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Management of Cancer During Pregnancy Guideline (00:34:50)
Dr. Alison Loren and Dr. Ann Partridge share the latest guideline from ASCO on the management of cancer during pregnancy. They highlight the importance of this multidisciplinary, evidence-based guideline and overarching principles for the management of cancer during pregnancy. Drs. Loren and Partridge discuss key recommendations from each section of the guideline, including diagnostic evaluation, oncologic management, obstetrical management, and psychological and social support. They also touch on the importance of this guideline and accompanying tools for clinicians and how this serves as a framework for pregnant patients with cancer. The conversation wraps up with a discussion on the unanswered questions and how future evidence will inform guideline updates. Read the full guideline, "Management of Cancer During Pregnancy: ASCO Guideline" at www.asco.org/survivorship-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02115 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Alison Loren from the Perelman School of Medicine of the University of Pennsylvania and Dr. Ann Partridge from Dana-Farber Cancer Institute, co-chairs on "Management of Cancer During Pregnancy: ASCO Guideline." Thank you for being here today, Dr. Loren and Dr. Partridge. Dr. Alison Loren: Thanks for having us. Dr. Ann Partridge: It's a pleasure. Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Partridge and Dr. Loren who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the meat of this guideline, to start us off, Dr. Loren, could you provide an overview of the scope and purpose of this new guideline on the optimal management of cancer during pregnancy? Dr. Alison Loren: Sure, thanks, Brittany. So this was really born out of I think a lot of passion and concern for this really vulnerable patient population. We have observed, and I am sure it is not any surprise to your audience, that the incidence of cancer in young people is increasing. And simultaneously, people are choosing to become pregnant at older ages, and so we are seeing more and more people with a cancer diagnosis during their pregnancy. And for probably obvious reasons, there is really no way to do randomized clinical trials in this population. And so really trying to assemble and articulate the best evidence for safely managing the diagnosis of cancer, the management of cancer once it is confirmed, being thoughtful about obviously the health of the mom, but also attending to potential risks to the developing fetus, and really just trying to be really comprehensive and balanced about all the choices for these patients when they are facing some really challenging decisions in a very emotionally fraught environment. And I think it is really emotionally fraught for the providers, too. You know, this is obviously an extremely intense, very emotional set of decisions, and so trying to provide a rudder essentially to sort of help people frame the questions and trying to make as evidence-based a set of recommendations as possible. Dr. Ann Partridge: And I would just add that "evidence-based" is a strong word here because typically our, as you just heard, our gold standard evidence is a randomized trial, but you can't do that in this setting, in general. And so, what we were able to do with the support of the phenomenal ASCO staff was to pull together kind of the world's literature on the safety and outcomes of treatments during pregnancy, as well as consensus opinion. And I think that is a really, really critical difference about this particular guideline compared to many of the other ones that ASCO does, where consensus and good judgment needed to kind of rule the day when evidence is not available. So, there is a lot of that in our recommendations. Dr. Alison Loren: That is such a good point. And I just, before we move forward, I just want to reflect that the composition of the panel was really broad and wide-ranging. We had maternal medicine specialists, we had legal and ethical experts, we had representatives who understand pharmaceutical industries' perspectives, and then medical oncologists representing the full spectrum of oncology diagnoses. And so it was a really diverse, in terms of expertise, panel, internationally composed to try to really get the best consensus that we could in the absence of gold standard evidence. Brittany Harvey: Absolutely. That multidisciplinary panel is really key to developing this guideline and, as you said, looking at the evidence and even though it does not reach the level of randomized trials, still critically evaluating it and reviewing that along with consensus to come up with optimal management for diagnosis and management of cancer during pregnancy. So then to follow that up, I would like to next review the key recommendations of the guideline across the main sections that the expert panel provided. First, I will throw this out to either of you, but what are the important general principles for the management of cancer during pregnancy? Dr. Ann Partridge: I think there were three major principles that we hammer home in the guidelines. One is that this is a team sport. It is multidisciplinary care that is necessary in order to optimize outcomes for the patient and potentially for the fetus. And that you really need to, from the beginning, bring in a coordinated team, including not just oncologists but obstetricians, maternal-fetal medicine specialists, neonatologists, ethics consultants, and obviously the patient and potentially her family. So that, I think, is one of the most important things. Second would be that obviously in a pregnancy, there are two potential patients and that the nuances of safety and risk from treatment is really wrapped up in where in the trimester of the pregnancy the patient is diagnosed, along with the kind of cancer that it is, both the urgency of treatment and the risk of the cancer, as well as the potential risks of any given intervention across the cancer continuum. It is a broad guideline in that regard. And then finally, and this is particularly timely given what is going on from a sociopolitical standpoint in the U.S., really thinking about informed consent and potential ethical as well as legal implications of some of the choices that patients might have when they are thinking about, in particular, continuing a pregnancy or potential termination. Dr. Alison Loren: And I will just add that I think that the key to all of this guidance is nuance and individualization and also making sure that patients and their care providers understand all the choices that are available to them and also the consequences of those choices. You know, nobody would choose to receive chemotherapy during pregnancy if that wasn't necessary. So there are risks to treatment, but there are also risks to not treatment. And making sure that in a suboptimal situation where you do not have a lot of evidence, trying to weigh, the best you can, the risks and benefits of all of the choices so that the patient can come to a decision about the treatment plan that is right for her. Brittany Harvey: Definitely. And those core concepts really set the stage for individualized care on what is necessary for appropriate multidisciplinary care, prioritizing both patient autonomy and informed decision making. With those core concepts and key principles in mind, I would like to move into the recommendations section of the guideline. So what are the key recommendations regarding diagnostic evaluation for pregnant patients with signs or symptoms of cancer? Dr. Alison Loren: I think the most important thing is to not delay, that there are very careful and well-thought-out recommendations for how to evaluate a potential cancer. And while there are certain things that we know can be harmful, particularly when certain dose thresholds are exceeded - for instance, abdominal imaging, there are certain radiographic thresholds that you don't want to exceed because of risk of harm to the embryo or fetus - there are still lots of options for diagnosing cancer during pregnancy. And again, thinking about the costs of not doing versus the cost of doing, right? It is really important to make the diagnosis of cancer if that is a consideration or a concern. And sometimes going directly to biopsies or getting definitive studies, even if there is a small risk to the developing fetus, is really essential because if the mom does not survive, of course, the fetus is also not going to survive. And so we need to be thinking first about the patient who is sitting in front of us, the woman who needs to know what is going on in her body so she can make good decisions about her health. So, I think that is a key principle in thinking about this. Brittany Harvey: Absolutely. So, following that diagnosis of a new or recurrent cancer, what is recommended for oncologic management of patients who are diagnosed with cancer during their pregnancy? Dr. Ann Partridge: So, I think the general principle is, again, cancer is such a wide number of diseases and even within diseases, a range of stages and risks and associated opportunities for risk reduction and/or treatment depending on the type of cancer. Just by example, in the work that I do, which is breast cancer, once someone has had a surgery in the early-stage setting, a lot of our treatment is about risk reduction. And that is very different than from what Alison does, which is treating people with leukemia, where it is kind of binary. If you do not treat, including with cytotoxic drugs, the patient and an unborn fetus will die, especially early in the pregnancy, obviously. So this is where cancers are very, very different. So I think taking the approach of what would you do if the patient were not pregnant? And what is the best treatment for that particular patient with that particular kind of cancer? And then applying the pregnancy and where the patient is in that pregnancy in terms of the trimester of the pregnancy, and what is safe and what is unsafe from the options that you would give her if she were not pregnant. And then if the patient is choosing to keep the pregnancy, which in my practice, many people come and they come to me because they want to hold onto their pregnancy and want to figure out how to make it work, coming up with a regimen that tries to give them kind of the best bang for the buck, the best possible breast cancer therapy with the least harm, when possible, to the fetus. It is a bit of a balance, right? And then we cannot always give people the best approach. And sometimes it comes down to making a decision to give up something that may improve their survival so as not to harm the fetus. And sometimes it goes the opposite direction where a patient will say, "Oh, that is going to improve my survival by 5% and you can't give it to me now? I am going to choose to terminate." Even though that is obviously a very, very difficult and challenging decision to make in this setting because they want to optimize their survival and ideally live on to potentially have another pregnancy in the future if that is something that is of interest to her. So these are really, really hard conversations as you can imagine, but that is kind of where we go. Dr. Alison Loren: Yeah, and I think this is where the need for more research and understanding is really key because sometimes questions come up. I guess I am thinking about like HER2-directed agents, which we know are contraindicated in pregnancy. But what about sequencing? Does it matter when you get it? Can you get it later? I think that is something that we don't really fully understand. And similarly, again, this is obviously like a breast cancer and blood cancer focused discussion because that is what we do, but thinking about managing blood cancers, certainly with acute lymphoblastic leukemia, there is actually a lot of options now that, you know, you could potentially use to temporize or sort of get somebody through a pregnancy relatively safely. I am focusing on the word "relatively" because we do not know what the long-term impact might be of potentially not optimal therapy in the long run. And then thinking about other things like timing of a bone marrow transplant relative to either delivery or termination. I mean, again, we really do not know what are the right sets of sort of timing considerations for those. So there are just a lot of unknowns. And I think trying to be sort of self-aware and humble and honest about those unknowns so that the patient can engage in the conversation in a way that is meaningful to her and make the decisions that make the most sense for her. I think the most important thing is to make sure that the patient feels supported and safe to make those decisions with as little regret as possible. Brittany Harvey: Yes, I think it is really important that you mentioned that there is a wide range of cancers here, and that means that care really needs to be individualized for each patient. I will also note, just in this section, that I found really informative while reading through the guideline the list of oncologic agents that may be offered in each individual trimester, whether it is contraindicated or it can be used with caution, or if there is relatively good safety data on it for prioritizing maternal treatment needs and balancing fetal safety at the same time. I think that is, that is really key. And I think readers will really like that section of the guideline to provide concrete information for them and their patients. Dr. Alison Loren: Thank you. We actually spent a lot of time on that table and just thinking about what it should look like, what the format ought to be, what the language ought to be. Because of course, at the end of the day, everything should be used with caution. So what does that actually mean? And we sort of tried to explicate that a little bit in like the footnotes. We really tried to leverage what we know from clinical experience, from package labels, from mechanism of action to try to be as clear and definitive as we could be without overstating or understating what we know. Dr. Ann Partridge: Yeah, and I think we are focusing on breast and leukemia because that is what we do. But the truth is much of the data comes from those two areas. Leukemia, not because it is so common, but because you do not really have choices to treat or not treat. And so for decades, they have been treating and saying, "We hope the progeny comes out okay." And for many agents it does. The babies are okay. And so, we have reasonable observational data. And then in breast cancer, there have been actually some prospective registry-type studies where people have been followed and treated when pregnant, and the progeny have been accounted for, and so we have some good experience in that way too. Again, not randomized trials, but at least data that suggests certain agents are safe. And increasingly, because of that, when we have had to treat patients, we have said, "Okay, let us do it on this registry so that we can at least learn from every patient that comes in in this situation." And so, I think we will have more and more data given the growing number of young adults with cancer and the delays in childbearing that are happening around the world, and particularly in Westernized countries. I wish we did not. We wish we did not see this problem, but of course, when we do, we have to make sure that we learn from it and try and get patients enrolled in these registries and any kinds of studies that are available. Dr. Alison Loren: Yeah, I will just underscore that to say that, you know, there is outcomes of pregnancy and then there is outcomes of pregnancy, right? So there is like, "Okay, the baby was born with 10 fingers and 10 toes, and they passed their Apgar, and they are doing all their developmental processes along the way." But what happens when they are 10 or 15 or 20? Are they maturing normally? Are they cognitively intact? And then, of course, it is really inseparable from what is the impact on a family of having the mom with cancer? And how does that impact childhood development and intellectual development? And so these are really, really important questions that are very difficult to answer given the longitudinal information that you need, but it is a really critical question that, you know, patients ask and we do not know the answer. Dr. Ann Partridge: Yeah, that actually leads me to one of the important principles in the guideline that is a little bit of a change from when I first started practicing, which is we have learned from the wider neonatology literature, as they have followed up on the children that were born prematurely, that it is actually better not to be premature and to keep the baby in utero as long as it is safe for the fetus and the mother as long as possible, ideally to term rather than delivering early and then giving the chemo after that or separating the chemo from before and after. We used to try and deliver early and then give agents, but now we typically will give agents that are safe to be given at the end of pregnancy, ideally close to term, a couple weeks out, to allow for the ability of count recovery, and you do not want to go into preterm labor with chemotherapy on board, but we used to go much earlier and have an argument with our maternal-fetal medicine doctors. "How early can you get them out?" And they would say, "How long can they stay in?" And increasingly, we have been able to try and compromise to go even later and allow the fetus to go to term because of the neonatal outcomes that in longer term there is a suggestion that the children are developing better in the long run if they are kept in utero for as long as possible. Dr. Alison Loren: Yeah, that is such a great point. I think that is probably the most important thing for people to take away. For anyone who sort of does this, I mean, no one does this regularly because it is a rare event, although I think it is increasing as I mentioned. But this idea that the third trimester is, most of us know, is primarily a time for growth. Most of the critical development has already occurred, and so administering most chemotherapy agents towards the end of the third trimester seems to be preferable long term than delivering them early. So that is a really big change. I think we used to try to sort of, "Oh, get them to 30 or 32 weeks and then deliver," but we really are trying to get them closer to term, 37 weeks or more, and then coordinating the treatment so that they are not nadiring, as Ann said, at the time of planned delivery. Brittany Harvey: Yes, and that is a really important point related to evidence-based care and why we have changed that practice. And so then that actually leads nicely into my next question. But as you both mentioned, this is an important collaboration between oncologists and obstetricians. So the next section of the guideline addresses obstetrical practice. And so beyond what is standard, what additional recommendations are there in obstetrical management for pregnant patients with cancer? Dr. Alison Loren: That is a great question. So I will say we were really struggling with like how much do we cover? Like this is an oncology guideline. We are not obstetricians. We certainly had great representation from our maternal-fetal medicine colleagues on the panel. But really trying to sort of give useful information without overstepping. And so I think that the main recommendations are to increase the frequency of fetal monitoring, make sure that there is close attention to blood counts in the patient. But I think there is really still a gap in terms of what we know about optimal management of a pregnant person who is receiving therapy and how to handle the pregnancy itself. The delivery should be a usual delivery. Our colleagues did not recommend a planned C-section. They recommended usual care in terms of planning for the delivery. Obviously, if a C-section is indicated, then it should be done, but it should not be planned this way because of the cancer diagnosis. And I guess the other thing that we mentioned in the guideline, although we were reluctant to push it too hard because of access to these specialized services, was evaluating the placenta after birth to ensure that there were no metastases in the placenta itself. Dr. Ann Partridge: Those are the main things, and judicious and prudent obstetrical care, as I think, you know, is trying to be practiced regularly with MFM. Typically these patients should be followed not by your average OB/GYN, but a maternal-fetal medicine specialist because these patients will have special concerns, especially if they are sick. So oftentimes, especially Alison's patients, are actually sick with leukemia. And so you are monitoring them a lot, whereas, you know, a breast cancer patient typically isn't sick, although they could get sick with their chemotherapy. And so we really want to hand-in-hand manage these patients with our MFM colleagues. Dr. Alison Loren: I think we also highlighted in the guideline just for the refresher purposes of the oncology community, generally which drugs that would be given in a normal oncology setting are safe to be given to a pregnant person. So we talked a little bit about what kinds of steroids are recommended, antiemetics, DVT prophylaxis, peripartum. These are things that we think about a lot in oncology, but just want to make sure that it sort of intersected appropriately with the care of a pregnant patient. Brittany Harvey: Definitely. That specialized care is really important for patients who are pregnant and have cancer. And then the last section of the recommendations addresses psychological and social support. As you both mentioned before, this is a highly emotional time and it can be difficult and challenging to make decisions. So what is recommended for the psychological and social support of pregnant patients with cancer? Dr. Ann Partridge: Well, as I said, it is really something that needs to be considered at the beginning, through the diagnostic period, all the way into survivorship. Ironically, even though it is a highly fraught, emotional situation, I find that my pregnant patients actually are extraordinarily resilient, and what they are really focused on often is the safety of the fetus, because again, many of the people that come to me, it is a highly wanted pregnancy. They are also focused on their own health, of course, and often you need to bring in social work, sometimes a psychologist, professionals who are there just to help manage their emotions while we are focusing on what do they need medically to be as healthy as possible, both for the again, the mother, the patient, and the fetus. It is very tricky, and I will say also bringing in sometimes people on the ethics team in the hospital to help, both from the "Are you recommending and giving something that is safe?" That is number one. And then number two, sometimes patients want to be treated with drugs that we do not have any safety data for in pregnancy. What are our obligations? I think most of us would say we would not treat someone if we do not have safety data and there is suspicion for concern. But where is that line in terms of the right thing to do by that patient? And so we are all beholden to our ethics colleagues to help us when we make decisions like that. You know, we all want to do right by the patient, but we have to uphold our oaths and legal obligations. I don't know if you have to add on that because it's very tricky. Dr. Alison Loren: It is, it is very hard. I mean, I think, you know, there is a lot of emotion, obviously any cancer diagnosis is extremely charged and people are already at sort of a heightened, you know, they are anticipating a new baby and planning around that. And so it is just an extremely disruptive is the smallest word I can think of to describe it. And I think that often there is a co-parent, there might be parents and in-laws and other siblings, and then there is care after delivery. And so it is just a very complex set of dynamics. And having both our ethics colleagues and our psychology and social work colleagues to sort of just pitch in and make sure that the patient is being supported. I think there are sometimes really difficult situations where maybe what the patient wants is different from what the father of the baby wants or what the rest of the family wants. And so that can be really challenging. And you never really know where those landmines are going to pop up. So it is good to have the team on board early and often. Dr. Ann Partridge: Yeah, I would add to that, the other thing here that I think is really important, like in all of medicine but especially in situations like this, this is where we have to be very careful as professionals not to impose our own ethical, moral, emotional, personal views on the patient and to try to reserve judgment as much as possible. We are their navigator with the most important evidence and information that we can provide in the current situation. And that is where this guideline is extraordinarily helpful, we hope, for clinicians in the years to come. And at the same time, we cannot necessarily impose our own views and what we would do on a patient or what we tell our daughters, sisters, friends, family members. It is very tricky in that way. And so sometimes not just support for the patient, but support for the care team may be warranted in some of these very fraught situations. Dr. Alison Loren: Yeah, that is such a great point. And I was sort of thinking that too. I mean, it is, of course, the patient is front and center, but these are really difficult situations to navigate. And I will just add also that a lot of times these patients end up in academic centers, which I think is that's where the expertise or even just the experience may be. But the downside of that is that, you know, the teams are constantly changing. You have a new resident, you have a new intern, you have a new attending, a new fellow. And so, you know, the patients may be subjected to lots of different ways of communicating and sometimes those perceived differences can be really challenging. So sort of team huddles to sort of make sure that everybody is reading from the same script and everyone is comfortable with how the information is being presented so that the patient does not feel more confused or more overwhelmed, that they are kind of getting a consistent message from the whole team that, "This is what we know, this is what we are recommending, here are your other choices, and here are the pros and cons of each of these options." Brittany Harvey: Yes, I think you have both touched on this and that bringing in appropriate experts to support both clinicians and patients and their decision-making and their mental health is really important for this section of the guideline. We have already discussed this a fair bit throughout our conversation, but in your view, what is the importance of this guideline and how will it impact both clinicians and pregnant patients diagnosed with cancer? Dr. Ann Partridge: I could start with that. We just talked about experts and having them all around, but the fact is most people do not have the experts all around when they are dealing with this. And I think this is, you know, an expert-based, evidence-based guideline where having this in one's back pocket, whether you are in rural Montana or at a major cancer center on either coast, you will be armed with the latest and the greatest in terms of what we know and what we do not know, and some very helpful algorithms for how to think through the process of dealing with a patient who is diagnosed during pregnancy, whichever type of cancer it is. We could not cover every single specific thing about every cancer, although it is a pretty long guideline and there is a lot of nuance in there. So you might find a lot about specific cancers. And I think that that will be very, very helpful for people who are faced with this situation in the clinics just to frame it out, think through. Sometimes there is no answer that is the perfect answer and then, you know, using this as kind of a scaffolding and phoning a friend who may have more experience to help guide you and guide the patient, most importantly. I think it will be very helpful in that regard. Dr. Alison Loren: Yeah, I think so too. And I have talked about that we are working on this guideline and the anecdotal feedback has been, "This is so helpful." Like there really has not been, I think, an all-in-one place, diagnostic considerations, radiographic considerations, staging, treatment, all the modalities, surgical, radiation, systemic chemotherapy. We tried to include, when we could, novel agents including targeted agents and monoclonal antibodies and bispecifics and cellular immunotherapies and non-cellular immunotherapies. We really, really tried to cover in 2025 what are people using to treat cancer and to try to give the most balanced view of what we think is is safe or reasonably safe and what we think is either unproven or known to be risky, really to have it be kind of a go-to, like all-in-one, as much information as we have about these really challenging cases. We tried to include, Ann mentioned, you know, specific cancers, and I think when there were specific things to shout out with specific cancers, we really tried to highlight that. Like, "Okay, lots of young patients with cancer have Hodgkin's lymphoma, so what is safe and what is not for that specific case?" Or, "What is safe or what is not when you are thinking about colon cancers?" And we have a shout-out in here about considering checking for DPD deficiencies in patients who are pregnant. And I know it is generally recommended nowadays, but certainly for people who are pregnant, you know, you really want to avoid excess toxicity. So I think just really trying to be attentive to specifics about certain cancers in young patients and what would be valuable for a practicing oncologist and obstetrician to know when you are faced with this situation. Dr. Ann Partridge: Yeah, and I think the other critical thing that is great about this guideline is it's a starting place. And I anticipate that we will be building on this guideline for many years to come. And remember that when first, I was not around then, but probably three or four decades ago, when chemotherapy was just coming out and patients were coming in pregnant, there was a feeling I am sure that was, "We cannot give this to this person because it is purposefully going to destroy cells. And when you destroy cells in a growing fetus, you are going to destroy or harm that fetus." And yet, people did not have great choices. It was get treated or die, especially with things like leukemia early on. And bold patients along with their oncologist said, "Bring it on." And that is how some of this literature has been born. And so moving forward, there will be either purposeful exposures or inadvertent exposures of some of our therapies where we will learn ultimately. And this is a place where we can update these guidelines. That is the beautiful thing about the ASCO guidelines is that they are constantly being thought about to be updated. And then when there is enough of a change in practice, they will be updated such that they will continue to inform how we do this in the years to come for patients who come in pregnant. Dr. Allison Loren: Yeah, and I will say I have been doing this long enough now, we were just talking about a different guideline, the fertility guideline earlier today, and over the 20 years that the fertility guidelines have been out, just the amount of research has really skyrocketed. And you can see as you look at each guideline how much we have learned, what we can say, "Yes, this is working," "No, this is not working." Like, it is stuff that we used to say, "Oh, we do not really know," and now we have answers. I think I speak for both of us when I say that we are hopeful that this will serve as, as Ann said, as a starting off point and really inspire people to ask the questions and do the research so that we can give better guidance moving forward, really trying to think about, you know, mechanisms and leaning on our colleagues in pharma and in the government who sort of think about safety and efficacy, to sort of make sure that they are contemplating not just non-pregnant patients, but also pregnant patients or as they are thinking about marking the package inserts with safety guidelines around this. Brittany Harvey: Yes, this is a critically important first guideline on the management of cancer during pregnancy, and we will look forward to continuing to build on that. I think as you mentioned, this guideline is far-reaching and has a lot of recommendations in it. And so both the full text of the guideline and those at-a-glance algorithms, figures, and tables will be really useful for clinicians in their clinic. Finally, to wrap us up, we have just been discussing this a little bit, but specifically, what are the outstanding questions on the management of pregnant patients with cancer, and where is this further research needed? Dr. Alison Loren: There are lots and lots and lots of unanswered questions. And I think if you look at the table, most of what we say is, "We are pretty sure this is okay, we are not so sure about this." I am paraphrasing, but we really just are operating in a paucity of what we would normally consider gold-standard evidence. It is hard to imagine, of course, there would ever be, as we mentioned in the beginning, randomized trials. But I think that preclinical data, mechanistic data, trying to think about including as we go through animal data, making sure that we are looking at female animals and pregnant animals so that we can sort of fully understand what the impact may be. And then I think thinking about more localized therapies around sort of radiation, you know, we are now moving into really hyper-focused radiation treatments like protons. Is that better because there is less scatter? Like I think those are real considerations that we just do not know the answer to. What do you think? Dr. Ann Partridge: I think so many unanswered questions, and this is a call to action to continue to and increase the documentation of the experiences and outcomes for patients diagnosed during pregnancy. Dr. Alison Loren: Yeah, and I think the long-term outcomes too are really going to be critical. Brittany Harvey: Yes, we will look forward to learning about more evidence across the spectrum of care to inform future updates to this guideline. So I want to thank you both so much for your work to develop this guideline, to review the extensive amounts of literature that you did, and work to create this guideline. And thank you also for your time today, Dr. Loren and Dr. Partridge. Dr. Alison Loren: Thanks. It was fun. Dr. Ann Partridge: Yeah, thank you. Brittany Harvey: And finally, thank you to all of our listeners for tuning into the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Management of Antineoplastic Extravasation: ONS-ASCO Guideline (00:13:28)
