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. 

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. 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."

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. 

An interview with Dr. Jarushka Naidoo from Johns Hopkins University, author on "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update." She discusses the identification, evaluation, and management of lung toxicities in patients receiving ICPis, focusing on pneumonitis in Part 5 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network-- a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Jarushka Naidoo from Johns Hopkins University in Baltimore, Maryland, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And, today, we're focusing on lung toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Naidoo.

JARUSHKA NAIDOO: Thank you. It's my pleasure to share updates on this guideline.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with a publication of the guidelines in the Journal of Clinical Oncology. Dr. Naidoo, do you have any relevant disclosures that are directly related to these guidelines?

JARUSHKA NAIDOO: Yes. So I have research funding in the last two years from Merck, AstraZeneca, and Bristol Myers Squibb. And I also have served in a consulting role-- or an advisory board capacity-- for Merck, AstraZeneca, Bristol Myers. And not specifically related to this work, but also Pfizer, Takeda, Daiichi Sankyo, and Kaleido Biosciences.

BRITTANY HARVEY: OK. Thank you for those disclosures. Then-- getting into the content of this guideline-- what are the immune-related lung toxicities addressed in this guideline?

JARUSHKA NAIDOO: Thanks, Brittany. So the main lung toxicity that is addressed in this guideline is immune checkpoint inhibitor pneumonitis, which-- as this audience knows-- is an uncommon, but potentially fatal toxicity particularly associated with anti-PD-1 or PD-L1 monotherapy, but can also occur with combination immunotherapy approaches.

In the guideline, we go through what is known about the natural history, risk factors, and then, of course, our comprehensive approach to identifying, evaluating, and managing this toxicity, which is defined as a focal or diffuse inflammation of the lung parenchyma.

We also identify that, while pneumonitis is the quintessential lung toxicity that can occur with immune checkpoint inhibitors, we also note that there are some other lung toxicities that have been reported on, but for which known we relatively little.

And this includes sarcoid-like granulomatous reactions, including subpleural micronodular opacities and hilar lymphadenopathy, as well as pleural effusions. And these have been associated with both CTLA-4 and the PD-1, PD-L1 immune checkpoint inhibitor therapies.

BRITTANY HARVEY: I appreciate that overview. So then, you mentioned the main toxicity here is pneumonitis. What are the key recommendations for identification, evaluation, and management of pneumonitis?

JARUSHKA NAIDOO: Thanks, Brittany. So yeah, this is a key focus of the guideline. So, as we're aware, pneumonitis is defined as a focal or diffused inflammation of the lung parenchyma and is a toxicity that was identified as one of the early toxicities in the early clinical trials of the PD-1 inhibitors.

The incidence of this toxicity is estimated at anywhere between 0% and 10%, and in large meta analyses, looks to be around 2% to 3% in terms of incidence. In terms of how to evaluate patients with suspected immune-related pneumonitis, the common symptoms would be cough, shortness of breath, fever, and chest pain.

And in a patient who has suspected pneumonitis, some of the first tests to be done would be to take a pulse oximetry and to do some chest imaging. Chest imaging is preferable with a CT scan with contrast in order to rule out alternative etiology, such as pulmonary embolus

For patients who are symptomatic-- which means CTCAE grade 2 or greater-- we also recommend a standard infectious workup, which is guided by institutional guidelines. But based on our ASCO guideline, we outline that this should include, at a minimum, a nasal swab, sputum culture and sensitivity, blood culture and sensitivity, and urine culture and sensitivity, as well as a standard COVID-19 evaluation.

When we come to the diagnosis of pneumonitis, we then evaluate that in terms of CTCAE grade. Where the grade of pneumonitis refers, firstly, to whether a patient has symptoms, and the proportion of the lung parenchyma that may be involved with pneumonitis on chest imaging.

Broadly speaking, patients with grade 1 pneumonitis are asymptomatic and usually identified on radiographic imaging almost incidentally. For these patients, we would recommend either holding immunotherapy or proceeding with close monitoring.

And we recommend that patients should have weekly physical exams and pulse oximetry offered, and consideration of further chest imaging if the diagnosis is uncertain, or to follow progress-- usually around every three to four weeks-- or, if a patient becomes symptomatic, it may be more often than this.

We also recommend that we may consider doing spirometry or DLCO evaluation as a repeat in these patients. Broadly, again, in terms of the evaluation of patients-- if patients are symptomatic from pneumonitis, which means they have a symptom related to radiographic features, then this would be called grade 2.

And usually, radiographically, patients have more of the lung parenchyma involved-- greater than 25%-- and require a medical intervention. And the management would be prednisone, 1 to 2 milligrams per kilogram per day, that is then tapered over 4 to six weeks, and immunotherapy is held during that time.

Importantly, in order to knuckle down the diagnosis of pneumonitis, we recommend consideration of doing a bronchoscopy with bronchoalveolar lavage sampling in order to truly rule out alternative infectious diagnoses or lymphangitis carcinomatosis. And for this reason, a transbronchial biopsy can also be considered. In some cases, we also consider treating with empiric antibiotics to cover infection if we feel that this remains in the differential diagnosis.

If patients do not clinically improve after 48 to 72 hours on prednisone, then we recommend treating at a higher grade, meaning grade 3, where patients have severe symptoms, hospitalization is required, and a larger proportion of the lung parenchyma is involved.

For these patients who have grade 3 or greater pneumonitis, we recommend permanently discontinuing immunotherapy, administering a higher dose of steroids at methylprednisolone, 1 to 2 milligrams per kilogram per day. And, once again-- if there is no improvement after 48 hours, we recommend a range of potential additional immunosuppressive approaches, which include either infliximab, mycophenolate mofetil, intravenous immunoglobulin, or cyclophosphamide.

And there are currently no recommendations as to which may be the optimum immunosuppressive approach, but there are a number of clinical trials aiming to elucidate the answer to this. Importantly, overall in patients who are symptomatic, it may also be appropriate to consult pulmonary medicine and infectious diseases teams to weigh in on the diagnosis and management going forward.

BRITTANY HARVEY: Great. Thank you for that clear, step-wise approach to the evaluation and management of pneumonitis. So then, in your view, Dr. Naidoo-- how will these recommendations for the management of lung toxicities impact both clinicians and patients?

JARUSHKA NAIDOO: I think it's very important for both clinicians and patients to be aware of the potential side effects of the treatment that patients are receiving with immune checkpoint inhibitors. We know that some toxicities from immunotherapy tend to be mild and can be managed quite well with corticosteroids or other approaches.

What we understand about lung toxicities is that, thankfully-- in the majority of cases-- pneumonitis will be well-controlled with corticosteroids and holding of immunotherapy. However, in a proportion of patients, pneumonitis may become severe and may even lead to treatment-related deaths.

And for that reason, both patients and clinicians need to be aware of what to look out for in terms of the symptoms of pneumonitis, and how to diagnose and manage this toxicity quickly and efficiently in order to avoid poor outcomes.

BRITTANY HARVEY: Absolutely. Those are excellent points for both clinicians and patients to keep in mind. So I really want to thank you for all of your work on these guidelines and for taking the time to speak with me today, Dr. Naidoo.

JARUSHKA NAIDOO: You're very welcome, Brittany. And thank you to the ASCO oncology community for the opportunity to share this important work.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive-care-guidelines. 

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

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An interview with Dr. Yinghong Wang from MD Anderson Cancer Center, author on "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update." She discusses the identification, evaluation, and management of gastrointestinal toxicities in patients receiving ICPis, including colitis and hepatitis in Part 4 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey. And today, we're continuing our series on the management of immune-related adverse events.

I am joined by Dr. Yinghong Wang from the University of Texas MD Anderson Cancer Center in Houston, Texas, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on gastrointestinal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Wang.

YINGHONG WANG: Thank you, Brittany. It's my great pleasure to be invited to participate in this education event. I'm happy to share my experience and the knowledge that I learned over all the research studies in this field and share with the readers or the community providers on this specific topic.

BRITTANY HARVEY: Great. Thank you. Then, first, before we get into the content, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Wang, do you have any relevant disclosures that are directly related to these guidelines?

YINGHONG WANG: I do have consulting services to two pharmaceuticals, but they're not related to the current guidelines that are published from the ASCO. They're Tillotts Pharma and Athenex Pharma.

BRITTANY HARVEY: OK. Thank you. Then, let's talk about these gastrointestinal toxicities. So first, what are the immune-related gastrointestinal toxicities addressed in this guideline?

YINGHONG WANG: So these particular guidelines have provided very detailed description on the incidence and clinical presentations and also recommendations on the evaluation and treatment for the upper and the lower gastrointestinal adverse events and the liver and even other organ toxicity, including the exocrine pancreas toxicities that are being categorized as GI field related to checkpoint inhibitor treatments.

BRITTANY HARVEY: OK. And then what are the key recommendations for the identification, evaluation, and management of colitis?

YINGHONG WANG: So colitis is definitely one of the most common organ to be involved in this category of toxicity-related checkpoint inhibitors. And that's why a lot more studies have been studied because the patient volume can allow enough power to run a lot of analysis. I think the summary that I would say-- the recommendations from the current ASCO Guidelines include the early recognition and evaluation with close monitoring for people who had suspicious symptoms for gastrointestinal adverse events and early stool inflammatory marker evaluation even in patients who had grade 1 symptoms. And very important to rule out alternative causes of the symptom presented, like infections or cancer metastases or some other medication-related side effects other than checkpoint inhibitors.

And the other important component of evaluation is endoscopy and the pathological evaluation for patients who had a positive stool inflammatory markers or if the patient has a presentation of colitis symptoms like bleeding. And also, the presence of ulcers on the endoscopy usually has been found to predict a steroid refractory disease course. Therefore, the early initiation of more potent treatment like biologic agents, such as infliximab or vedolizumab, is very critical. The other alternative medical treatment, like ustekinumab or tofacitinib or even fecal transplantation for refractory cases, should also be considered in the small portion of patients.

The disease monitoring while on the medical treatment is critical via the repeat endoscopy or following the fecal calprotectin level to guide the duration of treatment and the time to resume immune checkpoint inhibitor treatments if indicated. The rechallenge of these checkpoint inhibitors is possible among patients with GI toxicities, and the risk of GI toxicities is completely manageable. That's the brief summary of the GI recommendations.

BRITTANY HARVEY: Yeah. Thank you for that summary. And then just in addition to those key recommendations, is there anything additional about the identification, evaluation, and management of hepatitis?

YINGHONG WANG: Yeah. The hepatitis-- the incidence is not as common as colitis but can be severe in extreme cases. So it requires the equal attention to recognize and evaluate for liver toxicity after checkpoint inhibitors with close monitoring. We also need to rule out other alternative causes of the symptoms, including the infections, alcohols, iron overload, thromboembolic events, cancer metastases, et cetera. The imaging, on the other hand, is more critical for liver toxicity evaluation. This is a little bit different from using the endoscopy and biopsy for luminal GI tract toxicities. And the liver biopsy should also be considered in certain select cases through all other differential diagnosis and also the other alternative treatment other than corticosteroid, including azathioprine and mycophenolate mofetil, that are mentioned in the small case series and also listed in the current ASCO Guidelines.

BRITTANY HARVEY: Great. Thank you for that overview for both colitis and hepatitis. So then, in your view, how will these recommendations for the management of gastrointestinal toxicities impact both clinicians and patients?

YINGHONG WANG: Yeah. Given the increasing volume of patients experiencing the GI adverse events related to the checkpoint inhibitor cancer therapies and their related morbidities, so both the clinicians and patients need to be familiar with the clinical presentations and the time frame of onset to ensure early recognition and early diagnosis, especially serious complication and even mortality can occur due to the significant delay in appropriate treatment in extreme cases. So the updated guideline provided by ASCO and also other professional societies in the US or internationally can provide a great resources to the academic and community clinicians when they encounter these cases in their practice.

So ultimately, the implementation of appropriate management and future prospective clinical trials in this field for these challenging conditions should improve the patient's outcome of toxicities and also cancer. And that's the goal of our clinicians and academia providers, to be able to serve the patient better in the future.

BRITTANY HARVEY: Definitely. Well, thank you for sharing this summary with us today, for all of your work on these guidelines, and for taking the time to speak with me today, Dr. Wang.

YINGHONG WANG: Thank you very much for this opportunity. Please let me know if you have any questions.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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An interview with Dr. Milan Anadkat from Washington University & Dr. Aung Naing from MD Anderson Cancer Center, authors on "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update." They discuss recommendations for cutaneous toxicities in patients receiving ICPis, including rash, bullous dermatoses & SCAR in Part 3 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey. And today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Milan Anadkat from Washington University in St. Louis, Missouri. And Dr. Aung Naing from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, authors on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.

And today, we're focusing on cutaneous toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here Dr. Anadkat and Dr. Naing.

AUNG NAING: Thank you for having us.

MILAN ANADKAT: Thank you.

BRITTANY HARVEY: I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Anadkat, do you have any relevant disclosures that are directly related to these guidelines?

MILAN ANADKAT: As listed in the document, I don't have any direct disclosures. I do have a number of indirect disclosures, as I've consulted on similar topics in the past.

BRITTANY HARVEY: Thank you. Then Dr. Naing, do you have any relevant disclosures that are related to these guidelines?

AUNG NAING: I do not have.

BRITTANY HARVEY: Great, then let's get into the content of this guideline and the cutaneous toxicities that we're here today to talk about. So Dr. Naing, what are the immune-related cutaneous toxicities addressed in this guideline?

AUNG NAING: Well, with the advancement of immunotherapy, we've seen better response in our cancer patients. However, together with such positive outcomes, we are also seeing side effects caused by the immunotherapy. Disruption of the homeostatic mechanisms include a unique spectrum of side effects or immune related adverse events, commonly called IRAEs. The most common immune related adverse events in patients receiving checkpoint inhibitors are dermatitis, enterocolitis, transmitis, and endocrinopathies.

However, if you look at the most commonly reported IRAE of any grade, it is dermatologic toxicity. So here in this guideline, we addressed how to take care of the patients when they are having these side effects, particularly with the cutaneous toxicities. So when you look at that time to median onset of skin toxicities, it ranges from two to five weeks. And using CTCAE criteria for grading is a challenge for skin toxicity, as it may not reflect the true picture.

So, therefore, severity may be graded based on body surface area, tolerability, mobility, and durations. Those are the points also we discuss in this guideline. Broadly speaking, they are three groups of cutaneous IRAEs. They are rash inflammatory dermatitis, bullous dermatoses, and finally, Severe Cutaneous Adverse Reactions, SCAR. It is important to have thorough physical exam and rule out any other etiology of skin problems.

In general, it's also important to work closely with our colleagues from dermatology. While some of those low grade skin toxicities could be treated in outpatient setting, consulting the cases with dermatologists is important for higher grades of skin toxicities, such as bullous dermatoses and SCAR. My colleague, Dr. Milan Anadkat, will follow with a discussion on the role of dermatologists in taking care of patients with cutaneous toxicities caused by immunotherapy.

BRITTANY HARVEY: Thank you, Dr. Naing for reviewing those. So then you just mentioned three categories of toxicity. And I'd like to review the key recommendations for each. So Dr. Anadkat, starting with what is recommended for the identification, evaluation, and management of rash or inflammatory dermatitis?

MILAN ANADKAT: Thank you, Brittany. And thank you Dr. Naing for teeing up this discussion. I think, as was mentioned, there are three major categories of cutaneous toxicity that are seen from immunotherapy. By and large, the most common is rash or inflammatory dermatitis, from which there are multiple different phenotypes or looks by which physicians may be seeing.

The most common phenotypes within rash or inflammatory dermatitis, which account for over 90% of the cutaneous toxicity seen from immunotherapy, include lichenoid, which is a purple, flat topped bumpy rash that can involve the skin or the mucosal membranes. The psoriasiform, which resembles psoriasis, morbilliform, or oftentimes, maculopapular, which resembles a measles-like pink exanthem over the trunk, or generalized eczema and itching. So what's important is identifying the particular phenotype and categorizing it as an inflammatory dermatosis and excluding the other two phenotypes of cutaneous toxicity, such as bullous dermatoses or Severe Cutaneous Adverse Reactions.

BRITTANY HARVEY: Great, and then moving into that second category that you both mentioned, what are the key recommendations for bullous dermatoses?

MILAN ANADKAT: And so the key phenotypes for bullous dermatoses, by and large, is bullous pemphagoid, which is the most common phenotype seen in this category. Although other phenotypes resembling autoimmune bullous diseases, such as pemphigus or bullous drug reactions may also be seen. With bullous pemphigoid we see tense blisters, or tense bullae, frequently overlying a bed of erythema on the skin. Patients typically complain of considerable itching, far more than pain, with this category of eruption.

BRITTANY HARVEY: Got it. Thank you for reviewing that for bullous dermatoses. So then the third group is Severe Cutaneous Adverse Reactions. So what are the key recommendations there?

MILAN ANADKAT: And so the third group, being Severe Cutaneous Adverse Reactions, is a term used worldwide to encompass conditions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and DRESS or drug reaction with eosinophilia and systemic symptoms. These are, fortunately, rare, but can be life threatening skin eruptions.

They account for less than 1% of all skin reactions seen from immunotherapy. When practitioners are approaching a patient who may potentially have one of these conditions, patients typically will exhibit symptoms of malaise, fatigue, fever, and a dramatic cutaneous eruption, which will either present with peeling or sloughing of the top layers of the skin, or a generalized erythema covered with multiple sterile pinpoint pustules. Oftentimes, there are associated symptoms of lymphadenopathy and organ toxicity that is noticed simultaneously, such as hepatotoxicity, or eosinophilia, or acute renal failure.

BRITTANY HARVEY: Great, I appreciate you reviewing the identification of all three of those groups. So then I'd like to hear from you both on this last question. But in your view, how will these recommendations for the management of cutaneous toxicities impact both clinicians and patients?

AUNG NAING: I would say that recognition of the toxicity is really important, particularly if you can actually catch the toxicity when it is in the mild grade. If you take care of them, then you can actually stop them from being mild to severe toxicity. That's number one. Number 2 is in that way, we may not have to halt or stop the immunotherapy treatment that could be beneficial to the patients.

And also, working together with the dermatologists is very important, because as I discussed earlier, some of them, we could take care of as an outpatient. But there will be certain dermatology toxicities, where we need to work closely with our dermatologists. And please also remember that these are the guidelines. You will be seeing the patient in the setting. So I think using that guideline and clinical judgment, that would actually help our patients at large.

MILAN ANADKAT: I think that's excellent. One, I think, important aspect of these guidelines is not only to correctly identify the phenotypes of cutaneous toxicity, but as Dr. Naing mentioned, it assists in management of these toxicities. The goal of these guidelines, especially as it pertains to the skin toxicity, is to accurately identify what toxicity is occurring for the patient, but then more importantly, to guide on appropriate management strategies to allow the patient to continue on immunotherapy and minimize or avoid unnecessary treatment interruption or treatment discontinuation.

The guidelines assist in management strategies according to the severity by which patients present. And as mentioned, I think ultimate priority will be given to the practitioner directly treating the patient. But consideration towards not only extent of body surface area involved, but severity of cutaneous eruption is thoroughly reviewed. And in addition to phenotype, including such patient reported outcomes, such as degree of pain, itch, or interruption on activities of daily living help guide the degree of management that can be provided.

BRITTANY HARVEY: Those are excellent points. I want to thank you so much for your work on these guidelines and for taking the time to speak with me today, Dr. Naing and Dr. Anadkat.

