-sensitive and non-metastatic castration-resistant setting. So starting with what does the panel recommend for patients who are previously treated with androgen deprivation therapy alone in these previous settings and whose disease has now progressed to metastatic castration-resistant prostate cancer? Dr. Rohan Garje: There are multiple treatment options based on prior treatment received. So for patients who received only ADT for their castration-sensitive disease, the panel strongly urges to get HRR testing to check for homologous recombinant repair related changes, specifically for BRCA1 and BRCA2 mutations, because we have three studies which have really shown significant clinical benefit for patients who have BRCA1 and BRCA2 mutations with drugs such as the combination of talazoparib and enzalutamide or olaparib with abiraterone or niraparib with abiraterone. Unless we test for those mutations, we'll not be able to give these agents upfront for the patients. In the HRR testing, if patients have HRR alterations but they are in genes which are non-BRCA, the guideline panel recommends to utilize talazoparib and enzalutamide based combination therapies. Now, if they don't have HRR alterations then there are multiple treatment choices available. It could either include androgen receptor pathway inhibitors such as abiraterone with prednisone. We could also consider docetaxel chemotherapy. The alternate choices for androgen receptor pathways include enzalutamide or the newer agents such as apalutamide and docetaxel. So, as you can see there are multiple options available, but the panel definitely emphasizes to test for HRR testing because this gives patients access to more precision therapies at this point. There may be various scenarios where a unique drug may be available for a specific patient situation. For example, patients who have very limited disease burden and may have one or two metastatic lesions, after a multidisciplinary discussion, targeted local therapies such as radiation or potentially surgery could also be offered. In select patients who have very indolent disease where they are castrate-resistant based on slow rising PSA, low-volume disease or asymptomatic disease can consider sipuleucel-T. And in patients who have bone-only metastatic disease, we could also consider radium-223, which is primarily now utilized for patients who have symptomatic bone disease. Brittany Harvey: Great. I appreciate you reviewing all those options and talking about how important it is to tailor treatment to the individual patient. So then the next category of patients, what is recommended for those who have been previously treated with ADT and an androgen receptor pathway inhibitor and whose disease has now progressed to metastatic castration-resistant prostate cancer? Dr. Rohan Garje: So for patients who received ADT along with an androgen receptor pathway inhibitor, which we consider would be a most common cohort because most patients now in castration-sensitive setting are receiving androgen receptor pathway inhibitor. It was different in the past where five or six years back ADT alone was the most common treatment, but fortunately, with enough awareness and education, treatment choices have improved. Patients are now receiving ADT and ARPI as the most common choice of drug. Once again, at this point the panel emphasizes to consider HRR testing in there is enough data for us to suggest that patients who have alterations in the HRR pathway definitely will benefit with the PARP inhibitor. You know the multiple options, but specifically we speak about olaparib. And then if they are HRR-negative, we prefer patients receive agents such as docetaxel or if they are intolerant to docetaxel, consider cabazitaxel chemotherapy, options such as radium-223, and if they have a specific scenario such as MSI-high or mismatch repair deficiency, pembrolizumab could also be considered. The panel also discussed about the role of a second ARPI agent. For example, if patients progressed on one androgen receptor pathway inhibitor, the second androgen receptor pathway inhibitor may not be effective and the panel suggests to utilize alternate options before considering androgen receptor pathway inhibitor. There may be specific scenarios where a second ARPI may be meaningful, specifically, if alternate choices are not feasible for the concern of side effects or toxicities or lack of access, then a potential ARPI could be considered after progression on ARPI, but the panel definitely encourages to utilize alternate options first. Brittany Harvey: Great. Thank you for outlining those options as well for those patients. So then the next category, what is recommended for patients who have been previously treated with ADT and docetaxel? Dr. Rohan Garje: For patients who received ADT and docetaxel and were never treated with androgen receptor pathway inhibitors, the panel again emphasizes on HRR testing. If they have BRCA1 and 2 mutations, the combination therapies of talazoparib with enzalutamide, olaparib with abiraterone, or niraparib with abiraterone are all good choices. If they don't have BRCA mutations but they have other HRR mutations, the panel suggests to potentially utilize talazoparib with enzalutamide. And if they do not have any HRR alterations, the options could include androgen receptor pathway inhibitors such as abiraterone or enzalutamide. I want to emphasize that these are preferred options, but not the only options. As you can see, there are multiple options available for a particular clinical situation - so the ability of the physicians to access particular combinations, the familiarity of those drugs or the patient's unique situation where they have other medications which can potentially interact with a choice of agents. So I think based on access, based on cost and patients' concurrent illness with potential drug interactions can make one particular combination of therapy better over the other options. Brittany Harvey: Absolutely. That's key to keep in mind that access, contraindications, and cost all play a role here. So then the next set of recommendations. What are the key recommendations for patients who have previously been treated with ADT, an androgen receptor pathway