Dr. Tanya Thomas and Dr. Aparna Jotwani join the podcast to discuss the new Oncology Nursing Society and American Society of Clinical Oncology evidence-based guideline on the management of antineoplastic extravasation. They discuss recommendations from the expert panel on: management of extravasation of vesicant or irritant with vesicant properties antineoplastic agents, management of extravasation of paclitaxel or docetaxel, use & duration of thermal compress, and escalation of care. They share the importance of this comprehensive interdisciplinary guideline, highlight the algorithm as a useful tool for clinicians, and outline the outstanding questions related to the management of extravasation. Read the full guideline, "ONS/ASCO Guideline on the Management of Antineoplastic Extravasation" at www.asco.org/supportive-care-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP-25-00579 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. Tanya Thomas, clinical chair of the guideline and clinical nurse specialist from University of Virginia Health, and Dr. Aparna Jotwani, medical oncologist from Baylor College of Medicine, authors on "Management of Antineoplastic Extravasation: Oncology Nursing Society – American Society of Clinical Oncology Guideline." Thank you for being here today, Dr. Thomas and Dr. Jotwani. Dr. Aparna Jotwani: Thank you. Dr. Tanya Thomas: Thank you for having us. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Thomas and Dr. Jotwani, who have joined us here today, are available online with the publication of the guideline in JCO Oncology Practice, which is linked in the show notes. So then to dive into the content here, Dr. Thomas, could you start us off by providing an overview of both the scope and the objectives of this guideline? Dr. Tanya Thomas: Yes, so the objective of this guideline is to provide the evidence-based recommendations to help support our interdisciplinary teams, including the oncologist, the advanced practice providers, pharmacists, and nurses who are involved in the care and management of patients who are experiencing an extravasation of an antineoplastic agent. While rare, the antineoplastic and certain chemotherapy extravasations are oncologic emergencies. The recommendations are to minimize negative consequences and provide a standardized approach to the care when such an event occurs. Dr. Aparna Jotwani: I would add that our scope is limited to intravenous antineoplastic vesicants, irritants, and irritants with vesicant potential. The scope of the guideline applies to the care team for adult oncology patients receiving treatments through venous access. Outside the scope is management of extravasation during other routes of treatment administration, such as intraperitoneal, intravesical, and hepatic arterial infusion. Our recommendations regarding vascular access for therapy or interventions to prevent extravasations are also outside of the scope for this guideline. Brittany Harvey: Understood. I appreciate that background and understanding what's in scope and what's out of scope for this guideline. So then I'd like to pivot and talk about the key recommendations of this guideline across the clinical questions. So first, Dr. Jotwani, what does the panel recommend for patients with extravasation of vesicant or irritant with vesicant properties antineoplastic agents? Dr. Aparna Jotwani: The panel strongly recommends for all classes where an antidote exists to proceed with using the antidote. Recommendations for paclitaxel and docetaxel are specifically addressed in a recommendation. This is further detailed in Tables 1 and 4 within the guideline. Evidence on the use of antidotes for extravasation is limited to nonrandomized, uncontrolled, observational studies and case series. Placebo-controlled trials on this topic would be unethical. There is also a lack of comparative data for different antidote strategies. However, potential benefits of using the antidotes include tissue preservation and avoiding tissue necrosis. In developing the guidelines, we had an in-person roundtable discussion and weighed risks and benefits to ensure patient safety above all else. Brittany Harvey: I appreciate that description of the recommendation here. So then you just mentioned that there's a specific recommendation for paclitaxel and docetaxel. So what is recommended for those patients with extravasation of paclitaxel or docetaxel? Dr. Aparna Jotwani: So here, we conditionally recommended the specific use of hyaluronidase as the antidote. This was based on five studies that all used hyaluronidase as an antidote to lower the risk of tissue necrosis. In the studies included, with a subgroup of patients that experienced taxane-related extravasation, development of necrosis ranged from 0% to 0.83% among the patients who received an antidote. The potential harms associated with this were likely trivial. Brittany Harvey: Thank you for providing that recommendation as well. So then the next section of the guideline, Dr. Thomas, what does the expert panel recommend for use and duration of thermal compress? Dr. Tanya Thomas: So the expert panel actually recommends the use of thermal compresses, and the recommendations are based on the available literature for the various agents and the actual time frames most frequently used for the compress application. The utilization of a thermal compress is recommended for 15 to 20 minutes at a time for 3 to 4 times daily, at least for the first 48 to 72 hours after that extravasation occurs. The actual frequency and duration may vary based on the extent of the extravasation and the agent involved in that extravasation. The intent of the warm compress is to help disperse the agent and reduce the localized accumulation of the agent, whereas the cold compress, it actually helps prevent the dispersion or the spread of the agent while allowing the antidote to help neutralize that agent. Warm compresses are recommended for extravasations involving the vinca alkaloids, etoposide, oxaliplatin, and the taxanes - paclitaxel and docetaxel - only when coadministering the antidote hyaluronidase. The use of a cold compress is actually recommended for extravasations involving the anthracyclines, antimetabolites, alkylating agents, and taxanes when coadministration of the antidote hyaluronidase does not occur. Brittany Harvey: Understood. Those specific and actionable recommendations are really key for clinical practice. So then, following those recommendations, how does the guideline address escalation of care and surgical referral for patients with central line extravasation? Dr. Tanya Thomas: So this topic actually had a lot of discussion. And while there is not enough evidence to make strong recommendations, the expert panel recognized that surgical referrals should be considered in certain scenarios. Dr. Aparna Jotwani: We discussed that certain scenarios would include high-risk populations, such as patients that are receiving DNA-binding vesicants, those with high-volume estimated extravasation, and those with CTCAE grade 2, which would be erythema associated with symptoms such as edema, pain, induration, and phlebitis, or grade 3, which would be symptoms of ulceration or necrosis or concern for severe tissue damage, or grade 4, where you would have a life-threatening consequence extravasation, may have a greater likelihood of benefiting from surgical referral and/or escalation of care as deemed appropriate. Brittany Harvey: Great. And yes, it's really important to provide all of these recommendations that you've both just gone through, even when we're faced with very low evidence. So then, Dr. Thomas, in your view, what is the importance of this guideline, and how will it impact clinical practice? Dr. Tanya Thomas: So when extravasations occur in the clinical setting, members of the interdisciplinary team can be faced with barriers related to where to look for the information, how to find all the relevant information in one concise place, how to provide education to the patient about how to care for the site of extravasation in the home setting, and also when to escalate to specialized teams. This can actually cause some added stress and anxiety, and in certain circumstances, may lead to delays in efficient management. This guideline provides the resource clinicians have been looking for. It includes comprehensive recommendations for antineoplastic extravasations in one guideline while also providing a one-page algorithm with the key information regarding the management of the extravasations. This allows all levels of providers to have evidence-based recommendations regarding initial management of the extravasation, for instance, how to manage the infusion, key site assessment reminders, available antidotes, and the use of thermal compress; the required documentation, recommended follow-up scheduling, in addition to key aspects of the patient education. This type of guidance is not found in any other single document regarding antineoplastic extravasation. Having this document readily available at the point of care potentially can reduce time required for providers to search for management recommendations and also provide consistency in patient education and follow-up management scheduling. It reduces uncertainty within interdisciplinary teams and can help inform policy development for clinicians to approach extravasations with confidence. Brittany Harvey: Absolutely. I agree that this is an incredible resource for clinicians with the recommendations, the algorithm that you mentioned, and the supporting evidence that underpins these recommendations to really provide both efficient and effective care for patients. So beyond the impact for clinical practice, Dr. Jotwani, how will these guideline recommendations affect patients receiving antineoplastic treatment for cancer? Dr. Aparna Jotwani: Exactly. In addition to the clinical care team, we want to help and benefit our patients. So, oncology patients that experience extravasations are at risk for, aside of the side effects of tissue necrosis and infection, they also are at risk for delay of cancer treatment. In making these guidelines, we kept in mind the cost and the efforts for patients, additional visits that they could incur, additional time and supplies for care of the extravasation, as well as cost. Our guideline aims to provide an evidence-based approach to the care of oncology patients receiving antineoplastic intravenous therapy. While there are gaps in the data due to the nature of these events, based on careful literature review, these guidelines serve as a basis for quality, standardized oncology care during extravasation. Personally, I hope our graphics especially can be used across the systems to guide clinical care. Brittany Harvey: Definitely. We hope that these recommendations improve treatment and treatment outcomes for all patients receiving antineoplastic treatment for cancer. So then you've also just mentioned some gaps in the literature. So Dr. Thomas, I'd like to turn to you to wrap us up and ask, what are the outstanding questions for the management of antineoplastic extravasation? Dr. Tanya Thomas: Yes, that's a good question. Two of the main outstanding questions are related to the management of extravasations involving the novel agents and extravasations involving multi-agent regimens. The current literature regarding how to effectively manage the multi-agent regimens, for instance, there is no clear guidance for managing the extravasation for someone who is receiving a regimen that involves simultaneous administration of, let's say, a vinca alkaloid and an anthracycline. One of those agents requires a warm compress while the other requires a cold compress, and there are different antidotes for those two agents. Additionally, there has not been a lot of published information on the impact of extravasation of those novel agents like the antibody-drug conjugates. With the pace of the drug development, a subgroup of the guideline panelists actually are exploring case reports specific to novel agents to help inform some future work. Brittany Harvey: Yes, we'll look forward to learning more about how to address these ongoing issues and potentially impact guideline recommendations in the future as well. So I want to thank you both so much for your work to develop this incredibly important guideline, and thank you for your time today, Dr. Thomas and Dr. Jotwani. Dr. Aparna Jotwani: Thank you for the opportunity. Dr. Tanya Thomas: Yes, thank you. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. I also encourage you to check out the companion episode on this guideline on the ONS podcast, available on Amazon Music, Apple Podcasts, Spotify, and YouTube Music. And finally, you can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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. Kathleen Horst, Dr. Rachel Jimenez, and Dr. Yara Abdou discuss the updated guideline from ASTRO, ASCO, and SSO on postmastectomy radiation therapy. They share new and updated recommendations on topics including PMRT after upfront surgery, PMRT after neoadjuvant systemic therapy, dose and fractionation schedules, and delivery techniques. They comment on the importance of a multidisciplinary approach and providing personalized care based on individual patient characteristics. Finally, they review ongoing research that may impact these evidence-based guidelines in the future. Read the full guideline, "Postmastectomy Radiation Therapy: An ASTRO-ASCO-SSO Clinical Practice Guideline" at www.asco.org/breast-cancer-guidelines" TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-01747 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Kathleen Horst, expert panel chair from Stanford University; Dr. Rachel Jimenez, expert panel vice chair from Massachusetts General Hospital; and Dr. Yara Abdou, ASCO representative from the University of North Carolina, authors on "Postmastectomy Radiation Therapy: An American Society for Radiation Oncology, American Society of Clinical Oncology, and Society of Surgical Oncology Clinical Practice Guideline." Thank you for being here today, Dr. Horst, Dr. Jimenez, and Dr. Abdou. Dr. Kathleen Horst: Thank you for having us. Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Horst, Dr. Jimenez, and Dr. Abdou who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. Then to dive into the content that we are here today to talk about, Dr. Horst, could you start us off by describing what prompted the update for this joint guideline between ASTRO, ASCO, and SSO, and what is the scope of this 2025 guideline on postmastectomy radiation therapy? Dr. Kathleen Horst: Thank you. This joint guideline was last updated in 2016. Over the past decade, the treatment of breast cancer has evolved substantially. Newer systemic therapy regimens have increasingly personalized treatment based on tumor biology, and local therapy management has explored both the de-escalation of axillary surgery and more abbreviated courses of radiation therapy. Given these advances, it was important to revisit the role of postmastectomy radiotherapy in this modern era of breast cancer therapy. This updated guideline addresses four key questions, including postmastectomy radiation therapy after upfront surgery as well as after neoadjuvant systemic therapy. It also reviews the evolving role of various dose and fractionation schedules and optimal treatment techniques and dose constraints. Brittany Harvey: Excellent. I appreciate that background, Dr. Horst. So then, next, Dr. Jimenez, I would like to review the recommendations of this guideline across those four key questions that Dr. Horst just mentioned. So first, what does the panel recommend for PMRT for patients who received initial treatment with mastectomy? Dr. Rachel Jimenez: The panel provided pretty strong consensus that patients with positive lymph nodes or patients with large tumors involving the skin or the chest wall should receive postmastectomy radiation. However, the panel also recognized that the omission of postmastectomy radiation may be appropriate for select patients who have positive lymph nodes and have an axillary lymph node dissection if they have a low nodal burden and other favorable clinical or pathologic features. For patients without lymph node involvement at the time of surgery and no involvement of the skin or chest wall, postmastectomy radiation was not advised by the panel. Brittany Harvey: Understood. It is helpful to understand those recommendations for that patient population. Following that, Dr. Abdou, what are the key recommendations for PMRT for patients who received neoadjuvant systemic therapy before mastectomy? Dr. Yara Abdou: When we think about PMRT after neoadjuvant treatment, the key point is that the initial stage of presentation still matters a lot. So for example, if a patient comes in with more advanced disease, say a large primary tumor, like a clinical T4, or more extensive nodal disease, like an N2 or N3 disease, those patients should get PMRT, no matter how well they respond to neoadjuvant therapy, because we know it reduces the risk of recurrence and that has been shown pretty consistently. On the other hand, if there are still positive lymph nodes after neoadjuvant treatment, basically residual nodal disease, PMRT is also strongly recommended because the risk of local-regional recurrence is much higher in that setting. The gray area is the group of patients who start with a lower burden of nodal disease, such as N1 disease, but then become node negative at surgery. For those patients, we tend to individualize the decision. So if the patient is young or has triple-negative disease, or if there is a lot of residual disease in the breast even though the nodes are cleared, then radiation is probably helpful. But if everything has melted away with pCR in both the breast and the nodes, then it may be safe to omit PMRT in those patients. For patients with smaller tumors and no nodal involvement to begin with, like a clinical T1-T2 N0, if they are still node negative after neoadjuvant treatment, then PMRT is generally not recommended because their baseline recurrence risk is low. And finally, if the margins are positive and cannot be re-excised, then PMRT is recommended after neoadjuvant therapy. Brittany Harvey: Yes, those distinctions are important for appropriate patient selection. So then, Dr. Horst, we have just reviewed the indications for PMRT, but for those patients who receive PMRT, what are the appropriate treatment volumes and dose fractionation regimens? Dr. Kathleen Horst: The guideline addresses coverage of the chest wall and regional nodes with a specific discussion of the data regarding internal mammary nodal irradiation, which has been an area of controversy over many years. The guideline also reviews the data exploring moderate hypofractionation, or shorter courses of radiation therapy. The task force recommends utilizing moderate hypofractionation for the majority of women requiring postmastectomy radiation, which is likely to have a large impact on clinical practice. This recommendation is based on the evolving data demonstrating that a 3-week course of radiotherapy after mastectomy provides similar oncologic outcomes and minimal toxicity for most patients compared to the standard 5-week treatment course. Brittany Harvey: Thank you for reviewing that set of recommendations as well. So then, Dr. Jimenez, to wrap us up on the key questions here, what delivery techniques are recommended for treating patients who receive PMRT? Dr. Rachel Jimenez: So this portion of the guideline is likely to be most helpful for radiation oncologists because it represents the most technical part of the guideline, but we do believe that it offers some important guidance that has, to this point, been lacking in the postmastectomy radiation setting. So first, the panel recommends that all patients should undergo 3-dimensional radiation planning using CAT scan based imaging, and this includes contouring. So contouring refers to the explicit identification, using a drawing interface on the CAT scan imaging, by the radiation oncologist to identify the areas that are targeted to receive radiation, as well as all of the nearby normal tissues that could receive unintended radiation exposure. And we also provide radiation oncologists in the guideline with suggestions about how much dose each target tissue should receive and what the dose limits should be for normal tissues. Additionally, we make some recommendations regarding the manner in which radiation is delivered. So for example, we advise that when conventional radiation methods are not sufficient for covering the areas of the body that are still at risk for cancer, or where too high of a dose of radiation would be anticipated to a normal part of the body, that providers employ a technique called intensity modulated radiation therapy, or IMRT. And if IMRT is going to be used, we also advise regular 3-dimensional imaging assessments of the patient's body relative to the treatment machine to ensure treatment fidelity. When the treatments are delivered, we further advise using a deep inspiration breath-hold technique, which lowers the exposure to the heart and to the lungs when there is concern for cardiopulmonary radiation exposure, and again, that image guidance be used along with real-time monitoring of the patient's anatomy when those techniques are employed. And then finally, we advise that patients receiving postmastectomy radiation utilize a bolus, or a synthetic substance placed on the patient's skin to enhance radiation dose to the superficial tissue, only when there is involvement of the skin with cancer or other high-risk features of the cancer, but not for every patient who receives postmastectomy radiation. Brittany Harvey: Understood. And then, yes, you just mentioned that section of the guideline is probably most helpful for radiation oncologists, but I think you can all comment on this next question. What should all clinicians, including radiation oncologists, surgical oncologists, medical oncologists, and other oncologic professionals, know as they implement all of these updated recommendations? Dr. Rachel Jimenez: So I think one of the things that is most important when we consider postmastectomy radiation and making recommendations is that this is a multidisciplinary panel and that we would expect and encourage our colleagues, as they interpret the guidelines, to employ a multidisciplinary approach when they are discussing each individual patient with their surgical and medical oncology colleagues, that there is no one size fits all. So these guidelines are intended to provide some general guidance around the most appropriate techniques and approaches and recommendations for the utilization of postmastectomy radiation, but that we recognize that all of these recommendations should be individualized for patients and also represent somewhat of a moving target as additional studies, both in the surgical and radiation oncology realm as well as in the systemic therapy realm, enter our milieu, we have to adjust those recommendations accordingly. Dr. Kathleen Horst: Yeah, I would agree, and I wanted to comment as a radiation oncologist, we recognize that local-regional considerations are intertwined with systemic therapy considerations. So as the data evolve, it is critical to have these ongoing updates in a cross-disciplinary manner to ensure optimal care for our patients. And as Dr. Jimenez mentioned, these multidisciplinary discussions are critical for all of us to continue to learn and understand the evolving recommendations across disciplines but also to individualize them according to individual patients. Dr. Yara Abdou: I could not agree more. I think from a medical oncology perspective, systemic therapy has gotten much better with adjuvant CDK4/6 inhibitors, T-DM1, capecitabine, and immune therapy. So these are all newer adjuvant therapies, so the baseline recurrence risks are lower than what they were in the trials that established PMRT. So the absolute benefit of radiation varies more now, so smaller for favorable biology but still relevant in aggressive subtypes or with residual disease. So it is definitely not a one-size-fits-all. Brittany Harvey: Yes, I think it is important that you have all highlighted that multidisciplinary approach and having individualized, patient-centric care. So then, expanding on that just a little bit, Dr. Abdou, how will these guideline recommendations affect patients with breast cancer? Dr. Yara Abdou: So basically, reiterating what we just talked about, these guidelines really move us towards personalized care. So for patients at higher risk, so those with larger tumors, multiple positive nodes, or residual nodal disease after neoadjuvant therapy, PMRT remains essential, consistently lowering local-regional recurrence and improving survival. But for patients at intermediate or lower risk, the recommendations support a more selective approach. So instead of a blanket rule, we now integrate tumor biology, response to systemic therapy, and individual patient factors to decide when PMRT adds meaningful benefit. So the impact for patients is really important because those at high risk continue to get the survival advantage of radiation while others can be spared the unnecessary treatment and side effects. So in short, we are aligning PMRT with modern systemic therapy and biology, making sure each patient receives the right treatment for their situation. Brittany Harvey: Absolutely. Individualizing treatment to every patient will make sure that everyone can achieve the best outcomes as possible. So then, Dr. Jimenez, to wrap us up, I believe Dr. Horst mentioned earlier that data continues to evolve in this field. So in your opinion, what are the outstanding questions regarding the use of PMRT and what are you looking to for the future of research in this space? Dr. Rachel Jimenez: So there are a number of randomized phase III clinical trials that are either in active accrual or that have reported but not yet published that are exploring further de-escalation of postmastectomy radiation and of axillary surgery. And so we do not yet have sufficient data to understand how those two pieces of information integrate with each other. So for example, if you have a patient who has a positive lymph node at the time of diagnosis and forgoes axillary surgery aside from a sentinel lymph node biopsy, we do not yet know that we can also safely forgo radiation entirely in that setting. So we expect that future studies are going to address these questions and understand when it is appropriate to simultaneously de-escalate surgery and radiation. Additionally, there is a number of trials that are looking at ways in which radiation could be omitted or shortened. So there is the RT CHARM trial, which has reported but not yet published, looking at a shorter course of radiation. And so we do make recommendations around that shorter course of radiation in this guideline, but we anticipate that the additional data from the RT CHARM study will provide further evidence in support of that. Additionally, there is a study called the TAILOR RT trial, which looks at forgoing postmastectomy radiation in patients who, to Dr. Abdou's point, have a favorable tumor biology and a low 21-gene recurrence score. And so we are going to anticipate the results from that study to help guide who can selectively forgo postmastectomy radiation when they fall into that favorable risk category. So there are a number of questions that I think will help flesh out this guideline. And as they publish, we will likely publish a focused update on that information to help provide context for our colleagues in the field and clarify some of these recommendations to suit the latest data. Brittany Harvey: Absolutely. We will look forward to those de-escalation trials and ongoing research in the field to build on the evidence and look for future updates to this guideline. So I want to thank you for your work to update these guidelines, and thank you for your time today, Dr. Horst, Dr. Jimenez, and Dr. Abdou. Dr. Rachel Jimenez: Thank you. Dr. Yara Abdou: Thank you. Dr. Kathleen Horst: Thank you. Brittany Harvey: And then finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Geriatric Assessment Global Guideline (00:16:19)
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.
Oncology Medical Homes: ASCO-COA Standards Update (00:16:11)
Ms. Kim Woofter and Dr. John Cox discuss the latest updates to the evidence-based standards on oncology medical homes developed by ASCO and COA. These standards serve as the basis for the ASCO Certified program. They share the new and revised standards around topics including the culture of safety and just culture in oncology practice, geriatric assessment and geriatric assessment-guided management, and multidisciplinary team management. They expand on the importance of these standards for clinicians and oncology practices to ensure every patient receives optimal care. Read the complete standards, "Oncology Medical Homes: ASCO-Community Oncology Alliance Standards Update" at www.asco.org/standards. TRANSCRIPT These standards, clinical tools, and resources are available at www.asco.org/standards. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP-25-00498 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 Ms. Kim Woofter, a registered nurse in practice leadership and administration from AC3 Inc in South Bend, Indiana, and Dr. John Cox, a medical oncologist and adjunct faculty member from UT Southwestern Medical Center in Dallas, Texas, co-chairs on "Oncology Medical Homes, American Society of Clinical Oncology – Community Oncology Alliance Standards." Thank you for being here today, Ms. Woofter and Dr. Cox. Dr. John Cox: You bet. Ms. Kim Woofter: Thank you. Brittany Harvey: And then before we discuss these standards, I'd just like to note that ASCO takes great care in the development of its standards and ensuring that the ASCO Conflict of Interest Policy is followed for each guidance product. The disclosures of potential conflicts of interest for the expert panel, including Dr. Cox and Ms. Woofter, who have joined us here today, are available online with the publication of the standards in JCO Oncology Practice, which is linked in the show notes. So then, to dive into what we're here today to talk about, Dr. Cox, could you start us off by explaining what prompted an update to these ASCO-COA standards and what the scope of this update is? Dr. John Cox: Well, the ASCO-COA standards relative to defining and outlining Oncology Medical Home were initially published four or five years ago. At the time, we planned a regular update of the standards. So, in essence, this is a planned update. The whole program is built on the idea of continuous improvement. So, this update and future updates are prompted and defined by our literature, our science, the science of care delivery, and new developments and insights gained from studies and evaluations of care delivery methods, and informed by the practice. These standards are in place to underpin a program of care delivery by ASCO, the ASCO Certified, and as practices engage in this program, we are learning from them. The whole idea is to enlarge and improve how patients are cared for in practice. Brittany Harvey: Absolutely. It's great to have this iterative process to continue to review the evidence and update these standards that form the basis for ASCO Certified. So then, following that background, Ms. Woofter, I'd like to review the key points of the revised standards for our listeners. First, how do the revised standards address the culture of safety and just culture in oncology practice? Ms. Kim Woofter: I think safety is of utmost importance to all of us. So let me say that first and foremost. And what we know in oncology is our QOPI standards already address safety in the infusion suite process. So, safe delivery of chemotherapy agents and antineoplastics. It also talked about near misses and medication errors - absolutely essential, for sure. But what we need to do is look at a more systemic approach to safety because we know is processes throughout an organization they'll often cause you trouble. To do that, we know you need what we call a just culture, which is a very common term in today's workplace. But what it really means is it's a culture of open reporting of any potential for error, any potential for malfunction, and it can be in any place in the organization. So, what we are doing in our new standard is to say, look at your entire processes throughout the organization, and approach that in an open-minded way so that people don't feel scared to report things, and it's a really positive approach to intervening early and making sure that errors don't occur anywhere in the workplace. Brittany Harvey: Taking that systemic approach to look at overarching processes seems really key to ensuring safety in oncology practices. So then, the next new section, Dr. Cox, what are the new OMH standards surrounding geriatric assessment and geriatric assessment–guided management? Dr. John Cox: This is a challenging update for our standards. As many folks in practice recognize, there is a deep literature on recognizing the geriatric population in oncology. Geriatric - those in my age group over age 60, 65 - make up the majority of cancer patients in this country. And yet, there are many aspects that should be taken into account as you address treatment decisions in this population. ASCO's recognized this. There has been a guideline previously on geriatric assessment. It's been updated, and we really felt it's time that it be incorporated in any iteration of what oncology care delivery means, so, within the oncology medical home standards. In short, what the standard outlines is that practices that are using these standards, that are using this benchmark, should have a geriatric assessment for patients within the practice care and use that information to guide management. Now, the standard allows wide exploration of how practices meet this standard, but it really puts on the table that if an oncology practice in the United States, or anywhere in the world really, is adhering to a good practice, that they're going to include and recognize these assessments in practice. Ms. Kim Woofter: I would like to add that this is a highly discussed and reviewed standard. Many of our community practices were concerned that they would have the time and manpower to perform this assessment. We all know it reduces toxicities if done appropriately at treatment planning, and so the outcomes are better. And we really left it to the practices to define how they're going to implement it, understanding that it will evolve to every single patient, but maybe day one, it was a step approach to be able to implement. So, I was really proud of the team that - the expert panel - that said, okay, let's step into this, but we do think it's essential. Brittany Harvey: Absolutely. It's important to recognize that practices may have limited resources and time, and implementing it in the way that makes sense for them allows this to be a standard that can be used in practice. And it's great to have this geriatric assessment guideline integrated into these standards to improve care delivery. And we can provide a link to that guideline in the show notes of this episode as well (Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update). So then, following that section of the standards, Ms. Woofter, how do the updated standards now address multidisciplinary team management? Ms. Kim Woofter: Well, we address multidisciplinary team management in a more comprehensive way in the updated standard. We always thought that that was a critical piece when doing treatment planning, and we kind of highlighted it in a bigger way, understanding that not everybody has the same resources available at the time of treatment planning. And again, this was a much-discussed standard, in that that multidisciplinary team approach doesn't necessarily have to be in a tumor board or a prospective analysis of every case. It is actually a conversation between specialists, between the surgeon and pathologist and the medical oncologist. And we are saying, do what works for you, but we know that that team approach, every specialty coming to the table at time of treatment planning, truly provides better outcomes for our patients. And so we kind of reiterated that, understanding that again, it doesn't have to be a formal tumor board, but it has to be a dialogue between specialties. And we highlighted that again in the new standard. Brittany Harvey: Open communication of all team members is really critical to providing optimal care. Dr. Cox, I'd like to ask you, in your view, how will these updated standards impact both clinicians and oncology practices? Dr. John Cox: Well, our whole goal with discussing a comprehensive care model for oncology practice is to have a benchmark, to have an iteration of what good oncology care delivery looks like. So, our hope is that practices, all practices, whether you're participating formally in ASCO Certified, the marquee quality program for ASCO, or if you are simply running a practice or a team within an academic environment or institutional environment, these standards are to apply across the board wherever oncology is practiced - that you can look at these standards as a benchmark and compare what you are doing in your practice and where are the gaps. So ideally, we drive improved care across the board. You know, one thing I've learned over the last couple of years as ASCO Certified is getting spun up and using and implementing these standards, is practices are remarkably innovative. We've learned a lot by seeing how pilot practices have met the standards, and that's gone into informing how we can improve care delivery for all of our practices and, importantly, for the team members who are delivering this care. The fourth rail of burnout and the like is inefficiency that occurs in practice. And when you know you've got a good, spun-up, effective team, less burnout, less stress for practice. I hope clinicians and oncology practices will use this to help drive improvements in their care and gain insight into how they can approach practice problems in a better way. Kim, you've been leading practices. I have to ask you, your thoughts in leaning into this question. Ms. Kim Woofter: I think very well said, I will say that first. And what I love about this is for practice leaders who are new to our ecosystem, if you will, they need a playbook. It's "Where do I begin?" And Dr. Cox said it very well, no one does everything perfectly day one, but it's a step-by-step self-assessment approach to say, "How do I get to this gold standard?" I really love the standards because they are very comprehensive, everything from treatment planning to end of life. So it's the spectrum of the care we deliver in the oncology setting. So as a leader and an administrator, it is the standard I want all of my departments to understand, adhere to, and engage, and be excited about. We now have a baseline approach, and what's even more important, these standards will evolve as our intelligence evolves, as literature evolves. It's a system that will always grow and change, and that's what we love about it. It's not a one-and-done. So, I'm very proud of the fact that it gives them a road map. Brittany Harvey: Yes, these evidence-based standards provide a critical foundation for practices in ASCO Certified, for those team members you mentioned, and for quality improvement beyond just those individuals and practices as well. So then finally, to wrap us up, Ms. Woofter, what do these revised standards mean for patients receiving cancer treatment? Ms. Kim Woofter: Well, I think that's the most exciting part, is we all do this for our patients and the best outcomes for our patients and the best treatment plans for our patients and their families. And these standards, that is their core, their absolute core. So what it's going to do for a patient is they can say, "Am I at a practice that implements ASCO standards?" And if that is a 'yes', there's a confidence that, "I am in an evidence-based medicine thinking practice, I have a team around me, they will care for me not only at time of treatment planning but at the time of end of life, they will help me be part of that decision-making, and they will give me resources available to me in my community." So, it is a true comprehensive approach. As a patient, I have that comfort, that it is bigger than just a great doctor. It is a great team. As a patient, that would be very important to me and important to my family. That being said, Kim Woofter would love every practice to be ASCO Certified. Understanding that that isn't feasible day one, just to know that the practice is implementing and engaging the standards is the great place to start. Every patient can't go to an ASCO Certified practice day one, but our dream would be that everyone would adhere to those standards, engage those standards, believe them, educate their staff on what they mean, so that patient outcomes and satisfaction will be optimized for everyone. The other piece to this that we all know is if you give evidence-based medicine, cost-effective, efficient care, it's better for the system as a whole. And I'm not saying that insurance is our driver - certainly patient outcomes are our driver - but the whole ecosystem of oncology benefits when you do the right thing. Dr. John Cox: It's hard to add anything to Kim's good statements, but I just highlight that this whole area began with the patient-centered medical home, and every time we've met, patients and how we deliver care to patients is top of mind. I think that reflects our community. It reflects oncology as a whole. I don't know any oncologist or practice that is focused on anything else as the prime goal. Brittany Harvey: That's what I was just going to say. The ultimate goal here is to provide patient-centered care across where every single patient is receiving treatment and at every stage of that treatment. So, I want to thank you both so much for your work to update these standards, to review the evidence, and discuss with the experts on the panel to come up with the solutions that will help drive quality improvement across care delivery. So, thank you for that, and thank you for your time today, Dr. Cox and Ms. Woofter. And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the complete standards, go to www.asco.org/standards. You can also find many of our standards and interactive resources in the free ASCO Guidelines app, which is available on the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2025.1 Part 2 (00:15:16)
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.
Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2025.1 Part 1 (00:11:30)
Dr. Lyudmila Bazhenova is back on the podcast to discuss the latest update of the living guideline on therapy for stage IV NSCLC without driver alterations. She shares the studies the Expert Panel reviewed in the first- and second-line settings, including NIPPON, HARMONi-2, and DUBLIN-3. Although these studies do not impact the existing guideline recommendations, Dr. Bazhenova provides context and comments on ongoing trials that will influence the next iteration of the living guideline. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1" at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT 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-25-01062 Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on "Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1." It's great to have you back on the show today, Dr Bazhenova. Dr. Lyudmila Bazhenova: It's my pleasure to be here. Brittany Harvey: And then before we discuss this guideline update, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bazhenova, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, Dr. Bazhenova, this living clinical practice guideline for systemic therapy for patients with stage IV non–small cell lung cancer without driver alterations is updated on an ongoing continuous basis. So what prompted this latest update to the recommendations? Dr. Lyudmila Bazhenova: Living ASCO guidelines are designed to keep pace with rapidly evolving evidence that impacts treatment of our patients with lung cancer. As a committee, we are tasked with regular review of the published literature and determine if the new data warrants changes to existing recommendations. So in this recently published update, we evaluated new trials related to treatment of patients with metastatic lung cancer without driver alterations. Brittany Harvey: Excellent. Thank you for that explanation of the process. So, you just mentioned that the panel reviewed new trials for this update. So, which particular updated evidence did the panel review on first-line treatment options for patients with good performance status across histology and PD-L1 expression status, and how did this impact the recommendations? Dr. Lyudmila Bazhenova: For the first-line treatment option for patients without driver alterations, two studies met our criteria for review. One was the NIPPON trial from Japan, the second was the HARMONi trial. None of those two trials resulted in change in our guidelines, but I think they are giving us some additional information that would be useful for the way we treat patients with non–small cell lung cancer without driver alterations. For example, if we take those patients, we currently have several treatment options as a first line. One is monotherapy immunotherapy. You can give pembrolizumab as an example, and that was based on the KEYNOTE-024 and KEYNOTE-042 trials. Then we have a platinum doublet plus immunotherapy, and there are several trials that did that pathway. And then we have also an option of giving our patients dual IO immunotherapy combination, such as CheckMate 9LA and POSEIDON. At this point, we do not have any randomized trials comparing those three treatment modalities head-to-head. And the NIPPON trial was interesting to us because it was the first trial to compare CheckMate 9LA regimen, which is again, dual immunotherapy plus chemo, versus KEYNOTE-189 or KEYNOTE-407, which is a chemotherapy plus immunotherapy. And as a result of the study, while chemotherapy plus ipilimumab-nivolumab led to numerically higher overall survival, the difference was not statistically significant. And what is concerning in that trial is that we saw a higher number of treatment-related death occurring in nivolumab and ipilimumab arm compared to the pembrolizumab-chemotherapy arm. As a matter of fact, the trial was terminated early because of the increased risk of death. If you look at the treatment-related death in CheckMate 9LA, the 9LA study reported the treatment-related death to be 2%, and then in the NIPPON trial, the treatment-related death was 7%. Why is that happening? It's really difficult to say. The study was done in Japan. Maybe there is some pharmacogenomic differences between global population and Japan population. But certainly the higher rate of adverse events needs to be taken into account. Another interesting thing about this trial is that it did not show any differences in a subset analysis for patients with squamous histology as well as PD-L1 negative tumor. So while this does not change our current guidelines and CheckMate 9LA treatment still remains an appropriate treatment option, it kind of raises the possibility that this combination could be associated with a higher toxicity. And we do have a randomized US-based trial that is ongoing, and we are hoping that eventually we will be able to answer that question after the trial will be completed. The second trial we reviewed is HARMONi-2. So HARMONi-2 was a randomized, double-blind study which is conducted primarily in China, looking at bispecific PD-L1 and VEGF antibody called ivonescimab. And that took patients who were PD-L1 positive, as defined as more than 1% expression, and patients were randomized to pembrolizumab versus bispecific ivonescimab. And the study was positive. It showed improvement in median progression-free survival of 11 months versus almost 6 months in bispecific versus pembrolizumab. There were, however, higher grade 3 events in the ivonescimab arm. At this point, we are not changing our recommendations because this trial was done in an ex-US population, and we are awaiting a similar trial ongoing in the United States before we change recommendations and decide if ivonescimab needs to be included in our guidelines. Brittany Harvey: This context is very helpful when clinicians think through the data behind these options. And it's important that the panel reviews this evidence, even if it doesn't prompt a change to the recommendations. And we'll await results of those trials that you mentioned to further inform this guideline. So then beyond those studies for first line, what updated evidence did the panel review for second-line and subsequent treatment options for patients with good performance status, and how did this impact the recommendations? Dr. Lyudmila Bazhenova: So for second line, only one trial met the criteria, and that was DUBLIN-3. DUBLIN-3 is a phase 3 single-blind randomized trial comparing docetaxel versus docetaxel plus plinabulin. And the study enrolled patients with second or third line. They have to have had platinum-based chemotherapy and progressed. Plinabulin is an interesting compound. It's a small molecule tubulin binder that prevents polymerization of tubulin and appears to impact dendritic cell maturation and T-cell activation. This study enrolled 559 patients, randomly assigned them to two groups. And one important information about this study is that was a study that was envisioned before immunotherapy became a standard mainstream treatment for first-line therapy. And only 20% of patients had prior PD-1 exposure. So therefore, the results of that study need to be taken into context of this population no longer existing in the United States because we use PD-L1 inhibitors in the first line. And we saw that interesting in the plinabulin arm had lower rates of neutropenia but higher rates of serious adverse events. And at this point, we are not changing our guidelines for mainly two reasons. Number one, low number of patients that received prior treatment with first-line immune checkpoint inhibitors, as well as a modest overall survival benefit of this trial. Brittany Harvey: Understood. I appreciate you describing that study as well and why that evidence didn't prompt a change to those particular recommendations. So then, what should clinicians know as they implement this living guideline, and how does this new evidence impact clinicians and patients? Dr. Lyudmila Bazhenova: At this point, none of the studies that we reviewed resulted in a change in guidelines. We are still waiting for more global results from some of the studies that I highlighted. It shows that there's still a lot of questions we need to be answering in those patients. And I'm hoping that with future clinical trials, we will be able to definitively maybe recommend one treatment over another. But at this point, all the treatments that I mentioned before remain appropriate for patients with stage IV non–small cell lung cancer without driver alterations. Brittany Harvey: Definitely. And then you just mentioned that there's still a lot of outstanding questions in this field. You've mentioned a couple different studies where we're awaiting evidence. Beyond those that you already mentioned, what is the panel examining for future updates to this living guideline? Dr. Lyudmila Bazhenova: Right now, our next task is to come up with a full guidelines update. ASCO have certain rules for the guidelines committee members. And so we are gearing for a full guideline update, which hopefully will be ready by the end of 2025. Brittany Harvey: Excellent. We'll look forward to that full update of the living guideline, and we'll still await results of these ongoing trials to further inform this living guideline. So I want to thank you so much for your work to rapidly and continuously update this living guideline, and thank you for the time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: My pleasure. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Symptom Management for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors Guideline (00:19:20)
Dr. Kimberly Perez and Dr. Jaydira Del Rivero discuss the new guideline from ASCO on symptom management for well-differentiated GEP-NETs. They share the latest recommendations on managing symptoms related to hormone excess, including carcinoid syndrome and carcinoid heart disease, managing symptoms of functioning pancreatic neuroendocrine tumors, and also palliative interventions. Dr. Perez and Del Rivero share how to use this guideline in concert with the systemic therapy for tumor control in metastatic well-differentiated GEP-NETs guideline, and hope for the future for the treatment of gastroenteropancreatic neuroendocrine tumors. Read the full guideline, "Symptom Management for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline." Transcript This guideline, clinical tools, and resources are available on ASCO.org. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in JCO Oncology Practice. 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. Kim Perez from Dana-Farber Cancer Institute and Dr. Jaydira Del Rivero from the Center for Cancer Research at the National Cancer Institute, co-chairs on "Symptom Management for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline." Thank you for being here today, Dr. Del Rivero and Dr. Perez. Dr. Kim Perez: Thank you. Dr. Jaydira Del Rivero: Thank you so much for the invitation. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Perez and Dr. Del Rivero, who have joined us here today, are available online with the publication of the guideline in JCO Oncology Practice, which is linked in the show notes. So then to jump into the content here, first Dr. Del Rivero, could you provide an overview of the scope and purpose of this guideline? Dr. Jaydira Del Rivero: Yeah. Thank you so much. Well, first, we really wanted to thank ASCO for allowing us to develop these guidelines for the management of gastroenteropancreatic neuroendocrine tumors. I do want to mention that there is also another set of guidelines that I was very fortunate also to co-chair with Dr. Perez on the systemic management of gastroenteropancreatic neuroendocrine tumors. But when discussing these guidelines as well as with the different panelists, experts in this type of disease, we also realized that the management of these tumors are quite complex, not only from the management of the disease progression, but at the same time, management of the symptoms related to the hormone excess. And because of that, we like to thank ASCO for allowing us to then not only have a discussion on the systemic management of these tumors, but at the same time develop recommendations for the symptoms related to the different hormones that these neuroendocrine tumors may produce. These guidelines are for the management of grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors. These guidelines include the management of the different aspects and the symptoms related to hormone excess, such as carcinoid syndrome, carcinoid heart disease, how to manage carcinoid crisis, as well as the different symptoms and how to manage the functional pancreatic neuroendocrine tumors and as well as provide recommendations in the different treatments for these tumor types, not only from the systemic management but also from the surgical management as well as for liver-directed therapy options and the different aspects in terms of the palliative care of these patients to improve not only the symptoms related to the hormone excess caused by these tumors, but as well as to improve the quality of life. Brittany Harvey: Absolutely. And I appreciate that overview. And yes, we'll link the guideline on the Systemic Therapy for Tumor Control for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors in the show notes for our listeners so that they can refer to that companion guideline as well. So then you just described the several different categories of recommendations that this guideline covers on symptom management. So, Dr. Perez, I'd like to start reviewing some of those key recommendations of that guideline. So, starting with what are the key recommendations for carcinoid syndrome and carcinoid heart disease? Dr. Kim Perez: Thank you Brittany. Yeah, I also want to thank ASCO for inviting us to do this podcast today. Just to start, I think these guidelines will really add to what's available in the literature to provide a kind of a quick look for the community provider to manage carcinoid-related symptoms. I think the highlights that I would point out are we've all been using somatostatin analogs for the last few decades to manage symptoms, but with the newer treatments that are now available, we tried to highlight what does the literature support in regards to PRRT, what does the literature support in regards to using systemic therapy for disease management, but also the benefits that you will get from a symptom management perspective using other modalities. I think the highlight really is it's a multidisciplinary approach. We are now considering surgery and embolization or interventional radiology as a critical piece. And I think the third that I'd highlight is the fact that sometimes we get too focused on carcinoid syndrome and the symptoms will actually, may result from other things. And the highlight in the algorithms that we've provided is what other things cause carcinoid-related diarrhea. And let's not forget about that because we will find ourselves treating and patients getting very frustrated with persistence of symptoms when in actuality, we should be treating something else that is causing a very similar symptom. For carcinoid heart disease, I think there are more and more guidelines that are now available to provide guidance there, but I think the major advances are that we should be utilizing heart assessment with echocardiogram with lab values such as BMP. But also critical to this is consulting with our cardiology colleagues and making sure that we're identifying heart related issues that are resulting from hormone excess sooner than later because interventions on the earlier side can really make a significant impact on quality of life and associated comorbidities and mortality. Brittany Harvey: Thank you for reviewing those key points for both carcinoid syndrome and carcinoid heart disease symptom management. So then the next set of recommendations. Dr. Del Rivero, what are the key highlights for symptom management of functioning pancreatic neuroendocrine tumors? Dr. Jaydira Del Rivero: Yes, it's very important to recognize the symptoms related to hormone excess due to pancreas neuroendocrine tumors. Up to 10% of pancreas neuroendocrine tumors may produce different hormones. Among those hormones can be insulin, gastrin, glucagon, somatostatin. So it's important to know and understand that based on what a neuroendocrine tumor is, they may produce different types of hormones. The importance of these guidelines is to also recognize some of these symptoms and how to address that, because it's not necessarily in these tumor types besides the management of metastatic disease, and know the different options that we recommend for metastatic disease from the systemic therapy, such as chemotherapy or targeted therapies or PRRT. It's important to recognize the symptoms because based on the symptoms we may recommend a different approach. That's something that is important to acknowledge and recognize. Moreover, in certain functional pancreas neuroendocrine tumors, as Dr. Perez mentioned, is a multidisciplinary approach. And it's important to also discuss these different cases with your endocrinologist. You may need to have an experienced endocrinologist to manage, for example, the excess of insulin. And also discuss your cases with a surgeon and interventional radiologist because some of these approaches can certainly improve the symptoms related to hormone excess. I understand that sometimes medical oncologists in the communities may not have access to the multidisciplinary approach or have the different teams that can manage these tumors, and that's the reason why with these guidelines we wanted to establish the understanding of different symptoms associated with the hormone excess to these neuroendocrine tumors as well as how to manage this. For example, in the case of insulinoma, I think for the medical oncologist it is important to know that the everolimus is an option to be used for these tumors, not only to manage tumor progressions related to this tumor type at the same time, because everolimus as a side effect causes hyperglycemia, that can also improve some of the symptoms related to the excess of insulin besides the somatostatin agonist. I think these recommendations will allow the medical oncologist to recognize the symptoms and based on what the symptoms cause, then you can have a different approach that could be added to the systemic therapies options as well. Brittany Harvey: Yes, beyond systemic therapy, it's important to be recognizing symptoms to provide an individualized approach for every single patient. So then, following that overview of symptom management for functioning pancreatic neuroendocrine tumors, Dr. Perez, what is recommended regarding palliative interventions for patients with gastroenteropancreatic neuroendocrine tumors? Dr. Kim Perez: Yeah, great question. So I think what's unique to neuroendocrine tumors is that the palliative approach really mirrors what we would be doing for symptom management. Some of these patients are living a very long time with carcinoid related symptoms. And so the approach that we take for the carcinoid symptom control is going to mirror the palliative piece of it. I think for those who develop a burden of disease related symptoms, I think it mirrors what we do across the board for all cancer-related complications. And so I think what we attempted to highlight here and included one of our colleagues who focuses specifically on the field of palliative care and neuroendocrine tumors, was to never really lose sight of what we've been doing to care for symptom management throughout the patient's journey and to always rereview the etiology of the symptoms, ensure that we don't focus solely on carcinoid-related issues, but also the symptom management that we would apply to all patients with cancer-related burden symptoms. Brittany Harvey: Definitely. I think that's a helpful approach to consider when thinking about how to manage these palliative interventions as well. So then Dr. Del Rivero, what should clinicians know as they implement these symptom management recommendations? Dr. Jaydira Del Rivero: Yes, thank you so much for that question. As we have discussed in the last 10 or 15 minutes, we have discussed the different approaches on the management of gastroenteropancreatic neuroendocrine tumors. Clinicians, I think it's important to know that neuroendocrine tumors is a quite complex disease because we're not only addressing the management of tumor growth, but we're also addressing the management of the symptoms related to hormone excess and the complexity associated with that. When medical oncologists or clinicians implement these recommendations it's to understand what symptoms these tumors may cause related to the hormone excess but at the same time, how do we approach those symptoms? As Dr. Perez said that I think is very important is to recognize the different types of diarrhea. It doesn't mean that if the patient has worsening diarrhea, it doesn't mean that this is related to disease progression. So it's important to recognize so that way you can address that, because the type of diarrheas can be related because of the lanreotide or somatostatin agonist, it could be because of the prior surgery. I think it's important to recognize those in order to address the symptom. And the same with the gastroenteropancreatic neuroendocrine tumors. It's important to know what hormones they produce because there are different measurements that may be added to the systemic management of these tumors. I think that there are two aspects here, and that's the reason why these guidelines were implemented in the sense that not only we're going to manage disease progression of these tumors, or how do we manage the metastatic disease of these tumors, but at the same time, how do we manage the symptoms related to the hormone excess and the different complications. Moreover, I think, as we discussed earlier, we need to manage these tumors in a multidisciplinary approach. And something very important is not like one size fits all, because the treatment recommendations, it will depend on different characteristics in terms of the tumor presentations. And hormone excess is one of the important aspects to recognize so that way we can implement these recommendations that will definitely help the quality of life of these patients. Brittany Harvey: Absolutely. And using these guidelines in concert with the systemic therapy guidelines is key. And then beyond this impact for clinicians that Dr. Del Rivero has just outlined, Dr. Perez, what does this new guideline mean for patients with gastroenteropancreatic neuroendocrine tumors? Dr. Kim Perez: Yeah, I think that's an important highlight of this guideline. It really gives patients a voice. I think it recognizes the fact that these symptoms can go unmanaged or mismanaged or just missed, and patients commonly will come in feeling very frustrated and feeling very ill. And I think it will provide them a means to open up a conversation with their providers and say, "Hey, this is what I'm experiencing. Let's talk about what's available. How does this apply to me?" And I think that can be very empowering. I think it's really hard nowadays with so many sources and resources online and patients are really left wondering what are the bullet points that they should be bringing to their clinician appointments? And I think that these guidelines provide them a good framework for those discussions. Brittany Harvey: Yes, bringing these discussion points for patients is very important to be able to have those resources. And we have some patient resources and information available on the website for this guideline and we can link that in the show notes for listeners. So then you've both touched on the importance of this guideline for improving quality of life and we continue to see advancements in this field. So Dr. Del Rivera, what are the outstanding questions regarding symptom management and tumor control for gastroenteropancreatic neuroendocrine tumors? Dr. Jaydira Del Rivero: I have to say whenever somebody asks me that question, the word that I will say is I feel hopeful, because more than 10 years ago we didn't have that many options for gastroenteropancreatic neuroendocrine tumors. And it has been in the last decade or so that there has been more developments in the management of these tumors as well as the understanding of the symptoms related to these tumors. But that said, yes, we do need more therapies for gastroenteropancreatic neuroendocrine tumors. Of the treatment options that we have, we all know in the field that even though we have disease control by using the different options for the systemic management of gastroenteropancreatic neuroendocrine tumors, we need options where we can achieve an objective response, especially for these tumor types. But there is a significant volume of disease and we see a lot of these patients with gastroenteropancreatic neuroendocrine tumors. And now where the field is going is to make some of these therapies more effective, to develop more therapies as well. For example, immunotherapies, a different type of immunotherapy understand the tumor immune microenvironment of these tumors in order to develop therapies as well. From the antibody drug conjugates, I think that's a new way to also address or treat these tumor types, understanding about the different markers found on these tumors that way they can be addressed in different ways. Now with the development of new therapies, I think that's something that can help us as well not only have disease control and as well as having an objective response, but having a better objective response can certainly also help with the symptoms related to hormone excess too. In terms of other therapies, I think some of the issues that we encounter are like the refractory carcinoid diarrhea and how do we manage this. We do have therapies that can help us control the diarrhea in the refractory settings, such as telotristat. Telotristat is one of the newer medications that can help us control the refractory diarrhea. But that said, despite this, that we still encounter situations where it's sometimes difficult to control. I think in those situations it will be good to understand more about the biology of these tumors as well and how we manage. If there is a different time or how do we implement these options. I think there is so much to learn. But that said, I feel we're in hopeful times. We're understanding more about these tumors so that way we can help us develop better therapies not only to have control of the tumor growth as well having control of the symptoms. And it's the same with the pancreas neuroendocrine tumors in the metastatic setting. Sometimes it may be difficult to control this hormone excess. But understanding these and having therapies that can achieve more of an objective response, I think that will definitely help us more and manage these patients. But one aspect I want to mention, and Dr. Perez also mentioned as well, the fact that we have these guidelines that help us understand about the different symptoms related to hormone excess and how to address it, I think is very important because having symptoms related to hormone excess can be detrimental to the quality of life on patients with neuroendocrine tumors that may necessarily be related to disease progression and having this information is so important. And I'm hopeful for the different therapies. There's different clinical trials ongoing for neuroendocrine tumors and especially in the field of PRRT. And a lot of more information will come with the different alpha-PRRT and combination therapy. So more information to come in the next couple of years. So this is, in my opinion, hopeful times for this field. Brittany Harvey: It's great to hear that you're hopeful for all the developments in this field and we'll look forward to the development and discovery of new therapies and further research and then, hopefully incorporate those updates into guidelines in the future. So I want to thank you both so much for your work to develop these guidelines and thank you for your time today. Dr. Del Rivero and Dr. Perez. Dr. Jaydira Del Rivero: Thank you so much for having us. Dr. Kim Perez: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Systemic Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer Guideline Update (00:22:48)
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.
Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Rapid Update (00:09:22)
Dr. Nimish Mohile and Dr. Jaishri Blakeley share the new rapid recommendation update to the therapy for diffuse astrocytic and oligodendroglial tumors in adults guideline. They review the evidence from the INDIGO trial that prompted this update, and how to incorporate the use of vorasidenib into clinical practice. They discuss the importance of molecular testing, particularly for IDH1 or IDH2 mutations and outstanding questions for treatment of patients with oligodendrogliomas and astrocytomas. Read the latest update, "Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline Rapid Recommendation Update." Transcript This guideline, clinical tools, and resources are available at http://www.asco.org/neurooncology-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in Journal of Clinical Oncology. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Jaishri Blakeley from Johns Hopkins University School of Medicine and Dr. Nimish Mohile from the Department of Neurology and Wilmot Cancer Institute at the University of Rochester Medical Center, co-chairs on "Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: American Society of Clinical Oncology-Society for Neuro-Oncology Guideline Rapid Recommendation Update." Thank you for being here today, Dr. Blakeley and Dr. Mohile. Dr. Jaishri Blakeley: Thank you. Dr. Nimish Mohile: Thank you for having us. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Blakeley and Dr. Mohile who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content here, Dr. Mohile, could you start us off by describing what prompted this rapid update to the ASCO-SNO therapy for diffuse astrocytic and oligodendroglial tumors in adults guideline, which was previously published in 2021? Dr. Nimish Mohile: Yeah. So the key reason for this update is the publication of a study in 2023. And this was a study called the INDIGO study that looked at a new class of therapies, something called IDH inhibitors. And in this study with a drug called vorasidenib, changed how we think about the treatment of oligodendrogliomas and astrocytomas, so particularly the grade 2 oligodendrogliomas and grade 2 astrocytomas. Because of the results of that study, we decided that we needed to do an update to inform clinicians about some of these changes and how we might approach these tumors differently today. Brittany Harvey: Great. I appreciate that background. So then, based off the new data from the INDIGO study, what are the updated and new recommendations from the expert panel? Dr. Nimish Mohile: So the key findings from the INDIGO study involved people who had grade 2 astrocytomas and grade 2 oligodendrogliomas. And in the setting after surgery, they were treated with vorasidenib, and what they found is that this delayed the time to next intervention. And the key aspect of that is that it delayed when we could start radiation and chemotherapy in these patients. So what we did in the guidelines is that for both low grade oligodendrogliomas and low grade astrocytomas, we added one additional guideline statement. Our previous guideline in 2021 offered the options for observation or treatment with radiation and chemotherapy. And now in this guideline, we have options for observation, treatment with vorasidenib in those in whom we feel it is safe to defer radiation and chemotherapy, and then treatment with radiation and chemotherapy. So we've added in an additional option here. And the key message of the guideline is really on how, as clinicians, we think about using the vorasidenib and what the ideal setting for using the vorasidenib is. Brittany Harvey: Excellent. It's great to hear about this new option for patients. So then you were just talking about how we think about who to offer this IDH inhibitor to. So, Dr. Blakeley, what should clinicians know as they implement these new recommendations into practice? Dr. Jaishri Blakeley: Yes. So, first and foremost, let's go back to 2021, and a key note from those guidelines was the importance of molecular testing. And at that point, the importance of molecular testing, which in large part was focused on IDH1 or IDH2 mutations, was prognostic. We could say there's a difference in an IDH1 mutant astrocytoma and an IDH1 wild type astrocytoma, but we didn't have a specific therapeutic recommendation attached to that, like Dr. Mohile just said. And the big shift here is now we have a specific therapeutic for that population with IDH1 or IDH2 mutant glioma. So for clinicians, we hope that they've been getting molecular testing on newly diagnosed glioma already, but now there's an additional motivation to do so because it may change your treatment plan in the right circumstance. So since the publication of the phase III INDIGO study that Dr. Mohile mentioned, and the FDA approval of vorasidenib, if you meet the specified criteria in the clinical trial - which the guidelines point out is a little different than what's on the FDA label, so clinicians might want to dig into that a little bit - then there is a treatment option that is new and different than combined chemoradiation or radiation alone or observation. Brittany Harvey: I appreciate those clarifications there. So then also, Dr. Blakeley, how does this update impact patients with astrocytic or oligodendroglial tumors? Dr. Jaishri Blakeley: So first, patients also should know if they have IDH mutant gliomas. And this update only applies to people with IDH1/2 mutant glioma. Perhaps, we're not sure, it might only apply to people who are in the newly or newly-ish diagnosed category because the INDIGO study required that people were within the first five years of their surgical diagnosis and had not had other treatment. So there are a lot of people who have astrocytoma or oligodendroglioma who may or may not know their IDH1/2 status and may have already had another therapy - this update doesn't apply to them. We hope that future research will teach us about that. This update is for people who are newly diagnosed and just starting the journey to figure out the best therapy. It does say that if you do have that IDH1/2 alteration in your tumor, there is a drug therapy that is different from the drug therapies we would offer gliomas that do not have the IDH1/2 mutation. Brittany Harvey: Absolutely. I think both that emphasis on molecular testing is very important and also thinking about that study inclusion criteria and how it impacts who's eligible for this treatment. So then finally, Dr. Mohile, what are the outstanding questions about vorasidenib or other interventions for gliomas in adults? Dr. Nimish Mohile: I think the key question for clinicians is exactly who we're going to use this in. The challenges with inclusion criteria in clinical trials is they don't actually always match what we're seeing in the clinic. And I think it brings up the question of, in low grade oligodendrogliomas which we think of as very slow growing tumors, do we have the option outside of the strict inclusion criteria to use that drug in other settings? I think it brings up the question for some clinicians in some of the higher grade tumors, in the grade 3 tumors, we don't yet have data in that area and our guideline doesn't address that. But I think some will be asking what the clinical activity of vorasidenib is in that setting. There are some suggestions that the IDH inhibitors may impact seizure control, and I think that that's data that we're continuing to wait on. So I think that there's several outstanding questions there that we will have answers for hopefully in the next several years. I think the big question that we don't have an answer for and that will take a long time to know is whether the addition of vorasidenib in this setting actually improves how long people live. And given how long people with low grade oligodendrogliomas and low grade astrocytomas live today, we probably won't have an answer to that question for more than a decade. Brittany Harvey: Definitely. We'll look forward to these ongoing developments and eventually longer term data on overall survival on these agents. So, I want to thank you both so much for your work to rapidly include this information from this new trial. And thank you for your time today, Dr. Blakeley and Dr. Mohile. Dr. Jaishri Blakeley: Thank you so much. Dr. Nimish Mohile: Thank you Brittany. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/neurooncology-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer Guideline Update (00:20:51)
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.
Fertility Preservation in People with Cancer Guideline Update (00:32:09)
Dr. Irene Su and Dr. Alison Loren present the latest evidence-based recommendations on fertility preservation for people with cancer. They discuss established, emerging, and investigational methods of fertility preservation for adults and children, and the role of clinicians including discussing the risk of infertility with all patients. Dr. Su and Dr. Loren also touch on other important aspects of fertility preservation, including the logistics of referral to reproductive specialists, navigating health insurance, and costs. They also discuss ongoing research and future areas to explore, including risk stratification, implementing screening, referral, and navigation processes in lower resource settings, fertility measurements, and health care policy impacts. Read the full guideline update, "Fertility Preservation in People with Cancer: ASCO Guideline Update" at www.asco.org/survivorship-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02782 In this guideline, the terms "male" and "female" were defined based on biological sex, specifically focusing on reproductive anatomy at birth. "Male" refers to individuals born with testes, while "female" refers to those born with ovaries. The guideline, and this podcast episode, we will refer to individuals as "males" or "females" based on this definition. Brittany Harvey Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Irene Su from the University of California, San Diego, and Dr. Alison Loren from the University of Pennsylvania, co-chairs on "Fertility Preservation in People With Cancer: ASCO Guideline Update." Thank you for being here today, Dr. Su and Dr. Loren. Dr. Irene Su: Thanks for having us. Dr. Alison Loren: Thanks for having us. Brittany Harvey: Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Su and Dr. Loren, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content here, Dr. Loren, this is an update of a previous ASCO guideline. So what prompted this update to the 2018 guideline on fertility preservation? And what is the scope of this particular update? Dr. Alison Loren: Yeah, thanks, Brittany. So, yeah, a couple of things, actually. I would say the biggest motivation was the recognition that the field was really moving forward in several different directions. And we felt that the previous guidelines really hadn't adequately covered the need for ongoing reproductive health care in survivorship, including the fact that fertility preservation methods can be engaged in even after treatment is finished. And then also recognizing that there is increasing data supporting various novel forms of fertility preservation in both male and female patients. And we wanted to be able to educate the community about the wide array of options that are available to people with cancer, because it really has changed quite a bit even in the last six years. And then lastly, as I'm sure this audience, and you definitely know, ASCO tries to update the guidelines periodically to make sure that they're current. So it sort of is due anyhow, but I would say motivated largely by those changes in the field. Brittany Harvey: Great. I appreciate that background information. So then I'd like to dive a little bit more into those updates that you discussed. So, Dr. Su, I'd like to review the key recommendations across the main topics of this guideline. So starting with what are the recommendations regarding discussing the risk of infertility with patients undergoing cancer treatment? Dr. Irene Su: Thanks, Brittany. So for every child, adolescent, and adult of reproductive age who's been diagnosed with cancer, the recommendation remains that healthcare clinicians should discuss this possibility of infertility as early as possible before treatment starts, because that allows us, as reproductive endocrinologists and fertility specialists, to preserve the full range of options for fertility preservation for these young people. Where it's possible, I think risk stratification should be a part of the clinical infertility risk counseling and then the decision making. And then for patients and families who have an expressed interest in fertility preservation, and for those who are uncertain, the recommendation is to refer these individuals to reproductive specialists. And it turns out this is because fertility preservation treatments are medically effective for improving post-treatment fertility and counseling can ultimately reduce stress and improve quality of life, even for those who don't undergo fertility preservation. And as Dr. Loren said, a change in the guideline is specifically about continuing these discussions post-treatment yearly or when cancer treatments change because that changes their infertility risk or when pregnancy is being considered. Brittany Harvey: Absolutely. Discussing that risk of infertility at the beginning, before any treatment is initiated, and when treatment changes, is key. So then talking about the options for patients, Dr. Loren, what are the recommended fertility preservation options for males? Dr. Alison Loren: There has been a little bit of an evolution in options for male patients. The standard of care option which is always recommended is cryopreservation of sperm, or otherwise known as sperm banking. And this is something that should be offered ideally prior to initiating cancer directed therapy. The guideline does reflect the fact that we're starting to understand in a little bit more depth the impact of cancer-directed treatments on the health and quantity of sperm. And so trying to understand when, if ever, it's appropriate to collect sperm after initiation of treatment, but before completion of treatment remains an area of active research. But the current understanding of the data and the evidence is that sperm banking should be offered prior to initiating cancer-directed therapy. And all healthcare clinicians should feel empowered to discuss this option with all pubertal and post-pubertal male patients prior to receiving their treatment. We do offer a little bit more information about the ideal circumstances around sperm banking, including a minimum of three ejaculates of sufficient quality, if possible, but that any collections are better than no collections. We also talk about the fact that there is a relatively new procedure known as testicular sperm extraction, which can be offered to pubertal and post-pubertal males who can't produce a semen sample before cancer treatment begins. There remains no evidence for hormonal protection of testicular function - that has been a long-standing statement of fact and that remains the case. And then we also begin to address some of the potential risk of genetic damage in sperm that are collected soon after initiation of cancer-directed therapy. We are starting to understand that there is a degradation in the number and DNA integrity of sperm that can occur even after a single treatment. And so, really highlighting the fact that collecting samples, again, to Dr. Su's point, as early as possible and as many as possible to try to optimize biological parenthood after treatment. Brittany Harvey: Yes. Thank you for reviewing those options and what is both recommended and not recommended in this scenario. So then, following those recommendations, Dr. Su, what are the recommended fertility preservation options for female patients? Dr. Irene Su: There are a number of established and effective methods for fertility preservation for people with ovaries, and this includes freezing embryos, freezing oocytes, freezing ovarian tissue. For some patients, it may be appropriate to do ovarian transposition, which is to surgically move ovaries out of the field of radiation in a conservative gynecologic surgery, for example, preserving ovaries or preserving the uterus in people with gynecologic cancers. We do recommend that the choice between embryo and oocyte cryopreservation should be guided by patient preference and clinical considerations, their individual circumstances, including future flexibility, the success rates of embryo versus egg freezing that we detail more in the guideline, and legal considerations. And what is new in this guideline, as Dr. Loren alluded to earlier, is consideration of post-treatment fertility preservation for oocyte and embryo freezing. And this is going to be because, for some females, there's going to be a shortened but residual window of ovarian function that may not match when they are in their life ready to complete their families. And so for those individuals, there may be an indication to consider post-treatment fertility preservation. We clarify that gonadotropin releasing hormone agonists, GNRH agonists, while they shouldn't be used in the place of established fertility preservation methods, e.g., oocyte and embryo freezing, they can definitely be offered as an adjunct to females with breast cancer. Beyond breast cancer, we don't really understand the benefits and risks of GNRH agonists and feel that clinical trials in this area are highly encouraged. And also, that for patients who have oncologic emergencies that require urgent chemotherapy, these agonists can be offered because they can provide additional benefits like menstrual suppression. What's emerging is in vitro maturation of oocytes. It's feasible in specialized labs. It may take a little bit shorter time to retrieve these oocytes. There are cases of live births following IVM, in vitro maturation, that have been reported. But these processes remain inefficient compared to standard controlled ovarian stimulation. And therefore, it's really being treated as an emerging method. Finally, uterine transposition. It's experimental, but it's a novel technique for us. It's really moving the uterus out of the field of radiation surgically. We recommend that this is done under research protocols. So taken together, there are improvements in fertility preservation technology, and consideration of which of any of these methods really depends on tailoring to what is that patient's risk, what is the time that they have, what is feasible for them, and what is the effectiveness comparatively among these methods for them. Brittany Harvey: I appreciate you reviewing those recommendations and considerations of patient preferences, the clarification on GNRH agonists, and then those emerging and experimental methods as well. So then the next category of recommendations, Dr. Loren, what are the recommended fertility preservation options for children? Dr. Alison Loren: Thanks, Brittany. This remains a very challenging area. Certainly for older children and adolescents who have begun to initiate puberty changes, we support proceeding with previously outlined standard methods of either sperm or oocyte collection and cryopreservation. For younger children who are felt to be at substantial risk for harm to fertility, the really only options available to them are gonadal tissue cryopreservation, so ovarian tissue or testicular tissue cryopreservation. As Dr. Su mentioned, the ovarian tissue cryopreservation methods are quite effective and well established. There's less data in children, but we know that in adults and older adolescents that this is an effective method. Testicular cryopreservation remains experimental, and we suggest that if it is performed, that strong consideration should be given to doing this as an investigational research protocol. However, because these are the only options available to children, we understand there may be reasons why there might need to be some flexibility around this in the proper setting of informed consent and ascent when appropriate for children. Brittany Harvey: Absolutely. And so we've discussed a lot of recommendations on fertility preservation options. So, Dr. Loren, what is recommended regarding the role of clinicians in advising people about these fertility preservation options? Dr. Alison Loren: Yeah, this is a really important question, Brittany, and I think that we really hope to empower the entire oncology clinical team to bring these issues to the forefront for patients. We know from qualitative studies that oncology providers sometimes feel uncomfortable bringing these issues up because they feel inexpert in dealing with them or because it's so overwhelming. Obviously, these are usually younger patients who are not expecting a cancer diagnosis, and there can be quite a lot of distress, understandably, around the diagnosis itself and the treatment plan, and it can be sometimes overwhelming to also bring up fertility as a potential risk of therapy. We are seeing that as patients are becoming more familiar and comfortable kind of speaking up, I think, social media and lots of sort of online communities have raised this issue, that we're seeing that young people with cancer do spontaneously bring this up in their visits, which we really appreciate and encourage. But I think sometimes clinicians feel it's sometimes described as a dual crisis of both the cancer diagnosis and a risk to future fertility and it can be a really challenging conversation to initiate. I feel, and we hope that the guidelines convey, that the whole point is just to bring it up. We do not expect an oncology clinician of any kind, including social workers, nurses, to be able to outline all of the very complex options that are articulated in this guideline. And in fact, the reason that the co-chairs include myself, a hematologist oncologist, and Dr. Su, who's a reproductive specialist, is because we understand that the complex reproductive options for our patients with cancer require expert conversations. So we do not expect the oncology team to go into all the guideline options with their patients. We really just want to empower everyone on the team to bring up the issue so that we can then get them the care that they need from our colleagues in reproductive endocrinology so that they can be fully apprised of all of their options with enough time before initiation of treatment to be able to embark on whichever therapies they feel are most suited to their family planning wishes. Brittany Harvey: Absolutely. And then jumping off of that, as a reproductive endocrinologist, Dr. Su, what do you think clinicians should know as they implement these updated recommendations? Dr. Irene Su: I wholly echo what Dr. Loren has said about- this is a team effort and it's been really fun to work as a team of various specialties on this guideline, so we hope that the guideline really reflects all of the partnerships that have occurred. I think that what clinicians should know is it may be well worth spending some time in identifying a pathway for our patients. So that starts off with the oncology team. How are we going to screen? How are we going to screen with fidelity? And then from the time of screening, really anybody who has an interest or potentially is unsure about their future fertility needs, who are the reproductive specialists, male and female, that you are in the community with to refer to? What is that referral process going to be like? Is it emails? Is it a phone? Is it a best practice advisory in your electronic health record system? From our standpoint as fertility specialists, we need to spend some time implementing in this system a way to receive these referrals urgently and also be able to support insurance navigation. Because actually, what is really exciting in this field is for the purpose of equitable access, there is increasing insurance coverage, whether it is because employers feel that this is the right thing to do to offer, or 17 states and the District of Columbia also have state mandates requiring fertility preservation coverage by many insurances, as well as, for example, federal employees and active military members. So more than ever, there is a decreased cost barrier for patients and still early days, so navigating health insurance is a little bit challenging. And that is the role, in part, of navigators and fertility clinic teams to help support these patients to do that. Dr. Alison Loren: Forming these relationships and reinforcing them so early and often is really key. Because although these patients come up with some infrequency, when they occur, they're really emergencies and we want to make sure that there's a well-established path for these patients to get from their oncology clinicians to the reproductive specialists. And as Dr. Su said, whatever works best for your system - there's a lot of different ways that people have tackled these challenging referrals - but it is really important to have an expedited path and for the receiving reproductive specialist office to understand that these are urgent patients that need to be expedited and that the oncology clinician's responsibility is to make sure that that's communicated appropriately. Brittany Harvey: Definitely. Thinking in advance about those logistics of referral and navigating health insurance and cost is key to making sure that patients receive the care that they want and that they'd like to discuss with clinicians. So then, Dr. Loren, you touched on this a little bit earlier in talking about the dual crisis, but how does this guideline impact people diagnosed with cancer? Dr. Alison Loren: Well, what we're hoping is that this is sort of a refresher. I think that many or hopefully most or all oncology clinicians are aware that this is a potential concern. And so part of our hope is that, as this guideline rolls out, it'll sort of bring to the top of people's memories and action items that this is an important part of oncology care is the reproductive health care of our patients. And it's a critical component of survivorship care as well. We want to remind people that the field continues to advance and progress. In oncology, we're very aware of oncologic progress, but we may not be so aware of reproductive healthcare progress. And so letting people know, "Hey, there's all these new cool things we can do for people that open up options, even in situations where we might have thought there were no options before." It's a reminder to refer, because we're not going to be able to keep up with all the advances in the field. But Dr. Su and her colleagues will be able to know what might be an option for patients. I want to highlight that communication piece again because our reproductive colleagues need to know what treatments are going to be given, what the urgency is, what the risks are. And so part of our responsibility as part of the team is to make sure that it's clear to both our patients and our reproductive specialist colleagues what the risks are. And Dr. Su mentioned this earlier, but one really important open question is risk stratification. We know that not all cancer treatments are created equal. There are some treatments, such as high dose alkylating agents, such as cyclophosphamide or busulfan, or high doses of radiation directly to the gonadal tissue, that are extremely high risk for causing permanent gonadal harm very immediately after exposure. And there are other therapies, particularly emerging or novel therapies, that we really just have no idea what the reproductive impact will be. And in particular, as patients are living longer, which is wonderful for our patients, how do we integrate reproductive care and family building into the management of perhaps a younger person who's on some chronic maintenance therapies, some of which we know can harm either the developing fetus or reproductive health, and some of which we really don't know at all. And so there's a very large open question around emerging therapies and how to counsel our patients. And so we hope that this guideline will also raise to the forefront the importance of addressing these questions moving forward and helping our patients to understand that we don't necessarily have all the answers either, which we hope will enrich the discussion and really have it be a good example of shared decision making between the clinical teams and the patient, so that ultimately the patients are able to make decisions that make the most sense for them and reduce the potential for decision regret in the future. Dr. Su, I know you have spent a lot of time thinking about this. Dr. Irene Su: Yeah. I really echo this notion that not all cancer treatments are going to be toxic to future reproductive function. And as clinicians, I and colleagues know that patients want to know as much when there is no effect on their fertility, because that feels reassuring in that that prevents them from having to go through the many hoops that sometimes it can be to undergo fertility preservation, as it is to know high risk, as it is to know we don't know. This is key and central, and we need more data. So, for example, we often chat about, wouldn't it be great if from the time of preclinical drug development all the way to clinical trials, that reproductive health in terms of ovarian function, testicular function, fertility potential, is measured regularly so that we are not having to look back 30, 40, 50 years later to understand what happened. And so this is one of our key research questions that we hope the field takes note of going forward. Dr. Alison Loren: This is an important point. We focus greatly, as we should, on potential harms to fertility, making sure that there's access to all the reproductive options for young people with cancer. But to Dr. Su's point, not all therapies are created equal, and there are some therapies that are somewhat lower risk or even much lower risk, including, I'm a blood cancer specialist and so certainly in the patients that I take care of, the treatments related to AML, ALL, and some lymphomas are actually fairly low risk, which is why the post-treatment fertility preservation options are so important. And particularly for patients who potentially present acutely ill with acute leukemia do not have the time or the ability to engage in fertility preservation because of their medical circumstances, it's important to have that conversation. I want to emphasize to oncology clinicians that even if you know medically that this patient is unable to undergo fertility preservation techniques at the time of diagnosis of their cancer, that it's still appropriate to talk about it and to say, "We're going to keep talking about this, this is something that we're going to raise again once you're through this initial therapy. I'm not forgetting about this. It may not be something we can engage in now, but it's a future conversation that's important in your ongoing care." And then to think about pursuing options when possible, particularly for patients who may require a bone marrow transplant in their future, either due to higher risk disease at presentation or in the event of a relapse, we know that generally bone marrow transplants, because of the high intensity conditioning that they require for most patients who are young, that permanent gonadal insufficiency will be a fixture. And so there can be a window of time in between initial therapy and transplant where a referral might be appropriate. So my public service announcement is that it's never the wrong time to refer to a reproductive specialist. And sometimes people make assumptions about chemotherapy that, "Oh, they've already been treated, so there's nothing we can do," and I want to make sure that people know that that's not true and that it's always appropriate to explore options. Dr. Irene Su: I think we talk a lot about how important screening and referral is and I can imagine that it's hard to actually know how to implement that. One of our other research questions to look out for is that we see a lot of tertiary care centers that have put together big teams, big resources, and that's not always feasible to scale out to all kinds of settings. And so what's emerging is: What are the key processes that have to happen and how can we adapt this screening, referral, financial navigation process from larger centers to smaller centers to less resource settings. So I guess my public service announcement is there's research in this area, there's focus in this area, so keep an eye out because there will be hopefully better tools to be able to fit in different types of settings. And more research is actually needed to be able to trial these different screening, referral, navigation processes in lower resource settings as well. Brittany Harvey: Absolutely. It's important to think about the research questions on how to improve both the delivery of fertility preservation options and the discussion of it, and it's important to recognize, as you mentioned, the different fertility risks of different cancer directed treatment options and the importance to have the conversations around this. So then just to expand on this notion a little bit, Dr. Su, we've touched on the research needed here in terms of discussing fertility options with patients and referring and then also in some of the experimental and emerging treatment options. So, what are the other outstanding research questions regarding fertility preservation for people with cancer? Dr. Irene Su: A couple others I'd like to add and then have Dr. Loren chime in in case I missed anything in all of our discussions, there's so many wants. So head to head comparisons of which method is best for which patient and what the long term outcomes are: How many kiddos? Do we complete family building? That is still missing. Being able to invest in novel methods from - there's fertoprotective agents that are being tested, potentially spermatogonial stem cell transplant. These are closer to clinical trials to really early research on ovarian, testicular, uterine biology. This is needed in order to inform downstream interventions. One of the questions that is unanswered is: After treatment starts, when is it safe to retrieve oocytes? And so this is a question because, for example, for our leukemia patients who are in the middle of treatment, when is it safe to retrieve eggs? And we don't know. And then post-treatment, for people who have a reduced window, when do you optimally have the most number of eggs or embryos that you can cryopreserve? That's unknown. But I think the question around once treatment has started, is recent exposure of anti-cancer treatments somehow mutagenic or somehow toxic to the oocytes with regard to long term offspring health? That is unanswered. I'm going to scope out a little bit and maybe policy nerd this a little bit. It's been very exciting to see advocacy, advocacy from our patients, from our clinicians on trying to improve health care policy. Like how can we use mandates to improve this delivery? But we actually don't know because actually the mandates from states that require health insurance coverage for fertility preservation, they vary. And so actually what are the key ingredients and policies that will ultimately get the most patients to the care they need? That is in question and would be really interesting. And so what is a part of this guideline which is not often seen in clinical guidelines, is a call for what we think are best practices for health insurance plans to help patients be able to access. And so this means that we recommend being specific and comprehensive in the coverage of these established fertility preservation services that have been recommended. And this means, for example, an egg freezing covering the whole process from consultation to office visits, to ultrasounds and laboratories, to medicines, to the retrieval, and then to long term storage. Because particularly for the youngest of our patients, these gametes could be frozen for a number of years and may not always be so affordable without health insurance coverage. We think that fertility preservation benefits really should be at parity, that you should not be having more cost sharing on the patient compared to other medical services that are covered. This is an inequity and where possible we should eliminate prior authorization because that timing is so short between diagnosis and needing to start anti-cancer treatment. And so prior authorization having to go through multiple layers of health insurance is really a key barrier because we all know that health insurance literacy is limited for all of us. And so whatever we can do to support our patient for the intent of these benefits would be recommended. Dr. Alison Loren: That was so well said, Dr. Su. I'll take the oncology perspective and say that from our side, really being able to understand the risks of infertility and understanding better measurements of fertility capacity, understanding where our patients are - every patient is different. These conversations are very different for a 37-year-old than they are for a 17-year-old. And so what we haven't really talked about is the fact that certainly at least female patients, as they age, their reproductive potential declines naturally. And so their infertility trajectory may be accelerated, they may have a shorter timeline or have less reserve than younger patients. And so being able to tailor our risk discussions not just based on the specific treatments, but on the reproductive age of the patient sitting in front of us and really being able to tailor those to very personalized risks would be really helpful. Because, as Dr. Su mentioned, and I think, as many people know, undergoing fertility preservation techniques can be really arduous. Even if they're covered and paid for, and all of those logistics are easy, which they seldom are, the physical drain of having to do injections, go for labs, all of the parts of those therapies can be really difficult for patients. And so being able to really understand who needs to have these interventions and who could pass, and understanding what the risks are, as I mentioned earlier, for these novel and emerging therapies would be really helpful. Another really important aspect of future research questions is we would like to encourage all clinicians, both reproductive specialists and oncology clinicians, and also our young people with cancer, to participate in clinical studies pertaining to fertility measurements and preservation. We also exhort our industry colleagues to consider including important reproductive endpoints, including biomarkers of ovarian and testicular reserve, if possible, in clinical trials. It will enhance our ability to provide counseling and support for these therapies in the future to be able to understand what the true impact of infertility, family building and health of offspring to be able to include these data in prospective databases and trials. Brittany Harvey: Definitely. And I want to thank you both for raising those really important points. So we'll look forward to this ongoing research and optimizing policies for covering fertility preservation benefits for all patients with cancer. I want to thank you both so much for your work to update this critical guideline and talk about these important needs of people with cancer. And thank you for your time today, Dr. Su and Dr. Loren. Dr. Alison Loren: Thanks so much for having us. Dr. Irene Su: You're welcome. This was really fun. Dr. Alison Loren: It was fun. And I just will add that the team at ASCO is amazing and really made this a pleasure. Dr. Irene Su: I couldn't agree more. And from the point of being a fertility specialist, being invited to be a part of this with ASCO and with all of our colleagues, it's been really amazing. And so thanks for allowing us to contribute. Brittany Harvey: Definitely. And a big thanks to the entire panel as well. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Opioid Conversion in Adults with Cancer: MASCC-ASCO-AAHPM-HPNA-NICSO Guideline (00:20:19)
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.
Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2024.3 Part 1 (00:10:48)
Dr. Lyudmila Bazhenova joins us again to share the newest changes to the living guideline on therapy for stage IV NSCLC without driver alterations. She discusses new evidence reviewed by the panel and changes to second-line recommendations for patients with good performance status and HER2 overexpression, and what these updates mean in practice. We discuss ongoing evidence generation as we await further updates to these living guidelines. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3" at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02786 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on "Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3." It's great to have you back on the show today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It's my pleasure to be here as always. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline panel, including Dr. Bazhenova, who has joined us here today, are available online with the publication of the guide in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, first, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations has frequent updates to the recommendations. What prompted this latest update? Dr. Lyudmila Bazhenova: Living ASCO guidelines are created to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. As a committee, we review published literature on a specific topic at the regular intervals and determine if it alters any recommendations. This time, upon our literature review, we felt that there are new data that requires an update in the guidelines and therefore the guidelines were updated. Brittany Harvey: Great. Thank you for that updated information. So then it looks like the panel updated recommendations for second line and subsequent treatment options for patients with good performance status and HER2 overexpression. What is that updated recommendation from the panel? Dr. Lyudmila Bazhenova: Yes, this is correct. We now added an extra recommendation for patients with stage IV non-small cell lung cancer who have overexpression of the protein called HER2. HER2 overexpression with 2+/3+ level via immunohistochemistry is seen in approximately 8% to 20% of patients with lung cancer. And the data behind our recommendation comes from the DESTINY-Lung01 trial where patients with HER2 overexpression were treated with trastuzumab deruxtecan. And we saw that if patients with stage IV non-small cell lung cancer had a HER2 IHC score of 3+, overall response rate was seen at 53% and median duration of response was 6.9 months and, therefore, that in our opinion qualified for updated recommendation. We are still waiting for additional results that will be released later on another clinical trial where we see preliminary data presented at the World Conference of Lung Cancer in 2024. They looked at 36 patients also with HER2 overexpression and saw the overall response rate of almost 45%. It is important to highlight in this smaller study that a majority of the patients in the study were actually having EGFR mutation and the response rate in those patients who had an EGFR mutation was higher than the response rate in patients without EGFR mutations who just had a HER2 overexpression. So for now this is updated in the guidelines, but we will wait for additional data or formal publication of a World Lung Conference presentation and see if those recommendations need to be changed. Brittany Harvey: Understood, and I appreciate you providing the context of some of those ongoing developments as well. So then what should clinicians know as they implement this updated recommendation? Dr. Lyudmila Bazhenova: Number one, we should all start from remembering to test for HER2 via immunohistochemistry. There is a slight difference in what considers HER2 positive in lung versus breast. In lung, we use what's called the gastric scoring and the difference is the circumferential versus non circumferential staining of the membrane. And number two, immunohistochemistry is not always included in next generation sequencing panels. So when you order your next generation sequencing, I think it's important to know if your company that you're using is testing for HER2 via immunohistochemistry. And if it's not, make sure that you find a company that does or work with your local pathology department to make sure that this testing is offered. It is also important to know the difference between HER2 overexpression and HER2 exon 20 insertion mutation even though the treatment for those two abnormalities is the same, which is trastuzumab deruxtecan. But the benefit that you can cite your patients and the rigor of the literature supporting the usage of trastuzumab deruxtecan in mutation versus overexpression is different. Brittany Harvey: Yes. And as you mentioned, it's essential that, in the first place, patients are actually receiving the testing so that we know if they're eligible for these treatment options. So what additionally does this change mean for patients with stage IV non-small cell lung cancer and HER2 overexpression? Dr. Lyudmila Bazhenova: So for patients, it adds another treatment modality which is now FDA approved. So if there are patients listening to me, make sure that your physician has tested your tumor for HER2 overexpression. So I think proactive asking of your physician would be very appropriate in this situation. Brittany Harvey: Absolutely. And then earlier you mentioned an ongoing trial that the panel was looking to for the future. But what other additional trials did the panel review during this guideline update and what is the panel examining for future updates to this living guideline? Dr. Lyudmila Bazhenova: So at this point we reviewed three additional studies. The results of those studies did not make it into a change in guidelines. So we reviewed the HARMONi-2 trial. HARMONi-2 trial so far does not have an official publication and, as per our strategy on how we come up with ASCO guidelines, we need to wait for an official publication. So this is one thing we're going to be expecting in the future. Once this is published, we will review it and decide if we need to make an additional change in recommendations. For those of you who are not aware, HARMONi-2 trial used bispecific monoclonal antibody against VEGF and PD-1 and was a phase III randomized trial comparing their investigational product which is called ivonescimab over pembrolizumab for patients with PD-L1 more than 50. And again, we are waiting for the final publication to make our recommendation. The second trial we reviewed was a LUNAR trial and the LUNAR trial looked at addition of tumor treating fields to chemotherapy or immunotherapy in patients whose cancer progressed with platinum doublet. The key point about this study is that immunotherapy was not required to be administered in a first line setting which is a current standard of care in the United States. And even though the study met their primary endpoint of overall survival, there were more benefits in patients who were immunotherapy naive in the second line. And we felt that given the potential lifestyle implication of wearing a device for 18 hours per day, and the lack of evidence in immunotherapy-pretreated population, and the absence of data in the first-line setting where we currently using immunotherapy in the United States, we felt that there is insufficient data to definitely recommend addition of tumor treating fields to systemic chemotherapy for most patients. And we are waiting for additional trials that are ongoing in this setting to formalize or change our recommendations. And we also reviewed- the final study that we reviewed was TROPION-Lung01. TROPION-Lung01 study was a phase III study in post platinum doublet setting which compared efficacy of Dato-DXd and docetaxel and trials showed improvement in progression free survival but not in overall survival. And progression free survival benefit was more pronounced in non-squamous carcinoma histology subgroup and we felt that the results do appear promising, but the strength of evidence which was based on unplanned subgroup analysis was not sufficient enough to make a change in treatment recommendation at this time. Brittany Harvey: I appreciate your transparency on why some of that data did not prompt a change to recommendations at this time. And additionally, we'll look forward to those future published results and potential incorporation of new data into future versions of this living guideline. So, I want to thank you so much for your work to rapidly and continuously update this guideline and for your time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It is my pleasure. Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2024.3 Part 2 (00:15:20)
Dr. Jyoti Patel is back on the podcast to discuss the updates to the living guideline on therapy for stage IV NSCLC with driver alterations. She shares updated recommendations in the first- and second-line settings for patients with stage IV NSCLC and classical EGFR mutations, and the impact of these updates for clinicians and patients. We also look to the future to discuss ongoing developments in the field. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3" at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02785 Brittany Harvey: Welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3." It's great to have you back on the show today, Dr. Patel. Dr. Jyoti Patel: Thanks so much. Happy to be here. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline and in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this update, Dr. Patel, this clinical practice guideline for systemic therapy for patients with stage IV non small cell lung cancer with driver alterations is living, meaning that it's continuously reviewed and updated. So what data prompted this latest change to the recommendations? Dr. Jyoti Patel: Thanks so much. So it's really been an exciting time in the treatment of EGFR lung cancer, particularly this past year has required us to rethink approaches to front- and second-line therapy. In this particular update, we examined what patients in the front-line setting may be offered by their clinicians. And so we're talking about the population of classical EGFR mutations, so exon 19 and exon 21 L858R substitution. And so certainly for this population, osimertinib has a high level of evidence and should be offered to all patients at the time of diagnosis when they present with advanced disease. Our last update included a recommendation that patients could also get platinum doublet chemotherapy with osimertinib or osimertinib alone. This current recommendation also introduces another alternative therapy and that's the combination of amivantamab plus lazertinib. And so now, clinicians are faced with three really good options for their patients with EGFR exon19 deletion or L858R. Brittany Harvey: It's great to hear that there's this advance in the space, particularly for patients with these classical EGFR mutations that you mentioned. So what should clinicians know as they implement these new first-line recommendations? Dr. Jyoti Patel: I think it's become more complex than ever. Certainly, we know again that patients should get osimertinib in the frontline setting. But we've been kind of stuck at progression-free survival that's between a year and a half and two years. And so we've really been looking at opportunities to intensify therapy. So one could certainly be with chemotherapy or switching over to amivantamab, the bispecific antibody that targets EGFR and MET plus lazertinib, an oral TKI that's very similar in structure to osimertinib. And when you're talking to a patient, it's really a conversation about balancing efficacy with toxicity. Unfortunately, as we know, there aren't that many free lunches. And so if we think about what a patient is hoping for in their therapy and how we can further personalize treatment options, really is important to look at some of the analyses for this study. So in the study of amivantamab plus lazertinib, we know that there were increased toxicities with a combination of both therapies. In fact, up to 75% of patients had over grade 3 toxicities, versus about 43% of patients with osimertinib monotherapy. And we know if we look back at FLAURA2, almost two thirds of patients with osimertinib and chemotherapy had grade 3 toxicities, compared to 27% of patients with osimertinib alone. So we certainly see an increase in toxicities. Then we have to ask ourselves, are those paper toxicities or ones that really impact patients? And we know that amivantamab, for example, causes significant cutaneous toxicities. With both of these therapies, whether it's chemotherapy or adding amivantamab, there's the burden of infusional visits and increased time in the doctor's office. Certainly with chemotherapy, there can be an increased incidence of myelosuppression. And so when we're thinking about advising our patients, certainly we need to talk about the toxicities. But one thing that we've been able to do is to look at the patients that were included in this trial. And what we really find is that in higher risk cohorts, particularly those that we know historically have done less well with standard osimertinib, so patients, for example, with CNS metastasis, for those patients with co-mutations, it may be that that additive benefit is significant. And so one example I think would be from the MARIPOSA study, again, the study of amivantamab and lazertinib versus chemotherapy. What we can say is that patients who had co-mutations, so patients with EGFR mutations as well as TP53, lazertinib and amivantamab led to a hazard ratio of 0.65 compared to osimertinib alone. So that was 18.2 months versus 12.9 months. And so this may be really important to patients. And we also see conversely that patients with wild type TP53, so those patients who didn't have the mutation, probably had equivalent survival regardless of therapy. So certainly, we need to prospectively study some of these high-risk cohorts. We've only seen progression-free survival in these studies. And so at this juncture, we can advise our patients about toxicity, the improvements in certain categories of progression-free survival, but we really still don't know how this pans out in overall survival. In many of these studies, all patients do not necessarily cross over to the study arm and so they may have lost the benefit of subsequent therapy. Brittany Harvey: Absolutely. It's very important to talk about that balance of benefits and risks and particularly those toxicities that you discussed. So I appreciate reviewing that recommendation and the considerations for clinicians for first-line therapy. This update also included a second-line treatment update. What is that update for patients with EGFR alterations? Dr. Jyoti Patel: So this is where it gets super tricky because we have a frontline option with amivantamab and now we've had an update in the second line option. So what we said is that for patients who have progressed on an EGFR TKI, and in the United States, certainly that's predominantly osimertinib, or those in other parts of the world that may have gotten an earlier generation TKI, but do not have evidence of T790M or other targetable mutations, we can offer patients chemotherapy with or without amivantamab. And so certainly we have seen that this again leads to improved survival. There have also been a number of studies looking at incorporation of PD-L1 and anti-VEGF therapies. And what we can say, I think pretty clearly is that multiple phase 3 trials have really shown no benefit of the addition of PD-1 to platinum chemotherapy. But there are some emerging bispecific antibodies that may target PD-1 as well as VEGF, or combinations of antibodies that target both of those pathways that may improve outcome. At this juncture, I think we feel that the evidence surrounding chemotherapy plus amivantamab is strongest, but there is certainly work in this space that will be of interest. Now, what happens if your patient received amivantamab and lazertinib in the frontline setting and then has progression? And so we're trying to understand resistance mechanisms and opportunities for treatment. What the panel decided to recommend, based on the available evidence, was that certainly those patients should get platinum-based chemotherapy, but there may also be a role for antivascular endothelial growth factor targeting therapy such as bevacizumab in patients in whom it would be safe. Brittany Harvey: Great. I appreciate you detailing those recommendations when it gets complicated in the second-line setting. So what should clinicians know as they implement these second-line recommendations too? Dr. Jyoti Patel: So certainly the frontline setting matters significantly. So if a patient gets osimertinib in the frontline setting, we generally suggest that patients undergo repeat testing to see if they have another targetable mutation. If they don't, then I think preferred therapy would be chemotherapy with or without amivantamab. And amivantamab leads to a significant improvement in progression-free survival and response rate at the cost of increased risk of toxicity. For patients who get FLAURA2 in the frontline setting, chemotherapy plus osimertinib, it's a little bit of an unclear space. Those patients most likely would get docetaxel with or without ramucirumab. But there are other agents that we hope to have available to our patients in the near future. For patients who receive amivantamab and osimertinib, we recommend that those patients get chemotherapy probably with anti-VEGF as demonstrated by multiple trials that have shown the improved progression-free survival with introduction of an anti-VEGF agent. And we've seen evidence of amivantamab in the third line setting, so it is likely that this question about sequencing really takes center stage in our next set of trials. When you're talking to a patient, I think again, it's absolutely important to discuss: What are their goals? How symptomatic or how fast is their progression? Are there ways in which patients may benefit from spot treatment oligoprogression such as radiation? When is the right time for introduction of amivantamab and when do we think patients need chemotherapy? Is it up front or predominantly in the second-line setting? Brittany Harvey: Definitely. And then you've just touched on the goals of treatment for individual patients. So in your view, what does this update mean for patients with stage IV non-small cell lung cancer and an EGFR alteration? Dr. Jyoti Patel: For patients, this is a time in which shared decision making really needs to take center stage. So our best patients are those patients that are best informed not only about their disease but also have a good understanding about what is important to them and their families in terms of care. And so bringing that shared understanding to the table again helps us think about this particular cancer as more of a journey rather than just a one off treatment. Therapy will hopefully be prolonged, and so it's absolutely important that we address toxicities, make therapies more tolerable, again, with the shared goal of living long and living well. Brittany Harvey: Absolutely. Those are key points to making sure that patients are living both longer and have a good quality of life during that time as well. So then, before you mentioned the possibility of future sequencing trials and other ongoing developments. What additional studies or future directions is the panel examining for future updates to this living guideline? Dr. Jyoti Patel: So certainly we're thinking about trials that look at, for example, cfDNA clearance. So are there patients that do well and can we detect that early on without having to intensify therapy on day 1 so it may be that we add chemotherapy a little bit later. I think really exciting are some of the new bispecific. The HARMONi-A trial was a trial in China of a novel bispecific, ivonescimab. And this drug targets both PD-1 and VEGF and it was combined with chemotherapy. And this trial found almost a doubling of progression-free survival with this drug in combination chemotherapy in an EGFR patient population. That study is being planned and being run in the United States to see if we have similar outcomes with a more diverse population. So certainly that's exciting. There are a number of antibody drug conjugates that are being studied in the post-chemotherapy setting as well. And I think we'll likely soon see a better understanding of what co-mutations and burden of disease really mean when we're thinking about assigning treatment. So which patients, again, need intensification of therapy and which patients may do really well on just an oral agent that they're taking at home with more tolerable toxicity than dual treatment. Brittany Harvey: Yes, we'll look forward to continued developments in these fields and seeing some of those studies come to fruition. So with that, I want to thank you for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Patel. Dr. Jyoti Patel: Thanks so much, Brittany. It's really an exciting time for lung cancer and we hope that these updates really help physicians decide the best treatments for their patients. Again, it's a rapidly evolving landscape which is fantastic, but it does become more cumbersome to stay ahead of the literature. Brittany Harvey: Definitely. And so we appreciate your time and the panel's time spent reviewing this literature and providing this much needed information to clinicians everywhere. So finally, thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
TORS in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma Guideline (00:22:28)
Dr. Chris Holsinger shares the new guideline from ASCO on transoral robotic surgery (TORS) for patients with oropharyngeal squamous cell carcinoma. He reviews the evidence-based recommendations on baseline assessment, the role of TORS in HPV-positive and HPV-negative disease and in the salvage/recurrent setting, which patients are eligible or ineligible for TORS, and the role of adjuvant therapy. He discusses the importance of multidisciplinary collaboration and shared decision-making between patients and their clinicians. Read the full guideline, "Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline." TRANSCRIPT This guideline, clinical tools, and resources are available at asco.org. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Chris Holsinger from Stanford University, lead author on "Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline." Thank you for being here today, Dr. Holsinger. Dr. Chris Holsinger: Thanks, Brittany. We've been working together for years on these guidelines and what a pleasure to get to meet you at least virtually today. Brittany Harvey: Yes, it's great to have you on. And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Holsinger, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So let's jump into this important guideline. Dr. Holsinger, to start us off, can you provide an overview of both the scope and purpose of this guideline? Dr. Chris Holsinger: Absolutely. And again, thanks for the opportunity to be here, Brittany. I appreciate the invitation to participate in the ASCO Guidelines and to work with the great people on this paper that's now out there. I think it's a really important guideline to be published because it really talks about surgery, specifically transoral robotic surgery, a minimally invasive technique, as a new way to treat head and neck cancer. Why that's so important is that what is now known as head and neck cancer is completely different than what we saw even 25 years ago. Around the turn of the century, some really thoughtful epidemiologists working at Hopkins and UW in Seattle started to see this connection between the human papillomavirus and head and neck cancer. And since then we've seen this precipitous rise in the number of throat cancers specifically due to HPV. The results from the American Cancer Society showed last year that head neck cancer, in particular these cancers of the oropharynx, actually were one of the few cancers that still had an increasing incidence, I think it was around 2.5% per year. And other studies have shown that almost 50% of the cases we're seeing across the United States now are actually HPV-mediated throat cancers. That's bad news because we're seeing this rise in cases, but it's good news in the sense that this is a cancer that is highly curable and I think opens up a lot of different treatment avenues that we didn't have a couple of decades ago. And when patients are facing a mortality risk that's two or three times lower than the formerly HPV-negative smoking-driven cancers, it really behooves us as clinicians, as oncologists to think about treatment selection in a completely different way. And for years, the only function-sparing option, surgery certainly was not, was radiation therapy with concurrent cisplatin chemotherapy. In 2009, the FDA approved the use of surgical robotics using a transoral approach, a minimally invasive approach to resect the primary tumors and to perform neck dissection. And so now when patients walk in the door, they not only have this gold standard option in the path of radiation therapy with chemo, but also frontline surgery. And with some recent publications, especially the ECOG 3311 study, there's some really good evidence that for HPV-mediated throat cancers, we can actually de-escalate the intensity of adjuvant therapy when we start with surgery first. So who we choose that option for, which patients want that option - these are all really important new questions that we try to grapple with in these guidelines. Brittany Harvey: That background is really key for setting the stage for what we're about to talk about today. And so next I'd like to review the key recommendations across the clinical questions that the panel addressed. So you just talked about the importance of treatment selection. So to start that off, first, what is recommended for baseline assessment for patients with oropharyngeal squamous cell carcinoma who are being considered for transoral robotic surgery? Dr. Chris Holsinger: So I think here we tried in the guidelines to really standardize the workup and approach of this disease, in general, but with a strong focus on who might be a good surgical candidate. As I mentioned in the introduction, I mean, this is a disease that is very new. Our workup is in flux. And so what we tried to do, especially in items 1.2 and 1.3, is to really standardize and confirm that the tumor that we're dealing with, which oftentimes presents in a metastatic lymph node, is in fact associated with the human papillomavirus. So how biopsy is done, how high risk HPV testing is performed, whether you're doing that with an in situ hybridization, a DNA based study, or a p16 immunohistochemical study. And we try to tackle these issues first to really make sure that the patient population we're considering is actually indeed eligible for this kind of treatment de-escalation with surgery. Brittany Harvey: Understood. So it's important to consider which patients could be eligible for TORS upfront. So what is the role of TORS in patients with HPV-positive oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: Yeah, exactly. So I think first of all, surgery is ideally suited, and the robot is FDA approved for early-stage cancers - T1 and T2 cancers that are amenable to a minimally invasive approach. And we really try to emphasize, especially in our patient selection section of the guideline, who is really an ideal candidate for this. It's not just the T1 and T2 tumor. It's a tumor that is lateralized so that we can maybe consider managing the neck concurrently just on the side of the tumor, rather than doing bilateral neck dissection for most patients. Which patients might get the best functional outcome is a really critical component of this. And in fact, that actually goes back to a guideline that we didn't have time to chat about earlier, which is that we think every head neck cancer patient, whether or not they're being considered for transoral robotic surgery or frontline radiation therapy with cisplatin, every patient should have a pre-treatment assessment by a speech and swallowing expert. They're called different names across the country: speech language pathologists, speech pathologists, etc. But having a really good functional assessment of the patient's ability to swallow before treatment selection is really critical. And why that's important with frontline surgery is that there's a period of about one or two weeks after which that patient really needs intensive rehabilitation. And so for every patient being considered by TORS, we want to work really hand in hand with that speech pathologist to do pre-habilitation and then immediate post-operative rehab and then long longitudinal rehabilitation so that if radiation is needed down the road in a month, that patient just hopefully sails through this de-escalated treatment that we're offering. Brittany Harvey: Great. I appreciate you describing which patients can be considered for transoral robotic surgery. So beyond that, which patients with HPV-positive oropharyngeal squamous cell carcinoma aren't really good candidates for TORS? Dr. Chris Holsinger: We talked about that sort of ideal patient, but you know, we're not always living in an ideal world. And so I think it's important, and I'm really happy about the multidisciplinary discussions that led to these final guidelines because I think it helped engage radiation oncologists, medical oncologists, and surgeons around who's maybe not a good candidate for this because radiation therapy, with or without cisplatin chemotherapy, remains a good option for many of these patients. But I think the consensus, especially among the surgeons in this group, were that patients with tumors were more endophytic - that's the old fashioned oncology and surgical oncology term that refers to tumors that seem to not be as evident on the surface and have more of an infiltrative deep growth pattern - these are not ideal tumors. Whereas an exophytic tumor that's growing upwards, that's more readily seen on flexible endoscopy during a routine clinic assessment, or frankly, better seen on imaging, those exophytic tumors are better suited to a surgical approach because the surgeon has a better chance when he or she sees the tumor to get a good margin. When we can appreciate not just the surface mucosal margins that need to be taken, but also have a better chance to appreciate their depth. And with those infiltrative tumors, it's much harder to really understand how to get that deep margin, which in many cases is always the hardest. And so that's a long way to say that surgical decision making, patient selection is really critical when it comes to offering TORS as a multidisciplinary group. And then there are a few other things that we can quickly talk about before we move on to discussing adjuvant therapy. But I think there are some relative contraindications to patients who might have tumors arising in a palatine tonsil or tonsillar pillar, but which might grow significantly into the soft palate, such that a major palatal resection would be needed to get a good margin. For T1 and T2 tumors, we're not sure that that is an ideal candidate. And the other relative contraindication, but it's a hard and fast contraindication in my personal practice, is patients with extensive nodal disease. I think a patient who has preoperative extranodal extension, matted nodes, clinically and on MRI, you know pre-op they're going to need intensive post operative concurrent chemoradiation post-op that's maybe not the best patient for TORS, although there are some select cases where that that might make sense. But that's a quick overview of patient selection for TORS, Brittany. Hopefully, that's helpful. Brittany Harvey: That's definitely helpful. I think it's really important to consider not only who is eligible, but who isn't eligible for this de-escalation of treatment, and I appreciate you clarifying some of that. So then you've just also mentioned adjuvant therapy along with multidisciplinary discussion. So what is recommended regarding adjuvant therapy for patients who have resected HPV-positive oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: Definitely. And I think the post-operative discussion has to begin with great pre-op planning. And pre-op planning is really anchored in a really robust multidisciplinary team. So, we spoke earlier about the critical importance of getting speech language pathology involved initially, but they're part of a much larger team that includes not just a surgeon, but medical oncologist, a radiation oncologist and a dental oncologist - all of these specialties, and I could think of several others if we had time to chat further - this should also be really engaged in the care of these patients. But great decision making regarding adjuvant therapy really begins with a robust multidisciplinary consultation pre-op and we try to emphasize that in the guidelines. But just to return and answer your question very directly, I think adjuvant therapy is really the critical piece in getting that great functional outcome for a patient with HPV-mediated throat cancer. And I think traditionally patients who have a variety of different risks, based on a large study done again by the ECOG group, ECOG 3311, we showed that by stratifying patients based on their surgical pathology rather than on an estimate of disease extent, we can better stratify adjuvant therapy. And so the low risk patient is a patient with good margins and of course, good margin, we could spend another two hours discussing that. But good margins are greater than at least 1 to 3 millimeters superficially and a clear deep margin. Patients with lymph node metastases that are less than 3 cm and a single lymph node can sometimes be observed but most patients don't fall into that low risk category. Most patients fall into an intermediate risk where the margin is good and it's clear, but it might be close. That depends if you're talking about the superficial mucosal margin or the deep. But more often than not, we spend a lot of time considering the extent of lymph node involvement as it pertains to how adjuvant therapy is delivered. And I think for patients with less than 4 lymph nodes traditionally without extranodal extension, radiation therapy