AUNG NAING: Thank you.

MILAN ANADKAT: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe, so you never miss an episode.

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An interview with Dr. Bryan Schneider from the University of Michigan Health System and Dr. Kathryn Bollin from Scripps MD Anderson Cancer Center, co-chairs of the Management of Immune-Related Adverse Events Guideline Expert Panel. They discuss an overview of the "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update" in Part 1 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and I want to introduce you to our series on the Management of Immune-Related Adverse Events. ASCO has developed two guidelines for the management of immune-related adverse events, one for patients treated with immune checkpoint inhibitor therapy and a second for patients treated with CAR T-cell therapy.

Today, we'll be focusing on an overview of the Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. And we'll have authors join us for future episodes to discuss the key recommendations for organ-specific management for patients treated with immune checkpoint inhibitor therapy and an episode to discuss the management of immune-related adverse effects in patients treated with CAR T-cell therapy.

Today, I am joined by Dr. Bryan Schneider from the University of Michigan Health System in Ann Arbor, Michigan, and Dr. Kathryn Bollin from Scripps MD Anderson Cancer Center in San Diego, California, co-chairs on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy, ASCO Guideline Update and authors of the Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy, ASCO Guideline. Thank you for being here, Dr. Schneider and Dr. Bollin.

BRYAN SCHNEIDER: Thank you, Brittany.

KATHRYN BOLLIN: Thank you for having us.

BRITTANY HARVEY: I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Schneider, do you have any relevant disclosures that are related to this guideline?

BRYAN SCHNEIDER: I have research funding to my institution from Bristol Myers Squibb and Genentech Roche at the time of panel formation.

BRITTANY HARVEY: Thank you. And, Dr. Bollin, do you have any relevant disclosures that are directly related to this guideline?

KATHRYN BOLLIN: No disclosures.

BRITTANY HARVEY: Thank you. Then, let's talk about this guideline. So first, Dr. Schneider, what prompted this update to the Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy Guideline last published in 2018?

BRYAN SCHNEIDER: Yeah. The previous guideline was widely used and consistently one of the top read articles of the JCO over the last couple of years. And since the original guideline publication in 2018, new data have emerged on the management of immune checkpoint inhibitor toxicities. So our goal was to build on the original guideline with more treatment options, especially for patients who fail initial steroid treatment. New strategies have developed for the management of many toxicities, especially GI, cardiac, and heme toxicities. And ASCO and the panel felt it was important to present these new options to the providers in the community.

We also wanted to add sections that the providers would find valuable, including a table with many of the immunosuppressive agents used with typical dosages and schedules. We also added a table of commonly conducted testing while patients are on high-dose steroids as this is something many medical oncologists may not be used to handling as we typically do not have patients on steroids at high doses for several weeks or even months.

BRITTANY HARVEY: Understood. Then, in addition to those updates that Dr. Schneider just mentioned, Dr. Bollin, what is the general scope and purpose of this guideline?

KATHRYN BOLLIN: Yes. So the immune-related adverse event management guideline update and the CAR T-cell toxicity guideline serve to provide physicians that are prescribing these therapies with an understanding of the wide range of known potential toxicities of these agents and the best available evidence-based and expert opinion recommendations for their management. So up to 70% of patients treated with immune checkpoints will experience some form of immune-related adverse event, and nearly all patients getting CAR T-cell therapies experience toxicity. So recognition of the occurrence of these toxicities and appropriate management are essential for optimizing patient outcomes.

BRITTANY HARVEY: Definitely, those are key points. So then, Dr. Schneider, what are the overarching recommendations for the management of immune-related adverse events irrespective of the affected organ?

BRYAN SCHNEIDER: I think early recognition of the side effect is critical. So the guideline has typical signs and symptoms of each toxicity to help clinicians decide if this is occurring in their patients. Second, I think it's critical to grade the toxicity. We often don't do that with side effects related to traditional chemotherapy outside of clinical trials. So for example, if a patient has a platelet count of 75, I can't think off the top of my head what grade that is. I just know I'm going to hold chemotherapy for a week or two. But grading of the toxicity of these immune checkpoint therapies really is very important to decide whether patients can just be watched, whether they need to start steroids or whether they need to be admitted.

I think still corticosteroids and dose holds are the first steps that clinicians will do. The majority of these toxicities-- although it would be nice if we could personalize the treatment based on the particular side effect and what we see under the microscope if the particular affected organ is biopsied, I think, in broad strokes, corticosteroids can be implemented easily, and a lot of our oncologists can be comfortable doing this potentially without subspecialty help.

Having said that, I think multidisciplinary care is a must for the higher-grade side effects as, in oncology, we can't pretend to also be cardiologists, gastroenterologists, neurologists, dermatologist, and so on. And although there may be varying degrees of comfort from our subspecialists regarding the management of these toxicities, we do need their help for shared decision making, especially for the steroid refractory toxicities. We always want to emphasize a slow steroid taper oftentimes over at least four to six weeks. We get into trouble when we try to get them off the steroid quickly because they do have side effects that the patient may not enjoy. But oftentimes, we try to taper them quickly, and the side effect comes roaring back.

And then, finally, to escalate immunosuppression quickly if no improvement with high-dose steroids is observed, oftentimes, that's done even within just a few days. But commonly, in practice, there's still hope that the steroid will kick in two or three weeks down the road, and that's not a good strategy. If the patient's having significant symptoms and steroids aren't helping, they do need to go on to a more important immunosuppressant.

BRITTANY HARVEY: Those are important notes on the overarching management, particularly on how the adverse effects are different than those in patients treated with chemotherapy and the importance of multidisciplinary care. So then, Dr. Bollin, in your view, how will this guideline impact clinical practice?

KATHRYN BOLLIN: So the impact of this guideline update is actually very broad. As with the previous guideline, as Dr. Schneider alluded to earlier, it's been very frequently accessed by readers since it offers symptom outlines and algorithmic recommendations for early identification and the management of immune-related adverse events based on the severity and organ system involved. What's really important to understand is that while initially, as hematology-oncology physicians prescribing these agents, we're doing so in the setting of early phase clinical trials. We were learning about the toxicities, and those physicians were often managing the toxicities themselves. But now, with the exponential increase and the therapeutic indications for immune checkpoint therapies in cancer, the experience with the toxicities and their management and the questions have also followed suit with an exponential rise.

With this guideline update, we have experts among all of the internal medicine subspecialties that are now guiding the hematology-oncology physicians in immune-related adverse event management. We enlisted the experts in crafting this guideline update. So in summary, this serves not only as a tool for the prescribing hematology-oncology physicians but also for all of the subspecialists in the community and within academic centers for optimizing patient outcomes in the setting of immune-related adverse events.

BRITTANY HARVEY: Great. Yeah, it sounds like this update will be hugely important for practicing clinicians. So then, in addition to those points raised by Dr. Bollin, Dr. Schneider, what are the implications for patients receiving immune checkpoint inhibitor therapy?

BRYAN SCHNEIDER: So we really hope this will be an essential tool to help providers quickly treat patients when these toxicities present. Often, this is unexpected, and busy clinicians may be blindsided by these issues. So these guidelines will provide a quick resource to guide the workup and formulate a treatment plan that will expedite patient recovery. And ultimately, this should help promote quality of life for patients on these therapies and may help reduce trips to the emergency department, hospitalizations, and potentially allow the safe rechallenge of immune checkpoint therapy after resolution of the side effect.

Many centers have the advantage of subspecialty support with experience in managing these toxicities. But for providers who may not have immediate access to, say, hepatology or endocrinology, we hope these guidelines will help the oncology providers provide the best treatment to facilitate the optimal clinical outcome.

BRITTANY HARVEY: Absolutely, those are key for optimal care. Then, finally, Dr. Bollin, looking toward the future, what are the important outstanding questions and developing areas of research for the management of immune-related adverse events?

KATHRYN BOLLIN: So while our recognition of immune-related adverse events, the testing for them, and management strategies have greatly improved with the expanded use of and experience with these therapies, large gaps in our knowledge remain. Translational and basic science research efforts are underway to understand these gaps, such as with the intrinsic and extrinsic drivers of autoimmunity, such as those with HLA allelic variations and the microbiomes interplay with our immune systems.

There are also research efforts underway to develop rapid diagnostic tests to deploy early in the onset of irAE signs and symptoms and for the development of biomarkers and modeling tools that will aid us in predicting which patients are likely to experience immune-related adverse events. There have also been some interventional protocols that have attempted to prevent these immune-related adverse events by incorporating immune suppressants along with therapeutic agents. But so far, promising results with this strategy remain elusive.

In regard to treatment for immune-related adverse events, investigators are working to learn the best strategies for selective immune suppression rather than just the use of glucocorticoids that will control immune-related adverse events while maintaining the clinical benefit of these incredible anticancer therapies.

BRITTANY HARVEY: Thank you for highlighting those research gaps and both of you for your efforts to lead this guideline update. We'll be joined by authors on the guideline over the next episodes to review the key recommendations for organ-specific management in patients treated with immune checkpoint inhibitors and to review the recommendations for patients receiving CAR T-cell therapy. Stay tuned for these episodes highlighting the sections of the guidelines. And thank you for your time today, Dr. Schneider and Dr. Bollin.

KATHRYN BOLLIN: Thank you so much.

BRYAN SCHNEIDER: Thank you.

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

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An interview with Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center and Dr. Monalisa Ghosh from the University of Michigan Health System, authors on "Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline." They discuss recommendations for management of irAEs in patients treated with CAR T-Cell Therapy in Part 2 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

[MUSIC PLAYING]

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network. A collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today we're continuing our series on the management of immune-related adverse events. ASCO has developed two guidelines for the management of immune-related adverse events-- one for patients treated with immune checkpoint inhibitor therapy and a second for patients treated with CAR T-cell therapy.

In our last episode, you heard an overview of the Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Today, we'll be focusing on the Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline, and we'll have authors join us for future episodes to discuss the key recommendations for organ-specific management for patients treated with immune checkpoint inhibitor therapy.

Today, I am joined by Dr. Monalisa Ghosh, from the University of Michigan Health System in Ann Arbor, Michigan and Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center in New York, New York, authors on both Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline and Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.

Thank you both for being here, Dr. Ghosh and Dr. Santomasso. In addition, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline.

The full Conflict of Interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Ghosh, do you have any relevant disclosures that are directly related to this guideline?

MONALISA GHOSH: No. I do not have any relevant disclosures.

BRITTANY HARVEY: Thank you. And, Dr. Santomasso, do you have any relevant disclosures that are directly related to this guideline?

BIANCA SANTOMASSO: Yes. I'd like to disclose that I've served as a paid consultant for Celgene, Janssen Pharmaceutical, and Legend Biotech for advising them on the topics of CAR T-cell therapy side effects.

BRITTANY HARVEY: Thank you. Then, getting into these immune-related adverse events-- first, Dr. Ghosh, can you give us an overview of the scope and purpose of this guideline?

MONALISA GHOSH: Sure. The purpose of this guideline is to offer expert guidance and recommendations on the management of immune-related adverse events in patients treated with chimeric antigen receptor or CAR T-cell therapy.

This guideline offers guidance on the diagnosis, evaluation, and management of the most common toxicities of CAR T-cell therapy, which includes Cytokine Release Syndrome-- or CRS-- and immune effector associated neurologic syndrome-- or ICANS.

As well as other potential, but less common toxicities, such as Hemophagocytic Lymphohistiocytosis-- or HLH-- B-cell aplasia, prolonged and recurrent cytopenias, Disseminated Intravascular Coagulation-- or DIC-- and infections.

BRITTANY HARVEY: Great. Thank you. Then, Dr. Santomasso-- looking at this guideline, there's a few overarching recommendations. So, what are those general recommendations for the management of immune-related adverse events in patients receiving CAR T-cell therapy?

BIANCA SANTOMASSO: Yes. The overarching recommendations are, really, first to recognize that these side effects exist. And that, as such, it's important to recognize that patients who develop these toxicities or side effects after CAR T-cell therapy need to be evaluated, or managed in, or transferred to a specialty center that has experience with the management of these toxicities.

They're new toxicities. This is a new therapy. And patients are increasingly going to be managed in, or treated in, the outpatient setting, and, as such, they need to remain within a short distance of the treating center for about four to eight weeks post-therapy, and they should then return to their treating center upon experiencing any toxicities.

Finally, as its flu season and infection season, it is recommended that inactivated influenza and COVID-19 vaccination be performed on patients and also family members as well. And any patient who does have an active infection, the CAR T-cell infusion should be delayed until that infection has been successfully treated or controlled.

I often make a final point, which is that the immunogenicity of and efficacy of COVID-19 vaccines is uncertain in these patients with these agents, but the potential benefits outweigh the risks and uncertainties for most patients.

BRITTANY HARVEY: Thank you. Those are important points for patients and treating clinicians. So then, Dr. Ghosh-- as you mentioned, this guideline addresses the seven most common CAR-T-related toxicities, and I'd like to review the key recommendations for each of those.

So let's start with, what are the key recommendations for identification, evaluation, and management of cytokine-release syndrome?

MONALISA GHOSH: Well, Cytokine Release Syndrome is one of the two major toxicities that occur immediately or within a short time period after infusion of CAR T-cells. We have defined Cytokine Release Syndrome, or CRS, as an immune-mediated phenomenon that's characterized by various symptoms that are indicative of immune activation and inflammation.

And patients may experience signs and symptoms that could include fever, hypotension, hypoxia, tachycardia, shortness of breath, rash, nausea, headache, and various other symptoms that are a little less common. These symptoms are caused primarily by the release of cytokines.

Cytokines are the messengers of the immune system, and most of them are released by bystander immune and non-immune cells. We know that the onset of Cytokine Release Syndrome is variable depending on the CAR T-cell product that's used, as well as the patient population that's treated.

But it generally occurs anywhere from two to seven days after infusion of CAR T-cells, and in some rare cases can occur even a little bit later. A standard grading system has been developed and grade CRS, or Cytokine Release Syndrome, based on three parameters-- fever, hypotension, or low blood pressure; and hypoxia or low oxygen levels.

CRS is primarily managed with IL-6 antagonists because IL-6 is an inflammatory cytokine that has been shown to mediate a lot of the systemic effects that we see from Cytokine Release Syndrome. And one of the treatments is the monoclonal antibody tocilizumab, which acts against-- or blocks-- the IL-6 receptor.

CRS that is refractory to tocilizumab is generally treated with steroids. Then there's limited experience with additional therapies, especially in the setting of CRS, that does not respond to tocilizumab or steroids. There are other anti IL-6 therapies available. For example, siltuximab, which binds to IL-6 itself rather than the IL-6 receptor. However, there have been no direct comparative studies of these agents. Anakinra, which is also an IL-1 receptor antagonist has also been shown to mitigate CRS in some CAR T-cell recipients that have high grade CRS.

BRITTANY HARVEY: OK. Thank you for reviewing those management strategies. So, following that-- Dr. Santomasso, what are key recommendations for identification, evaluation, and management of immune effector cell-associated neurotoxicity syndrome?

BIANCA SANTOMASSO: Sure. Immune Effector Cell-associated Neurotoxicity Syndrome-- also known as ICANS-- is the second most frequent severe toxicity that can be seen after CAR T-cell therapy. So, what is ICANS? These are transient neurological symptoms that occur in the days after infusion, most commonly with CD19 CAR T-cell therapy.

And the clinical manifestations of ICANS include encephalopathy, which is confusion, behavioral changes, expressive aphasia, or other language disturbance, change in handwriting or other fine motor impairment or weakness, and tremor and headache can also be seen.

In more severe cases, patients can become obtunded with a depressed level of consciousness or even develop seizures, and they may require a higher level of ICU care, such as intubation for airway protection. And in very rare cases, malignant cerebral edema may develop, which may be fatal.

ICANS can occur at the same time as Cytokine Release Syndrome, or can also occur several days after or shortly after CRS resolves, so it's important to have a high index of suspicion even after Cytokine Release Syndrome has resolved, but typically the side effects are self-limited and occur within the one month after infusion.

Most symptoms lasts between 5 and 17 days, and the time of onset duration and severity of ICANS may really vary depending on the CAR T-cell product used or the disease state of the patient. So, what do I mean by that? Patients with high disease burden seem to be at increased risk for severe ICANS, so kind of knowing the disease that the patient has and the burden of disease is important.

And then also there may be product-specific differences as well, so reviewing the product label is important as well because each may have its own risk evaluation and mitigation strategies that inform both the duration and the frequency of monitoring for ICANS after infusion.

For evaluation of ICANS, we recommend, again, the ASTCT ICANS grading system. These allow for monitoring of several different aspects of neurologic function in these patients. Mental status changes are really what define the onset of ICANS.

So for CRS, it's fever; for ICANS, it's mental status changes. And the severity of the mental status change can be determined by a standardized score known as the ICE score, which stands for Immune Effector Cell-associated Encephalopathy score.

This is a simple 10-point scoring metric where points are assigned for orientation to year, month, city, hospital, ability to name three objects, ability to follow simple commands, write a standard sentence, and count backwards from 100 by tens.

And for children younger than age 12 or those with developmental delay, The Cornell Assessment of Pediatric Delirium, also known as the CAPD, can be used in placement of the ICE assessment. Prior to CAR infusion, patients should be evaluated, including with an ICE score, for their baseline neurologic status.

And what's nice is that this ICE assessment can be used as a daily screen after CAR infusion for the onset of ICANS during at-risk period. Then, other than the ICE score, there are four other neurologic domains that contribute to ICANS grading, and that's level of consciousness, seizures, severe motor weakness, and signs and symptoms of elevated intracranial pressure or cerebral edema, and patients are graded according to the most severe symptom in any of the five domains.

So for patients who develop ICANS, it's recommended that they have workup, including blood work, CRP, CBC, comprehensive metabolic panel, fibrinogen, and coagulation tests. Neuroimaging with a non-contrast CT of the brain should be done and considering MRI of the brain in patients who are stable enough.

In addition, electroencephalogram and lumbar puncture should be considered. And the electroencephalogram is really to rule out subclinical seizures, and the lumbar puncture is to assess the opening pressure-- or the pressure within the central nervous system-- and also to send studies to rule out infection. And again, these all have to be considered on an individual case by case basis, but are things to keep in mind.

So for treatment of ICANS, the mainstay of treatment is, really, supportive care and corticosteroids. Tocilizumab, while it seems to rapidly resolve Cytokine Release Syndrome and most symptoms, actually does not resolve ICANS and may worsen it, so steroids are really typically used.

The typical steroid is dexamethasone at a dose of 10 milligrams, and the interval really depends on the grade of the ICANS. Because of the possibility that tocilizumab may worsen neurotoxicity, ICANS really takes precedence over low grade CRS when the two occur simultaneously.

And patients who don't show improvement within 24 hours after starting steroids or other supportive measures should have CSF evaluation and neuroimaging. Often treatment of seizures-- many patients are put on Keppra and levetiracetam or other anti-seizure medicine if they develop ICANS, and patients with grade 3 or greater ICANS may need an ICU level of care and escalation of steroid doses.

The steroids are continued until ICANS improves to grade 1 and then tapered as clinically appropriate. And the most important thing to remember is that ICANS just needs to be monitored very closely as patients may worsen as some steroids are tapered. They also may improve rapidly after steroids are started, so steroids should be tapered quickly as patients improve.

And, again, as with CRS, there's limited experience with other agents, such as Anakinra and siltuximab, but those could be considered in severe or refractory cases.