inhibitor, and docetaxel who now have mCRPC? Dr. Rohan Garje: Yes. In this group, the options remain, again, broad. We utilize PSMA imaging here specifically and if they are positive on PSMA imaging, lutetium-177 is a good option. If they do not have PSMA-positive disease on PSMA imaging but if they have HRR alterations, olaparib could be utilized. And if they are negative on PSA imaging, they don't have HRR alterations, then alternate options could include cabazitaxel, radium-223. And if they have MSI-high or deficiency in mismatch repair, pembrolizumab could be utilized in this setting. Brittany Harvey: Thank you for outlining those options as well. So then next the panel addressed treatment options for de novo or treatment emergent small cell neuroendocrine carcinoma of the prostate. What are those key recommendations? Dr. Rohan Garje: Yes. This is a very high unmet need group because there are limited clinical trials, especially prospective clinical trials addressing treatment options for this group. Most of our current guidelines are always an extrapolation from lung small cell cancer based guidelines, but the panel recommends to utilize cisplatin or carboplatin along with etoposide as a preferred choice for this group. Also, an alternate option of carboplatin along with cabazitaxel could be considered for this cohort. The panel also encourages participation in clinical trials. There are numerous trials ongoing now in smaller phase studies and I think it's important for patients to consider these trials as well, because this will give them access to newer agents with potential biological targets. In addition to these agents in specific scenarios or potentially case by case basis, because we don't have prospective data, so we have made it as a select case by case basis to consider adding immunotherapy along with platinum-based chemotherapy followed by maintenance immunotherapy, which is currently a standard of care in small cell lung cancer. But the data is so limited in prostate cancer, so the panel suggested that it has to be a case by case basis only. The alternate options also include lurbinectedin, topotecan, tarlatamab upon progression on platinum-based chemotherapy. Brittany Harvey: Yes. It's important to have these recommendations in these unique situations where there is really a lack of data. So then the final set of recommendations I'd like to cover, what does the panel recommend for how clinicians should assess for response while patients are on systemic therapy and what scans are recommended for this response assessment? Dr. Rohan Garje: Yes. Again, this is another strong emphasis of the panel for global assessment of the patients. Traditionally, patients and physicians per se are heavily reliant on PSA as an accurate marker for response. This is in fact true in earlier phases of prostate cancer either in castrate-sensitive setting or localized prostate cancer setting. But as patients evolve into castrate-resistant, we don't want to heavily rely on PSA alone as a marker of response. The panel suggests to incorporate clinical response, radiological response, and also include PSA as a component, but not just rely primarily on PSA. So the panel also suggests that patients should get a bone scan and a CT scan every three to six months while on treatment to assess for appropriate response or for progression. And now one key important aspect, we are all aware about the evolving role of PSMA-based imaging with several of these new agents that are currently available. We do acknowledge these scans definitely have an important role in the care for patients with metastatic prostate cancer. Currently, the utility is primarily to select patients for lutetium-based therapy and also in situations where the traditional scans such as technitium 99 bone scan or CT scan are equivocal, then a PSMA-based imaging can be helpful. Now we are also aware that there are newer studies coming up, prospective data coming up for the role of PSMA-based imaging for response assessment. We are hoping to update the guidelines if we get access to newer data, but currently we have not recommended the utility of PSMA-based imaging for response assessments. Brittany Harvey: Understood. And I appreciate you describing where there is data here and where there's a lack of data to currently recommend. And we'll look forward to future updates of this guideline. Coming back to – at the start you mentioned how much has changed since the last guideline update. So Dr. Garje, in your view, what is the importance of this update and how will it impact both clinicians and patients with metastatic castration-resistant prostate cancer? Dr. Rohan Garje: The updated guidelines are designed to have a significant impact on clinical practice and also patient outcomes by providing clinicians with a comprehensive evidence-based framework for managing patients with metastatic CRPC. And also, by using these guidelines can make informed decisions, can select therapies tailored to patients' unique genomic status, clinical situation, where they are in the course of the cancer based on what they received previously. Also utilizing these guidelines, we can potentially improve patient outcomes, improve survival, and importantly have efficient use of healthcare resources. Brittany Harvey: Absolutely. We're always looking for ways to improve patient outcomes and survival. I want to wrap us up by talking a little bit about the outstanding questions in this field. So earlier you had mentioned about prospective data to come about PSMA PET scans, but what other outstanding questions are there for patients with metastatic castration-resistant prostate cancer? And what evidence is the panel looking forward to for future updates? Dr. Rohan Garje: We do have now rapidly evolving data specifically about the utility of the radiopharmaceutical lutetium-177 prior to chemotherapy. We are hoping that with newer data we can make some changes to the guideline based on that. We are also looking at newer drugs that are coming up in the pipeline, for example, androgen receptor degraders. We are looking at data that might potentially help based on bispecific T-cell engagers and newer radiopharmaceuticals. So I think in the next few