will suffice for adjuvant therapy after TORS. And the question of dose then comes up. Are we talking 50 Gray, the experimental arm that showed real promise in the ECOG 3311 trial, or 60 Gray or more traditional dose? And that is a topic definitely for another podcast, which we should do with a radiation oncologist online. I don't want to get into the weeds with that, but I refer you to our guidelines and Bob Ferris and Barbara Burtness' paper from JCO in 2021 for further details about that. But then for patients with positive margins with more than four lymph nodes, but especially patients with extranodal extension, the role of radiation therapy and chemotherapy is really absolutely critical. Because these patients and while they only accounted for around 20% to 30% of patients that we're seeing in this new era of TORS, they're the ones that we're really focusing on how can we do better because their overall survival is still good, it's 90%, but it's not as good as the patients we're seeing with a low and intermediate risk. So that's a brief overview there. Brittany Harvey: I appreciate that overview. And yes, we'll refer listeners to the full guideline, which is linked in the show notes of this episode to learn more about the intricacies of the radiation therapy that you mentioned. So then we've talked a lot about patients with HPV-positive disease, but what is the role of TORS in patients with HPV-negative disease? Dr. Chris Holsinger: I think TORS still has a role for these patients. Our colleague in India, Surender Dabas, has a really nice series that shows that for HPV-negative patients, this is a way for early stage cancers to potentially escalate the intensity of treatment for a disease that does worse than this new HPV-positive we're seeing in the US. So I think there's a good signal there. I think more study needs to be done and I think those studies, in fact, are underway in India and other countries. I hope that we can, as an oncology community here in the United States, also tackle this disease, which is still a significant part of the disease we face in head and neck oncology. Brittany Harvey: Yes, we'll look forward to more data coming out for HPV-negative disease. So then, the last clinical question that the guideline panel addressed: What is the role of TORS in the salvage or recurrent setting? Dr. Chris Holsinger: So we wrap up the guidelines tackling this topic. It's definitely something for the experienced TORS surgeon in consultation with that multidisciplinary team. Oftentimes, we are still seeing many patients who need salvage surgery and I think, while TORS alone could be a really effective treatment option, TORS with a microvascular reconstruction is oftentimes what is needed for these patients who, with recurrence, do often present with an RT 2, 3, 4 tumor. In my own practice, I found that using TORS as a way to minimize the superficial mucosal extent and then delivering that tumor through a traditional lateral pharyngotomy, then neck dissection and then having a microvascular flap inset done after that really provides the best possible chance for good long term function and of course control of the tumor. Here, I definitely refer the listener to some great work done out of the Royal Marsden with Vin Paleri, who we're happy to have on our TORS guideline panel for his RECUT study that really grapples in some detail with these very issues. Brittany Harvey: Excellent. And so we've covered a lot of the recommendations here that were made by the panel and you've touched a little bit about how this changes things for clinicians in practice. But what should clinicians know as they implement these new recommendations? Dr. Chris Holsinger: One thing as we close, I hope that in the future we can really start to grapple with this concept of patient selection. I think these guidelines help establish that TORS is a great oncologic option with - really the only option for treatment de-escalation in the here and now. Radiation therapy and cisplatin concurrent chemotherapy is going to be an option that is such an important choice for patients. And I think where I hope the field goes in the future is figuring out which patient wants one of these options. And I think certain patients really want that tumor taken out and others just the idea of surgery is not something that makes sense for them. How we in the context of a multidisciplinary team, really engage that patient, elicit their treatment preferences and then through considering treatment eligibility criteria that we've spelled out here for surgery and can be spelled out for chemo RT, bringing all that together in a formal shared decision making process is really where I hope the field will be going in the next few years. And hopefully these guidelines help to pave the way there. Brittany Harvey: Definitely the aspect of care by a multidisciplinary team and talking with patients to go through shared decision making is key to implementing these guidelines. So then, in that same vein, what do these recommendations mean for patients with oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: I think the central take home message for patients should be that especially if you have a T1 and T2 tumor, it's really important to have that consultation with a surgeon who knows how to do TORS and has a busy practice, but then also having an honest discussion up front about what the functional outcomes would be both with surgery and also chemo RT. And I think just knowing all those different options, that multidisciplinary treatment selection process is going to be that much more robust. And I think more right decisions will get made and we'll see less decisional regret down the road, which I think is a long term goal of our field. Brittany Harvey: Absolutely. That discussion of preferences is key. So then to wrap us up, you touched on this a little bit earlier in talking about ongoing research and data, particularly in the field of HPV-negative disease, but what are the outstanding questions regarding TORS in this patient population? Dr. Chris Holsinger: Yeah, I think that in addition to this work around shared decision making, I really hope that we'll embrace shared decision making in the context of future clinical trial. I think where we are now is you have surgeons saying, "Hey, TORS and 50 gray is a great option. Why aren't we doing that?" And then our colleagues, perhaps across the aisle, if I can use a political metaphor, are saying, "Well, where's the comparative data? Can we even do a randomized clinical trial between surgery and radiation?" Well, Christian Simon in Lausanne in Switzerland is trying to do this in a small pilot study being led by the EORTC, and I would encourage American investigators to consider something analogous. But I think how we solve this question of I think treatment choice is going to be pivotal for any such trial to ever be done. And then finally, I think, how will the changing treatment landscape around immunotherapy change this? There's some really provocative data that dates back to 1996 in a JCO paper from Ollivier Laccourreye and the University of Paris experience that showed induction chemotherapy followed by function preserving surgery in the larynx was a really powerful strategy for organ preservation, and that has never been followed up in the United States. And so especially with the upcoming presentation of KEYNOTE-689, will we be doing neoadjuvant approaches for patients and then following them by minimally invasive surgery or lower dose radiation? I think these are going to be some exciting new areas of study and I can't wait to see how this might evolve so we can refine the treatment - still get those great outcomes, but reduce those late toxicity. Brittany Harvey: Yes. We'll look forward to this ongoing research to continue to move the field forward. So, Dr. Holsinger, I want to thank you so much for your time to develop this important guideline. It's been great to have you on the podcast to discuss it today. Dr. Chris Holsinger: Well, thanks a lot Brittany. It's nice to finally meet you. Brittany Harvey: Likewise. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer Guideline Update (00:19:04)
Dr. Stéphanie Gaillard and Dr. Bill Tew share updates to the evidence-based guideline on neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer. They highlight recommendations across ten clinical questions, addressing initial assessment, primary cytoreductive surgery, neoadjuvant chemotherapy (NACT), tests and/or procedures that should be completed before NACT, preferred chemotherapy regimens, timing of interval cytoreductive surgery (ICS), hyperthermic intraperitoneal chemotherapy (HIPEC), post ICS-chemotherapy, maintenance therapy, and options for those without a clinical response to NACT. They highlight the evidence supporting these recommendations and emphasize the importance of this guideline for clinicians and patients. Read the full guideline update, "Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update" at www.asco.org/gynecologic-cancer-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Stéphanie Gaillard from Johns Hopkins University and Dr. Bill Tew from Memorial Sloan Kettering Cancer Center, co-chairs on "Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update." Thank you for being here today, Dr. Gaillard and Dr. Tew. Dr. Bill Tew: Thank you for having us. Dr. Stéphanie Gaillard: Yeah, thank you. It's great to be here. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Gaillard and Dr. Tew, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, first, Dr. Tew, could you describe what prompted this update to the neoadjuvant chemotherapy for ovarian cancer guideline? And what is the scope of this update? Dr. Bill Tew: Yeah. It's been almost a decade since ASCO first published its neoadjuvant chemotherapy guidelines for women with newly diagnosed ovarian cancer, and over that 10-year period, there's really been a major shift in how oncologists treat patients in the U.S. If you look at the National Cancer Database, between 2010 and 2021, the proportion of patients with advanced ovarian cancer who underwent primary surgery fell from about 70% to about 37%. And there's been a doubling in the amount of neoadjuvant chemotherapy used. So we wanted to take a look at that and really both highlight the appropriate patient populations for primary surgery versus new adjuvant chemotherapy, as well as review any studies that have been published since then. There's been, I think, about 61 trials published, nine randomized trials alone in the last 10 years. And the scope of the guideline was really not only the neoadjuvant chemotherapy and surgical questions, but also to touch upon some new treatments that have come to the forefront in newly diagnosed ovarian cancer, including heated intraperitoneal chemotherapy or HIPEC, as well as the integration of maintenance therapy, particularly bevacizumab and PARP inhibitors. Brittany Harvey: Understood. That's a large amount of new evidence to review in this Update. Then, next, Dr. Gaillard, I'd like to review the key recommendations across the 10 clinical questions that the guideline addressed. So, starting with: What is recommended regarding initial assessment for patients with newly diagnosed pelvic masses and/or upper abdominal or peritoneal disease? Dr. Stéphanie Gaillard: Sure. So in talking about the first guidelines, the first one that we addressed was how to do the initial assessment for these patients. And first, and probably most critically, it's important to recognize that these patients really should be evaluated by a gynecologic oncologist prior to initiation of any therapy, whether that means a primary cytoreductive surgery or neoadjuvant chemotherapy, because really, they are the best ones to determine the pathway that the patient should take. The initial assessment should involve a CA-125, a CT of the abdomen and pelvis with oral and IV contrast, if not contraindicated, and then also chest imaging, in which a CT is really the preferred modality. And that helps to evaluate the extent of disease and the feasibility of the surgical resection. Now, there may be some other tools that could be helpful to also refine this assessment. So, for example, a laparoscopy can really help to determine the feasibility of surgical resection as well as the extent of disease. Further imaging, such as diffusion-weighted MRI or FDG-PET scans can be helpful, as well as ultrasounds. And then also an endometrial biopsy. And that was newly added because there really has been a divergence of treatment for endometrial cancer versus ovarian cancer. And so it's really important to determine upfront where the source of the disease is coming from. Brittany Harvey: I appreciate you describing those recommendations surrounding initial assessment. So following this assessment, Dr. Tew, which patients with newly diagnosed advanced epithelial ovarian cancer should be recommended primary cytoreductive surgery? Dr. Bill Tew: The key thing here is if the GYN oncology surgeon feels that they have a high likelihood of achieving a complete cytoreduction with acceptable morbidity, the panel overwhelmingly agrees that primary cytoreduction surgery should be recommended over chemotherapy. And we know that surgery is really the cornerstone to achieving clinical remission. And our concern is that neoadjuvant chemotherapy may be overused in this fit population. Sometimes it is challenging to determine truly if a patient has a high likelihood of complete cytoreduction or what is acceptable morbidity. But an evaluation with performance status, fitness, looking at age or frailty, nutritional status, as well as a review of imaging studies to plan and determine for who is the right patient for primary surgery is key. Brittany Harvey: And then the title of this guideline, Dr. Gaillard, for which patients is neoadjuvant chemotherapy recommended? Dr. Stéphanie Gaillard: Yeah. So there's really two patient populations that we think are best suited to receive neoadjuvant chemotherapy. Those may be patients who are fit for a primary cytoreductive surgery, but they're unlikely to have a complete cytoreduction if they were to go to surgery directly. And so that's where neoadjuvant chemotherapy can be very helpful in terms of increasing the ability to obtain a complete cytoreduction. The second population is those who are newly diagnosed who have a high perioperative risk, and so they're not fit to go to surgery directly. And so it may be better to start with neoadjuvant chemotherapy and then do an interval cytoreductive surgery. Again, I just want to emphasize the importance of including a gynecologic oncologist when making these determinations for patients. Brittany Harvey: Absolutely. So then the next clinical question. Dr. Tew, for those patients with newly diagnosed stage 3 to 4 epithelial ovarian cancer, what tests and or procedures are recommended before neoadjuvant chemotherapy is delivered? Dr. Bill Tew: The key test is to confirm the proper diagnosis, and that requires histological confirmation with a core biopsy. And this was a point the panel strongly emphasized, which is a core biopsy is a much better diagnostic tool compared to cytology alone. But there will be cases, exceptional cases, where a core biopsy cannot be performed. And in those settings, cytology combined with serum CA-125 and CEA is acceptable to exclude a non-gynecologic cancer. The other reason why cord biopsy is strongly preferred is because we already need to start thinking about germline and somatic testing for BRCA1 and 2. This information is important as we start to think about maintenance strategies for our patients. And so having that information early can help tailor the first-line chemotherapy regimen. Brittany Harvey: So then you've described who should be receiving neoadjuvant chemotherapy, but Dr. Gaillard, for those who are receiving neoadjuvant chemo, what is the preferred chemotherapy regimen? And then what does the expert panel recommend regarding timing of interval cytoreductive surgery? Dr. Stéphanie Gaillard: Sure. So for neoadjuvant chemotherapy, we generally recommend a platinum taxane doublet. This is especially important for patients with high grade serous or endometrioid ovarian cancers, and that's really because this is what the studies had used in the neoadjuvant trials. We recognize, however, that sometimes there are individual patient factors, such as advanced age or frailty, or certain disease factors such as the stage or rare histology that may shift what is used in terms of chemotherapy, but the recommendation is to try to stick as much as possible to the platinum taxane doublet. And then in terms of the timing of interval cytoreductive surgery, this was something that the panel discussed quite a bit and really felt that it should be performed after four or fewer cycles of neoadjuvant chemotherapy, especially in patients who've had a response to chemotherapy or stable disease. Sometimes alternative timing of surgery can be considered based on some patient centered factors, but those really haven't been prospectively evaluated. The studies that looked at neoadjuvant chemotherapy usually did the interval cytoreductive surgery after three or four cycles of chemotherapy. Brittany Harvey: For those patients who are receiving interval cytoreductive surgery, Dr. Tew, earlier in the podcast episode, you mentioned a new therapy. What is recommended regarding hyperthermic intraperitoneal chemotherapy? Dr. Bill Tew: Yeah, or simply HIPEC as everyone refers to it. You know, HIPEC isn't really a new therapy. HIPEC is a one-time perfusion of cisplatin, which is a chemotherapy that has been a standard treatment for ovarian cancer for decades. But the chemotherapy is heated and used as a wash during the interval cytoreductive surgery. And since our last guideline, there has been a publication of a randomized trial that looked at the use of HIPEC in this setting. And in that study there was improved disease-free and overall survival among the patients that underwent HIPEC versus those that did not. So we wanted to at least emphasize this data. But we also wanted to recognize that HIPEC may not be available at all sites. It's resource-intensive. It requires a patient to be medically fit for it, particularly renal function and performance status. And so it's something that could be discussed with the patient as an option in the interval cytoreductive surgery. One other point, the use of HIPEC during primary surgery or later lines of therapy still is unknown. And the other point is this HIPEC trial came prior to the introduction of maintenance PARP inhibitors. So there's still a lot of unknowns, but it is a reasonable option to discuss with appropriate patients. Brittany Harvey: I appreciate you reviewing that data and what that updated recommendation is from the panel. So then, Dr. Gaillard, after patients have received neoadjuvant chemotherapy and interval cytoreductive surgery, what is the post ICS chemotherapy recommended? Dr. Stéphanie Gaillard: The panel recommends some post ICS chemotherapy, as you mentioned. This is typically to continue the same chemotherapy that was done as neoadjuvant chemotherapy and so preferably platinum and taxane. And typically we recommend a total of six cycles of treatment, although the exact number of cycles that is given post-surgery can be adjusted based on different patient factors and their response to treatment. Importantly, also, timing is a factor, and we recommend that postoperative chemotherapy begin within four to six weeks after surgery, if at all feasible. Brittany Harvey: Absolutely. Those timing recommendations are key as well. So then, Dr. Tew, you mentioned this briefly earlier, but what is the role of maintenance therapy? Dr. Bill Tew: Maintenance therapy could be a full podcast plus of discussion, and it's complicated, but we did want to include it in this guideline in part because the determination of whether to continue treatment after completion of surgery and platinum based therapy is key as one is delivering care in the upfront setting. So first off, when we say maintenance therapy, we are typically referring to PARP inhibitors or bevacizumab. And I would refer listeners to the "ASCO PARP Inhibitor Guideline" that was updated about two years ago, as well as look at the FDA-approved label indications. But in general, PARP inhibitors, whether it's olaparib or niraparib, single agent or olaparib with bevacizumab, are standard treatments as maintenance, particularly in those patients with a germline or somatic BRCA mutation or those with an HRD score positive. And so it's really important that we emphasize germline and somatic BRCA testing for all patients with newly diagnosed ovarian cancer so that one can prepare for the use of maintenance therapy or not. And the other point is, as far as bevacizumab, bevacizumab is typically initiated during the chemotherapy section of first-line treatment. And in the guidelines we gave specific recommendations as far as when to start bevacizumab and in what patient population. Brittany Harvey: Great. Yes. And the PARP inhibitors guideline you mentioned is available on the ASCO guidelines website and we can provide a link in the show notes for our listeners. So then, the last clinical question, Dr. Gaillard, what treatment options are available for patients without a clinical response to neoadjuvant chemotherapy? Dr. Stéphanie Gaillard: Yeah, this is a tough situation. And so it's important to remember that ovarian cancer typically does respond to chemotherapy initially. And so it's unusual to have progressive disease to neoadjuvant chemotherapy. So it's really important that if someone has progressive disease that we question whether we really have the right diagnosis. And so it's important to, I think at that point, obtain another biopsy and make sure that we know what we're really dealing with. In addition, this is where Dr. Tew mentioned getting the molecular profiling and genetic testing early in the course of disease. If that hasn't been done at this point in time, it's worth doing that in this setting so that that can also potentially help guide options for patients. And patients who are in those situations, really, the options are other chemotherapy regimens, clinical trials may be an option, or in some situations, if they have really rapidly progressing disease that isn't amenable to further therapy, then initiation of end-of-life care would be appropriate. Brittany Harvey: I appreciate you both for reviewing all of these recommendations and options for patients with advanced ovarian cancer. So then to wrap us up, in your view, what is both the importance of this guideline update and how will it impact clinicians and patients with advanced ovarian cancer? Dr. Bill Tew: Well, first off, I'm very proud of this guideline and the panel that I work with and Dr. Gaillard, my co-chair. The guideline really pulls together nicely all the evidence in a simple format for oncologists to generate a plan and determine what's the best step for patients. The treatment of ovarian cancer, newly diagnosed, is really a team approach - surgeons, medical oncologists, and sometimes even general gynecologists - and understanding the data is key, as well as the advances in maintenance therapy and HIPEC. Dr. Stéphanie Gaillard: For my part, I'd say we hope that the update really provides physicians with best practice recommendations as they navigate neoadjuvant chemotherapy decisions for their patients who are newly diagnosed with ovarian cancer. There is a lot of data out there and so we hope that we've synthesized it in a way that makes it easier to digest. And along that regard, I really wanted to give a special shout out to Christina Lacchetti, who just put in a tremendous effort in putting these guidelines together and in helping to coordinate the panel. And so we really owe a lot to her in this effort. Dr. Bill Tew: Indeed. And ASCO, as always, helps guide and build a great resource for the oncology community. Brittany Harvey: Absolutely. Yes, we hope this is a useful tool for clinicians. And I want to thank you both for the large amount of work you put in to update this evidence-based guideline. And thank you for your time today, Dr. Gaillard and Dr. Tew. Dr. Stéphanie Gaillard: Thank you. Dr. Bill Tew: Thank you for having us. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Germline and Somatic Genomic Testing for Metastatic Prostate Cancer Guideline (00:16:25)
Dr. Evan Yu presents the new evidence-based guideline on genetic testing for metastatic prostate cancer. He discusses who should receive germline and somatic testing with next-generation sequencing technologies, what samples are preferred for testing, and the therapeutic & prognosistc impacts of genetic testing. Dr. Yu emphasizes the need for awareness and refers to areas of active investigation and future research to improve personalized therapies for patients with metastatic prostate cancer. Read the full guideline, "Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline" at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02608 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. Evan Yu from the University of Washington and Fred Hutchinson Cancer Center, lead author on "Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline". Thank you for being here today, Dr. Yu. Dr. Evan Yu: Thanks for having me on. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline, including Dr. Yu, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, Dr. Yu, to start us off on the content of this guideline, could you first provide an overview of both the purpose and scope of this guideline? Dr. Evan Yu: Yeah, absolutely. So I think the one key thing to recognize is that prostate cancer is the highest incidence of all cancers in males. Additionally, it's the second highest cause of mortality in males, and that's about 35,000 deaths in 2024. So with that being said and done, it's a disease where we need to do better. And part of that is recognizing that we now have many targeted therapies, precision medicine type of therapies, but unlike a lot of other cancers out there, prostate cancer patients are not always getting sequencing, next generation DNA sequencing, let's say, to identify both inherited and also spontaneously develop what we call somatic mutations in their tumor. And I suspect that's partially because other cancers like breast cancer, we're so used to- in the first line, you present the patient, you throw out their estrogen receptor status, progesterone receptor status, HER2, ER/PR HER2; in lung cancer it's EGFR, ALK, ROS1, etc. In things like prostate cancer, things like BRCA2 have major important patient treatment implications and potentially family counseling and downstream cascade testing implications. But it hasn't made their way into that first-line presentation yet. And for that reason, there are some studies out there that show that testing in the community may be as low as 15% of patients with metastatic prostate cancer. We want to bring awareness to that and hopefully increase testing down the road so that we can better help our patients with metastatic prostate cancer. Brittany Harvey: Absolutely. It's important to get these targeted therapies to the patients who can benefit most. Using that context, I'd like to next review the key recommendations of this guideline across the six clinical questions that the panel addressed. So, starting with: Who should receive germline testing with next generation sequencing technologies? Dr. Evan Yu: Yeah. We think that it's common enough that everyone with metastatic prostate cancer should receive germline genetic testing. And the reason for that is there have been studies that have looked at this and have shown that 12% of men with metastatic prostate cancer have some sort of inherited germline mutation in a gene, mostly DNA repair genes. But 12% have something that is inherited and that loved ones, first degree relatives, siblings, offspring might have also inherited. Now, most of these are in the DNA repair genes, but that being said and done, there's not only treatment implications for the patient, where there are newer drugs that that patient could get treated with, but other loved ones that might have inherited these gene mutations, that these things can cause other cancers as well - not just prostate cancer, but breast cancer, endometrial cancer, ovarian cancer, pancreatic cancer. So, it's very important to test, with as high of an incidence as 12%, to test, and if you identify it in a patient, it's our job to talk to the patient about it and talk to them about the pros and cons of family counseling and talking to their loved ones and potentially having their loved ones get tested. Because if they test positive, then their doctors may want to know and may screen them very, very aggressively and differently for a whole host of other cancers. And the whole idea is you find the cancer very early and cure the patients before the cancer really takes hold and has the ability to spread so we can save a lot of lives down the road. Brittany Harvey: Absolutely. This germline testing is important not just for the patient, but has wider implications for their families as well, as you mentioned. So then, beyond those recommendations for germline testing, which patients should receive somatic testing with next-generation sequencing technologies? Dr. Evan Yu: So let's talk a little bit about somatic testing. So germline again, as we know, is inherited. The patient inherited it in every single cell in their body, then it becomes very easy, many of these are cancer predispositions for them to lose the other allele and then to have biallelic loss and then develop the cancer. Now, somatic just means it spontaneously occurred. Certainly, it's not going to occur in every cell in the body, but you can get one hit, lose one allele and then lose the other allele. And if that gene is truly carcinogenic and leading to that cancer, then that can have implications potentially for treatment as well. So we recommend that all patients with metastatic prostate cancer also undergo somatic next-generation sequencing testing. We recognize that at this point in time it's only those with metastatic castration-resistant prostate cancer or hormone-resistant prostate cancer, which is a later disease state where there are drugs that may target those mutations, for instance, like PARP inhibitors, but that early identification for a patient population that's fit and that can benefit from these therapies makes sense so that you know it's in place already and you have your treatments outlined and mapped out for the future. So we recommend it for everybody - somatic testing also for everyone with metastatic prostate cancer. Brittany Harvey: Understood. And then when patients are receiving that somatic testing, what is recommended for somatic testing? Primary tumor archival tissue? Fresh metastatic biopsy tissue? Or circulating tumor DNA testing? Dr. Evan Yu: We recommend that in the initial setting when you're first diagnosed, that archival tissue samples are fine and preferred. But circulating tumor DNA is good when there's no accessible archival tissue, or if the archival tissue, let's say, is very old and it's been sitting around for a long time, or you can't get it anymore because it's many years back when maybe a patient had a prostate needle biopsy. So if it's not accessible, then we recommend ctDNA. We believe that is preferred and also that ctDNA is recommended in a situation where you can't easily biopsy a metastatic site. Sometimes it's just not in a safe area to go after. Sometimes it's just a small lesion. So in general, we recommend tissue when available, and when we think that the tissue sample will yield clean results, if not, then we recommend doing ctDNA at that point in time. Brittany Harvey: So you have described who should get germline and somatic genomic testing. But what are the therapeutic impacts of this germline or somatic testing for single gene genetic variants? Dr. Evan Yu: We pulled this panel together and we met like every single month for like 12 months straight, and part of it was to review the literature. And as part of this literature review, we were able to pull a whole bunch of different trials. I think there was like 1713 papers we identified in the literature search. Eventually, we narrowed it down because with ASCO, we want to present the data with the highest level evidence, level 1 evidence, randomized controlled prospective data. And after reviewing 1713 papers, we narrowed it down to 14 papers. With those 14 papers, if you look at it, there are a lot of things that we think may have implications for treatment or prognosis, but we didn't feel was the highest level of evidence that we could support. So the things that have the highest level of evidence that we can support are certain DNA repair gene alterations, especially BRCA2, and treatment with PARP inhibitors because there are many PARP inhibitor prospective trials that show progression-free survival benefit and even overall survival benefit. And so that's the type of study that achieved the level of evidence that we could include. So I would say BRCA1 and BRCA2 highest level of evidence and PARP inhibitor use also is included in that. Brittany Harvey: Understood. I appreciate you reviewing those therapeutic options. So then, the last clinical question, which you just touched on briefly, but what are the prognostic impacts of germline and/or somatic testing? Dr. Evan Yu: Whenever you do testing, especially if you use panel testing, you find a lot of information. There's a lot of different mutations and some of which are VUSs (variants of unknown significance) where we don't quite know what it means yet, but we can track that, especially if it's germline. But with somatic, we find lots of things that have implications, but maybe just not treatment implications. A perfect example is p53. p53 is one of the most common tumor suppressor gene mutations on all cancers, but in prostate cancer they can occur and they can usually occur late, although there can even be germline inherited p53 alterations. There's no treatment that targets p53 right now, but we know that if you have a p53 mutation that those patients may have more aggressive disease and that prognostic information is important to give to the patient. And I think it's important for future clinical trial design