BRITTANY HARVEY: Understood. I appreciate you going through when and how clinicians should screen for ICANS and those key management points. So, in addition to that-- Dr. Ghosh, what are the key recommendations regarding cytopenias?

MONALISA GHOSH: So cytopenias can occur post-CAR T-cell infusion, and they can occur either in the early phase or in the later phase after CAR T-cell infusion. Meaning that they can occur early within the first few days to weeks post-CAR T-cell therapy or could even occur months to years later.

These cytopenias include anemia, thrombocytopenia, leukopenia, neutropenia. Many patients may present with fatigue, weakness, shortness of breath, lightheadedness, frequent infections, fevers, bruising, and bleeding, and the symptoms usually are consistent with how they would present otherwise with anemia, thrombocytopenia, or neutropenia.

Acute cytopenias within three months of CAR T-cell therapy are more common. This is due to usually the lymphodepleting chemotherapy that is administered prior to CAR T-cell therapy. Most patients receive a combination of fludarabine and cyclophosphamide prior to CAR T-cell infusion, or they may receive another agent, such as bendamustine. Most patients also come into CAR T-cell therapy with low lymphocyte counts from previous therapies.

Early cytopenias, as I mentioned, are generally due to lymphodepleting chemotherapy or other recent therapies. There also could be an immune-mediated process due to the CAR T-cells. Usually prolonged cytopenias which occur beyond three months post-CAR T-cell infusion can be seen in a small number of patients.

And the mechanism of prolonged cytopenias is really unclear at this time, but likely multifactorial. Most recipients of CAR T-cells who have prolonged cytopenias beyond three months post-CAR T-cell infusion should have a standard workup to rule out other common causes, such as vitamin or nutritional deficiencies.

They should also have testing such as bone marrow biopsy and scans to rule out relapse disease-- relapse lymphoma or leukemia, for instance, that could be causing these cytopenias. Other examples would be myelodysplastic syndrome or other bone marrow failure syndromes. So cytopenias are generally managed with supportive care including growth factor and transfusion support. This applies to both cytopenias in the early period post-CAR T-cell therapy or more delayed prolonged cytopenias.

In patients who have prolonged cytopenias of unclear cause that could be immune-mediated, other interventions such as high dose IVIG or even steroids could be considered depending on the situation. For those that have cytopenias in the first few months post-CAR T-cell therapy, generally they are monitored and treated with supportive care, and these cytopenias eventually resolve in the majority of patients.

BRITTANY HARVEY: Great. Those are important considerations. Then, Dr. Santomasso, what are the key recommendations regarding Hemophagocytic Lymphohistiocytosis?

BIANCA SANTOMASSO: The major recommendations for the identification, evaluation, and management of Hemophagocytic Lymphohistiocytosis, or HLH-- this is also known as macrophage activation syndrome. First, let's just start by saying that this is a dysfunctional immune response, and it's basically characterized by macrophages which are revved up and hyperactive and also possibly lymphocytes as well.

There are high levels of pro-inflammatory cytokines during this state and tissue infiltration, and hemophagocytosis, and organ damage. This can occur outside of the context of CAR T-cell therapy, either as a primary HLH or secondary HLH that can be either triggered by infections, or autoimmune disease, or cancer-- especially hematological malignancies, but HLH has also been observed as a rare complication of CAR T-cell therapy. And outside of the setting of CAR T-cell therapy, HLH is defined by fever, cytopenias, hyperferritinemia-- or high ferritin level-- as well as bone marrow hemophagocytosis.

And what's interesting is that this is very similar to what's seen during Cytokine Release Syndrome, and that can make it difficult for patients who have moderate to severe CRS to distinguish that from HLH. The laboratory results may be very similar. So the key to recognizing HLH is really to have it on your differential even though it occurs rarely after CAR T-cell therapy. It may occur with slightly different timing and may require more aggressive treatment.

The lab alterations can include, again, as I mentioned, these elevated levels of several cytokines, such as interferon gamma. We can't normally send those in the hospital or the clinic, but sometimes soluble IL-2 receptor alpha can be sent and serum ferritin can be sent, and that's an especially useful marker.

There have been diagnostic criteria for CAR T-cell-induced HLH that have been proposed, and these conclude very high ferritin levels-- over 10,000-- and at least two organ toxicities that are at least grade 3, such as transaminitis, increased bilirubin, renal insufficiency or oliguria, or a pulmonary edema, or evidence of hemophagocytosis in bone marrow or organs.

Unlike other forms of HLH that occur outside of the context of CAR T-cell therapy, the patients may not have hepatosplenomegaly, lymphadenopathy, or overt evidence of hemophagocytosis. So just because a patient may not show those yet doesn't mean that HLH shouldn't be considered.

If we see patients that have a persistent fever without an identified infection source or worsening fever, we basically should be considering HLH and doing the appropriate workup and treatment. Patients with HLH often have low fibrinogen, high triglycerides, and also cytopenias as well.

The treatment-- just as there's an overlap kind of in the signs and symptoms, the treatment and the clinical management overlaps as well with CRS, so tocilizumab is typically administered. But corticosteroids should really be added for these patients, especially if there's clinical worsening or grade 3 or greater organ toxicity.

And if there's insufficient response after 48 hours of corticosteroid therapy plus tocilizumab, many centers consider adding another medication such as Anakinra. I'll finally make a comment that, outside of the context of CAR T-cell therapy, HLH is sometimes treated with cytotoxic chemotherapy, such as etoposide.

This approach generally is not used as a first line for patients undergoing CAR T-cell therapy due to etopiside's documented toxicity to T lymphocytes. And generally, the corticosteroids, plus the anti IL-6 agent, plus Anakinra is considered the first line of management.

BRITTANY HARVEY: Got it. That's an important note on the management of HLH, and a great note on distinguishing CRS and HLH. So in addition, Dr. Ghosh-- what are the recommendations for management of B-cell aplasia?

MONALISA GHOSH: B-cell aplasia, it's a disorder that's caused by low numbers or absent B-cells. And this is particularly relevant to CD19 directed CAR T-cell therapy, which is what most of the CAR T-cell therapies that are available right now target. They target CD19, and CD19 is present on normal as well as malignant B-cells.

So most patients who receive anti-CD19 CAR T-cell therapy will develop B-cell aplasia at some point, and B-cell aplasia may be temporary or prolonged. It usually does, on one hand, indicate ongoing activity of the CD19 CAR T-cells and can be used as a surrogate marker.

And increase in CD19 CAR T-cells could, in some patients, signal impending relapse, or dysfunction, or absence of activity of CD19 CAR T-cells. B-cell aplasia in CAR T-cell recipients is really due to, as I mentioned, an on-target, off-tumor effect. It can be prolonged and there is variability in rates of prolonged B-cell aplasia.

The most significant consequence of B-cell aplasia is that it can lead to low immunoglobulin production. And immunoglobulin production is a very important part of the immune response by providing antibody-mediated immunity, so patients may present with frequent infections and low immunoglobulin levels.

For most CAR T-cell recipients, this can be managed with infusions of Intravenous Immunoglobulins-- IVIG. However, the presence of B-cell aplasia can also present other challenges-- especially during this current pandemic, as Dr. Santomasso alluded to earlier, that it is unclear if patients will be able to mount a sufficient enough antibody response to the COVID-19 vaccines available since they cannot produce significant amounts of antibodies. This is an active area of research. However, we do advise that all CAR T-cell recipients do get the COVID vaccine and also other seasonal vaccines, such as the influenza vaccine.

So it remains to be seen. We need some more long-term follow-up studies on how many people who receive CD19-directed CAR T-cell therapy will have prolonged B-cell aplasia and what the consequences will be. At this time, it is suggested that patients have their IgG levels monitored and-- if possible-- their actual B-cell numbers monitored.

And if their IgG levels drop below a certain number, then they may receive IVIG infusions intermittently. We recommend in this guideline using 400 as a possible cutoff for IgG levels prior to administering IVIG. However, if patients have higher IgG levels and they have recurrent or life threatening infections, infusion of IVIG is recommended as a consideration to help boost the antibody response.

BRITTANY HARVEY: OK. As you mentioned, those challenges are particularly relevant now. So then, Dr. Santomasso, what are the key recommendations regarding Disseminated Intravascular Coagulation?

BIANCA SANTOMASSO: Disseminated Intravascular Coagulation is a disorder that's characterized by systemic pathological activation of blood clotting mechanisms, which results in both clot formation throughout the body and also bleeding. There's an increased risk of hemorrhage as the body is depleted of platelets and other coagulation factors.

So it's basically important for clinicians to be aware that DIC-- or Disseminated Intravascular Coagulation-- can occur after CAR T-cell therapy, and it can occur either with or without concurrent Cytokine Release Syndrome. The treatment is primarily supportive care and replacing the factors, such as fibrinogen-- based on the levels-- and also replacing factors based on partial thromboplastin time and bleeding occurrences.

But corticosteroids and IL-6 antagonist therapy can be used if there is concurrent CRS or in the setting of severe bleeding complications. There is limited evidence for other interventions.

BRITTANY HARVEY: Great. Appreciate you reviewing those. So then, the last category of toxicity addressed in this guideline-- Dr. Ghosh, what are the key recommendations for identification, evaluation, and management of infections?

MONALISA GHOSH: So a variety of infections can be seen after CAR T-cell therapy. And there are many factors that can lead to infection after CAR T-cell therapy including the presence of cytokines, such as neutropenia or leukopenia and B-cell aplasia that we earlier discussed-- leading to low immunoglobulin production and protection.

As well as the increased risk of infection due to use of high-dose steroids to treat CAR T-cell-related toxicities, such as ICANS or CRS. Early after the infusion of CAR T-cell therapy-- that is, within three months-- patients often develop neutropenia due to lymphodepleting chemotherapy and/or the CAR T-cells themselves.

And these patients are particularly susceptible to infection, so most of the infections that occur early on tend to be bacterial infections, and a few fungal infections have been observed as well. Patients who receive high-dose steroids for high grade CRS or ICANS have been shown to have increased serious infectious complications including bacterial infections, fungal infections, as well as viral reactivations.

Infectious complications that occur later are often due to hypogammaglobulinemia due to B-cell aplasia and reduced production of immunoglobulins. And treatment is typically directed at the infectious source, as it would be even if these patients did not have CAR T-cell therapy.

There are some prophylactic antimicrobials that are recommended for CAR T-cell recipients who have prolonged cytopenias. Especially those with prolonged neutropenia should be on some sort of bacterial and/or fungal prophylactic antimicrobials.

Patients should also be monitored for hypogammaglobulinemia long term and should receive intravenous immunoglobulins as needed. As we have mentioned a couple of times already, being very aware that these patients are also more susceptible to seasonal infection, such as influenza, is important, and so vaccinations are very important for this patient population. Vaccinating against influenza and vaccinating against COVID-19.

BRITTANY HARVEY: Thank you both for reviewing those key points for the most common CAR T-related toxicities. So, just to wrap us up-- Dr. Santomasso-- in your view, how will this guideline impact both clinicians and patients?

BIANCA SANTOMASSO: Well, I think we've seen now that cell therapy is really one of the major advances in cancer treatment in the past decade. And I think it's reasonable to expect more of these cell therapies to be developed, and we'll hopefully see their use extend beyond very specialized centers.

But CAR T-cell therapy side effects are manageable if they're recognized, so I think this guideline helps that, and they're reversible with proper supportive care. They can be serious and they require close vigilance and prompt treatment. But, again, we believe this guideline and recommendations will help members of clinical teams with both the recognition and management of all of these toxicities, and that will help patients by increasing their safety.

BRITTANY HARVEY: Great. That's important to note that these toxicities can be severe, but are also manageable. So I want to thank you both for your work on these guidelines and for taking the time to speak with me today, Dr. Santomasso and Dr. Ghosh.

BIANCA SANTOMASSO: Our pleasure.

MONALISA GHOSH: Absolutely. It was my pleasure.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events in patients treated with immune checkpoint inhibitors. To read the full guidelines, go to www.asco.org/supportive care guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

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An interview with Dr. Manish Shah from New York Hospital and Weill Cornell Medicine, co-chair on "Immunotherapy in Patients with Locally Advanced Esophageal Carcinoma: ASCO Guideline Rapid Recommendation Update." He discusses the results of the Checkmate 577 trial and the updated recommendation of the Treatment of Locally Advanced Esophageal Carcinoma Guideline. For more information, visit www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at ASCO.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Manish Shah from New York Hospital and Weill Cornell Medicine in New York, NY, co-chair of the Locally Advanced Esophageal Carcinoma guideline expert panel and lead author on the Immunotherapy in Patients with Locally Advanced Esophageal Carcinoma: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Shah.

MANISH SHAH: Absolutely. Thank you very much for having me.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline is available online. Dr. Shah, do you have any relevant disclosures that are directly related to this guideline?

MANISH SHAH: Yes, so I do have relationships with many of the companies that make checkpoint inhibitors. And in fact, we are being supported by Bristol Myers Squibb on a first-line study of chemotherapy with nivolumab. We've also been supported by Merck on a pre-operative study of chemotherapy with radiation and pembrolizumab.

BRITTANY HARVEY: Thank you for that information. Then so what prompted this rapid update to the Treatment of Locally Advanced Esophageal Carcinoma: ASCO Guideline?

MANISH SHAH: Yes, so recently there was a landmark study that was practice-changing in the space, published in the New England Journal of Medicine by Ronan Kelly and colleagues. And this was the report of CheckMate 577, the use of adjuvant nivolumab in resected esophageal or gastroesophageal junction carcinoma. And this was a positive study that led to important changes in practice. And we felt that this was worthy and worthwhile of getting it out there to the community.

BRITTANY HARVEY: Great. Then based off this new data from CheckMate 577 on nivolumab, what is the updated recommendation?

MANISH SHAH: Sure. So previously, the data available was that patients who receive chemotherapy and radiation and then went on to receive surgery, that those patients with esophageal cancer had no further treatment recommendations. This study, CheckMate 577, actually examined nivolumab in that context. So patients who received chemotherapy and radiation and then underwent surgery, if they had some residual disease at the time of the surgical resection, even if they had a major response but there was some residual cancer in the surgical specimen, patients were eligible for randomization. And about 800 patients were randomized, 2 to 1, to receive nivolumab versus placebo in this context.

And the primary endpoint in the study was disease-free survival. And patients who received nivolumab had a median disease-free survival of 22.4 months compared to placebo, which was the previous standard of care. The median disease-free survival in that group was 11.0 months, so almost a doubling of the disease-free survival. The hazard ratio was 0.69. And that was highly significant, with a p value of 0.001. So there was a 31% improvement in reducing the risk of recurrence with adjuvant nivolumab. So based on that trial, we have updated the guideline to recommend adjuvant nivolumab for patients who have received chemotherapy and radiation and surgery, and then had some residual disease in the surgical specimen.

A key distinction is that about 20% to 30% of patients will have had a pathologic complete response. These patients were not eligible for the trial. And so at this time, patients who have had a complete response, the current guidelines remain the same, where there's no further treatment indicated.

BRITTANY HARVEY: OK, it seems like this study provided a strong signal to update that recommendation. I appreciate you going through the details of that study, and particularly the patients that were eligible to participate. So then, how will this guideline impact patients with locally advanced esophageal cancer?

MANISH SHAH: Yeah, I think that this is a key thing. Because 70% to 75% of patients have residual disease at the time of resection. And still, even if you've had a major pathologic response, the risk of recurrence for many patients is still high, greater than 50%.

Of note also I'd highlight that the study included adenocarcinoma and squamous cell cancer. And the results were positive in both groups. So based on that, I think that this will be highly impactful for a majority of patients with esophageal cancer, both adenocarcinoma and squamous cell cancer, who, as I said, underwent chemoradiation and surgery and had residual disease in the surgical pathologic specimen.

BRITTANY HARVEY: That's good to hear that this will have a positive impact for these patients. So then what are the outstanding clinical questions regarding treatment of these patients?

MANISH SHAH: Yeah, so I think that there are a lot of outstanding questions. I think one question which is currently being studied is the use or integration of checkpoint inhibition therapy prior to surgery. So that's being examined in an inter-group study in the United States, as well as several company-sponsored studies across the globe. And a concept there is that, if you're giving chemotherapy with radiation and a checkpoint inhibitor all combined, you might be able to have even the higher benefit from activation of the immune system against the cancer than in the adjuvant setting where you're trying to treat microscopic minimal disease. So that's one question.

And the other key question, which was actually raised by the clinical trial itself was the CPS scoring system. So CPS means Combined Positive Score. This is a way to examine the level of PD-L1 expression in the tumor and its microenvironment. And it's not a great biomarker, but it's the best biomarker available. And it is predictive of who would benefit. So patients who have a higher CPS score are more likely to benefit from a checkpoint inhibitor. A post hoc analysis of this study suggested that tumors that had a CPS score of less than 5 had less benefit. So although the FDA approval for adjuvant nivolumab was independent of the CPS score, I think, with time, we'll have more information on the potential impact of CPS or other biomarkers on which patients really may benefit from adjuvant therapy.

So I think, on the positive end, patients now have options. And I think they're clinically significant and meaningful. But it does, as you point out, highlight new questions that will be answered in due course.

BRITTANY HARVEY: Great. And we'll look forward to the results of those studies that address some of those questions. So thank you for your efforts to issue this rapid update and for taking the time to speak with me today, Dr. Shah.

MANISH SHAH: Oh, absolutely. It was a pleasure to be here. Thanks so much, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.ASCO.org/gastrointestinal-cancer-guidelines. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

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An interview with Dr. Nadine Tung and Dr. Dana Zakalik, co-chairs on "Adjuvant PARP Inhibitors in Patients with High-risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update." They discuss the results and impact of the OlympiA trial, the updated recommendation, and outstanding questions on the use of PARP inhibitors in the adjuvant setting. For more information, visit www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

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ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.ASCO.org. My name is Brittany Harvey, and today I'm interviewing Dr. Nadine Tung from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and Dr. Dana Zakalik from Beaumont Health in Royal Oak, Michigan, co-chairs of the Management of Hereditary Breast Cancer Guideline Expert Panel and this rapid recommendation update, Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Guideline Recommendation Update. Thank you for being here, Dr. Tung and Dr. Zakalik.

DR. ZAKALIK: Thank you for having us.

DR. TUNG: Thank you so much. Pleasure to be here.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online. Dr. Tung, do you have any relevant disclosures that are directly related to this guideline topic?

DR. TUNG: I do receive research funding from AstraZeneca, as I run a trial using a PARP inhibitor in breast cancer.

BRITTANY HARVEY: Thank you. And Dr. Zakalik, do you have any relevant disclosures?

DR. ZAKALIK: I do not.

BRITTANY HARVEY: Thank you. Then let's get into the meat of this rapid recommendation update. So, Dr. Tung, what prompted this rapid update to a recommendation from the Management of Hereditary Breast Cancer Guideline?

DR. TUNG: The OlympiA Trial, which was presented at ASCO this past June and published the same day in the "New England Journal of Medicine." OlympiA was a large Phase III trial, which demonstrated that a year of adjuvant olaparib, a PARP inhibitor, significantly improved both invasive disease-free survival by nearly 9%, and distant disease-free survival by a similar improvement, in germline BRCA mutation carriers with HER2-negative breast cancer and a high risk of recurrence. Overall survival was numerically better with olaparib, but it didn't yet reach significant improvement as a stringent p-value was required for this early reporting.