years, we will definitely update all the guidelines again. But this time we are trying to do it more proactively. We are following a newer model. We are calling it as 'living guidelines' where we are actually utilizing week by week updates where we look at the literature and see if there is any potential practice impacting change or publication that comes up. And we are trying to incorporate those changes as soon as they are available. That way patients and practicing physicians can get the latest information available through the guidelines as well. Brittany Harvey: That's great to hear. Yes, we'll await this data that you mentioned to continuously update this guideline and continue to improve patient outcomes for the future. So Dr. Garje, I want to thank you so much for your time to update this guideline. It was certainly a large amount of recommendations, and thank you for your time today, too. Dr. Rohan Garje: Thank you so much for having me here. And it's always nice talking to you. Brittany Harvey: And finally, thank you to our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Ko Un "Clara" Park and Dr. Mylin Torres present the latest evidence-based changes to the SLNB in early-stage breast cancer guideline. They discuss the practice-changing trials that led to the updated recommendations and topics such as when SLNB can be omitted, when ALND is indicated, radiation and systemic treatment decisions after SLNB omission, and the role of SLNB in special circumstances. We discuss the importance of shared decision-making and other ongoing and future de-escalation trials that will expand knowledge in this space. Read the full guideline update, "Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: ASCO Guideline Update" at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-00099 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. Ko Un "Clara" Park from Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Dr. Mylin Torres from Glenn Family Breast Center at Winship Cancer Institute of Emory University, co-chairs on "Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: ASCO Guideline Update." Thank you for being here today, Dr. Park and Dr. Torres. Dr. Mylin Torres: Thank you, it's a pleasure to be here. Brittany Harvey: And before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Torres and Dr. Park, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. To start us off, Dr. Torres, what is the scope and purpose of this guideline update on the use of sentinel lymph node biopsy in early-stage breast cancer? Dr. Mylin Torres: The update includes recommendations incorporating findings from trials released since our last published guideline in 2017. It includes data from nine randomized trials comparing sentinel lymph node biopsy alone versus sentinel lymph node biopsy with a completion axillary lymph node dissection. And notably, and probably the primary reason for motivating this update, are two trials comparing sentinel lymph node biopsy with no axillary surgery, all of which were published from 2016 to 2024. We believe these latter two trials are practice changing and are important for our community to know about so that it can be implemented and essentially represent a change in treatment paradigms. Brittany Harvey: It's great to hear about these practice changing trials and how that will impact these recommendation updates. So Dr. Park, I'd like to start by reviewing the key recommendations across all of these six overarching clinical questions that the guideline addressed. So first, are there patients where sentinel lymph node biopsy can be omitted? Dr. Ko Un "Clara" Park: Yes. The key change in the current management of early-stage breast cancer is the inclusion of omission of sentinel lymph node biopsy in patients with small, less than 2 cm breast cancer and a negative finding on preoperative axillary ultrasound. The patients who are eligible for omission of sentinel lymph node biopsy according to the SOUND and INSEMA trial are patients with invasive ductal carcinoma that is size smaller than 2 cm, Nottingham grades 1 and 2, hormone receptor-positive, HER2-negative in patients intending to receive adjuvant endocrine therapy, and no suspicious lymph nodes on axillary ultrasound or if they have only one suspicious lymph node, then the biopsy of that lymph node is benign and concordant according to the axillary ultrasound findings. The patients who are eligible for sentinel lymph node biopsy omission according to the SOUND and INSEMA trials were patients who are undergoing lumpectomy followed by whole breast radiation, especially in patients who are younger than 65 years of age. For patients who are 65 years or older, they also qualify for omission of sentinel lymph node biopsy in addition to consideration for radiation therapy omission according to the PRIME II and CALGB 9343 clinical trials. And so in those patients, a more shared decision-making approach with the radiation oncologist is encouraged. Brittany Harvey: Understood. I appreciate you outlining that criteria for when sentinel lymph node biopsy can be omitted and when shared decision making is appropriate as well. So then, Dr. Torres, in those patients where sentinel lymph node biopsy is omitted, how are radiation and systemic treatment decisions impacted? Dr. Mylin Torres: Thank you for that question. I think there will be a lot of consternation brought up as far as sentinel lymph node biopsy and the value it could provide in terms of knowing whether that lymph node is involved or not. But as stated, sentinel lymph node biopsy actually can be safely omitted in patients with low risk disease and therefore the reason we state this is that in both SOUND and INSEMA trial, 85% of patients who had a preoperative axillary ultrasound that did not show any signs of a suspicious lymph node also had no lymph nodes involved at the time of sentinel node biopsy. So 85% of the time the preoperative ultrasound is correct. So given the number of patients where preoperative ultrasound predicts for no sentinel node involvement, we have stated within the guideline that radiation and systemic treatment decisions should not be altered in the select patients with low risk disease where sentinel lymph node biopsy can