and direction. So we do not recommend making treatment recommendations or changes based on these prognostic only biomarkers at this point in time. But we do recommend that, based on this, we can design intensification trials for those patients who have these poor risk biomarkers and de-intensification trials for patients who may have a good risk biomarker. So for instance, SPOP is a gene where we think these patients may have better outcomes, they might respond better to certain hormonal therapies like abiraterone. I say might because the level of evidence isn't quite there. But what I would say is that these prognostic only biomarkers, we just don't think they cut the mustard yet to be able to make treatment decisions. But we do think that they can drive counseling for the patient and potential selection and trial design for the future to say, "Okay. This is a patient population that has a more aggressive cancer. We need to be more aggressive in treating these patients." "This patient population might have a less aggressive cancer. Maybe we can de-intensify and say side effects and quality of life may be better for the patients." Brittany Harvey: Definitely. It's important for thinking through how to personalize care for these patients. So then you've talked about this a little bit in talking through the recommendations, but could you expand on what is the importance of this guideline and how it will impact both clinicians and patients with metastatic prostate cancer? Dr. Evan Yu: Yeah, I think the number one thing is awareness. I think the data's out there and people that are in my field, they know this. But by evidence of the fact that it's not first-line presentation lingo that everyone's talking about things like BRCA status, it means it hasn't necessarily disseminated all the way through. So it's increasing awareness of the fact that both germline and somatic alterations can occur and that these may have impacts on the patient for their treatment and their prognosis, and basically to increase testing for the future. I really think that in the future, there'll be other reasons that we may want to serially even retest and we may find that there may be mutations that develop as mechanisms of resistance that might guide therapy down the road. So we need to get people to start doing this for everyone with metastatic prostate cancer, because someday we might be doing it not just once, but over and over again. Brittany Harvey. Absolutely. We hope this guideline reaches a wide audience and that these recommendations can be put into practice. Finally, you've talked about how not all the data in the field has yet risen to the level of evidence that made it into the guidelines. So what are the outstanding questions in future research areas for both germline and somatic genomic testing for metastatic prostate cancer? Dr. Evan Yu: It was in our discussion, but it clearly- it's not common enough for there to be randomized prospective trials that would reach that level of evidence to make it in this guideline recommendation. But we all know that for any solid tumor, you can get mismatched repair deficiency, microsatellite instability leading to hypermutation or high tumor mutational burden. And that happens in maybe 3 to 5% of patients with metastatic prostate cancer as well. There is evidence and data that these patients can potentially benefit from immunotherapies like pembrolizumab. But again, it's just not common enough for there to be those randomized prospective controlled trials out there. But we mention it because we know it's FDA-approved across all the tumor types, so we felt like we have to mention it because that's something that has treatment implications for the patient. But also, I alluded to this earlier, I think an area of active investigation is the tried and true number one driver of prostate cancer, which is androgen receptor. Testosterone binds to androgen receptors, stimulates it. That's how androgen deprivation therapy works. That's how abiraterone and the amides like enzalutamide, apalutamide, darolutamide, that's how they all work. But even beyond that, we're starting to identify that maybe 15%, 20% of patients with metastatic castration resistant prostate cancer have androgen receptor mutations. And there are newer classes of therapies like androgen receptor degraders like CYP11A1 antagonist that lead to complete adrenal annihilation of other steroid hormones that might promiscuously stimulate these androgen receptor mutants. These things develop as mechanisms of resistance, and in the future, we might want to serially test- and that's an active area of investigation in the future, to say you've been treated, let's say, with androgen deprivation therapy and abiraterone for years. There are certain mutations that might develop as a resistance mechanism. We might need to serially test somebody because you didn't have that mutation earlier on, but later in the disease course you might. And then there might be a new drug X out there that we would want to use. Again, we need the data, we need the randomized prospective controlled trials, but they're happening out there. And somewhere down the road we may rewrite this guideline and have a lot more recommendations to add to it. Brittany Harvey: Yes, we'll look forward to more research in this field to better provide targeted therapies for patients with metastatic prostate cancer across the treatment paradigm. And we'll look forward to report outs from those trials that you mentioned. So I want to thank you so much for your work to develop this guideline and thank you for your time today, Dr. Yu. Dr. Evan Yu: Thank you so much. It's wonderful to be here today. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Treatment of Pleural Mesothelioma Update (00:10:37)
Dr. Hedy Kindler joins us on the podcast to discuss the latest update to the treatment of pleural mesothelioma guideline. She discusses the latest changes to the updated recommendations across topics including surgery, immunotherapy, chemotherapy, pathology, and germline testing. Dr. Kindler describes the impact of this guideline and the need for ongoing research in the field. Read the full guideline update, "Treatment of Pleural Mesothelioma: ASCO Guideline Update" at www.asco.org/thoracic-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02425 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. Hedy Kindler from the University of Chicago, lead author on "Treatment of Pleural Mesothelioma: ASCO Guideline Update." Thank you for being here today, Dr. Kindler. Dr. Hedy Kindler: Thank you so much. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kindler, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this podcast episode, first, Dr. Kindler, can you provide an overview of the purpose and scope of this guideline update on pleural mesothelioma? Dr. Hedy Kindler: The initial ASCO practice guideline on mesothelioma, which we published in 2018, was quite comprehensive, but since that time incredible progress has been made which has truly transformed the management of this disease. So we felt it was really important to update the guideline now, focusing on four key areas: the role of surgery, new systemic treatments, pathologic insights, and germline testing. Brittany Harvey: Great. Thank you for highlighting those key areas of the guideline. And so I'd like to next review the key updated recommendations for our listeners. So starting with what are the new updates for surgery? Dr. Hedy Kindler: So surgery has always been controversial in meso, with significant geographic variation in its use. Now, it's even more controversial. Recent randomized data from the MARS 2 trial, placed in the context of other data we also reviewed in this update, suggest that surgical cytoreduction should not be routinely offered to all patients based solely on anatomic resectability. Surgery should only be offered to highly selected patients with favorable prognostic characteristics. This includes comprehensively staged patients with early-stage epithelioid tumors. Patients should preferably be treated at centers of excellence which have documented low morbidity and mortality, and this should also be done in the context of multimodality therapy and preferably within clinical trials. Brittany Harvey: Understood. I appreciate you reviewing those recommendations for who surgery should be offered to. So following those, what are the main recommendations for immunotherapy for treating pleural mesothelioma? Dr. Hedy Kindler: So for a disease in which for 16 years there was only one FDA-approved regimen, pemetrexed and platinum, the pace of recent changes in systemic therapy has been a welcome change with the FDA approval of doublet immunotherapy in October of 2020 and the approval of chemo immunotherapy just a few months ago in September of 2024. Now that we have choices, we've tried to help clinicians determine the optimal treatment regimen for the individual patient. Doublet immunotherapy with ipilimumab and nivolumab should be offered as a first-line systemic option to any mesothelioma patient. For patients with non-epithelioid histology, doublet immunotherapy is hands down the recommended regimen based on the dramatic improvement in survival from 8.8 to 18.1 months for immunotherapy compared with chemo. For patients with previously untreated epithelioid mesothelioma, either ipilimumab-nivolumab immunotherapy or platinum-pemetrexed chemotherapy are reasonable options. Therapy can be individualized based on the patient's comorbidities, acceptance of differing toxicities. and treatment goals. Chemoimmunotherapy with pembrolizumab, pemetrexed, and carboplatin is a newer treatment option for patients with newly diagnosed pleural mesothelioma. This regimen is noteworthy for its very high objective response rate of 62%. Brittany Harvey: It's great to have those new options to improve outcomes for patients. Beyond the chemoimmunotherapy recommendation that you just described, what are the highlights for chemotherapy recommendations? Dr. Hedy Kindler: So pemetrexed platinum-based chemotherapy with or without bevacizumab still plays a role in this disease and should be offered as a first-line treatment option in patients with epithelioid histology. This regimen is not recommended in patients with non-epithelioid disease unless they have medical contraindications to immunotherapy. Pemetrexed maintenance chemotherapy following pemetrexed-platinum chemotherapy is not recommended. Brittany Harvey: Thank you for reviewing those recommendations as well. So then next, what are the important changes regarding pathology? Dr. Hedy Kindler: Well, one fun fact is that we've changed the name of the disease. It's no longer malignant mesothelioma. Now it's just mesothelioma. Since the non-malignant mesothelial entities have been renamed, all mesos are now considered malignant, so there's no need to use the prefix malignant in the disease name. Mesothelioma should be reported as epithelioid, sarcomatoid, or biphasic because these subtypes have a clear prognostic and predictive value. Knowing the subtype helps us decide on whether chemotherapy or immunotherapy is the optimal treatment for a patient, so it must be reported. Additionally, within the epithelioid subtype, histologic features, including nuclear grade, some cytologic features, and architectural patterns should be reported by pathology because they have prognostic significance. Pathologists have recently identified a premalignant entity, mesothelioma in situ, which can be found in patients with long standing pleural effusions and should be considered in the differential diagnosis. In the appropriate clinical setting, additional testing, including BAP1 and MTAP IHC should be performed. Brittany Harvey: Definitely. These pathologic recommendations are important for treatment selection. So in that same vein, in the final section of the recommendations, what are the updated recommendations from the panel regarding germline testing? Dr. Hedy Kindler: This is one of our most important recommendations, that universal germline testing should be offered to all mesothelioma patients. The proportion of patients with mesothelioma who have pathogenic or likely pathogenic germline variants is similar to other diseases in which universal germline genetic testing and counseling are now the standard of care. This is most commonly observed in the tumor suppressor gene BAP1 and this not only affects cancer risk in patients and their family members, but also has key prognostic significance. For example, pleural mesothelioma patients with BAP1 germline mutations who receive platinum-based chemotherapy live significantly longer, 7.9 years compared to 2.4 years for those without these mutations. Thus, we recommend that all patients with mesothelioma should be offered universal germline genetic counseling and/or germline testing. Brittany Harvey: So there were a large amount of new and updated recommendations in this update. So in your view Dr. Kindler, what is the both importance of this update and how will it impact both clinicians and patients with pleural mesothelioma? Dr. Hedy Kindler: Even as we were researching and writing this update, new data kept emerging which we needed to include. So it's clearly a time of great progress in the management of this disease. We've comprehensively reviewed and analyzed the extensive emerging data and provided clinicians with a roadmap for how to incorporate these new advances into their management of this disease. Brittany Harvey: Absolutely, that is key for optimal patient care. So you've just mentioned emerging data and rapid evidence generation, so what future research developments are being monitored for changes in the treatment of pleural mesothelioma? Dr. Hedy Kindler: Despite these recent advances in disease management, mesothelioma continues to be a lethal cancer, and there's clearly a need to develop better treatments. This includes ongoing studies of novel immunotherapeutic agents such as bispecific antibodies, cell therapy using chimeric antigen receptors targeting mesothelioma tumor antigens, and precision medicine approaches to target tumor suppressor genes. Finally, strategies for early cancer detection and prevention are vital for individuals predisposed to develop mesothelioma due to BAP1 and other germline mutations, as well as for those who are occupationally or environmentally exposed to asbestos. Brittany Harvey: Absolutely. We'll look forward to these new updates to continue development in the field. So thank you so much for this mountain of work to update this guideline, and thank you for your time today, Dr. Kindler. Dr. Hedy Kindler: Thank you so much. It's been a pleasure. Thank you for asking me to do this. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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. Van Morris presents the new evidence-based guideline on systemic therapy for localized anal squamous cell carcinoma. Dr. Morris discusses the key recommendations from the Expert Panel, including recommended radiosensitizing chemotherapy agents, dosing and schedule recommendations, the role of induction chemotherapy and ongoing adjuvant chemotherapy, and considerations for special populations. He emphasizes the importance of this first guideline from ASCO on anal squamous cell carcinoma for both clinicians and patients with stage I-III anal cancer, and ongoing research the panel is looking to for the future. Read the full guideline, "Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline" at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02120 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. Van Morris from MD Anderson Cancer Center, co-chair on "Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline." Thank you for being here today, Dr. Morris. Dr. Van Morris: Thank you for having me. On behalf of our committee who put together the guidelines, I'm really excited to be here and talk with you today. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Morris, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this guideline, Dr. Morris, can you provide an overview of both the purpose and the scope of this guideline on stage I to III anal squamous cell carcinoma? Dr. Van Morris: So anal cancer is considered a rare malignancy for patients in the United States and across the world as well. Even though it's not something we see as commonly, for example, as the adjacent colorectal cancer, this still is a cancer that is rising in incidence every year in the United States. And really, despite the presence of the preventative HPV vaccines, which we hope will ultimately prevent and eradicate this cancer, we still expect the incidence to continue to rise in the coming decades before we really start seeing numbers begin to decrease as a result of the vaccine. So this is an alarming trend for which oncologists will continue to see likely more and more cases and new diagnoses every year. So we wanted to review the most recent literature and provide oncologists up to date recommendations for how they can best take care of patients with a new diagnosis of localized anal cancer. Brittany Harvey: Absolutely. I appreciate that background and context to set the stage for this guideline. So then next I'd like to review the key recommendations of this guideline. So starting from the first clinical question, what are the recommended radiosensitizing, doublet or single chemotherapy agents for patients with stage I to III anal cancer? Dr. Van Morris: It's true that really the standard treatment for patients with localized anal cancer has not changed over the last literally half century. When the Nigro regimen was first reported back in 1974, 50 years ago, the standard of care for patients with a new diagnosis of localized anal cancer centers around concurrent chemotherapy and radiotherapy. And we looked at the various randomized control trials and the highest level of evidence which has been reported over the past decades, and really for most patients, the standard of care continues to remain doublet cytotoxic chemotherapy in combination with radiation. We reported that the most commonly, and I think most accepted, regimen here is a combination regimen of 5-FU, intravenous 5-fluorouracil with mitomycin C. And this most commonly is given on a week 1 to 5 regimen. The 5-FU, we recommended a dose of 1000 milligrams per meter squared per day on days 1 to 4 and then on days 29 to 32 of the radiation treatment. And then the mitomycin C, looking at various trials, has been given at a dose of 10 milligrams per meter squared on day 1 and day 29, or alternatively a single dose of mitomycin C at 12 milligrams per meter squared on day 1. I think that the thing that's important for clinicians and patients alike to remember is that this chemotherapy can be very toxic in patients who are undergoing a curative-intent therapy for this diagnosis of localized anal cancer. I think it's just important for oncologists to be watching closely the blood counts for the patients to make sure that the myelosuppression doesn't get too bad. And then in select cases, if that is the case, when the oncologist opts to go for the day 1 and day 29 dosing, it may be prudent, if the myelosuppression is too excessive, to consider withholding that day 29 dose. Brittany Harvey: Great. Thank you for providing those recommendations along with some of those dosing and the schedule recommendations from the expert panel. So are there any other alternate dose or schedule recommendations from the expert panel? Dr. Van Morris: Yeah, but I think that we saw with the ACT II data that was a randomized trial that was done out of the UK that compared 5-FU mitomycin with 5-FU cisplatin as two different doublet cytotoxic regimens, that overall outcomes were very similar between the two regimens in terms of curative outcomes for patients treated whether 5-FU mitomycin or 5-FU cisplatin. So certainly there is evidence supporting the use of cisplatin as a second cytotoxic agent with 5-fluorouracil. In the ACT II study that was given at a dose of 60 milligrams per meter squared on days 1 and 29 along with the 5-FU at the regimen I talked about previously. There is other lower level of evidence data suggesting that even the 5-FU and cisplatin can be given on a weekly schedule and that that can be safe. Actually, at my institution at MD Anderson, that is our standard practice pattern as well. There's also the option when we're thinking about giving pelvic radiation for patients with lower GI cancers, many oncologists in the treatment of localized rectal adenocarcinoma are accustomed to using capecitabine as a chemosensitizer in patients with localized rectal cancer. If I'm giving chemoradiation for a patient with localized anal cancer, can I substitute the intravenous 5-FU with oral capecitabine? And although the evidence is not as strong in terms of available data with regards to randomized controlled trials, there certainly is data that suggests that capecitabine may be an acceptable alternative in lieu of intravenous 5-fluorouracil that would be given at a dose of 825 milligrams per meter squared on days of radiation. But certainly, I think that that's a feasible approach as well and maybe even associated with less hematologic toxicity than intravenous 5-FU would be. Brittany Harvey: Great. It's important to understand all the options that are out there for patients with early-stage anal squamous cell carcinoma. So in addition to those chemoradiation recommendations, what is recommended from the expert panel regarding induction chemotherapy or ongoing adjuvant chemotherapy for this patient population? Dr. Van Morris: When we think about treating patients with lower GI cancers with curative intent therapies, when we think about the more common rectal adenocarcinoma, oncologists may be used to giving chemoradiation followed by subsequent cytotoxic chemotherapy. But actually when you look at the data for anal cancer, really there's not any data that strongly supports the use of either induction chemotherapy prior to chemoradiation or adjuvant post-chemoradiation chemotherapy. The RTOG 98-11 study was a trial which evaluated the role of induction 5-fluorouracil prior to chemoradiation and did not show any survival benefit or improved outcomes with the use of induction chemotherapy in a randomized control trial setting. The ACT II trial, which I referenced earlier, was a 2 x 2 design where patients were either randomized to concurrent chemoradiation with 5-FU mitomycin C or concurrent chemoradiation with 5-FU cisplatin. But then there was a second randomization after chemoradiation where half of the study participants received adjuvant cisplatin 5-fluorouracil after completion of their chemo radiation, or the other half were randomized to the standard of care, which of course would be observation. And what that trial showed was that there was no added benefit with the addition of post-chemoradiation cytotoxic chemotherapy. So we look at these data and say that in general, for the general population of patients with localized stages I to III anal cancer, there really is no supporting data suggesting benefit of either induction chemotherapy or adjuvant chemotherapy. And to that end, really it's concurrent chemoradiation remains the standard of care at this time for patients with a new diagnosis of localized anal cancer. Brittany Harvey: Absolutely. It's just as important to know what is not recommended as it is to know what is recommended for these patients. And so I thank you for explaining the evidence behind that decision from the panel as well. So then, are there any other considerations for special populations that oncologists should consider? Dr. Van Morris: I think so. I think that anal cancer is a disease where we don't see that many patients being diagnosed earlier at a younger age, especially in relation to the alarming trend of early onset colorectal cancer that we're currently seeing right now. So there may be patients who come with a new diagnosis of localized anal cancer who are an octogenarian at an advanced age or may have other significant medical comorbidities. And if that is the case, we get called about this quite frequently from outside institutions. I have an 85 year old who is coming to my clinic with this diagnosis. I don't feel comfortable giving this patient doublet cytotoxics, what options do I have? Especially given other organ dysfunction that may precede this diagnosis. And I think that in that case, there are times when it's okay safely to drop the mitomycin C and opt for single agent 5-fluorouracil as a single cytotoxic agent. So I think that that would be something that we've certainly incorporated into our practice at our institution. There's also an association between various autoimmune disorders, patients on immunosuppression, even persons living with HIV being at higher risk for this virally associated cancer. So I think that, again, if the patient is coming with baseline immunosuppression for these reasons prior to treatment, certainly kind of being in tune to the potential for hematologic toxicity. And watching these patients very closely as they're getting chemoradiation remains really important. Brittany Harvey: Definitely. So, you've just discussed some of those comorbidities and patient characteristics that are important for clinicians to consider when deciding which regimens to offer. So in addition to those, in your view, what is the importance of this guideline and how will it impact clinical practice for clinicians who are reading this guideline. Dr. Van Morris: Chemoradiation remains a very effective option and most patients will be cured with this diagnosis and with this treatment. So it's important to make sure that these patients are able to safely get through their treatment, minimizing treatment delays due to toxicities which may come about because of the treatment, and really help to carry them over the finish line so that they have the best likelihood for achieving cure. So we really hope that these data will provide oncologists with a readily available summary of the existing data that they can refer to and continue to help as many patients as possible achieve and experience a cure. Brittany Harvey: Absolutely. So then to build on that, it's great to have this first guideline from ASCO on anal squamous cell carcinoma. But how will these new recommendations affect patients with stage I to III anal cancer? Dr. Van Morris: I certainly hope it will allow patients and oncologists to know what their options are. It certainly is not a one size fits all treatment approach with regards to the options which are available. Depending on the patient, depending on the various medical conditions that may accompany them, these treatments may need to be tailored to most safely get them through their treatment. Brittany Harvey: I appreciate you describing the importance of this guideline for both clinicians and patients. So what other outstanding questions and future research do you anticipate seeing in this field? Dr. Van Morris: It's a really good question and I think that there is a lot coming on the horizon. Even though the standard treatment has really not changed over the last half century, I think it still remains true that not all patients will achieve cure with a chemoradiation treatment. So a recent trial has completed enrollment in the United States, this is the EA2165 trial led by one of our committee members, Dr. Rajdev and Dr. Eng as well, that's looking at the use of nivolumab anti PD-1 immunotherapy after completion of concurrent chemo adiation. So in that trial, patients were randomized to concurrent chemoradiation followed by either observation or six months of adjuvant anti PD-1 therapy. We're really awaiting the results of that. Hopefully if we see an improvement with the addition of nivolumab following concurrent chemoradiation, our hope would be that more patients would be able to achieve a cure. So we're certainly looking forward to the outcomes of that EA2165 study. And then I think one question that we often get from our patients in the clinics is, "What is the role of circulating tumor DNA in the management of my disease?" And really, to date there have been some series which have shown that we can assess patients or circulating tumor DNA after completion of their concurrent chemo radiation that may need to start about three months after to give time for the radiation to wear off and most accurately prognosticate that. But I think that this will be a powerful tool moving forward, hopefully, not only in the surveillance to identify patients who may be at high risk for recurrence, but ultimately to translate that into next generation clinical trials which would treat patients at higher risk for recurrence by virtue of a detectable circulating tumor DNA result. In doing so, hopefully cure even more patients with this diagnosis. Brittany Harvey: Yes, we'll look forward to these developments and hope to add more options for potential treatment and surveillance for patients with anal cancer. So, I want to thank you so much for your work to develop these guidelines and share these recommendations with us and everything that the expert panel did to put this guideline together. Thank you for your time today, Dr. Morris. Dr. Van Morris: Thank you. And thank you to ASCO for helping to keep this information out there and ready for oncologists for this rare cancer. Brittany Harvey: Absolutely. And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Systemic Therapy for SCLC Rapid Update (00:14:28)