And I say early reporting because the trial was reported early after the first event-driven interim analysis showed a benefit with olaparib. 1,800 patients had been enrolled with a median follow up of 2 and 1/2 years at the reporting. But the follow up was 3 and 1/2 years for the first 900 patients enrolled, known as the maturity cohort. And it was comforting that the significant improvement in invasive disease-free survival and distant disease-free survival was also seen when just looking at that maturity cohort. So for those who might think that it's too early and that these benefits might not hold up with longer follow up, it's very comforting that in that maturity cohort with longer follow up, the results were really the same.

And last year, ASCO published guidelines on managing patients with hereditary breast cancer, including women with inherited BRCA mutations, meaning a pathogenic or likely pathogenic variant. At that time, PARP inhibitors were recommended only for BRCA carriers with metastatic disease, based on the OlympiAD and EMBRACE trials. So when OlympiA was published, we felt the need to update the guidelines to recommend olaparib in the early-stage setting for some germline BRCA carriers.

BRITTANY HARVEY: So then, based off this new data from the OlympiA trial, Dr. Zakalik, what is the updated recommendation from the guideline expert panel?

DR. ZAKALIK: The updated recommendation states that for patients with early-stage, HER2-negative breast cancer with a high risk of recurrence, and who carry a germline BRCA1 or 2 mutation, one year of adjuvant olaparib should be offered after completion of adjuvant or neoadjuvant chemotherapy and local treatment, including radiation therapy. And this data was specific to a high risk of recurrence subgroup of these patients, defined as, for those with triple-negative breast cancer having a tumor over two centimeters, or with any involved lymph nodes, or for those who received neoadjuvant chemo, any residual disease in the triple-negative setting was sufficient to qualify.

For patients with hormone receptor positive disease, these were high-risk patients for recurrence, again, and that was defined as having at least four positive lymph nodes, or any residual disease following neoadjuvant therapy. But in addition, having a clinical stage and pathologic stage estrogen receptor status and tumor grade, otherwise called the CPS+EG score, of greater than or equal to three, which is really defined as looking at estrogen receptor status grade and clinical and pathologic stage. So again, a high-risk group for risk of recurrence was included in this study. And again, in order to apply these findings, we have to be mindful of patients who meet these inclusion criteria as being high-risk for recurrence. Again, both in the triple-negative hormone receptor-positive setting, if they met these criteria, there was a significant benefit in terms of outcome in lowering the risk of recurrence.

BRITTANY HARVEY: I appreciate you going through that recommendation. So then, given that updated recommendation. Dr. Tung, what should clinicians know as they implement the use of adjuvant olaparib into clinical practice?

DR. TUNG: For those who have not used olaparib, it's worth saying that it's an oral medication. Typically patients take two pills twice a day. And it's important to be familiar with the side effects. I would say that generally, olaparib is well-tolerated. But it can have side effects. And the two most common are nausea, and then anemia. So for the nausea, we use the typical antiemetics we would use for any chemotherapy. And it's worth saying to patients who do have nausea that quite often, that lessens with time. It decreases. So I would say nausea's one of the side effects. Some patients can have fatigue, although I don't think that's all that common.

And anemia is the other one. And we do check bloodwork monthly for patients on olaparib. The anemia can come suddenly, even after months of really not having any. And grade 3 anemia was probably the most common, grade 3 or higher, toxicity that was seen in OlympiA, although it's only 9% of patients that had grade 3 or higher anemia. But I would say those are the two side effects to look for most. And then I think one other thing that's worth saying is that for the BRCA carriers with triple-negative breast cancer, currently our standard therapy for patients who have residual disease after neoadjuvant chemotherapy is capecitabine. But olaparib should not be given with capecitabine. There is no safety data for that. So oncologists are going to need to choose between what I think is our standard therapy right now, capecitabine, and olaparib. And there's no data directly comparing these two medications in the early-stage setting.

But in the metastatic setting in BRCA carriers, in both OlympiAD and EMBRACE, olaparib was compared to chemotherapy. And olaparib with superior. And in both of those studies, about half the women in the chemotherapy arms received capecitabine. And olaparib, again was superior. So olaparib may be the better choice in the early-stage setting. But I can't say that there's any direct data. But the message would be not to give them together. And I think it would be better probably not to give capecitabine first and then olaparib, because there's some data that the earlier you give a PARP inhibitor the better.

BRITTANY HARVEY: Those are important notes for clinicians and particularly for safety. So then building on that, Dr. Zakalik, how will this update impact patients with breast cancer?

DR. ZAKALIK: This data will significantly impact the therapeutic options that we have for patients with high-risk disease in the setting of a BRCA germline mutation. And that will happen in the sense that patients who have these certain specific features that render them high-risk will now be able to be offered a very impactful therapy that has been shown in this landmark study to significantly decrease their risk of recurrence. And these are patients who otherwise would face a significant risk of potentially facing a recurrence in the future. So the outcomes we anticipate to be dramatically improved for patients who have triple-negative or high-risk hormone receptor-positive breast cancer in the setting of a BRCA germline mutation.

But furthermore, whereas genetic testing in the past was predominantly focused on identifying individuals who are at high risk for developing breast cancer so that we can offer early detection or prevention options, this is the first time that we're able to broadly apply the benefit of molecular genetic testing for hereditary risk to therapy for patients with early nonmetastatic breast cancer. So as clinicians who see patients with breast cancer, it is further made more important to recognize what the guidelines are for genetic testing. To think of whether a patient meets criteria that are currently outlined for genetic testing, as this will have a significant potentially major impact on patients' outcome. And already in the clinic, we have been focused on recognizing who may have a BRCA mutation. Obviously, this data will make that even more important, because this therapy is so beneficial for patients. And I think going forward, it will fuel a discussion of possibly reevaluating who gets genetic testing, now that it's particularly important not to miss patients who have BRCA mutations when they develop breast cancer.

So I think that physicians who are in the clinic will not only have a therapeutic option, but also will be hopefully recognizing more patients who have a BRCA mutation in that the therapy is so markedly better now with this new data. And in the future, we may possibly expand our guidelines for testing. And I think that remains to be determined, based on a number of factors that go into this decision.

BRITTANY HARVEY: Well then, you've both touched on this a bit, regarding outstanding questions for both genetic testing and the use of capecitabine. But finally, Dr. Tung, given this recent study and guideline update, what are the outstanding questions regarding the use of PARP inhibitors in the adjuvant setting?

DR. TUNG: Right. We have already listed a couple. The capecitabine question is one that I won't repeat. And I think who gets tested would be another one that Dana just mentioned. I think a big one, as of yesterday, is immune therapy. Yesterday, the FDA approved pembrolizumab, based on the KEYNOTE-522 study for patients with triple-negative breast cancer. And that population in KEYNOTE was very similar to the one in OlympiA for BRCA carriers, namely patients with T2 tumors, or involved axillary lymph nodes. So for BRCA carriers, we're going to have to make some decisions here, namely, should they receive pembrolizumab and olaparib together, for those who have residual disease after neoadjuvant chemotherapy. I think everyone right now is digesting KEYNOTE-522 and this FDA approval. And so that's something that will have to be worked out.

I know in other diseases there is safety data for the combination of pembrolizumab and olaparib. But again, I think that's something that we're all going to have to sort out. I don't think there's going to be any data forthcoming immediately about the use of pembro, olaparib, and the combination, et cetera for our patients. So that's a big one I think another question that comes up is, how long after a BRCA carrier finishes their chemotherapy and local therapy are they eligible to take olaparib? What about patients that finished six months ago, or a year ago, or longer? And again, I don't think there are any data for that, and we're going to have to use some clinical judgment. There was precedent for this kind of question when adjuvant trastuzumab was approved and in 2005, when the adjuvant trials demonstrating such an impressive benefit for trastuzumab were announced and published.

I remember that we were administering trastuzumab to patients who'd completed their chemotherapy within the last year. So I think for many, that may be a timeline that makes sense. But again, there are no data. So still questions, and we're going to as always have to use some clinical judgment. And others, Dana, that you can think of?

DR. ZAKALIK: No. I think this is tremendously exciting new data. It really provides hope for patients who are young, often, when they're diagnosed. Because hereditary breast cancer tends to manifest itself at a young age. And so for our women in the prime of their life, when they have high risk and develop breast cancer, I think this just really gives us tremendous hope and opportunity for improving the lives and saving lives in the future of patients who have high-risk disease. Very exciting data.

DR. TUNG: Yeah, I agree completely. I think the investigators are really to be congratulated. This was a very large study. 1,800 BRCA carriers, international study. Very hard to do with a situation, a disease that's relatively uncommon. Only 3% to 5% of all breast cancer. So really a terrific effort with a significant, major impact for our BRCA carriers with breast cancer.

BRITTANY HARVEY: Definitely. This is an exciting update for patients with breast cancer. And we'll look forward to hearing more research about those outstanding questions that you mentioned. So I want to thank you both for your efforts to update this guideline recommendation so quickly, and provide evidence-based recommendations for both clinicians and patients. And thank you for taking the time to speak with me today, Dr. Zakalik and Dr. Tung.

DR. ZAKALIK: Thank you.

DR. TUNG: My pleasure.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. For more information, visit www.ASCO.org/breast-cancer-guidelines. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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An interview with Dr. Beverly Moy from Massachusetts General Hospital, co-chair on "Chemotherapy and Targeted Therapy for Patients With HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update." Updated guidance addresses optimal sequence of therapy & indications for treatment regimens. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey. And today I'm interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, co-chair and lead author on chemotherapy and targeted therapy for patients with HER2 negative metastatic breast cancer that is either endocrine pre-treated or hormone receptor negative ASCO guideline update. Thank you for being here, Dr. Moy.

BEVERLY MOY: Thanks for having me, Brittany.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic?

BEVERLY MOY: I do not have any relevant disclosures related to this guideline topic.

BRITTANY HARVEY: Great. Thanks so much. Then let's get into what this update covers. So first, what prompted the update of this ASCO guideline and what does the scope of this guideline update?

BEVERLY MOY: So this guideline update was developed to address both chemotherapy and targeted therapy for women with advanced HER2 negative breast cancer that is either endocrine pre-treated or hormone receptor negative. So it really focuses on chemo and targeted therapy.

The original ASCO clinical treatment guideline was published in 2014 and really focused on chemotherapy, since that was generally the standard of care at that time. Since 2014, however, there have been several important new therapies that have become available based on robust evidence from numerous clinical trials.

These include, but are not limited to, BOLERO-6 and PEARL trials for hormone receptor positive HER2 negative metastatic breast cancer, the ASCENT and EMBRACE trials for triple negative metastatic breast cancer, and the EMBRACA trial for metastatic breast cancer associated with germline BRCA1 or 2 mutations. So it really was important to update the guideline in a fairly urgent matter.

BRITTANY HARVEY: Great. Well, then this guideline addresses four overarching clinical questions. For each of these, I'd like to review the key recommendations for our listeners. So starting with question one, is there an optimal sequence of chemotherapy and/or targeted therapy for patients with triple negative metastatic breast cancer either with or without BRCA1 or BRCA2 germline mutations?

BEVERLY MOY: So clinical question one really focused on patients with metastatic triple negative breast cancer. So for patients with metastatic triple negative disease, the first key question is, what is the Programmed cell Death Ligand 1, or what we call PD-L1 status? If the disease is PD-L1 positive, then patients may be offered first line therapy with an immune checkpoint inhibitor plus chemotherapy. And that's a very important development.

If the disease, however, is PD-L1 negative, patients should be offered single agent chemotherapy rather than combination chemotherapy, unless they have symptomatic or immediately life-threatening disease, and you really need to get a response more quickly. In those cases, combination chemotherapy can be used.

After the first line, if patients with metastatic triple negative breast cancer have received at least two prior therapies, then they should be offered treatment with the new antibody drug conjugate called sacituzumab govitecan, which is a very exciting development in the treatment of metastatic triple negative breast cancer.

If the patient has a germline BRCA1 or 2 mutation and has metastatic triple negative disease and have been previously treated with chemotherapy, then they may be offered treatment with an oral PARP inhibitor rather than chemotherapy, also a very exciting development that this guideline update addresses.

BRITTANY HARVEY: Great. Thank you for reviewing those recommendations for triple negative metastatic breast cancer. So then next for clinical question two, what are the indications for chemotherapy versus endocrine therapy in endocrine pre-treated estrogen receptor positive metastatic breast cancer?

BEVERLY MOY: So clinical question two focuses on women or patients with metastatic hormone receptor positive breast cancer who have developed progressive disease on a prior endocrine therapy with or without targeted therapy. So really is focusing on patients with metastatic hormone receptor positive breast cancer that have become fairly resistant to endocrine therapy alone. These patients may be offered treatment with either endocrine therapy with or without a targeted therapy or single agent chemotherapy.

Brittany, I think it's important for listeners to realize that there is another important clinical practice guideline update that's being released simultaneously with this guideline. And that one is called endocrine therapy and targeted therapy for hormone receptor positive metastatic breast cancer. This other guideline update will describe in detail recommendations for the various targeted therapies that can be used with endocrine therapy, such as CDK4/6 inhibitors, PI 3-kinase inhibitors, and others.

So I encourage everyone to read this guideline as well. Importantly, both guidelines state that treatment choice should be based on individualized patient and provider assessment of preferences, risks, and benefits.

BRITTANY HARVEY: Great. And thank you for pointing out that companion guideline. Listeners can also listen to a podcast episode with Dr. Burstein on that particular guideline, which will be available in our podcast feed.

So then next, what are the key recommendations for the third question in the guideline, which is, is there an optimal sequence of non-endocrine agents for patients with hormone receptor positive but HER2 negative metastatic breast cancer who are no longer benefiting from endocrine therapy, either with or without BRCA1 or BRCA2 germline mutations?

BEVERLY MOY: So this third question really focuses on patients with hormone receptor positive HER2 negative disease and the optimal sequence. Essentially what we recommend is that germline BRCA1 or 2 patients with metastatic hormone receptor positive HER2 negative breast cancer who are no longer benefiting from endocrine therapy, those patients may be offered an oral PARP inhibitor in the first through third line setting rather than chemotherapy. And that is evidence that is evolving and important, and that's what the guideline recommends at this time.

BRITTANY HARVEY: Great. And then clinical question four was the last question addressed in this guideline update. And what did the panel say regarding at what point should a patient be transitioned to hospice or best supportive care only?

BEVERLY MOY: So this obviously is an incredibly important question for clinicians and oncologists to consider. The current literature and evidence does not allow us, at this time, to make a firm recommendation regarding at which point a patient's care should be transitioned to hospice or best supportive care only.

When to transition is a decision that really needs to be shared between the patient and clinician in the context of an ongoing conversation regarding goals of care. The conversation of that integration of supportive care and eventual consideration of hospice care really should start early in the management of metastatic breast cancer. And these conversations have to occur throughout.

I would also refer listeners to other important clinical treatment guidelines on the ASCO website about incorporation of palliative and supportive care for patients with metastatic cancer. I think those are incredibly valuable guidelines.

BRITTANY HARVEY: And then you've touched on this a bit as you've talked about the recommendations, but in your view, what is the importance of this guideline update? And how will these updated recommendations impact both clinicians and patients?

BEVERLY MOY: I think that this is an extremely important guideline update. It provides really important clinical guidance about the new use of immune checkpoint inhibitors, which really is the first time immune checkpoint inhibitors are clearly recommended for the treatment of breast cancer. It also provides important clinical guidance about this new antibody drug conjugate, sacituzumab govitecan, and PARP inhibitors for the treatment of metastatic breast cancer.

These are all important and effective new treatments for breast cancer. And every clinician should be aware of their optimal uses. I will point out that many unanswered questions remain. And that was really an exciting part of doing this guideline update to look at these unanswered questions, such as what we described earlier, the optimal time to transition to best supportive care only and the widespread use of molecular tumor profiling. As treatments get more complicated and the entire oncology community are increasingly tasked to absorb new data, ASCO guidelines are enormously helpful in giving people an easy to access tool that takes into account the latest data.

BRITTANY HARVEY: Great. Thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Moy.

BEVERLY MOY: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at surveymonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss episode.

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An interview with Dr. Harold Burstein from Dana Farber Cancer Institute in Boston, MA, chair on "Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Update." This guideline updates recommendations on use of alpelisib, and the role of biomarkers and CDK4/6 inhibitors. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

[MUSIC PLAYING]

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcasts.asco.org.

My name is Brittany Harvey. And today I'm interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute in Boston, Massachusetts, chair and lead author on endocrine treatment and targeted therapy for hormone receptor-positive HER2 negative metastatic breast cancer ASCO guideline update. Thank you for being here, Dr. Burstein.

HAROLD BURSTEIN: Glad to be with you.

BRITTANY HARVEY: First I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Burstein, do you have any relevant disclosures that are related to this guideline topic?

HAROLD BURSTEIN: I do not.

BRITTANY HARVEY: Great, thank you. Then let's delve into the content of this guideline. So first, what prompted the update of this guideline and what is the focus of this update?

HAROLD BURSTEIN: So this guideline focuses on metastatic breast cancer, and in particular, estrogen receptor-positive HER2 negative metastatic breast cancer. Worldwide in 2021, actually breast cancer became the most commonly diagnosed cancer in the world, excepting superficial skin cancers.

And so it is a true global health problem. And the most common type of breast cancer is estrogen receptor-positive HER2 negative breast cancer, which accounts for 70% to 75% of all cancer diagnoses in the breast cancer space, and as a consequence, also accounts for 70% to 75% of the cases of metastatic breast cancer. So it's really important from a public health point of view and a quality point of view, both in the United States and globally, to have current up-to-date guidance for the management of this most common form of breast cancer that we have.

In addition, there have been several innovations in the way of targeted therapies that are coming into place for advanced ER-positive breast cancer. And increasingly, we are using genomic tests to help us understand how best to treat patients with advanced ER-positive breast cancer. So those two initiatives-- the interest in genomic testing and the use of targeted therapies-- all warranted and justified an update to the guidelines.

BRITTANY HARVEY: Great. Thank you for reviewing that landscape of where we are in clinical practice for this guideline. So then I'd like to review the key recommendations that this guideline addresses. So first, should alpelisib be given to post-menopausal women and to male patients with hormone receptor-positive HER2 negative PIK3CA-mutated advanced or metastatic breast cancer?

HAROLD BURSTEIN: So alpelisib, as you indicated, is a new drug. It is now FDA approved. And it is a protein kinase targeted inhibitor. And it goes after the PIK3CA-mutated tumors. And in a seminal study called the SOLAR-1 study, there was randomization to endocrine therapy alone with fulvestrant or endocrine therapy plus alpelisib for ER-positive HER2 negative breast cancer.

And that study showed two important things. First was that in women whose tumors did not have a PIK3CA mutation, there was no benefit for alpelisib. However, in the women whose tumors did have a PIK3CA mutation, there was an improvement in progression-free survival with the use of this targeted drug alpelisib.

So based on that, the guidelines now incorporate alpelisib into the treatment algorithm. And as a corollary, it means that all patients who have ER-positive metastatic breast cancer now need testing of the tumor to see if they have a PIK3CA mutation because that's going to guide therapy.

In the guideline, we now suggest that this be a standard thing to do-- to test all tumors for PIK3CA mutation. And in those cases where there is a PIK3CA mutation to add alpelisib-based therapy with endocrine treatment typically in second or subsequent lines of therapy.

BRITTANY HARVEY: Great. And thank you for reviewing the evidence base behind that recommendation. So next, what is recommended regarding the role of biomarkers in treatment selection for patients with hormone receptor-positive metastatic breast cancer?