be omitted. Those are the patients who are postmenopausal and age 50 or older who have negative findings on preoperative ultrasound with grade 1 or 2 disease, small tumors less than or equal to 2 cm, hormone receptor-positive, HER2-negative breast cancer who undergo breast conserving therapy. Now, it's important to note in both the INSEMA and SOUND trials, the vast majority of patients received whole breast radiation. In fact, within the INSEMA trial, partial breast irradiation was not allowed. The SOUND trial did allow partial breast irradiation, but in that study, 80% of patients still received whole breast treatment. Therefore, the preponderance of data does support whole breast irradiation when you go strictly by the way the SOUND and INSEMA trials were conducted. Notably, however, most of the patients in these studies had node-negative disease and had low risk features to their primary tumors and would have been eligible for partial breast irradiation by the ASTRO Guidelines for partial breast treatment. So, given the fact that 85% of patients will have node-negative disease after a preoperative ultrasound, essentially what we're saying is that partial breast irradiation may be offered in these patients where omission of sentinel node biopsy is felt to be safe, which is in these low risk patients. Additionally, regional nodal irradiation is something that is not indicated in the vast majority of patients where omission of sentinel lymph node biopsy is prescribed and recommended, and that is because very few of these patients will actually end up having pathologic N2 disease, which is four or more positive lymph nodes. If you look at the numbers from both the INSEMA and the SOUND trial, the number of patients with pathologic N2 disease who did have their axilla surgically staged, it was less than 1% in both trials. So, in these patients, regional nodal irradiation, there would be no clear indication for that more aggressive and more extensive radiation treatment. The same principles apply to systemic therapy. As the vast majority of these patients are going to have node-negative disease with a low risk primary tumor, we know that postmenopausal women, even if they're found to have one to three positive lymph nodes, a lot of the systemic cytotoxic chemotherapy decisions are driven by genomic assay score which is taken from the primary tumor. And therefore nodal information in patients who have N1 disease may not be gained in patients where omission of sentinel lymph node biopsy is indicated in these low risk patients. 14% of patients have 1 to 3 positive lymph nodes in the SOUND trial and that number is about 15% in the INSEMA trial. Really only the clinically actionable information to be gained is if a patient has four or more lymph nodes or N2 disease in this low risk patient population. So, essentially when that occurs it's less than 1% of the time in these patients with very favorable primary tumors. And therefore we thought it was acceptable to stand by a recommendation of not altering systemic therapy or radiation recommendations based on omission of sentinel nodes because the likelihood of having four more lymph nodes is so low. Dr. Ko Un "Clara" Park: I think one thing to add is the use of CDK4/6 inhibitors to that and when we look at the NATALEE criteria for ribociclib in particular, where node-negative patients were included, the bulk majority of the patients who were actually represented in the NATALEE study were stage III disease. And for stage I disease to upstage into anatomic stage III, that patient would need to have pathologic N2 disease. And as Dr. Torres stated, the rate of having pathologic N2 disease in both SOUND and INSEMA studies were less than 1%. And therefore it would be highly unlikely that these patients would be eligible just based on tumor size and characteristics for ribociclib. So we think that it is still safe to omit sentinel lymph node biopsy and they would not miss out, if you will, on the opportunity for CDK4/6 inhibitors. Brittany Harvey: Absolutely. I appreciate you describing those recommendations and then also the nuances of the evidence that's underpinning those recommendations, I think that's important for listeners. So Dr. Park, the next clinical question addresses patients with clinically node negative early stage breast cancer who have 1 or 2 sentinel lymph node metastases and who will receive breast conserving surgery with whole breast radiation therapy. For these patients, is axillary lymph node dissection needed? Dr. Ko Un "Clara" Park: No. And this is confirmed based on the ACOSOG Z0011 study that demonstrated in patients with 1 to 3 positive sentinel lymph node biopsy when the study compared completion axillary lymph node dissection to no completion axillary lymph node dissection, there was no difference. And actually, the 10-year overall survival as reported out in 2017 and at a median follow up of 9.3 years, the overall survival again for patients treated with sentinel lymph node biopsy alone versus those who were treated with axillary lymph node dissection was no different. It was 86.3% in sentinel lymph node biopsy versus 83.6% and the p-value was non-inferior at 0.02. And so we believe that it is safe for the select patients who are early stage with 1 to 2 positive lymph nodes on sentinel lymph node biopsy, undergoing whole breast radiation therapy to omit completion of axillary lymph node dissection. Brittany Harvey: Great, I appreciate you detailing what's recommended there as well. So then, to continue our discussion of axillary lymph node dissection, Dr. Torres, for patients with nodal metastases who will undergo mastectomy, is axillary lymph node dissection indicated? Dr. Mylin Torres: It's actually not and this is confirmed by two trials, the AMAROS study as well as the SENOMAC trial. And in both studies, they compared a full lymph node dissection versus sentinel lymph node biopsy alone in patients who are found to have 1 to 2 positive lymph nodes and confirmed that there was no difference in axillary recurrence rates, overall survival or disease-free survival. What was shown is that with more aggressive surgery completion axillary lymph node dissection, there were higher rates of morbidity including