Dr. Greg Kalemkerian reviews the latest evidence-based rapid update from the Expert Panel on systemic therapy for small cell lung cancer. He discusses the updated recommendations for patients with limited-stage SCLC based on the ADRIATIC trial, and for patients with relapsed SCLC based on the DeLLphi-301 trial. Dr. Kalemkerian shares insights on what these changes mean for clinicians and patients, and highlights new trials in progress to provide more options for patients diagnosed with SCLC. Read the full rapid update, "Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/thoracic-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02245 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Greg Kalemkerian from the University of Michigan, lead author on, "Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update". Thank you for being here today, Dr. Kalemkerian. Dr. Greg Kalemkerian: Thank you. Thank you for the invitation. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kalemkerian, who has joined us here today, are available online with the publication of the update in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this rapid update, Dr. Kalemkerian, what prompted this update to the Systemic Therapy for Small Cell Lung Cancer Guideline, which was previously published in 2023? Dr. Greg Kalemkerian: So even though the original guideline only came out a year ago, the past year we've seen two significant advances in small cell lung cancer with two reports, one in limited stage with the addition of immunotherapy, the other in the addition of a new immunotherapeutic agent in relapsed small cell lung cancer. Brittany Harvey: It's great to have this new data in the small cell lung cancer space. So based on these new changes, what are the updated recommendations from the expert panel? Dr. Greg Kalemkerian: So the first recommendations have to do with patients with limited-stage small cell lung cancer based on the ADRIATIC trial which added consolidation durvalumab for patients who had not had progression after standard chemotherapy and radiotherapy. And this study demonstrated a significant improvement in overall survival with about a 10% improvement in both 2- and 3-year overall survival, up to a 57% overall survival at 3 years for the patients receiving consolidation durvalumab. And based on those findings, we updated the recommendation for the standard treatment for limited-stage small cell lung cancer such that it included the use of consolidation immunotherapy with durvalumab for up to two years in patients who had had no disease progression, and completion of concurrent chemoradiotherapy for limited-stage small cell lung cancer. Of course, those patients would be those who do not have contraindications to the use of immunotherapy. As a corollary to that recommendation, for patients who have poorer performance status, so performance status of 3 or 4, who had had initial treatment perhaps with sequential chemotherapy and radiotherapy, if their performance status improves with their initial treatment, then it would also be reasonable to add consolidation immunotherapy for those patients as long as their performance status maintains improvement and they have no evidence of progression. The other update of the guidelines had to do with patients with relapsed small cell lung cancer and that was based on the DeLLphi-301 trial which was a phase II study looking at the use of tarlatamab, a bispecific T cell engager, binds to both DLL3 and CD3 in order to increase the immune killing of small cell lung cancer cells. So what this study did was it treated patients who had had at least two prior regimens. So this is third-line or beyond was what the population that this study looked at. And the majority of these patients had already had some immune checkpoint therapy. They all had good performance status and it did allow patients with brain metastases to be included in the study. When we look at the patients who received the approved 10 milligram dose of the drug, the response rate was about 40%. Responses were seen in both patients with sensitive and refractory based on the time since their prior treatment and the median duration of response was 10 months, which is much better than anything we've seen before with relapsed small cell lung cancer patients, remembering that all these patients were also third-line or beyond. So based on the results of the DeLLphi-301 trial, we updated two of the recommendations regarding relapsed small cell lung cancer. In the first one, we stated that in patients with relapsed small cell lung cancer with a chemotherapy free interval of less than 90 days, single agent systemic therapy would be considered standard of care, and that the preferred agents would include topotecan, lurbinectedin, or, now, tarlatamab. We did mention as a qualifying statement that single-agent chemotherapy is preferred over multi-agent chemotherapy. And the second recommendation was that, in patients with relapsed small cell lung cancer with a chemotherapy interval longer than 90 days, the rechallenge with a platinum-based regimen or single-agent chemotherapy was considered standard and the preferred agents for single agent therapy would be topotecan, lurbinectedin, or tarlatamab being added in the recent study. Tarlatamab was approved by the FDA for use in patients with relapsed small cell lung cancer with no stipulations with regard to the treatment. Brittany Harvey: Understood. I appreciate you describing those updated recommendations along with the supporting data for both limited stage small cell lung cancer and relapsed small cell lung cancer. So then, what should clinicians know as they implement these new and updated recommendations into practice? Dr. Greg Kalemkerian: So with regard to the ADRIATIC trial or the consolidation durvalumab being added for limite- stage small cell lung cancer patients, I think the important considerations are that this was done after patients had demonstrated no progression of disease after chemotherapy and radiotherapy, so the initial treatment does not change with platinum-etoposide plus definitive radiotherapy being recommended. The addition of durvalumab is going to be potentially useful in patients generally with good performance status, so performance statuses 0 to 1, and we still have to pay attention to the patients who may have contraindications to immunotherapy, things like interstitial lung disease, autoimmune problems that do occur in patients with small cell lung cancer where they develop paraneoplastic autoimmune syndromes such as Lambert-Eaton myasthenic syndrome. Those patients with those types of preexisting conditions would not be good candidates for immunotherapy use. So still having the tailored treatment to the individual patient is what's most important. The duration of the durvalumab was up to two years and not beyond that, so following those specific guidelines for the use of durvalumab in patients with limited-stage small cell lung cancer. With regard to tarlatamab, tarlatamab is an immunotherapy treatment. So we still do have the exclusions of people who have had prior severe immune-related adverse events, people who have pneumonitis, people who have interstitial lung disease, people with autoimmune neurologic problems we can see with small cell lung cancer, these patients should not be considered good candidates for the use of tarlatamab. The study did include patients who had had treated and asymptomatic brain metastases and there is some evidence that tarlatamab can have some control of brain metastases. So that's not necessarily an exclusion. Tarlatamab does have some other specific considerations to it in that 51% of patients had some evidence of cytokine release syndrome (CRS). Only 1% of those patients had grade 3 CRS. So even though they had frequent fevers and hypotension and hypoxia, it was generally not severe. But this concern for CRS and also for neurologic complications after treatment does require that patients be admitted to the hospital for a 24-hour observation period during the first and second doses. Subsequent to that, patients can be observed for some time after the infusion in the outpatient setting. But they also need to have very clear and strict guidance for when they go home about what things to look for. Looking for fevers, looking for shortness of breath, looking for any neurologic changes. It's a good idea for them to have a caregiver with them in order to observe them during that time. Most of these complications occur during the first or second cycles, but it is a drug that is going to require significant education not only of our staff, but also of the patients in order to ensure that the drug's used safely. Brittany Harvey: Absolutely. For these new options, it's important to tailor cancer treatment to the individual patient and the factors that you mentioned and be mindful of these potential toxicities. So, it's always great to learn of new options for patients. But in your view, how will this update impact patients with small cell lung cancer? Dr. Greg Kalemkerian: Well, clearly we need longer term follow up. So, with regard to the limited-stage small cell lung cancer situation, that's a curative situation. We have been curing patients with limited-stage disease with chemotherapy and radiotherapy for several decades now, but the cure rates were relatively low with about 25%, 30% of people becoming long term survivors. Now the hope is with the durvalumab being added on, that we can increase that number. Thus far, we have three-year survival data with a three-year survival of 57% overall survival and we're hoping that that is maintained over time and that we're not just delaying recurrences, but that we're actually preventing recurrences and helping people live longer, as has been seen with non-small cell lung cancer in stage III disease with the addition of durvalumab to chemoradiotherapy. So hopefully, we will be improving the cure rate of people with limited-stage small cell lung cancer. There are several other trials with immunotherapy in this space coming down the line and we're anxiously awaiting not only long term follow up from ADRIATIC, but also initial data from studies such as KEYLYNK and ACHILLES and NRG-LU005. So all of these studies in the next few years are hopefully going to guide treatment for limited-stage small cell lung cancer and hopefully improve the long term survival outcomes. With regard to tarlatamab, unclear at this point what the long term outcomes are going to be. Is a 40% response rate substantially better than what we've seen before? Well, lurbinectedin also had about a 40% response rate in patients who had sensitive disease, but the duration of response does look longer. And there are some patients now who have been on this study that are doing very well for quite long periods of time with the drug. So, the hope here also is that we will have some small subset of patients who continue to do better for long periods of time. Whether that'll translate into a cure or not, way too early to know, clearly hoping to add another brick in the wall so that we can keep the disease at bay, at least for a longer period of time for these patients. How we will integrate tarlatamab into the regimens is a bit unclear. Whether most of us will start using it as second-line therapy or whether we will use perhaps lurbinectedin or topotecan as second-line and tarlatamab as third-line, we're all going to have to work that out based on the potential toxicities, the logistical complications of using the drug at this point in time. But I do think that it's nice to have more options to add to our armamentarium to treat this very, very challenging and difficult disease. Brittany Harvey: Definitely. So, you've just discussed the need for both longer term follow up here along with some important ongoing trials in this space. So we'll look forward to future readouts of those trials to learn more about caring for patients in small cell lung cancer. So, I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Kalemkerian. Dr. Greg Kalemkerian: Okay. Again, thank you for the invitation, Brittany, and thanks to ASCO for developing the whole guideline structure to help all of us take better care of our patients. Brittany Harvey: Absolutely. And also thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full update, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2024.2 (00:09:53)
Dr. Lyudmila Bazheova share the latest updates to the ASCO living guideline on therapy for stage IV non-small cell lung cancer with driver alterations. She discusses changes for patients with EGFR driver alterations in both the first- and second-line setting, and reviews the evidence supporting these updated recommendations, from trials such as MARIPOSA, MARIPOSA-2, CheckMate 722, and KEYNOTE-789. Stay tuned for future updates to this continuously updated guideline. Read the full update, "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2." at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02133 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, lead author on "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2." Thank you for being here, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It is my pleasure. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bazhenova, who has joined us on this episode today, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes. So then, to kick us off on the content here, Dr. Bazhenova, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is being updated routinely as a living guideline. So what prompted the update to the recommendations in this latest version? Dr. Lyudmila Bazhenova: Living ASCO Guidelines are developed to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. In this recently published guideline, we reviewed new evidence for patients with metastatic lung cancer harboring driver alterations. We reviewed evidence from four published studies, MARIPOSA, MARIPOSA-2, CheckMate 722 and KEYNOTE-789 that resulted in updated guidelines. Brittany Harvey: Great. And then based off those four trials that you just mentioned, what are the updated recommendations for patients with stage IV non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution? Dr. Lyudmila Bazhenova: In the previous guideline, we detailed FLAURA 2 study which was presented and published in the past. In this guideline, we specifically highlighted a phase 3 MARIPOSA trial which took patients with untreated advanced non-small cell lung cancer which harbored classical EGFR mutations such as EGFR deletion 19 and L858R. In this study, patients were randomly assigned to receive amivantamab plus lazertinib or osimertinib or lazertinib alone. And the study showed that the primary endpoint which was progression-free survival was longer with amivantamab plus lazertinib compared to osimertinib, and numerically the progression free survival was 23.7 months with ami-lazertinib versus 16.6 months with osimertinib which was statistically significant. The challenge that we have to face when discussing that option with our patients is increased toxicity with amivantamab and lazertinib combination. For example grade 3 treatment adverse events were 75% with amivantamab and lazertinib and 43% with osimertinib. So this will require shared decision making between our patients and ourselves. We also noticed in the guidelines that there was a subgroup analysis of that study showing that the patients with a higher disease burden, central nervous metastasis or brain metastasis as well as disease which considered to be a higher risk such as commutation, for example, p53 and liver metastasis, they might benefit from intensified therapy. However, another thing that we are highlighting in the guideline is that at this point we do not know how the intensification of therapy will change overall survival of our patients. So one needs to take into account increased toxicity with that combination. Brittany Harvey: So then Dr. Bazhenova, in addition to those updates for first line therapy, what are the updated recommendations for second line therapy? Dr. Lyudmila Bazhenova: For patients who have progressive disease on osimertinib or other EGFR tyrosine kinase inhibitors, we also updated our guidelines highlighting MARIPOSA 2 study. In the MARIPOSA 2 study, patients were assigned to chemotherapy versus amivantamab plus lazertinib plus chemotherapy versus amivantamab plus chemotherapy. And both of the amivantamab arms showed superiority in progression-free survival compared to chemotherapy alone arm and therefore this becomes an additional treatment option for our patients who develop resistance to osimertinib. In addition, we also updated the results which highlight the lack of efficacy of immunotherapy in the patients who progressed on osimertinib. There were two studies that we highlighted. One of them was a CheckMate 722 which randomly assigned patients with metastatic non-small cell lung cancer whose cancer has progressed on EGFR tyrosine kinase inhibitor to receive either chemotherapy or chemotherapy plus nivolumab which is an immune checkpoint inhibitor. And the second study was KEYNOTE-789 which had a very similar study design. Again, patients who progressed on EGFR TKI also were assigned to receive chemotherapy plus pembrolizumab or chemotherapy alone and in both of those studies there was no improvement in progression-free survival when adding immunotherapy to chemotherapy. So for all your patients who are progressing on EGFR tyrosine kinase inhibitors and you're thinking if additional immunotherapy is necessary, we now have two randomized phase 3 studies telling us that immunotherapy should not be used in addition to chemotherapy for patients who develop progression on osimertinib. Brittany Harvey: Understood. I appreciate you talking about the evidence that supports these latest recommendations from the expert panel. So then you've already touched on this a little bit in mentioning shared decision making and discussing toxicity with these new therapies, but what should clinicians know as they implement these new recommendations and how do these new recommendations fit into the previous recommendations made by the panel? Dr. Lyudmila Bazhenova: Our previous recommendations did not include a MARIPOSA trial, so did not include amivantamab and lazertinib. So in our current guidelines for patients with newly diagnosed treatment-naive EGFR classical mutations, we have three options. Number one is osimertinib, number two is osimertinib plus chemotherapy based on the FLAURA study that we highlighted in the prior version of the guidelines. And the third is amivantamab plus lazertinib. At this point, we do not have any randomized head-to-head studies of those combinations with an exception of FLAURA 2 which is osimertinib plus chemo versus osimertinib. And so the decisions will have to be made on a cross-trial comparison, taking into account patient wishes if they would like to receive chemotherapy or amivantamab plus lazertinib, understanding that this combination will result in increased toxicity. Brittany Harvey: Absolutely. I appreciate you detailing those considerations. So then finally, what do these new options mean for patients with non-small cell lung cancer and an EGFR alteration? Dr. Lyudmila Bazhenova: As a patient, it is important to also be aware of what options we have and have a direct dialogue with the physician, with the treating physician, trying to understand what option will fit with each individual patient's goals, life goals, as well as toxicity concerns. Brittany Harvey: Definitely. It's always great to have more options for patients and it's also important to discuss all of those options with their clinician as well. So I want to thank you so much for your work on this update and thank you for your time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: My pleasure. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Management of Locally Advanced Rectal Cancer Guideline (00:12:23)
Dr. Sepideh Gholami and Dr. Aaron Scott join us to discuss the latest evidence-based guideline from ASCO on the management of locally advanced rectal cancer. They review the recommendation highlights on topics including assessment, total neoadjuvant therapy, timing of chemotherapy, nonoperative management, and immunotherapy. Additionally, we discuss the importance of this guideline for both clinicians and patients, and the outstanding research questions in the management of locally advanced rectal cancer. Read the full guideline, "Management of Locally Advanced Rectail Cancer: ASCO Guideline" at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.01160 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. Aaron Scott from the University of Arizona Cancer Center and Dr. Sepideh Gholami from Northwell Health, co-chairs on, "Management of Locally Advanced Rectal Cancer: ASCO Guideline." Thank you for being here, Dr. Scott and Dr. Gholami. Dr. Sepideh Gholami: Thank you for having us. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Scott and Dr. Gholami, who have joined us here today, are available online with a publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to kick us off on the content of this episode, Dr. Gholami, first, what is the purpose and scope of this guideline on locally advanced rectal cancer? Dr. Sepideh Gholami: Well, I think, historically, this is the group of patients with locally advanced rectal cancer for which we've used multiple therapies to address their management. And with the advent of the total neoadjuvant approach, we really have seen tremendous changes. So the purpose really of these guidelines was to consolidate the various approaches that we've had in several clinical trials and to provide the oncology community a general management recommendation guideline to really optimize the outcomes for these patients. And I would further notice that with the specifics to like which patients are included for these, so we define patients with locally advanced rectal cancer as any of those patients with T3 or T4 tumors and/or lymph node positive disease. Brittany Harvey: Great. I appreciate you providing that background and context of this guideline. So then, next, I'd like to review the key recommendations of this guideline. So, Dr. Scott, starting with the first section of the guideline, what are the recommendations for assessment of locally advanced rectal cancer? Dr. Aaron Scott: Yeah, thank you. So really, we were charged with trying to answer, I think, several very important questions as it comes to the treatment of locally advanced rectal cancer. And the first step in doing so is to define the patient group. So, as far as the first section goes in the assessment, we were really charged with defining what locally advanced rectal cancer means. We think that this is best done with a high resolution pelvic MRI, dedicated rectal sequence prior to any treatment for risk assessment and proper staging, and the use of standardized synaptic MRI is recommended that includes relation of the primary tumor to the anal verge, sphincter complex, pelvic lymph nodes, the mesorectal fascia, otherwise known as the MRF, and includes assessment of the EMVI tumor deposits and lymph nodes. Brittany Harvey: I appreciate you reviewing those highlights for assessment of locally advanced rectal cancer. So following that, Dr. Gholami, what does the panel recommend regarding total neoadjuvant therapy and standard neoadjuvant chemotherapy for patients with proficient mismatch repair or microsatellite stable tumors? Dr. Sepideh Gholami: Yeah, thanks so much for that question, Brittany. I would say that the guidelines really provide a lot more details, but in general, the consensus was that TNT should be offered as really initial treatment for patients with low rectal locally advanced rectal cancers or those who have higher risk for local and distant metastases. Those risk factors included anyone with either T4 disease, extramural vascular invasion and/or tumor deposits identified on the MRI for any threatening of the mesorectal fascia or the intersphincteric plane. Brittany Harvey: Excellent. So then, Dr. Gholami just discussed who should be offered TNT. But Dr. Scott, what are the recommendations regarding timing of TNT? Dr. Aaron Scott: So the way I take this question, think about this question, is a lot of the work that we put toward defining whether chemoradiation plus consolidation versus induction chemotherapy is the right choice, and there are a lot of implications to consider in this situation. The panel recognizes that the decision to proceed with chemoradiation followed by chemo versus chemotherapy followed by chemoradiation often depends on logistics regarding the time to treatment start, concern for distant metastases, and desire for local control that may impact surgical decision making. When we look at the subgroup analysis for overall survival of patients treated with TNT, it doesn't seem to matter which approach you take. Either induction or consolidation doesn't seem to have an impact on overall survival. However, there are other outcomes that may be of importance. Based on the CAO/ARO/AIO-12 randomized phase II trial, both pathologic complete response rates and sphincter sparing surgery were numerically higher with consolidation chemo. That said, there was no difference in disease free survival. So if you have a patient that really wants to consider some sort of sphincter sparing surgery, or a patient has a highly symptomatic disease burden, etc., these are patients that we would recommend starting with chemoradiation followed by consolidation chemotherapy. Brittany Harvey: Understood. And so you have both mentioned radiation included in treatment regimens. So Dr. Gholami, what is recommended in the neoadjuvant setting? Short course radiation or long course chemoradiation? Dr. Sepideh Gholami: Yeah, we actually had a really long discussion about this, but I think in general the consensus was that if radiation is included in any patient's treatment plan, neoadjuvant long course chemoradiation is preferred over short course RT for patients with locally advanced rectal cancer. And really the recommendation was based on the long term results that we've seen from the RAPIDO phase 3 clinical trial, which showed a significant higher rate of five year local regional failure with a total neoadjuvant approach with short course of 10% compared to the standard chemo RT with only 6% of the local recurrence rate. So that's why they opted for the long course, if the patients can actually tolerate it. Brittany Harvey: Excellent. I appreciate reviewing the recommendation and the supporting evidence that the panel reviewed to come to those recommendations. Then following that, Dr. Scott, for those patients who have a complete clinical response after initial therapy, what is recommended regarding nonoperative management? Dr. Aaron Scott: First, I would like to just say that this is really an area that still remains somewhat controversial and needs more investigation to best select patients for this approach. This topic was not systematically reviewed for the ASCO guideline. However, the expert panel was surveyed and most agreed with the time interval used in the OPRA phase 2 trial, which assessed patients for clinical complete response within eight weeks plus or minus four weeks after completion of TNT. Expert panel members and reviewers noted that if the radiation therapy component of TNT is delivered first, then an eight week interval following subsequent chemotherapy may result in a prolonged period of no treatment and therefore a first assessment of this response in this scenario would occur on the earlier side of the recommended interval. If a near clinical complete response is noted, then reevaluation within eight weeks is recommended to assess for developing a clinical complete response. Brittany Harvey: Absolutely. That information is helpful to understand what is recommended regarding nonoperative management and clinical complete responses. Then the final clinical question, Dr. Gholami, for patients with tumors that are microsatellite instability high or mismatch repair deficient, which treatment strategy is recommended? Dr. Sepideh Gholami: Yeah, I think we really came up to summarize that in general, when there is no contraindication to immunotherapy, then patients with MSI high tumors should be really offered immunotherapy. The evidence for this recommendation was relatively low, though, just due to the small sample size of the data that's currently available. But we did want to highlight that the data is very promising, but a definitive recommendation by the committee should be validated in future larger clinical trials. Brittany Harvey: Absolutely. Well, thank you both for reviewing the highlights of these recommendations for each clinical question. Moving on, Dr. Scott, in your view, what is the importance of this guideline and how will it impact both clinicians and patients with locally advanced rectal cancer? Dr. Aaron Scott: This would be the first guideline through ASCO to spell out management options for locally advanced rectal cancer. This has largely been needed due to the increased number of phase II and III trials investigating the specific patient population that have investigated a variety of different TNT approaches and treatment combinations utilizing systemic therapy, radiation, and surgical treatment. So, in this guideline, we really set out to define what locally advanced rectal cancer is, have organized and analyzed impactful large randomized studies to address multimodality therapy, and have consolidated this information into what we consider a concise and generalizable approach to help clinicians and patients individualize their management based on specific clinical pathologic features of their cancer. Brittany Harvey: Yes, this has been a mountain of work to review all the evidence, consolidate it into a concise review of that evidence, and develop recommendations for best clinical practice for management of locally advanced rectal cancer. So then, finally, to wrap us up, Dr. Gholami, what are the outstanding questions regarding management of locally advanced rectal cancer? Dr. Sepideh Gholami: Yeah, I think I just want to reiterate, Brittany, what you mentioned, this was a tremendous amount of body work, and we really would like to thank the committee and everyone from ASCO to help us with creating these general guidelines. I think one of the outstanding questions really still remains is the use of circulating tumor DNA as a management tool for patients with rectal, locally advanced rectal cancer. And also, I think outside of what we can think of the straightforward populations to deduce from PROSPECT, be really interested to see what other patient populations, for example, could also potentially maybe avoid radiation therapy. And lastly, I think we really wanted to highlight that this guideline really focuses on the locally advanced, and it would be great to see future guidelines for early stage rectal cancer which will be forthcoming. Brittany Harvey: Definitely. We'll look forward to answering those outstanding questions and for upcoming guidelines on earlier stage rectal cancer. So, I want to thank you both so much for, as you said, the tremendous amount of work that went into these guidelines and thank you for taking the time to speak with me today, Dr. Scott and Dr. Gholami. Dr. Aaron Scott: Thank you. Dr. Sepideh Gholami: Thank you so much for having us. Appreciate it. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please read and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 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.
Management of Stage III NSCLC Rapid Update (00:08:02)
Dr. Megan Daly presents the latest rapid recommendation update to the ASCO management of stage III NSCLC guideline, based on data from the phase III randomized LAURA trial, presented at the 2024 ASCO Annual Meeting, and subsequently published. She discusses the results of the trial, shares the updated recommendation from the expert panel, and the impact for both clinicians and patients. We also discuss future research in the area and exciting new developments to watch out for in the field. Read the full rapid update, "Management of Stage III Non-Small Cell Lung Cancer: ASCO Rapid Guideline Update" at www.asco.org/thoracic-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-01324. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Megan Daly from the University of California Davis Comprehensive Cancer Center, lead author on, "Management of Stage III Non–Small-Cell Lung Cancer: ASCO Rapid Guideline Update." Thank you for being here today, Dr. Daly. Dr. Megan Daly: Thanks for having me, Brittany. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Daly, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to start us off on the content of this update, first, this guideline was updated based off new evidence presented at the 2024 ASCO Annual Meeting. Dr. Daly, could you describe the trial that prompted this rapid update to the management of stage III non-small cell lung cancer guideline? Dr. Megan Daly: The trial that prompted this update is the LAURA trial. The LAURA trial was a phase III randomized trial conducted in patients with unresectable stage III non-small cell lung cancer harboring EGFR mutations, either exon 19 deletions or L858R insertions. Patients in this trial were randomized 2:1 between the third generation EGFR tyrosine kinase inhibitor osimertinib or placebo, and osimertinib or placebo were continued until progression or other reasons for discontinuation. Osimertinib was found to provide a considerable benefit in progression free survival, with a hazard ratio of 0.16. The median progression free survival for patients randomized to osimertinib was 39.1 months, and for patients on the placebo arm, it was 5.6 months. We did not yet have overall survival data from the LAURA trial. The data is not mature, but the considerable progression free survival benefit noted with osimertinib has drawn a lot of interest to this trial. Brittany Harvey: Absolutely. Thank you for describing the results of those trials and the endpoints. So then, based on this new evidence, what is the updated recommendation from the guideline expert panel? Dr. Megan Daly: The updated recommendation from the panel is that patients with unresectable stage III non-small cell lung cancer with an EGFR exon 19 deletion or exon 21 L858R mutation may be offered consolidation osimertinib after definitive chemoradiotherapy, which can be either platinum-based chemotherapy and thoracic radiation given either concurrently or sequentially. Our evidence quality is moderate and the strength of the recommendation is strong. Brittany Harvey: Great. And thank you for reviewing both the strength of the recommendation there as well as the evidence quality rating. So it's great to have this new option for patients. So what should clinicians know as they implement this new recommendation? Dr. Megan Daly: I think it's important for clinicians to know when they're counseling patients about considering osimertinib to understand that first, the LAURA trial enrolled patients who had common EGFR mutations. So exon 19 deletions or L858R mutations. Patients with other uncommon EGFR mutations were not included in the trial. It's important to know that overall survival data is not yet mature. We do not know yet whether the use of consolidation osimertinib leads to a survival benefit at this time. We only know that it leads to a progression-free survival benefit as compared to placebo. I think it's also important to know that there was increased toxicity noted on the experimental arm. Grade 3 or higher adverse events was significantly higher with the use of osimertinib. So these are all important considerations when counseling patients and considering the use of osimertinib. Brittany Harvey: Absolutely. Those are definitely key points, as you mentioned, to consider. And you've already touched on this a little bit. But how does this change impact patients living with stage III non-small cell lung cancer? Dr. Megan Daly: We do see in the LAURA trial a rather remarkable benefit for progression-free survival. The progression-free survival, as I already mentioned, increased from 5.6 months median on the control arm to 39.1 months on the experimental arm with consolidation osimertinib. So this is an exciting new option for patients with unresectable stage III non-small cell lung cancer who have one of these mutations to extend their progression-free survival by almost three years. And we hope that this progression-free survival benefit will end up translating into a considerable overall survival benefit as well. So, certainly, the overall survival data is eagerly awaited. Brittany Harvey: Definitely, this is a promising option for patients, and we look forward to future readouts of long-term data on this trial. So that's one of the outstanding questions here. But what other outstanding questions are there regarding the management of stage III non-small cell lung cancer? Dr. Megan Daly: I think what many of us question when we look at this data is whether we could extrapolate to the use of other targeted agents with other less common oncogenic driver mutations. Unfortunately, the answer is we simply don't know yet. We hope to see some ongoing data in the resectable setting. Doing randomized trials with rare oncogenic drivers in unresectable stage III lung cancer is very difficult, unfortunately, and there's always a degree of extrapolation for clinicians when trying to figure out how to best manage our patients. But for me, that's one of the biggest outstanding questions I think specifically ties into interpreting the LAURA trial and other related trials in patients with oncogenic driver mutations. I think there's still many outstanding questions about how we continue to improve outcomes for our patients with unresectable stage III non-small cell lung cancer, questions about how we optimize our radiation regimens to have the best possible local control while reducing toxicity. We still need to continue to have randomized trials looking at questions on optimizing radiation, optimizing concurrent chemotherapy, whether there are any settings where we might be able to reduce or omit chemotherapy in place of some of these newer agents. These are all outstanding questions that hopefully will be answered over the next several years. We also continue to have open questions about when patients are more appropriate for surgery and more appropriate for non-surgical options, those borderline patients with N2 nodes who may technically be surgical candidates or could potentially be downstaged with neoadjuvant therapy. So, I think there's a lot of exciting work going on in stage III right now. Brittany Harvey: Absolutely. We'll look forward to that more data that you mentioned for more optimal individualized options for these patients with stage III non-small cell lung cancer. And I want to thank you so much for your time to rapidly update this guideline based off new evidence presented and then published. And thank you for your time today, Dr. Daly. Dr. Megan Daly: Thank you, Brittany. It's great to be on here. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions 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.