HAROLD BURSTEIN: So there are two different ways of thinking about biomarkers. One is traditional biomarkers, such as estrogen receptor, progesterone receptor, and HER2. Those are familiar to all clinicians who have been dealing with breast cancer. The second is to think about some of the newer technologies, including tumor genomic sequencing and the kind of mutational analysis we just discussed with the PIK3CA mutations.

So in the breast cancer space, there are some important innovations in that latter genomic or genetic testing. One, of course, is the PIK3CA mutation testing that we now recommend for all cancers. That can be done on the primary tumor, or it can be done on cell-free or circulating tumor DNA samples from the bloodstream in most cases.

The other kind of testing we do relates to ESR1 mutations. And one of the reasons that tumors become resistant to aromatase inhibitors is that they acquire mutations in the estrogen receptor itself, so-called ESR1 activating mutations. Those mutations mean that the estrogen receptor is on even in the absence of estrogen. And that accounts for probably 50% to 60% of the resistance that we see in treatment with aromatase inhibitors.

So the panel really struggled with this because, on the one hand, this is not a uniformly accepted way to decide how to treat patients. On the other hand, there are a lot of data that women whose tumors have ESR1 mutations get negligible benefit from ongoing use of aromatase inhibitor therapy.

So this recommendation fell into sort of our practice suggestions, which is that if you have the information on ESR1, then it probably is the case that there's very little, if any, role for ongoing aromatase inhibitor treatment. This fell short of the highest level in endorsement because, first, it's not a uniformly tested assay. And secondly, it's important to remember that these tumors can still benefit from ongoing anti-estrogen therapy with different anti-estrogens like fulvestrant.

And finally, and perhaps this is the most practical issue, the way you become ESR1 mutated is usually through exposure to aromatase inhibitors. And if you've already had a patient with extensive exposure to AIs, and they need ongoing anti-estrogen therapy in the metastatic setting, it usually means you're switching treatment anyway. So that's an example of where we're sort of on the frontier of thinking about dynamic changes in the tumor as a way to select treatment for ER-positive metastatic disease.

BRITTANY HARVEY: Great. That's helpful for a clinical interpretation of the recommendations and incorporating these into practice. So the final question that was addressed in this focused update was, what is the role of CDK4/6 inhibitors in the treatment of patients with hormone receptor-positive metastatic breast cancer?

HAROLD BURSTEIN: So CDK4/6 inhibitors are another tyrosine kinase inhibitor class of drugs that has really emerged as an important part of first-line therapy for ER-positive metastatic disease. There have been multiple randomized trials looking at either first-line therapy with an aromatase inhibitor with or without a CDKI4/6 inhibitor, or second-line treatment typically with fulvestrant with or without a CDKI4/6 inhibitor in the metastatic setting. And the panel was able to update the guidance here based on the maturation of multiple randomized trials, as well as extensive subset analyses that have been performed by investigators associated with the individual pharmaceutical-led studies and by the FDA itself.

So here are some important takeaways. The first is that in long-term follow-up, these drugs as a class are improving overall survival for women with ER-positive HER2 negative metastatic breast cancer. And for that reason, they are a very important part of the standard armamentarium for ER-positive disease. It's important to say that they also delay the onset of need for chemotherapy, and in general, are associated with a very well preserved quality of life. So this is a big win for patients with ER-positive metastatic breast cancer.

We typically recommend them in the first-line setting. So if a patient has de novo metastatic disease, then they should get an endocrine therapy such as an aromatase inhibitor with a CDK4/6 inhibitor. If they've previously had adjuvant aromatase inhibitor treatment or recur while on adjuvant endocrine therapy, we often move to fulvestrant plus a CDKI4/6 inhibitor. Both settings have shown substantial benefit for this class of drugs.

It's important that clinicians understand the side effects of these drugs. Neutropenia and diarrhea are common side effects associated with the various drugs. And because of the prevalence of ER-positive metastatic disease, it's really important for clinicians and all those who care for advanced breast cancer patients to know how to manage those side effects carefully.

The panel discussed controversial issues, I suppose you might say, in the management. What about patients who have truly minimal metastatic disease? There aren't a lot of data on how best to think about those patients. And we all can imagine on a case-by-case basis an individual who might not need a CDK4/6 inhibitor at a given moment in time.

But what was impressive when we pulled all the data was that in subset analyses, it's really hard to find a group of patients that does not benefit from the incorporation of these drugs. So that included premenopausal women who also get concurrent ovarian suppression and then endocrine therapy plus the CDK4/6 inhibitor. It included women with bone-only metastatic disease. It included women whose tumors were ER-positive but PR negative, or had other variations in ER expression. It included patients who had less rather than more metastatic cancer, including visceral disease.

So in the literature, one is hard-pressed to see a subset that does not benefit meaningfully from this class of drugs. So we really wanted to reiterate in the algorithms just how important these are. They should be the standard first-line treatment for metastatic disease either paired with an AI or with fulvestrant.

And so one of the other nice things that the update gave us was the opportunity to put in some fresh sort of algorithm flow sheets. I would very much encourage people to look at that. They make fantastic PowerPoint or downloadable Twitter documents if you are so inclined. But it's very clear the way the treatment should flow, which is the initial therapy is endocrine treatment plus a CDK4/6 inhibitor. While the patients are getting that, we typically test for PIK3CA mutations. In second line, if it's a PIK3CA mutated, you have the option of using alpelisib. You also might consider an older drug for PIK3CA wild type tumors called everolimus. We reiterated that recommendation in the guideline.

Finally, one more thing to touch on that is emerging in the guidelines we generated and in the parallel guideline process for the ASCO guidance on chemotherapy-resistant or refractory breast cancer is the importance of genetic testing all patients who have metastatic breast cancer to look for the possibility of a BRCA1 or BRCA2 deleterious mutation, because there now is FDA approval for PARP inhibitors in the setting of metastatic disease.

And one of the interesting things is that as we test more and more, we're seeing that not all the patients who are found to have a BRCA1 or 2 mutation meet the classic criteria for genetic testing-- strong family history, or say, triple-negative breast cancer. So it's really important to test, because that class of drugs, the PARP inhibitors, can be immensely helpful in women with ER-positive metastatic disease when they harbor a BRCA1 or 2 mutation.

One of the things the guideline panel wrestled with and ended up putting into the sort of clinical discussion, as opposed to the strong guidance, was the 1% of patients who have PALB2 mutations. So PALB2 mutation, another hereditary predisposing factor for breast cancer. Most tumors that arise in PALB2 mutation carriers are in fact estrogen receptor positive.

And a very small study, now published in the JCO, has suggested that those patients have a very high likelihood of response to PARP inhibitors. Because there were only like 15 patients in that cohort, we didn't feel that this warranted clear endorsement in the guidelines. But at the same time, everyone on the panel acknowledges that this is an active drug in that rare subset of tumors with PALB2 mutations in addition to the BRCA1 or 2 mutations.

So the takeaway here is that genetic testing should be standard for all patients with advanced metastatic breast cancer to see if the patient is a candidate for a PARP inhibitor-based therapy.

BRITTANY HARVEY: Definitely. Well, thank you for reviewing all of those updated recommendations and highlighting some of the ones that were still relevant to this guideline.

HAROLD BURSTEIN: Work in progress.

BRITTANY HARVEY: Yeah, definitely. And then finally, what is the importance of this guideline update? And how will it impact both clinical practice and what does it mean for patients?

HAROLD BURSTEIN: Well, I think guidelines like this have multiple purposes. The first is to sort of describe the state of the art. And while breast cancer is a very common disease, and most clinicians who take care of a lot of cancer patients will see a lot of advanced breast cancer, I think it's still helpful to articulate the rationale for these treatment recommendations.

And one of the great things about the ASCO guideline process is the thoroughness of the literature review, the thoroughness of the search to make sure we're including all important publications, and the thoughtfulness that the panel, which includes experts, patient advocates, quality of life expertise, all those things bring to bear on really thinking through what makes sense and what does not for our patients based on the best science available. So I think it is an important activity to really sort of benchmark where we're at.

The second thing we've tried to do in the guideline is to introduce areas of nuanced discussion, because not every patient is the same. And I think for those who are interested and take the time to read the guideline, there really is a very nice discussion about how our panel thought about when best to use this approach and when to use a different approach.

Third, there's extensive discussion of the side effects and the appropriate management of the side effects. These are drugs that do carry risks. And while by oncology standards, many of them are, quote, "well tolerated," unquote, there's no doubt that there are side effects to these drugs. And it's important for clinical teams to know how to manage them.

Finally, I think by putting forward all the evidence, you make clear to investigators, to drug companies, to patients and advocates, and others who are involved in the review of new drugs what the benchmarks are and what the criteria should be for designing clinical trials and for approving new drugs. And I think we've done a nice job of framing that discussion quite handsomely in this guideline and to all of the ASCO guidelines.

BRITTANY HARVEY: Great. Well, thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Burstein.

HAROLD BURSTEIN: Happy to join you and thanks very much.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at SurveyMonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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An interview with Dr. Robin Zon from Michiana Hematology Oncology in Mishawaka, IN, co-chair on "Telehealth in Oncology: ASCO Standards and Practice Recommendations." The standards address telehealth implementation, doctor-patient relationships, roles of advanced practice providers & allied health professionals, multidisciplinary cancer conferences, and teletrials. Read the standards at www.asco.org/standards. Suggest a topic for standards development at www.surveymonkey.com/r/standardssurvey.

TRANSCRIPT

[MUSIC PLAYING]

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcasts.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Robin Zon from Michiana Hematology Oncology in Mishawaka, Indiana, co-chair on the "Telehealth in Oncology: ASCO Standards and Practice Recommendations." Thank you for being here Dr. Zon.

ROBIN ZON: Thank you so very much for having me here with you, to discuss this very important topic and work, which was undertaken by an expert panel of ASCO incredible volunteers and ASCO staff lead, Erin Kennedy.

BRITTANY HARVEY: Great. Then first I'd like to note that ASCO takes great care in the development of its standards and ensuring that the ASCO conflict of interest policy is followed. The full conflict of interest information for the expert panel is available online with the publication of the standards in the JCO Oncology Practice. Dr. Zon, do you have any relevant disclosures that are directly related to these standards?

DR. ROBIN ZON: No. I do not have any relationships to disclose related to the subject.

BRITTANY HARVEY: Thank you. Then let's get into the content of these telehealth standards. So first, can you give us a general overview of the purpose and scope of these standards for telehealth in oncology?

DR. ROBIN ZON: Well, absolutely. The service background, pre-pandemic, telehealth was utilized less than 1% of the time for oncology ambulatory visits. With, of course, a subsequent rapid adoption of digital health, in response to the public health emergency. This uptake of technology intervention was then further facilitated by the Centers for Medicare and Medicaid Services increased flexibility and reimbursement for these services.

In response to the COVID-19 pandemic, ASCO published an interim policy statement on telemedicine. The signal is positions on emerging policy issues, as well as the road to recovery report, which presented ASCO's recommendations for modifying pre-pandemic policies and practices to improve high-quality patient care, wherein ASCO membership identified a need for more detailed oncology-based telemedicine. So these standards were created in response to this need. It is important to note that these standards include an endorsement of existing general guidelines as published by the American Medical Association Telehealth Implementation Playbook and the American Telemedicine Association's Quickstart Guide.

BRITTANY HARVEY: That background and context is helpful for our listeners. So, then these standards, reading through them, they address six questions. I'd like to review the key points in each section for our listeners. So the first section, which patients should be seen via telehealth versus in-person? And what are the important implementation considerations for oncology telehealth visits?

DR. ROBIN ZON: Those are great questions, Brittany. Generally speaking, patients should always have the option for in-person visits when feasible. But when appropriate infrastructure and personnel are available, telehealth visits are suitable for treatment or long term management visits, in addition to family conferences, genetic counseling, second opinion evaluations, consent form discussions for pre-research trial participation, or when care access issues exist. I would refer the audience to the bottom line box which highlights the 18 described visits, as well as the preferred in-person consultation recommendations.

So from an operations standpoint, the standards include recommendations for practices to develop their own policies and procedures for these types of visits, frequency of visits, and documentation requirements for all clinical visits. Additionally, patients need to be oriented to the technology being utilized and have real time access to troubleshoot and support, if there are technology issues. The panel strongly advocated the quality of care should be equivalent to in-person visits. Thus to support this concept, the standards include, key performance indicators evaluation, policies for interventions delivered asynchronously, automated reminders, and inclusion of patients and caregivers involvement, if new technologic interventions are developed.

BRITTANY HARVEY: Great. I think those specifics you outlined will be helpful both for clinicians and practices, as they implement telehealth. So then, how should the establishment of the physician-patient relationship occur within the context of telehealth in oncology.

DR. ROBIN ZON: Well, both state and federal policies permitting telemedicine to cross state lines, should include a provision requiring that the doctor-patient relationship be established, prior to provision of any telemedicine services. As a reminder to the listener, the ASCO position statement, Telemedicine Cross-State Licensure, was recently approved by the Board of Directors and references a valid doctor-patient relationship as outlined by the American Medical Association.

This includes establishment of relationship by face-to-face examination or consultation with another physician, who has an ongoing doctor-patient relationship with the patient, or meets the standards of establishing a doctor-patient relationship, if included, in clinical practice guidelines developed by a major medical specialty society. I would refer the audience then to this ASCO position statement, for a much more detailed discussion regarding this topic. Importantly, the doctor-patient relationship should include the usual follow-up and care responsibilities and include opportunity for in-person visits at the physical location of the physician practice.

BRITTANY HARVEY: Then following those recommendations for the physician-patient relationship, what is the guidance for when patients may see an advanced practice provider?

DR. ROBIN ZON: Well, the panel recommends that practices follow established standards, policies, and algorithms that govern when Advanced Practice Providers, also known as APPs, or physicians should conduct the televisit based on the disease, treatment, or decision inflection point. However, the panel advises that practices should also review and comply with state and local regulations, for advanced practice provider supervision, including on how the APPs and physicians form teams.

BRITTANY HARVEY: Understood. And then further, in addition to those, what is the role of allied health professionals in oncology-specific telehealth interventions?

DR. ROBIN ZON: And just to orient the audience, when we refer to allied health professionals, we are referring to health professionals who are valued oncology team members. But they're distinct from physicians and nurses. That said, the expert panel referred to the Clinical Oncology Society of Australia, also known as COSA, Tele-oncology Guidelines, which provides guidance for oncology telehealth in rural and remote Australia. This evidence base was the largest for allied health professionals supportive interventions, delivered by both telephone and video conferencing. So due to the strength of the COSA evidence base, the expert panel endorses these recommendations, and refers to the utilization of telephone-based support systems, computerized screening, hybrid tele-practice systems, and video conferencing, as instruments for allied services delivery.

BRITTANY HARVEY: Great. And then the standards went into specifics regarding multidisciplinary cancer conferences. So how should discussion occur at virtual multidisciplinary cancer conferences, compared to in-person MCC meetings?

DR. ROBIN ZON: Well, as many of you know, many practices, in both academia and community settings, consider cancer conferences, which we also refer to as tumor boards, as essential for high quality patient care. Therefore, virtual cancer conferences replace these face-to-face meetings. The expert panel endorses the recommendations by the University of Pittsburgh Medical Center, for implementation of a virtual cancer conference. These include finalization of the agenda, one day in advance, secure video conferencing software, prioritizing complicated cases, and documentation and evaluation guidance. The expert panel also suggests that practices follow institutional guidelines, allowing the discussion to be directed by the presenter. And that there be no recording of the conference taking place without prior legal review.

BRITTANY HARVEY: Once again I find those specifics will be very helpful and explicit for clinicians. So then the last question that was addressed in these standards, how can telehealth be incorporated into clinical trials in oncology?

DR. ROBIN ZON: Well, utilization of telehealth and clinical trials are recommended, as a method for increasing recruitment, while reducing patient burden. Importantly, I want to emphasize that the expert panel endorses these recommendations prevail, beyond COVID-19 pandemic restrictions. This includes consideration for a hub and spoke model for patient enlistment. As well as recommendations to facilitate the conduct of teletrials, which are modifications intended to reduce risk during the pandemic, but also results in increased accessibility, reduced costs, and are less time-consuming.

BRITTANY HARVEY: Thank you for reviewing all of those key statements that were highlighted in the standards. So then, in your view, Dr. Zon, what is the importance of these standards to clinicians, and how will their implementation impact clinical practice?

DR. ROBIN ZON: Well, as I mentioned earlier, telehealth was very uncommonly utilized in cancer care, prior to the pandemic. However, with the soaring use of this intervention, there was a noted gap specific to oncology standards beyond the general telehealth guidance. These standards, then, are designed to assist the cancer care team in delivering the highest quality patient care, similar to the face-to-face quality care the oncologists strive to provide on a daily basis.

Furthermore, what we have witnessed, from both the practice responses and the convening of many experts in the delivery of telecare, is the flexibility to swiftly change and harness innovation among our colleagues worldwide. Telehealth, then, has the potential to improve care beyond the pandemic. And these standards serve as a roadmap for telecare best practices to continue to develop and address the needs for rural communities, patients with poor access to care, increase overall clinical trial participation, support patient education, and become one strategy, in a toolbox of other strategies, to help narrow the gap in disparate care.

BRITTANY HARVEY: Great. And then you've started to touch on this already, and talking about access to telehealth and how that impacts patients. But finally, how will these standards affect patients?

DR. ROBIN ZON: With regards to patients, what we learned from this evidence review, is that patient satisfaction is high. And they appreciate the convenience, flexibilities, and time and cost savings, as a result of telehealth options. I can share from my own practice that my patients were very grateful that we were able to provide telecare during the pandemic, and even now, as restrictions lessen, they're very thankful to have that opportunity. Many oncology patients want this option to continue for the future, and do not believe their clinical care was compromised.

However, oncology patient-reported outcomes and ongoing patient satisfaction evaluations must continue, along with the assessment of how the continuing challenges of broadband access, lack of technologic devices, or even familiarity with some technology, may serve as barriers to this care model. These standards are meant to assure the same high quality care for patients who choose to use this intervention, as they would if it were in person.

BRITTANY HARVEY: Definitely. Well, thank you for your work on these evidence-based standards directed at delivering high quality and accessible oncology care. And thank you for taking the time to speak with me today Dr. Zon.

DR. ROBIN ZON: And thank you so very much for this opportunity.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the standards go to www.asco.org/standards. Additionally, our annual survey for standard topics is open for submissions suggest a topic for standard development at www.surveymonkey.com/r/standardssurvey. Our standards survey. The link is also available in the episode notes of this podcast. If you have enjoyed what you heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

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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.

An interview with Dr. Valeria Mercadante from University College London, Dr. Siri Beier Jensen from Aarhus University, and Dr. Douglas Peterson from UConn Health, authors on "Salivary Gland Hypofunction and/or Xerostomia Induced by Non-Surgical Cancer Therapies: ISOO/MASCC/ASCO Guideline." This guideline provides evidence-based recommendations for interventions to prevent, minimize, and manage salivary gland hypofunction and xerostomia in patients receiving nonsurgical cancer therapy. Read the full guideline at www.asco.org/supportive-care-guidelines. Suggest a topic for guideline development at www.surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcasts.asco.org.