lymphedema, shoulder pain and paresthesias and arm numbness, decreased functioning of the arm and so there was only downside to doing a full lymph node dissection. Importantly, in both trials, if a full lymph node dissection was not done in the arm that where sentinel lymph node biopsy was done alone, all patients were prescribed post mastectomy radiation and regional nodal treatment and therefore both studies currently support the use of post mastectomy radiation and regional nodal treatment when a full lymph node dissection is not performed in these patients who are found to have N1 disease after a sentinel node biopsy. Brittany Harvey: Thank you. And then Dr. Park, for patients with early-stage breast cancer who do not have nodal metastases, can completion axillary lymph node dissection be omitted? Dr. Ko Un "Clara" Park: Yes, and this is an unchanged recommendation from the earlier ASCO Guidelines from 2017 as well as the 2021 joint guideline with Ontario Health, wherein patients with clinically node-negative early stage breast cancer, the staging of the axilla can be performed through sentinel lymph nodal biopsy and not completion axillary lymph node dissection. Brittany Harvey: Understood. So then, to wrap us up on the clinical questions here, Dr. Park, what is recommended regarding sentinel lymph node biopsy in special circumstances in populations? Dr. Ko Un "Clara" Park: One key highlight of the special populations is the use of sentinel lymph node biopsy for evaluation of the axilla in clinically node negative multicentric tumors. While there are no randomized clinical trials evaluating specifically the role of sentinel lymph nodal biopsy in multicentric tumors, in the guideline, we highlight this as one of the safe options for staging of the axilla and also for pregnant patients, these special circumstances, it is safe to perform sentinel lymph node biopsy in pregnant patients with the use of technetium - blue dye should be avoided in this population. In particular, I want to highlight where sentinel lymph node biopsy should not be used for staging of the axilla and that is in the population with inflammatory breast cancer. There are currently no studies demonstrating that sentinel lymph node biopsy is oncologically safe or accurate in patients with inflammatory breast cancer. And so, unfortunately, in this population, even after neoadjuvant systemic therapy, if they have a great response, the current guideline recommends mastectomy with axillary lymph node dissection. Brittany Harvey: Absolutely. I appreciate your viewing both where sentinel lymph node can be offered in these special circumstances in populations and where it really should not be used. So then, Dr. Torres, you talked at the beginning about how there's been these new practice changing trials that really impacted these recommendations. So in your view, what is the importance of this guideline update and how does it impact both clinicians and patients? Dr. Mylin Torres: Thank you for that question. This update and these trials that inform the update represent a significant shift in the treatment paradigm and standard of care for breast cancer patients with early-stage breast cancer. When you think about it, it seems almost counterintuitive that physicians and patients would not want to know if a lymph node is involved with cancer or not through sentinel lymph node biopsy procedure. But what these studies show is that preoperative axillary ultrasound, 85% of the time when it's negative, will correctly predict whether a sentinel lymph node is involved with cancer or not and will also be negative. So if you have imaging that's negative, your surgery is likely going to be negative. Some people might ask, what's the harm in doing a sentinel lymph node biopsy? It's important to recognize that upwards of 10% of patients, even after sentinel lymph node biopsy will develop lymphedema, chronic arm pain, shoulder immobility and arm immobility. And these can have a profound impact on quality of life. And if there is not a significant benefit to assessing lymph nodes, particularly in someone who has a preoperative axillary ultrasound that's negative, then why put a patient at risk for these morbidities that can impact them lifelong? Ideally, the adoption of omission of sentinel lymph node biopsy will lead to more multidisciplinary discussion and collaboration in the preoperative setting especially with our diagnostic physicians, radiology to assure that these patients are getting an axillary ultrasound and determine how omission of sentinel lymph node biopsy may impact the downstream treatments after surgery, particularly radiation and systemic therapy decisions, and will be adopted in real world patients, and how clinically we can develop a workflow where together we can make the best decisions for our patients in collaboration with them through shared decision making. Brittany Harvey: Absolutely. It's great to have these evidence-based updates for clinicians and patients to review and refer back to. So then finally, Dr. Park, looking to the future, what are the outstanding questions and ongoing trials regarding sentinel lymph node biopsy in early-stage breast cancer? Dr. Ko Un "Clara" Park: I think to toggle on Dr. Torres's comment about shared decision making, the emphasis on that I think will become even more evident in the future as we incorporate different types of de-escalation clinical studies. In particular, because as you saw in the SOUND and INSEMA studies, when we de-escalate one modality of the multimodality therapy, i.e., surgery, the other modalities such as radiation therapy and systemic therapy were "controlled" where we were not de-escalating multiple different modalities. However, as the audience may be familiar with, there are other types of de-escalation studies in particular radiation therapy, partial breast irradiation or omission of radiation therapy, and in those studies, the surgery is now controlled where oftentimes the patients are undergoing surgical axillary staging. And conversely when we're looking at endocrine therapy versus radiation therapy clinical trials, in those studies also the majority of the patients are undergoing surgical axillary staging. And so now as those studies demonstrate the oncologic safety of omission of a particular therapy, we will be in a position of more balancing of the data of trying to select which patients are the safe patients for omission of certain types of modality, and how do we balance whether it's surgery, radiation therapy, systemic therapy, endocrine therapy. And that's where as Dr. Torres stated, the shared decision making will become critically important. I'm a surgeon and so as a surgeon, I get to see the patients oftentimes first, especially when they have early-stage breast cancer. And so I could I guess be "selfish" and just do whatever I think is correct. But whatever the surgeon does, the decision does have consequences in the downstream decision making. And so the field really needs to, as Dr. Torres stated earlier, rethink the workflow of how early-stage breast cancer patients are brought forth and managed as a multidisciplinary team. I also think in future studies the expansion of the data to larger tumors, T3, in particular,reater than 5 cm and also how do we incorporate omission in that population will become more evident as we learn more about the oncologic safety of omitting sentinel lymph node biopsy. Dr. Mylin Torres: In addition, there are other outstanding ongoing clinical trials that are accruing patients right now. They include the BOOG 2013-08 study, SOAPET, NAUTILUS and the VENUS trials, all looking at patients with clinical T1, T2N0 disease and whether omission of sentinel lymph node biopsy is safe with various endpoints including regional recurrence, invasive disease-free survival and distant disease-free survival. I expect in addition to these studies there will be more studies ongoing even looking at the omission of sentinel lymph node biopsy in the post-neoadjuvant chemotherapy setting. And as our imaging improves in the future, there will be more studies improving other imaging modalities, probably in addition to axillary ultrasound in an attempt to accurately characterize whether lymph nodes within axilla contain cancer or not, and in that context whether omission of sentinel lymph node biopsy even in patients with larger tumors post-neoadjuvant chemotherapy may be done safely and could eventually become another shift in our treatment paradigm. Brittany Harvey: Yes. The shared decision making is key as we think about these updates to improve quality of life and we'll await data from these ongoing trials to inform future updates to this guideline. So I want to thank you both so much for your extensive work to update this guideline and thank you for your time today. Dr. Park and Dr. Torres. Dr. Mylin Torres: Thank you. Dr. Ko Un "Clara" Park: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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. Mellar Davis discusses the joint guideline from MASCC, ASCO, AAHPM, HPNA, and NICSO on opioid conversion in adults with cancer. He reviews the limited evidence, and the formal consensus process used to develop the guideline. He shares the key recommendations on pre-conversion assessment, how opioid conversion should be conducted, including opioid conversion ratios, and post-conversion assessment. We touch on gaps and questions in the field and the impact of these new recommendations. Read the full guideline, "Opioid Conversion in Adults with Cancer: MASCC-ASCO-AAHPM-HPNA-NICSO Guideline" at www.asco.org/supportive-care-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline in the Supportive Care in Cancer, https://link.springer.com/article/10.1007/s00520-025-09286-z 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. Mellar Davis from Geisinger Medical Center, lead author on "Opioid Conversion in Adults with Cancer: Multinational Association of Supportive Care and Cancer, American Society of Clinical Oncology, American Academy of Hospice and Palliative Medicine, Hospice and Palliative Nurses Association, Network Italiano Cure di Supporto and Oncologia Guideline." Thank you for being here today, Dr. Davis. Dr. Mellar Davis: Thank you. I'm glad to be here. Brittany Harvey Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Davis, who has joined us here today, are available online with the publication of the guideline, which is linked in our show notes. So then, to dive into the content here, Dr. Davis, can you provide an overview of both the scope and purpose of this guideline on opioid conversion in people with cancer? Dr. Mellar Davis: This is an important topic in management of cancer pain and this topic came up as a result of a survey that MASCC had done, which involved 370 physicians in 53 countries. They were queried about how they change or convert one opioid to another, which is a common practice, and we found that there was quite a divergence in opioid conversion ratios. To step back a little bit, about two thirds of patients with advanced cancer have moderate to severe pain and most of the time they're managed by opioids. But about 20% or 40% require a switch either because they have an adverse reaction to it or they don't respond to it, or the combination of both. Rarely, it may be that they need a route change, perhaps because they have nausea or vomiting. So, the opioid conversion works basically because of the complexity of the new opioid receptor which has at least four exons to it as a result of that non-cross tolerance between opioids. As a result of the survey, we convened a group of specialists, 14 international specialists, to look to see if we could develop an international guideline. And we did a systematic review which involved viewing 21,000 abstracts and we came up with 140 randomized trials and 68 non-randomized trials. And after reviewing the data, we found that the data was really not strong enough to provide a guideline. As a result, ASCO, MASCC, the AAHPM, the HPNA and the Italian Group formed a supportive network that allowed us then to do a Delphi guideline based upon ASCO modified criteria for doing Delphi guidelines. And so we then involved 27 additional international experts informing the guideline to it. And this guideline is then the result of the Delphi process. It consists basically of a pre-conversion ratio recommendations, conversion ratios, which is actually a major contribution