My name is Brittany Harvey, and today I'm interviewing Dr. Valeria Mercadante from University College London and University College London Hospitals Trust in London, United Kingdom, Dr. Siri Beier Jensen from Aarhus University in Aarhus, Denmark, and Dr. Douglas Peterson from the School of Dental Medicine and Neag Comprehensive Cancer Center UConn Health in Farmington, Connecticut, authors on "Salivary Gland Hypofunction and/or Xerostomia Induced by Non-Surgical Cancer Therapies: International Society of Oral Oncology, Multinational Association of Supportive Care in Cancer, and American Society of Clinical Oncology Guideline."

Thank you for being here, Dr. Mercadante, Dr. Beier Jensen, and Dr. Petersen.

DR. VALERIA MERCADANTE: Thank you. It's a pleasure to be here.

DR. DOUGLAS PETERSON: Thank you.

DR. SIRI BEIER JENSEN: Thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Mercadante, do you have any relevant disclosures that are directly related to this guideline topic?

DR. VALERIA MERCADANTE: No, I do not have any relevant disclosure.

BRITTANY HARVEY: Thank you. And Dr. Beier Jensen, do you have any relevant disclosures that are directly related to this guideline?

DR. SIRI BEIER JENSEN: No, I have no conflicts to declare related to this guideline topic.

BRITTANY HARVEY: Thank you. And finally, Dr. Peterson, do you have any relevant disclosures that are related to this guideline topic?

DR. DOUGLAS PETERSON: No. No related conflicts to declare.

BRITTANY HARVEY: Thank you. Then let's delve into some of the content of the guideline. First, Dr. Mercadante, can you give us an overview of this guideline's scope and purpose?

DR. VALERIA MERCADANTE: Of course. These clinical practice guidelines focus on the prevention and management of salivary gland hypofunction and xerostomia due to non-surgical cancer therapies. This is something we are deeply passionate about because nonsurgical cancer therapies, including all type of radiation regimens, chemotherapy, and biological cancer therapy, can damage the glands in our mouth that produce saliva, resulting in xerostomia, which we define as patient-reported subjective sensation of dryness and salivary gland hypofunction, which we define as reduced salivary flow rate as measured objectively.

And this condition may last for several months or may become permanent. And because saliva serves so many important function, xerostomia may lead to a range of other symptoms that can impact patient quality of life. And therefore, ASCO, MASCC, and ISOO decided to update the findings of their two previous systematic reviews published in 2010 and provide a practical, evidence-based approach in a multidisciplinary setting to address this important topic.

BRITTANY HARVEY: Great. Thank you for that background. So then I'd like to review the key recommendations of this guideline. This guideline covers two clinical questions, one on prevention and one on management. So Dr. Peterson, starting with prevention, what are the key recommendations regarding pharmacologic and non-pharmacologic interventions for the prevention of salivary gland hypofunction and/or xerostomia induced by non-surgical cancer therapies?

DR. DOUGLAS PETERSON: Thank you, Brittany. As you've noted, the guideline is framed in the context of two clinical questions, prevention, and then followed by the management once the condition has occurred. Relative to prevention, there were eight recommendations, all of which were directed to reducing the risk of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer. And as with other ASCO guidelines, each of these recommendations was in turn supported by text directed to literature review and analysis and clinical interpretation.

So let me just briefly highlight the eight recommendations on prevention. Recommendation 1.1 was that intensity-modulated radiation therapy, IMRT, should be used to spare major and minor salivary glands from a higher dose of radiation. This was a very strong, well-evidenced recommendation. The evidence quality was high. The strength of the recommendation was strong.

Recommendation 1.2 is that other radiation modalities that limit cumulative dose to an irradiated volume of major and minor salivary glands as one or more effectively than IMRT may be offered. Recommendation 1.3 reads that acupuncture may be offered during radiation therapy for head and neck cancer to reduce the risk of developing the symptom of xerostomia.

Recommendation 1.4, systemic administration of the sialogogue bethanechol may be offered during radiation therapy for head and neck cancer. Recommendation 1.5-- and this is an important different type of recommendation-- vitamin E or other antioxidants should not be used to reduce the risk of radiation-induced salivary gland hypofunction and xerostomia. And this is because of the potential adverse impact of these antioxidants on cancer-related outcomes and the lack of evidence of benefit.

In addition to those five recommendations, there were three recommendations for which the evidence was insufficient. In the panel's view, it was important to delineate these three recommendations in the context of current clinical practice as well as opportunities for future research that we'll talk about in a little bit.

The three recommendations for which there was insufficient evidence are 1.6. -- The panel was unable to make a recommendation for or against the use of submandibular gland transfer administered before head and neck cancer treatment. This limitation is due to the current amount of evidence associated with this surgical intervention, submandibular gland transfer, in relation to ever-evolving contemporary radiation modalities.

Recommendation 1.7-- evidence remains insufficient for a recommendation for or against use of the following three interventions during radiotherapy for head and neck cancer. The three interventions are oral pilocarpine, amifostine in association with contemporary radiation modalities, and low-level laser therapy.

And then, finally, Recommendation 1.8-- the evidence remains insufficient for or against the use of several interventions, including selected radiation technology, for example, boost radiation or hyper or hypofractionated radiation therapy, Transcutaneous Electrical Nerve Stimulation or TENS, human epidermal growth factor, and selected complementary medicines. And again, the evidence is insufficient in the panel's view for a recommendation for or against these and several other interventions that are listed in the guideline.

So I'll now turn the microphone back to Brittany.

BRITTANY HARVEY: Great. Thank you for reviewing those prevention recommendations and explaining the evidence that supported those as well. That's very helpful. So following that, Dr. Beier Jensen, what are the key recommendations on pharmacologic and non-pharmacologic interventions for the management of salivary gland hypofunction and/or xerostomia induced by non-surgical cancer therapies?

DR. SIRI BEIER JENSEN: The key recommendations for the management of salivary gland hypofunction and xerostomia induced by cancer therapies are based on the principles of stimulation of the salivary reflex and lubrication of the oral tissues of, say, the mucosa and the teeth. The recommendations 2.2, 2.3, 2.4, and 2.5 address this stimulatory approach.

If there is residual secretory capacity of the salivary glands, stimulation of natural saliva secretion may be provided by chewing or taste stimuli. This can be regular use of sugar-free lozenges, sugar-free candies, or sugar-free non-acidic chewing gum. In patients who have their natural teeth, it's important to be aware that if acidic candies are used to stimulate saliva secretion, then it should be a special nonerosive preparation for dentate patients that will say that they do not dissolve the tooth substance.

Pharmacological stimulation is also an option by prescription medication such as oral pilocarpine and cevimeline in countries where this is available. This may result in systemic adverse effects that limit use in some patients. So the gustatory and masticatory salivary reflex stimulation, Recommendation 2.2, the evidence-based quality was intermediate, and the strength of the recommendation was moderate.

And for the pharmacological stimulation by pilocarpine and cevimeline, it was evidence-based, high-quality, and strong recommendation strength. For patients who have salivary gland hypofunction or xerostomia induced by radiation therapy for head and neck cancer, stimulation of saliva secretion may also be provided by acupuncture, transcutaneous electrical stimulation, or acupuncture-like transcutaneous electrical stimulation, although the evidence base here is less strong than for the other stimulatory management options mentioned. This is addressed in Recommendation 2.4 and 2.5.

If the residual secretory capacity of the salivary glands is low or maybe even nonexistent, then regular lubrication of the oral mucosa and teeth is of relevance. This is addressed in Recommendation 2.1. Such lubrication may be provided by topical application of mucosal lubricants and saliva substitutes, which are agents directed at ameliorating xerostomia and other salivary gland hypofunction-related symptoms.

It is of importance to notice that available stimulatory and lubricating options all provide transitory increased salivary flow rates and transitory relief from xerostomia. If you would like to review the specific recommendations, they can be found in the manuscript.

BRITTANY HARVEY: Great. Thank you for reviewing those recommendations on the management of salivary gland hypofunction and/or xerostomia. So Dr. Peterson, you mentioned this earlier, but there are some cases in the guideline in which evidence was insufficient to make recommendations. And you went through a few of these areas. So what areas of future research did the panel discuss?

DR. DOUGLAS PETERSON: Thanks, Brittany. The panel worked very carefully to relate the quality of evidence to strength of each of the recommendations. In addition to providing important context regarding clinical prevention and treatment of xerostomia salivary hypofunction, novel directions for future research were therefore identified. And I'll just briefly delineate these future directions.

Studies directed to the continued, rapidly-evolving radiation technology such as proton therapy and volumetric modulated art therapy or VMAT, as well as the length of time after this treatment is completed, for example, one to five years after completion of treatment, these studies are needed to assess the relationship of this rapidly-evolving technology to the long-term adverse oral events such as salivary gland hypofunction and xerostomia as well as advanced dental disease and osteoradionecrosis as well.

Importantly, and the panel spent quite a bit of time deliberating this, ethical considerations must continue to be paramount in the study designs. And this is pertinent relative to this guideline. An important issue is that implementation of randomized clinical trials comparing current and novel radiation therapy modalities is typically precluded for ethical reasons. So this is a barrier to address, and the panel wanted to call attention to the scientific and clinical community.

In addition to the radiation technology itself, two additional future research directions also represent potential strategic advances in the field as well. First, radiosensitivity of parotid gland stem cells. For example, it has been recently shown that not all constituents of the parotid gland are equally radiosensitive because of an unequal distribution of the stem cells within the gland. This and related biologic concepts should be incorporated in future randomized controlled trials of head and neck cancer patients.

Secondly, novel regenerative medicine options may be used to spare, optimize, or restore salivary gland function after treatment. The guideline addresses these innovative treatment approaches in the context of both the current state of the science as well as opportunities for future research. I'll turn the microphone back to Brittany.

BRITTANY HARVEY: Great. Thank you, Dr. Peterson, for reviewing those areas where additional research would be helpful. So next, in your view, Dr. Mercadante, what is this guideline's importance and how will it affect clinicians?

DR. VALERIA MERCADANTE: Thank you for this question. We believe these guidelines offer an opportunity for any clinician involved in non-surgical cancer therapies-- oncologists, dentists, dental specialists, dental hygienists, oncology nurses, clinical researchers, advanced practitioners. We all have an essential role in supporting our patients for the entire journey by optimizing symptoms management and improve our patients quality of life.

These guidelines thus suggest a preventative and treatment course, but we've also delineated what we feel is common practice between experts and what areas would need further research to provide, as Dr. Peterson beautifully described, an ethical framework for future studies in this field.

BRITTANY HARVEY: Great. Thank you so much. So finally, Dr. Beier Jensen, how will these guideline recommendations impact patients?

DR. SIRI BEIER JENSEN: Well, for patients who live with these complications during cancer treatment or as [INAUDIBLE] of cancer therapies, these guideline recommendations on prevention and management of salivary gland hypofunction and xerostomia will enable them evidence-based and with the help of professional health care providers to support the natural functions of saliva and promote their oral comfort and health.

BRITTANY HARVEY: Great. Well, thank you all, Dr. Mercadante, Dr. Beier Jensen, and Dr. Peterson for taking the time to work on this guideline and produce evidence-based recommendations for clinicians and patients. And thank you for taking the time to speak with me today.

DR. BEIER JENSEN: Thank you.

DR. DOUGLAS PETERSON: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines.  Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at www.SurveyMonkey.com/r/ascoguidelinesurvey by August 1st. The link is also available in the episode notes of this podcast.

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

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An interview with Dr. Muriel Brackstone from London Health Sciences Centre and Dr. Tari King from Dana Farber and Brigham and Women's Cancer Center, authors on "Management of the Axilla in Early-Stage Breast Cancer: OH (CCO) and ASCO Guideline." This guideline addresses management & timing of surgical and radiotherapeutic treatment of the axilla in early breast cancer. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I am interviewing Dr. Muriel Brackstone from London Health Sciences Center in London, Ontario and Dr. Tari King from Dana-Farber and Brigham and Women's Cancer Center in Boston, Massachusetts, authors on "Management of the Axilla in Early-Stage Breast Cancer" Ontario Health (Cancer Care Ontario) and American Society of Clinical Oncology Guideline." Thank you for being here Dr. Brackstone and Dr. King.

DR. MURIEL BRACKSTONE: Thank you.

DR. TARI KING: Thank you for having us.

BRITTANY HARVEY: First, I'd like to note that we take great care in the development of our guidelines in both the ASCO and Ontario Health Cancer Care Ontario program and evidence-based care. Conflict of interest policies were followed for this guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Brackstone, do you have any relevant disclosures that are directly related to this guideline topic?

DR. MURIEL BRACKSTONE: No, I don't have any conflicts to disclose.

BRITTANY HARVEY: Thank you. And Dr. King, do you have any relevant disclosures that are directly related to this guideline topic?

DR. TARI KING: No, I do not have any relevant disclosures.

BRITTANY HARVEY: Great, thank you. Then let's get into some of the content of this guideline. So first, Dr. Brackstone, can you give us a general overview of what this guideline covers?

DR. MURIEL BRACKSTONE: Sure. This guideline reviews how best to diagnose and treat any lymph node spread in breast cancer patients with early-stage disease. It also reviews the role of radiation and surgery in treating the axilla to reduce the risk of regional cancer recurrence in these patients.

BRITTANY HARVEY: Great, thank you. Then I'd like to review some of the key recommendations that this guideline covers. So this guideline addresses five specific objectives. So I'd like it if we could go through each of those.

So for each of these objectives, could you give an overview of those high level recommendations? First, Dr. King, the first objective is about which patients with early-stage breast cancer require auxiliary staging.

DR. TARI KING: Yes, thank you. So I think the two main takeaway points from this objective-- the first is that sentinel lymph node biopsy really is the standard of care for axillary staging for all breast cancer patients when it is felt that information about the lymph node status is necessary. So this really is in the majority of patients that we see and care for with early-stage breast cancer.

We want to know the status of the axillary lymph nodes. That's important in our subsequent treatment recommendations. And there's really no role for axillary lymph node dissection as a staging procedure any longer. Sentinel lymph node biopsy is the staging procedure of choice.

Now, there are some patient populations, however, where we may decide that we don't need the information from the axillary lymph nodes to make subsequent treatment recommendations. And one particular group which is called out in this guideline is for those women who are over the age of 70 with early-stage, again, clinically node-negative hormone receptor-positive, HER2-negative breast cancer, where the information from the sentinel lymph node biopsy is not going to alter subsequent systemic therapy recommendations.

And this is really based on several lines of work demonstrating that omitting sentinel node in these older women, again, with hormone receptor-positive, HER2-negative breast cancer, does not negatively impact their long term outcomes. And so this is an opportunity for us to tailor our approach to a particular patient population without having a negative impact.

BRITTANY HARVEY: Great, thank you, and thank you for reviewing for which patients this is specifically targeted to. So then for the second objective, Dr. Brackstone, is further auxiliary treatment indicated for women with early-stage breast cancer who did not receive neoadjuvant chemotherapy and are sentinel lymph node-negative at diagnosis?

DR. MURIEL BRACKSTONE: No. We use this guideline to confirm that in patients who have early-stage disease and go to surgery first, so they're not having neoadjuvant chemotherapy. And in those patients, if their sentinel lymph node excision for staging is negative, that no further axillary surgery is required. Now, with regards to axillary radiation, it may be considered in the subset of patients whose breast cancer risk is high for recurrence-- so the triple negative subtype, patients who are under 50 years of age, or those with medial tumors.

BRITTANY HARVEY: OK. And then Dr. King, for the third objective, which axillary strategy is indicated for women with early-stage breast cancer who did not receive neoadjuvant chemotherapy and are pathologically sentinel lymph node-positive at diagnosis after a clinically known negative presentation?

DR. TARI KING: Thank you. Yes, so this recommendation really addresses a very large population of our breast cancer patients. Those that present with clinical T1 and T2 but node-negative early-stage breast cancer, we take them to the operating room. We perform a sentinel biopsy, and about 20% to 30% of them will actually end up having positive lymph nodes.

And traditionally, we thought that we needed to do axillary lymph node dissection in the setting of positive nodes. But we now have multiple clinical trials that have addressed this question. And we now know that it is safe to avoid lymph node dissection in women found to have one or two positive sentinel nodes.

We've had trials that have compared lymph node dissection to axillary radiotherapy or lymph node dissection to observation alone. And with either of those strategies, we've seen excellent local control in the women who have not undergone lymph node dissection. And so it really provides us, again, an opportunity to dial back or tailor our therapies to the patient's individual disease burden.

Now, certainly, patients that have more than one or two positive nodes, and the guideline specifically states how to manage patients with three or more positive nodes. And those patients do need additional axillary treatment, either in the form of lymph node dissection or lymph node dissection plus axillary radiotherapy and in some scenarios. Also, the guideline is very clear to define that there are some differences in the level of recommendation for women undergoing breast-conserving surgery and found to have one or two positive nodes as opposed to women undergoing mastectomy and found to have positive nodes.

So certainly, we have the larger body of data in the breast-conserving therapy group, but the guideline is very clear to also highlight the data that is available for the mastectomy group. And again, the overall recommendation is that not everybody with positive nodes needs additional lymph node dissection. And that we have alternatives which we know minimize the morbidity of our treatments.

BRITTANY HARVEY: Great. Thank you for addressing the evidence base behind both of those recommendations as well. So following that, Dr. Brackstone, for the fourth objective, what axillary treatment is indicated? And what is the best timing of axillary treatment for women with early-stage breast cancer? And when is neoadjuvant chemotherapy used?

DR. MURIEL BRACKSTONE: Right. So this guideline was really used to formalize a recommendation against repeating the sentinel lymph node biopsy procedure twice in patients, before and after chemotherapy. We really found that the risk of false negativity in a repeat procedure was too high. So for patients who are having neoadjuvant chemotherapy-- so patients with higher risk cancers-- the axillary ultrasound is useful to guide a biopsy of any suspicious lymph nodes to document if they're positive.

If the clinical exam and the ultrasound are both negative, then the sentinel lymph node excision should be done at the time of surgery after chemotherapy. If they do have a positive lymph node that's confirmed by biopsy before their chemotherapy, and those lymph nodes respond really well to chemotherapy and are no longer palpable, then their staging can occur by sentinel lymph node procedure at the time of surgery. And that avoids what we have standardly done up to now, which is the axillary dissection and the risk of lymphedema that comes with that.

If the sentinel lymph nodes are negative when you're doing your surgery after neoadjuvant chemotherapy, then we are recommending that no axillary lymph node dissection is required. If any of the lymph nodes are positive after neoadjuvant chemotherapy through the sampling technique, then a completion axillary lymph node dissection is still recommended, at least for now, until the results of some ongoing clinical trials looking at avoiding axillary node dissection are completed, which will be in the next several years. In both of those scenarios, however, locoregional radiation is still recommended.

BRITTANY HARVEY: Great, thank you for providing some clarity around those specific scenarios. So then finally, Dr. King, regarding the fifth and last objective, what are the best methods for identifying sentinel nodes?

DR. TARI KING: Thank you. Yes, so this objective encompasses several different clinical scenarios as well. The first being, when you are performing a sentinel lymph node biopsy procedure, do you need to use single tracer or do you need to use dual tracers to help you identify the lymph nodes? We know that in the up upfront surgery setting that you can absolutely identify the nodes with a very low false-negative rate with a single tracer. And this guideline highlights that single tracer is appropriate in patients who are undergoing upfront surgery.

The guideline suggests that the physicians start with radiocolloid, and if there is a good signal, then blue dye can be omitted. In contrast, though, in patients that are receiving neoadjuvant chemotherapy, the data there supports really that the use of dual tracer is important and improves the identification rate, as well as decreases the false-negative rate of the procedure. This recommendation also includes guidance on when ultrasound should be used.