of this guideline, and then what to do after converting someone to another opioid. Our target audience was not only oncologists, but also we wanted to target nurses, pharmacists, hospitalists, primary care physicians, patients and caregivers. Brittany Harvey: I appreciate that background information, particularly on the evidence that is underpinning this and the lack of quality of evidence there, which really transformed this into a formal consensus guideline. We're glad to have all of these organizations coming together to collaborate on this guideline. So then next I'd like to review the key recommendations. So starting with, what is recommended for pre-conversion assessment? Dr. Mellar Davis: In regards to pre-conversion, physicians and clinicians need to be aware of pain phenotypes. That is, there are pains that are more opioid refractory than others, such as neuropathic pain, hence, they may be more resistant to the opioid that you're converting to. One needs to be aware of the fact that patients may not be compliant, they're either afraid of opioids not taking what was prescribed, so it's important to query patients about whether they are taking their opioid as prescribed. Occasionally, there are patients who will divert their medication for various reasons. Pain may be poorly controlled also because of dosing strategies that are poorly conceived, in other words, giving only 'as needed' opioids for continuous cancer pain. And there are rare circumstances where an opioid actually induces pain and simply reducing the opioid actually may improve the pain. The other issue may be cancer progression. So that poorly controlled pain or rapidly increasing pain may actually be a result of progressive cancer and changing treatment obviously will be important. And you need to assess the pain severity, the quality of the pain, the radiating localizing effects, which does require not only a physical exam but also radiographic examinations. But the other thing that's very important in opioid conversions are pain scales with function. A significant number of patients don't quite understand a numerical scale which we commonly use: 0 to 10, with 10 being severe pain and 0 being no pain. They may in fact focus more on function rather than on pain severity or pain interference with daily activities or roles. Sometimes patients will say, "Oh, my pain is manageable," or "It's tolerable," rather than using a numerical scale. Choices of opioids may be based on cost, drug-drug interactions, organ function, personal history or substance use disorder so that one will want to choose an opioid that's safe when converting from one to another. And obviously social support and having caregivers present and understanding the strategy in managing pain will be important. Brittany Harvey: Thank you, Dr. Davis, for reviewing those pre-conversion assessment considerations and particularly the challenges around some of those. So, following this pre-conversion assessment, what are the recommendations on how opioid conversion should be conducted? Dr. Mellar Davis: Opioid conversions are basically the safe dose. People have used the term 'equianalgesia', but the panel and the consensus group felt that that would be inappropriate. So a conversion ratio is the dose at which the majority of patients will not experience withdrawal or adverse effect. It would be the safe dose. Thereafter, the dose will need to be adjusted. So, in converting, that's only the first step in managing pain, the doses need to be adjusted to the individual thereafter. There are a significant number of conversions that are done indirectly, that is that there has not been a study that has looked at a direct conversion from one opioid to another in which one needs to convert through another opioid. We call that a 'morphine equivalent daily dose'. So, most of the time a third opioid is used in the conversion. It allows you then to convert when there hasn't been a direct study that has looked at conversion between those two opioids, but it is less accurate and so one has to be a little bit more careful when using morphine daily equivalents. We found, and I think this is the major advantage to the guideline, is that commonly used opioids - oxycodone, morphine, hydromorphone - we did establish conversion ratios to which we found in the MASCC guideline they were widely divergent and hope that actually, internationally, they will be adopted. We also found some conversion ratios for second-line opioids. However, we felt also that an opioid like methadone, which has a unique pharmacology, should be left to experts and that experts should know at least several ways of converting from morphine usually to methadone. There is what appears to be a dose-related increased potency of methadone relative to morphine, which makes it more difficult, particularly at higher doses, to have an accurate conversion ratio. Most patients will have transient flares of pain. We came up with two suggestions. One is using a 10 or 15% of the around-the-clock dose for the breakthrough dose, but we also realized that there was a poor correlation between the around-the-clock dose and the dose used for transient flares of pain. And so the breakthrough dose really needs to be adjusted to the individual responses. There was also a mention of buprenorphine. One of the unique things about buprenorphine is that if you go from high doses of a drug like morphine to buprenorphine in a stop-start dosing strategy, you can precipitate withdrawal. And so one has to be careful and have some experience in using buprenorphine, which can be an effective analgesic. Brittany Harvey: Yes, I think that the conversion ratios that you mentioned that are in Table 3 in the full guideline are a really useful tool for clinicians in practice. And I appreciate the time that the panel and the additional consensus panel went through to develop these. I think it's also really key what you mentioned about these not being equianalgesic doses and the difficulties in some of these conversions and when people need to really look to specialists in the field. So then, following opioid conversion, what assessments are recommended post-conversion? Dr. Mellar Davis: Post-conversion, probably the cardinal