As you just heard from Dr. Brackstone that they do recommend ultrasound prior to neoadjuvant chemotherapy. But in patients undergoing upfront surgery, again, with early-stage disease, clinically node-negative disease, the guidelines states that preoperative axillary ultrasound staging is not recommended. But in anybody who has suspicious or potentially abnormal nodes, then preoperative axillary ultrasound is recommended to confirm nodal status.

And then finally, it is important to note that nodal staging cannot be solely performed with axillary ultrasound. So sentinel lymph node biopsy is still, again, indicated even if the ultrasound is negative. There are many clinical trials going on around the world right now to address that question.

But right now, the evidence still certainly supports that we cannot rely on a negative axillary ultrasound, and sentinel lymph node biopsy should be performed.

BRITTANY HARVEY: Great. Well, thank you both for reviewing those key recommendations around the objectives. So then Dr. Brackstone, in your view, what is the importance of this guideline? And how will it both impact clinicians and patients?

DR. MURIEL BRACKSTONE: Thank you. I would say for clinicians that the guideline was written in an effort to collate all of the clinical trial data and the variable practice patterns across institutions in an effort to standardize treatment. In order to deescalate therapies that don't improve patient outcomes. And hopefully, provide some clarity for clinicians who treat breast cancer.

For patients, I would say that deescalating treatments that are entrenched as standard, but where data demonstrates no known significant disease-free survival or overall survival benefit, that these are important because patients can suffer long term side effects from treatments, such as lymphedema, that could potentially be avoided if they're not clinically indicated.

BRITTANY HARVEY: Great. Thank you both so much for your work on these evidence-based recommendations. And for taking the time to give a summary to our listeners, Dr. Brackstone and Dr. King.

DR. TARI KING: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines.  Additionally, our annual survey for guideline topics is open for submissions.

Suggest a topic for guideline development at www.surveymonkey.com/r/ascoguidelinesurvey by August 1. The link is also available in the episode notes of this podcast. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

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An interview with Kim Woofter, RN from Advanced Centers for Cancer Care and John V. Cox, DO, MBA from UT Southwestern Medical Center, co-chairs on "Oncology Medical Home: ASCO and COA Standards." They review the standards for the OMH model, which is a system of care delivery that features coordinated, efficient, accessible, evidence-based care and includes a process for measurement of outcomes to facilitate continuous quality improvement. For more information, visit www.asco.org/standards.

TRANSCRIPT

[MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm interviewing Kim Woofter, RN from the Advanced Centers for Cancer Care in South Bend, Indiana, and John Cox, DO, MBA, from UT Southwestern Medical Center in Dallas, Texas, co-chairs on Oncology Medical Homes, American Society of Clinical Oncology, and Community Oncology Alliance Standards. Thank you for being here, Ms. Woofter and Dr. Cox.

JOHN COX: You bet.

KIM WOOFTER: Thank you for having us.

BRITTANY HARVEY: I'd like to note that ASCO takes great care in the development of its standards and ensuring that the ASCO conflict of interest policy is followed. The full conflict of interest information for the expert panel is available online with the publication of the standards in JCO Oncology Practice. Ms. Woofter, do you have any relevant disclosures that are directly related to these standards?

KIM WOOFTER: No, I don't have anything to disclose.

BRITTANY HARVEY: Thank you. And Dr. Cox, do you have any relevant disclosures that are related to these standards?

JOHN COX: I do not.

BRITTANY HARVEY: Great. Then let's talk a little bit about these standards. So first, can you give us a general overview of the purpose and scope of these standards for the Oncology Medical Home or OMH model?

KIM WOOFTER: Sure. I'll start this one out. The purpose was to collaboratively define a care delivery system with a standardized set of expectations and goals, and it all centered around the delivery of high quality, cost-effective care. And one of the reasons this is so important to all of us right now is to be ready for value-based care. We all need to really have a care delivery system that's patient-centric and has a standardized set for all of us to follow. Dr. Cox, do you see this any differently, or what would you have to say?

JOHN COX: No, I think you've said it well, Kim. I think one of the challenges we all have when we talk about Oncology Medical Home or a system of care is to be challenged to address that question in a simple answer. I would give the predicate that we have had a blossoming of the complexity of oncology care in our science, yet one of the thorny issues that faces oncology practice is how do we equitably and efficiently provide quality oncology care.

And if you were to challenge many clinicians to define how they provide quality oncology care, you get diverse opinions about that. The Oncology Medical Home certification program and the system of care that Kim highlighted attempts to put forward a comprehensive set of standards that helps us define what quality oncology care looks like and to answer those questions in care delivery.

BRITTANY HARVEY: Great. Then, given that scope, what are the key statements made by the expert panel in these standards?

JOHN COX: I'll take a stab at that, but also offer a little bit of insight into the development of Oncology Medical Home. We actually had some 20 years of history with different medical home certification programs to draw on, including significant contributions by oncologists who have worked in different programs to help define what Oncology Medical Home is. So when we took on this project, a collaborative project between ASCO and the Community Oncology Alliance, COA, we drew upon that great history of previous certification programs.

These programs focused on different aspects of care delivery, including aspects that are focused on improving patient engagement and access to practice, ensuring that evidence-based medicine is provided in a practice, looking at how quality is measured and how that feedback is given to practices and how that feedback is used to have quality improvement programs, focusing on palliative and end-of-life care, and addressing one of the unique features of medical oncology delivery, which is the delivery of chemotherapy and how we do that safely. So this was a very comprehensive set of standards. Kim, I don't know if you want to add to this.

KIM WOOFTER: No, I think you stated that very well. And the piece that I really love about this project, and what we focused heavily on, is the equitable delivery of care. We all fundamentally believe that every cancer patient deserves and has the right to high quality, cost-effective care, and this was just the baseline. And I think Dr. Cox explained it very well, that one of the key elements is the quality improvement process, or the re-evaluation continually of how we deliver care, the outcomes of care, the patient satisfaction with that care.

So as we developed this, we knew this was just the foundation. This is the starting point. We've brought some unity around the discussion. We've used evidence to come up with these standards and really defined what's gone on prior to this time. And what's exciting is this is just the beginning of what will evolve over the years to come.

BRITTANY HARVEY: Great. It sounds like this is a really comprehensive document. So I'm reading through the standards. It looks like there's a little bit of a deeper dive on two subcomponents of the OMH model-- first, clinical pathways, and second, survivorship care plans. How do the standards address these two?

JOHN COX: Oh, I'll dive in first again. And not to step on Kim at all about this, but many of the listeners to this podcast will be very familiar with ASCO guideline development. And the traditional clinical guidelines are completely infused and based on an evaluation of what the evidence base is. Care delivery is a bit more complex. Much of care delivery focuses on best practices that have been learned in practice through trial and error-- observation, if you will.

So many of the standards that are in Oncology Medical Home certifications are really based on best practices. However, we knew that we would be challenged to evaluate those standards that had significant cost or significant resource dedication in a practice. If we were going to build those aspects of a certification program forward as being a best practice in a care delivery model, we would need to justify, or at least examine, what evidence base is present to show that it had value.

Two of the most consequential standards that are going to require significant resource development by any practice is the measurement of evidence base through a pathway program. The other one was the significant discussion that has been around survivorship and survivorship care plans. So those two areas of the standards we took a deep dive in in this process. Kim, do you want to add to this?

KIM WOOFTER: Yeah. I really appreciate Dr. Cox's description. He's spot on, as always. I think having managed to practice myself for many, many years, the struggle with the implementation of a clinical pathway program and survivorship care plans or for survivorship program have always been somewhat difficult. And what I love about the standards is we clearly define that pathways are no longer a homegrown list of what I like to do or how I like to treat. It is absolutely evidence-based. Your pathways have to truly reflect the importance of clinical research and what that has done to lead up to the intelligence of that delivery.

What I think is so important, too, is ASCO still did a little bit of work and set the pathway for us on this in that it needs to be a comprehensive list. It needs to have systematic review. We have to demonstrate adherence to pathways and also document when somebody goes off a pathway. And I think that's very important as you manage a practice and as you prepare for this delivery system. It's no longer what we do in the back room. It's very well-defined and very measurable.

As far as survivor care plans, I love that we have migrated a little bit on this standard. I think the nation has migrated. Over the years-- and I'll include the COC in this discussion. Originally, it was check the box, have a survivorship care plan and a visit to explain what the future would look like. And we now know that isn't the best way to handle survivorship.

Patient satisfaction and outcomes are much better when we have a survivorship program. And that's what the standard calls out. It is not just a care plan or a piece of paper. It is support. It is ongoing evaluation of the patient. It's integration with the primary care and when to transition back to primary care. So what's exciting is it is now a program versus just a care plan.

BRITTANY HARVEY: Thank you both for explaining the evidence-based reasoning behind those two components. So then you've both noted earlier the importance of these standards for quality oncology care. So why are these standards important, and how will their implementation impact clinicians?

KIM WOOFTER: I'll jump in to why I think they're important-- and I think the whole industry, the whole ecosystem of oncology care thinks they're important-- is we need standardization. We need real, evidence-based standardization. And we need to prepare ourselves in all settings-- community oncology practice settings, academic settings-- for the value-based care that we're going to be required to deliver every day, all day. And clinicians, I believe, will embrace this. They'll embrace this because it's taken away some of the ambiguity of what care delivery should look like, and it levels the playing field, if you will.

It also helps with the dialogue with patients and their employers. I think we could all argue that patients and employers are the ultimate payers. And they now have a mechanism by which they can evaluate, am I getting the highest quality, most affordable care? And these Oncology Medical Home standards will be the foundation for that discussion. And I'm excited that everyone will be involved in that discussion. So I think that's why they're very important.

BRITTANY HARVEY: Great. And then, finally, how will these standards impact patients?

JOHN COX: Well, I think our whole goal in delivering efficient and quality oncology care is to be very patient focused. I would underline that this entire concept of an Oncology Medical Home is built around a patient centered care. So every standard that this program identifies has the patient at the center of care. And I think anybody who reads through the standards can see that every aspect of this is focused on some issue that they can relate to patients in their practice stumbling over.

We have this wonderful technology of care. But right now, I would challenge oncology practice universally that as our science has become more complex, patients are having to jump through more hoops to get that quality care. Specialization breeds fragmentation. What we want this program to do is to define what a oncology practice must do to help that patient have a coordinated care approach for all aspects of their cancer journey.

And I want to come back and just put a coda, a real strong statement, is this is a care delivery system. We are trying to take as comprehensive view of the delivery of oncology practice in the certification program as we can. It's not intended to parse. It's intended to focus on the patient and to provide a comprehensive system of care.

The other challenge is we know that the only way there can be efficient and easily accessible practices that can provide this kind of care is that they be adequately funded. And though this certification program does not speak to funding directly-- this is about the quality of care delivery-- we wanted to build a program that payers in industry could look at and build their reimbursement systems around. We hope that as new reimbursement models, alternative payment models come to bare, that if practices are pursuing this certification program, they will be able to meet the demands of the payer and apply this toward a comprehensive, meeting the standards of any alternative payment program.

And to that end, I really want to defer maybe a little more discussion of this to Kim. Kim, we sort of present two ends of the barbell, if you will, of care delivery. I, a practitioner, Kim is on the point of the sword in dealing with her practice about the reimbursement issues and contracting. So when we talk about this, what is the impact for patients?

Part of that is recognizing that patients have insurance. They have employers. They have people who are paying for this care. And that's really important to address. Kim, I'm long-winded. Maybe I'm trying to wrap too much into this answer. But I'll let you add to the issues of reimbursement and how this affects patients.

KIM WOOFTER: Well, thank you, Dr. Cox. You're never too long-winded. I always love to hear you speak, and your insight is spot on. And I think, from a patient's perspective, what's exciting about this program is it engages and empowers patients right from the beginning. You'll see, very well spelled out in the standards, that one of the requirements is that you educate that patient about what an Oncology Medical Home really means, what the components are. And that empowerment of the patient allows them to be part of the voice for quality oncology.

As we work with their payers, their employers, the patient themselves understand the value of what we are doing in collaboration. They understand that we provide them access, 24/7 access, you'll see, as part of the requirement. And they understand very well and can help us communicate to everybody in the ecosystem that this comprehensive package is what gives them the highest quality, allows them, like I said, the most access. It allows them safe chemo delivery. And as they communicate that, it will become the desired standard.

The patient is absolutely the ultimate winner here. Everything we do as clinicians and administrators is based around the patient. Outcomes, satisfaction, end-of-life initiatives. And I believe by putting this comprehensively and well-defined into one set of standards, we have helped the patient to achieve that goal.

BRITTANY HARVEY: Well, it sounds like these standards will have a real positive impact for patients and quality oncology care delivery. So I want to thank you both for your work on the development of these Oncology Medical Home standards and for taking the time to speak with me today, Dr. Cox and Ms. Woofter.

KIM WOOFTER: It was our pleasure.

JOHN COX: It's our pleasure.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the standards, go to www.asco.org/standards. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe so you never miss an episode.

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An interview with Dr. Zeba Aziz from Hameed Latif Hospital in Lahore, Pakistan, Dr. William Burke from Stony Brook University Hospital in Stony Brook, NY, and Dr. Keiichi Fujiwara from Saitama Medical University International Medical Center in Saitama, Japan, authors on "Assessment of Adult Women with Ovarian Masses and Treatment of Epithelial Ovarian Cancer: ASCO Resource Stratified Guideline." This guideline provides recommendations in three resource-constrained settings on diagnosis and staging of adult women with ovarian masses and treatment of patients with epithelial ovarian (including fallopian tube and primary peritoneal) cancer. Read the full guideline at www.asco.org/resource-stratified-guideline.

TRANSCRIPT

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today, I'm interviewing Dr. Zeba Aziz from Hameed Latif Hospital in Lahore, Pakistan, Dr. William Burke from Stony Brook University Hospital in Stony Brook, New York, and Dr. Keiichi Fujiwara from Saitama Medical University International Medical Center in Saitama, Japan, authors on Assessment of Adult Women with Ovarian Masses in Treatment of Epithelial Ovarian Cancer: ASCO Resource Stratified Guideline.

Thank you for being here, Doctors Aziz, Burke, and Fujiwara. First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline and the Journal of Clinical Oncology, Global Oncology. Dr. Burke, do you have any relevant disclosures that are directly related to this guideline topic?

DR. WILLIAM BURKE: I do not.

BRITTANY HARVEY: And Dr. Fujiwara, do you have any relevant disclosures that are related to this guideline topic?

DR. KEIICHI FUJIWARA: Yes. I have the consultancy for the PARP inhibitors development.

BRITTANY HARVEY: Thank you. And then Dr. Aziz, do you have any relevant disclosures that are related to this guideline?

DR. ZEBA AZIZ: No, I don't.

BRITTANY HARVEY: Thank you. OK, so first, Dr. Burke, can you give us a general overview of what this guideline covers?

DR. WILLIAM BURKE: Sure, Brittany. The purpose of this guideline is to provide expert guidance in treatment of adult women 18 years and older with epithelial ovarian cancer, including fallopian tube and primary peritoneal cancer, to clinicians, public health leaders, patients, and policymakers in a resource-constrained setting. To do this, ASCO has established a process for development of resource stratified guidelines, which includes a mixed methods of evidence-based guideline development, adaptation of the clinical practice guidelines to other organizations, and formal expert consensus. This guideline summarizes the results of this process and presents resource-stratified recommendations. The recommendation of this guideline centers around the four key clinical questions pertaining to the care of women with ovarian cancer.

BRITTANY HARVEY: Great. And then, as you just mentioned, this is a resource-stratified guideline. So Dr. Fujiwara, can you tell our listeners about the four-tier resource stratification used for the development of this guideline?

DR. KEIICHI FUJIWARA: Oh, yes. So we have the four tiers resource stratification, which were basic, limited, enhanced, and maximum. So for the basic, it's the core resources or fundamental services that are absolutely necessary for any public health or primary health care systems to function. So the basic levels of this typically are applied in our single clinical interactions. For the limited, so this is the second tier resources or services that are intended to produce major improvements in outcomes such as, for instance, cost-effectiveness, and are attainable with a limited financial means and modest infrastructures. So the limited level of service may involve single or multiple interactions. And the third  tier is enhanced. The third tier resources or services that are optional, that are important, enhance the level of resources should produce further improvements in the outcome and to increase the number of the quality of options in the individual choices. Lastly, the fourth tier is a maximal, so high-level or state of the art resources, or services that may be used or are available in some high-resource countries, and/or may be recommended for the high resource setting guidelines that do not adapt to resource constraints, but that nonetheless should be considered for a lower priority than those resources or services listed in the other categories on the basis of extreme cost and/or impracticality for the broad use of the resource-limited environment.

BRITTANY HARVEY: Great. Thank you for going over those. So next, I'd like to review the key recommendations of this guideline. This guideline addresses four overarching clinical questions. So first, Dr. Aziz, what are the key diagnostic and staging recommendations for patients with symptoms of epithelial ovarian cancer?

DR. ZEBA AZIZ: Thanks, Brittany. Basically, as pointed out, we have three levels. The basic level usually involves one or two encounters, and at the basic level, the doctor makes a clinical assessment of a suspected ovarian mass, takes a good history and physical, and the family history is also important at the same time. At the basic level, one can do a chest X-ray and an ultrasound to confirm the suspicion, and then the doctor should ideally send the patient to a limited or an enhanced level-- wherever the patient can go. At the limited and enhanced level, again, you have to do diagnostics, which include a CT scan and an MRI if it's available and feasible.

You can do the biomarker studies for CA125 and CEA level, and to make a diagnosis, you can do a CT-guided biopsy. You can also do a cell cytology and if a cell block preparation can be made through cell block. Very rarely, if need be, and if you think that you need to make a diagnosis and you can't do anything else, laparoscopy can be done. Once the diagnosis is made, you then go for staging. And the staging is usually done when you're doing a CT scan and you do an abdominal and pelvic CT scan. You do a CT scan of the chest if you think it's needed. Otherwise, a chest ray will suffice. And then you go forward and get a diagnostic workup done and send it to the surgeon for either and decide on a multidisciplinary with a neoadjuvant or surgical assessment testing.

BRITTANY HARVEY: Great. Then so next, Dr. Fujiwara, what are the overarching recommendations for surgery with women with stage one to four epithelial ovarian cancer?

DR. KEIICHI FUJIWARA: Yes. So the purpose of the surgery is to diagnose, stage, and/or for treatment. So we strongly recommended the ovarian cancer surgery should be performed by trained gynecological oncologists or surgeons with oncologists' surgical expertise. If it is not suitable, we strongly recommend to refer those patients to the highest-resourced level center with an oncology surgical care capacity.

For the staging purpose, where the feasible patients with a presumed early stage ovarian cancer should undergo surgical staging by train surgeons. In basic setting, surgical staging is not feasible. Thus, it is not recommended. For the treatment purpose of the women with advanced ovarian cancer, which is a stage three or four, should receive optimal surgical debulking to remove all visible disease to improve overall survival by trained surgeons.

BRITTANY HARVEY: Great. And then Dr. Burke, what are the key recommendations for optimal adjuvant and systemic therapy for patients with stage one to four epithelial ovarian cancer?

DR. WILLIAM BURKE: Sure. Well, one of the most important things is that access to appropriate evidence-based chemotherapy agents, contraindications to chemotherapy, and potential side effects of chemotherapy should be evaluated and managed in every patient. Basic resource settings that most likely lack the capacity to provide safe administration of chemotherapy should refer patients to a higher level center for evaluation. Limited settings without skilled capacity should refer patients to settings with access to specialized care. Some other notes include that clinicians should be able to document pathology and stage to determine eligibility for adjuvant chemotherapy.