recommendation is close observation for response and for toxicity. And I think that probably summarizes the important parts of post-conversion follow up. So assessment should be done 24-48 hours after conversion and patients followed closely. Assessment scales should include patient personalized goals. Now, it used to be in the past that we had this hard stop about a response being below 4 on a 0 to 10 scale, but each patient has their own personal goals. So they gauge the pain severity and their function based upon response. So a patient may function very well at "a severity of 5" and feel that that is their personal goal. So I think the other thing is to make sure that your assessment is just not rote, but it's based upon what patients really want to achieve with the opioid conversion. The average number of doses per day should be assessed in the around-the-clock dose so those should be followed closely. Adverse effects can occur and sometimes can be subtle. In other words, a mild withdrawal may produce fatigue, irritability, insomnia and depression. And clinicians may not pick up on the fact that they may be actually a bit under what patients have or they're experiencing withdrawal syndrome. It's important to look for other symptoms which may be subtle but indicating, for instance, neurotoxicity from an opioid. For instance, visual hallucinations may not be volunteered by patients. They may transiently see things but either don't associate with the opioid or are afraid to mention them. So I think it's important to directly query them, for instance, about visual hallucinations or about nightmares at night. Nausea can occur. It may be temporary, mild, and doesn't necessarily mean that one needs to stop the second opioid. It may actually resolve in several days and can be treated symptomatically. Pruritus can occur and can be significant. So close observation for the purposes of close adjustments are also necessary. As we mentioned, you want to start them on an around-the-clock of breakthrough dose, but then assess to see what their response is and if it's suboptimal then you'll need to adjust the doses based both upon the around-the-clock and the breakthrough dose or the dose that's used for breakthrough pain. Also looking at how patients are functioning, because remember that patients frequently look at pain in terms of function or interference with their roles during the day. So, if patients are able to do more things, that may, in fact, be the goal. Brittany Harvey: Thank you for reviewing all of these recommendations across pre-conversion assessment, how opioid conversion should be conducted, including conversion ratios, and what assessments are recommended after opioid conversion. I think it's really important to be watching for these adverse events and assessing for response and keeping in mind patient goals. So, along those lines, how will these guideline recommendations impact both clinicians and people with cancer? And what are the outstanding questions we're thinking about regarding opioid conversion? Dr. Mellar Davis: I think it's important to have a basic knowledge of opioid pharmacology. There's, for instance, drugs that are safer in liver disease, such as morphine, hydromorphone, which are glucuronidated. And there are opioids that are safer in renal failure, such as methadone and buprenorphine, which aren't dependent upon renal clearance. I think knowing drug-drug interactions are important to know. And sometimes, for instance, there may be multiple prescribers for a patient. The family physician's prescribing a certain medication and the oncologist is another, so being aware of what patients are on, and particularly over-the-counter medications which may influence opioid pharmacokinetics. So complementary medications, for instance, being aware of cannabis, if patients are using cannabis or other things, I think, are important in this. There are large gaps and questions and that's the last part of the guideline that we approach or that we mentioned that I think are important to know. And one is there may be ethnic differences in population in regards to clearance or cytochrome frequencies within communities or countries, which may actually alter the conversion ratios. This has not been explored to a great extent. There's opioid stigmata. So we are in the middle of an opioid crisis and so people have a great fear of addiction and they may not take an opioid for that reason, or they may have a relative who's been addicted or had a poor experience. And this may be particularly true for methadone and buprenorphine, which are excellent analgesics and are increasingly being used but may in fact have the stigmata. There are health inequalities that occur related to minority groups that may in fact not get the full benefit of opioid conversions due to access to opioids or to medical care. Age, for instance, will cause perhaps differences in responses to opioids and may in fact affect conversion ratios. And this may be particularly true for methadone, which we have not really explored to a great extent. And finally, the disease itself may influence the clearance or absorption of an opioid. So for a sick patient, the opioid conversion ratio may be distinctly different than in a healthy individual. This is particularly seen with transdermal fentanyl, which is less well absorbed in a cachectic patient, but once given IV or intravenously has a much longer half life due to alterations in the cytochrome that clears it. And so conversion ratios have frequently been reported in relatively healthy individuals with good organ function and not that frequently in older patient populations. So just remember that the conversion ratios may be different in those particular populations. Brittany Harvey: Yes. So I think a lot of these are very important things to consider and that managing cancer pain is key to quality of life for a lot of patients and it's important to consider these patient factors while offering opioid conversion. I want to thank you so much for your work to review the existing literature here, develop these consensus-based recommendations and thank you for your time today, Dr. Davis. Dr. Mellar Davis: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.