If pathology confirmation is not possible due to patient or resource limitation, alternatives can be discussed. Clinicians should not administer systemic treatment, adjuvant chemotherapy, to patients with ovarian low malignant potential tumors or early stage, microinvasive borderline tumors, independent of stage. Combination chemotherapy with paclitaxel and carboplatin is the standard of care for adjuvant therapy in ovarian cancer. However, single agent carboplatin may be utilized due to resource limitation or patient characteristics. Only in enhanced settings, highly selected cases can be assessed for appropriate evidence based intraperitoneal chemotherapy following optimal debulking, where there are resources and expertise to manage the toxicities.

BRITTANY HARVEY: Great. And then the last overarching clinical question-- Dr. Aziz, what is recommended for patients with recurrent epithelial ovarian cancer?

DR. ZEBA AZIZ: You know, with recurrent ovarian epithelial cancer is a tough option, especially in patients residing in the low-middle income countries. Supportive care treatment should be started together with whatever we have to do. So there are three options. There's one patient who presents with a rising CA125 with no evidence of disease and asymptomatic. We can elect to follow these patients, and it's easier to follow them until they become symptomatic or they have evidence of disease. If you have small volume disease which is resectable, you send them to an enhanced level setting, ideally where surgery can be done.

Then you also look at patients and divide them into platinum resistant or platinum sensitive. If they're platinum sensitive, you can give a platinum-containing regimen, but if they're platinum resistant, you can put them on a non-platinum chemotherapy-- a single agent or whatever-- but these patients are tough to manage in that part of the world.

BRITTANY HARVEY: Definitely. Well, thank you all for reviewing each of those key recommendations. The full recommendations are available in the guideline, but those are some important highlights. Thank you very much. So Dr. Burke, in your view, what is the importance of this guideline, and how will it change practice?

DR. WILLIAM BURKE: Sure. Well, I think the importance of this guideline is that it globally targets health care providers, including gynecologic oncologists, surgeons, nurses, and palliative care clinicians, as well as non-medical community members, including patients, caregivers, and members of advocacy groups, providing them with resource-stratified clinical guidelines, recommendations that can be implemented across many health settings. The guideline will hopefully raise awareness among frontline practitioners, and provide guidance to provide adequate services in the face of varied and sometimes limited resources we see throughout the world.

BRITTANY HARVEY: Great. And Dr. Aziz, how do you envision that these guidelines can be applied in low and middle income regions?

DR. ZEBA AZIZ: These are extremely important guidelines for our part of the world. Remember that there are about 70 low-middle income countries, and all these countries-- and within each country-- there's marked variability in training of physicians who encounter cancer patients. There's also difficulty by the patients in accessing a few tertiary care centers, cancer care centers which are present, and most of all, financial implications, because you have to go there, you have to stay there, you have to get your chemotherapy, and this is true for the marginalized population.

You also have to remember that more than 50% of our patients are treated in a limited resource setting, and the availability of enhanced resources are very difficult for them. And these limited settings are in public sector hospitals, where the doctors-- some of the doctors are very good, but the physicians or surgeons are overworked. They have resources ranging from minimal to moderate, depending on the funds available. And because they're overworked and there are few working hours, detailed counseling of the patient is infrequent because there are a large number of patients there. And the majority of surgeries, which is the cornerstone of ovarian cancer, is done by the postgraduate fellows who are there. Sometimes the senior consultants do surgeries, but most of the time, it is done by them.

First time chemotherapy is easier to deliver because it does not have any expensive medicines. There are a lot of generics for carboplatin and taxanes regimen available, so it's not a major problem. But treating the side effects, again, becomes very expensive, and the patients have to come back and forth. The relapsed disease is very difficult to treat because we don't have too many options there and it is expensive. We've also seen that patients who are treated at an enhanced level do much better. Their survival outcomes are better, the supportive care treatment is better, and the progression-free survival is also better.

BRITTANY HARVEY: Great. Thank you for reviewing that information. And then finally, Dr. Fujiwara, Dr. Aziz touched on this a bit on how it impacts patients, but how else do you view that these guideline recommendations will affect patients?

DR. KEIICHI FUJIWARA: Yes. As Dr. Aziz said and Dr. Burke said, this guideline is written for the patients around the world in a different medical environment. So I think that it is very useful resource of information for patients to receive the best ovarian cancer treatment that suits the actual situation of each country or regions.

BRITTANY HARVEY: Great. Well, thank you all for your work on these important guidelines. It sounds like they're going to have a real impact globally, and so I really appreciate both all of your work on these guidelines, and also for taking the time to speak with me today, Dr. Aziz, Dr. Burke, and Dr. Fujiwara.

DR. ZEBA AZIZ: Thank you, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/resource-stratified-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

An interview with Dr. Jennifer Griggs from University of Michigan and Dr. Gary Lyman from Fred Hutchinson Cancer Research Center & University of Washington, co-chairs on "Appropriate Systemic Therapy Dosing for Obese Adult Patients with Cancer: ASCO Guideline Update." This guideline updates recommendations on appropriate dosing of systemic antineoplastic agents – including cytotoxic chemotherapy, checkpoint inhibitors, and targeted therapies – for obese adults with cancer. Read the full guideline at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

[MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at podcasts.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Jennifer Griggs from the University of Michigan and Dr. Gary Lyman from Fred Hutchinson Cancer Research Center and University of Washington, co-chairs on appropriate systemic therapy dosing for obese adult patients with cancer ASCO guideline update. Thank you for being here, Dr. Griggs and Dr. Lyman.

DR. GARY LYMAN: Thank you, Brittany.

DR. JENNIFER GRIGGS: Thanks for having us.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Griggs, do you have any relevant disclosures that are directly related to this guideline topic?

DR. JENNIFER GRIGGS: No, I don't.

BRITTANY HARVEY: And Dr. Lyman, do you have any relevant disclosures related to this guideline?

DR. GARY LYMAN: I have no relevant disclosures to this guideline.

BRITTANY HARVEY: Great. Thank you, both. Then let's get into the substance of this guideline update.

So Dr. Lyman, can you explain what prompted an update to this guideline on appropriate dosing for obese adult patients with cancer last published in 2012, and what is the scope of this update?

DR. GARY LYMAN: Thank you, Brittany. Yes, this is an update of a previous guideline, several years old, that was prompted by evidence that there was wide variation in how chemotherapies at that time were being dosed, particularly in the overweight and obese population. Some were capping the dose, some were giving the full weight-based dosing, and all sorts of permutations in between. So that guideline was greeted, I think quite favorably, and, in fact, led to changes in clinical practice in many institutions and I believe also in the cooperative group research networks.

Since that time, however, a whole array of new therapies have come along. These, we'll talk about briefly in this podcast, include the novel targeted therapies based on molecular targets, as well as the new checkpoint inhibitors, and other monoclonal antibody therapies, where the dosing issues, in general, are different for many of these agents. And specifically for patients who are overweight and obese, we thought it was important that we update this guideline, review the evidence in total appropriate to the dosing of these new agents in overweight and obese patients, and make updated recommendations that would be more relevant to that practice of oncology in 2021.

BRITTANY HARVEY: Great. Thank you for explaining the previous version of the guideline and for explaining the expanded scope. So given that, I'd like to review those key recommendations made in this guideline. So Dr. Griggs, what are the recommendations regarding dosing of cytotoxic chemotherapy in obese adults with cancer?

DR. JENNIFER GRIGGS: With rare exception, we recommend, and the evidence supports, using actual body weight when we calculate doses. So whether it's just per kilogram, milligrams per kilogram for example, or per meter squared, using body surface area, we recommend that the actual body weight of the patient be used with no compromise or capping, no maximizing the dose as if it were calculated using 2 meter squared for example. There's no evidence that that's necessary to avoid side effects, and, in fact, there's increasing evidence that doing so, that limiting the doses in patients, is associated with decreased benefit of the treatment.

Since the original guideline came out, there's been no convincing evidence that has made us change our recommendation. So again, in brief, we recommend that actual body weight be used in calculating the target dose for cytotoxic chemotherapy.

BRITTANY HARVEY: Great. Thank you. That's very clear for clinicians. So Dr. Lyman, you mentioned this in your introduction to the scope of this guideline, what are the recommendations for dosing of checkpoint inhibitors and targeted therapy in obese adults with cancer?

DR. GARY LYMAN: Well, Brittany, these are the new agents that I referred to in the introduction that have appeared in broad usage in oncology and other disciplines since our 2012 guideline recommendation. Many of these are monoclonal antibodies, and they just generally have a wider therapeutic index and distribute an extracellular fluid and plasma with less correlation with body size descriptors, such as weight or body surface area. They may be, in fact, in some cases are amenable to fixed dosing schedules.

So this has all led to a whole array of new agents approved by the FDA for cancer therapies that are being dosed on a wide variety of means, some based on dosing like we have done for classical chemotherapy that Dr. Griggs discussed using body surface area, in some cases body weight, and then some being dosed base on fixed dosing-- fixed size regardless of the body size that the patient represents. So it gets a little complicated, because currently the monoclonal antibodies and many of these therapies are dosed in different ways, versus fixed dosing is recommended for some of the immunotherapies, alemtuzumab, afatinib, as well as targeted therapies like pertuzumab, which are relatively recent.

And then weight-based dosing, milligram per kilogram, is used for other checkpoint inhibitors, like ipilumumab, as well as other monoclonals like bevacizumab and trastuzumab among others. And then again some were still dosing based on body surface area, such as rituximab and cetuximab. So the bottom line is these agents will be dosed and the approved dosing by the FDA will generally be based on the schedule and dosing that was used in the pivotal clinical trials. And different companies in different disease areas have chosen different ways of dosing these.

So for us, with this guideline, and this is true of overweight and obese patients in particular, we recommend dosing these agents based on the FDA approved dose and schedule for that agent. But be aware, as I indicated, that it will vary from agent to agent and category of agent from one to the other. Because of the convenience and perhaps some safety issues related to fixed dosing, additional data has been submitted to the FDA for some agents, nivolumab, for instance, and pembrolizumab, to suggest that a different dosing schema, fixed dose schema can be used, and that has led to a modification in those dosing recommendations.

So even if you think you know, if you're not using these agents day in and day out, you really should check and make sure you're using the currently recommended dosing. And final point is, in the overweight and obese patient, any dose modification because of adverse events or scheduling changes should be applied independent of the patient's obesity or overweight status. In other words, any dose modification that you would apply a healthy weight patient is the same type of dose modification you should apply in the overweight and obese patient and not modify solely based on the patient's weight or obesity status.

BRITTANY HARVEY: Definitely. Great. That was actually going to be my next question. So Dr. Griggs, do you have anything to add about for obese adult patients with cancer who experience high grade toxicity-- should clinicians modify dosing and schedules differently than they would for non obese patients?

DR. JENNIFER GRIGGS: Well, as Dr. Lyman says, the same with checkpoint inhibitors and targeted therapies, we don't recommend and the evidence doesn't support making changes in a different way. That is, there's no interaction between obesity status and the recommendation through dose modification. So in a patient who has severe toxicity related to chemotherapy as well as the targeted agents and checkpoint inhibitors, we recommend that standard dose modifications be made, and moreover that if the patient does better that one consider dose escalation again, if there were for example another concurrent illness that might have contributed in part to the toxicity. So if that other factor resolves, let the dose be increased again to try to maintain that relative intensity dose over time that we consider ideal.

BRITTANY HARVEY: Great. Thank you for reviewing that for the cytotoxic agents in addition to the immune checkpoint inhibitors and targeted therapies. So then, Dr. Lyman, the last clinical question of this guideline-- how should body surface area be calculated?

DR. GARY LYMAN: Well, this is the issue alluding to when I mentioned that there could be safety concerns with these complex calculations. And we tried to make it simple in the guidelines. There are multiple BSA-- Body Surface Area-- calculators out there. You can search them on the web, you can go to textbooks, and there's a whole range of them.

And we actually looked at this. This goes back to the original guideline, and it holds true today, that if you compare that the dose calculated by these different calculators, it's very close to one another. So our bottom line recommendation-- if you're going to use body surface area for calculating the dose of conventional cytotoxic therapy or any of these other agents where that dosing approach is recommended, any of these calculators are going to give you a safe and hopefully effective dose of the therapy. And we don't prefer or recommend one over the other.

Again, there are many on the web. Many institutions have their preferred and may even have embedded the calculator within the EMR or computer order entry system. Many prefer the Mosteller, the Du Bois, the Boyd, there's a whole variety of these, but all of them will generally yield very similar calculations. We haven't mentioned, and just to point out, as most oncologist know certainly, is one drug group, a specific agent, carboplatin is dosed differently. And for carboplatin, we calculate the dose based on a target area under the curve and GFR, so that the Calvert formula calculates the dose differently for carboplatin. And that's for historical as well as pharmacologic reasons.

So again, as Dr. Griggs mentioned, for classical chemotherapy, body surface area is the most common one. But any of the approved calculators or available calculators will give you essentially the same dosing recommendation. And I would follow what's recommended by your institution.

BRITTANY HARVEY: OK. Well, thank you both for reviewing the key recommendations in this guideline update. So finally, Dr. Griggs, in your view, why is this guideline update important, and how will it impact both clinicians and patients with cancer?

DR. JENNIFER GRIGGS: Dr. Lyman and I have viewed this as a really important guideline and guideline update. Because, as we know, the prevalence of obesity is increasing and obesity is associated with an increase in the risk of cancer-- many cancers, not all. And moreover, people who are obese tend to have worse outcomes. And so to try to level out and keep people from systematically what we consider underdosing people who are obese with chemotherapy is very likely to improve outcomes for an important group of our patients.

In addition, the update, because it's been updated now since 2012, we have more evidence that what we're recommending, what the evidence has supported thus far historically and in trials, is actually safe. There's been no signals, in other words, that the original guideline needed to be altered for certain patients or drugs. And now, with this update, we're pretty confident, based on what we know from the FDA and clinical trials, that using actual body weight is not just appropriate, but it's also recommended. So it's an important issue for the population and for our patients, and it's important for clinicians to have the confidence to use actual body weight when calculating anticancer drug doses.

BRITTANY HARVEY: Great. Thank you, both, for all the work you did to update this evidence-based guideline and thank you for taking the time today to speak with me on the podcast, Dr. Griggs and Dr. Lyman.

DR. GARY LYMAN: Thank you, Brittany.

DR. JENNIFER GRIGGS: Thanks, Brittany. We want to thank our co-authors on the guidelines, as well as the ASCO staff for their tremendous work.

DR. GARY LYMAN: Yes, we couldn't do it without all of them, and it's a tremendous team effort.

BRITTANY HARVEY: Definitely. We thank them all as well. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

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An interview with Jessica Geiger, MD, from Cleveland Clinic and Patrick Ha, MD, from the University of California, San Francisco, co-chairs on "Management of Salivary Gland Malignancy: ASCO Guideline." This guideline provides recommendations for preoperative evaluation, surgical procedures, radiotherapy techniques, the role of systemic therapy, and follow-up evaluations for patients with salivary gland malignancies. Read the full guideline at www.asco.org/head-neck-cancer-guidelines.

TRANSCRIPT

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Jessica Geiger from Cleveland Clinic and Dr. Patrick Ha from the University of California San Francisco, co-chairs of management of salivary gland malignancy ASCO guideline. Thank you for being here, Dr. Geiger and Dr. Ha.

DR. PATRICK HA: Thank you, Brittany.

DR. JESSICA GEIGER: Thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Geiger, do you have any relevant disclosures that are directly related to this guideline?

DR. JESSICA GEIGER: No, I don't.

BRITTANY HARVEY: And Dr. Ha, do you have any relevant disclosures that are related to this guideline?

DR. PATRICK HA: No, I do not.

BRITTANY HARVEY: Thank you both. Then let's talk about some of the content of this guideline. So first, Dr. Geiger, can you give us a general overview of the purpose and the scope of this evidence-based guideline on the management of salivary gland malignancy?

DR. JESSICA GEIGER: Sure. So salivary gland cancers-- they're relatively rare, and they encompass a wide variety of both histologies, but also biologic behaviors of cancers. This is a very multidisciplinary tumor, so surgeons, radiation oncologists, pathologists, medical oncologists-- they all play an integral role in treating these patients. And the purpose of this guideline was to bring all of these disciplines together and to develop an as strong as possible, evidence-based way of approaching the diagnosis of such cancers and then approaching it from all modalities of therapy-- surgical, radiotherapy, systemic therapy-- in a very evidence-based and organized fashion.

BRITTANY HARVEY: Great, then as you just mentioned, this is a multidisciplinary guideline, and it covers six different subtopics on the management of salivary gland malignancy-- preoperative evaluation, surgical management, radiotherapy, systemic therapy, follow up, and treatment options for recurrent and metastatic disease. I'd like to go through and review the key recommendations from each of those sections for our listeners.

So first, Dr. Ha, what is the guideline recommend regarding preoperative evaluation for patients with salivary gland malignancy?

DR. PATRICK HA: Great, so I'd first like to start off by saying that we were focusing on salivary gland malignancy. So again, these are tumors where we may not know the diagnosis, but we're suspicious of this being cancer as opposed to a benign tumor.

So along those lines, there are many different imaging recommendations-- first off, that some sort of imaging would be helpful if there's a suspicion of cancer, and then drilling down a little bit more specifically if there is concern about bone involvement. And then CT scan was recommended if it was more of a concern about the soft tissue or perineural invasion or skull-based invasion, then MRI was suggested. And we did spend some time focusing on the strength of and the importance of tissue biopsies, either with fine needle aspiration biopsy or core needle biopsy as a real helpful tool to help clinicians determine what sort of procedures and care this patient might need.

Additionally, with the onset of more understanding of the pathology in the markers, it was felt that using these biopsies-- these FNAs or core biopsies-- to perform either molecular or immunohistochemical studies could further help clarify what the diagnosis would be and thus lead to sort of more specific and defined treatment subsequently.

BRITTANY HARVEY: And then following those evaluation and imaging and biopsy recommendations, what are the key surgical recommendations?

DR. PATRICK HA: Yeah, so again this is probably known to most people-- that when it is considered resectable, the surgery is really the mainstay upfront management option for these patients. We spent some time looking at the different types of surgeries and felt that it was a bit up to the discretion of the surgeon, but it depends on the location as to what type of surgery exactly needs to be done. But the idea is obviously we would want a complete resection of it and margins where possible.

And then we address the nodes and the ability for these cancers to sometimes spread regionally. And basically, if these are high risk or high grade cancers, specifically if there are things like the grade of the tumor itself-- the type-- and then whether there were other concerning features about it, than a neck dissection electively would be offered.

If there were N positive disease, then the neck dissection definitely should be performed. And then there was discussion as well about the facial nerve and how to manage that, wherein the evidence mostly reported trying to preserve the facial nerve whenever possible.

And then we did talk a little bit about the possibility of palliative resection, which can occur sometimes in the presence of distant metastatic disease upon presentation. And it was felt again that there is a palliative component to surgery if the metastatic disease didn't seem to be rapidly progressive or imminently lethal. So these are all the difficult decisions that we discussed regarding surgery.

BRITTANY HARVEY: OK, thank you. Then Dr. Geiger, how does this guideline address radiotherapy for patients with salivary gland malignancy?

DR. JESSICA GEIGER: Well, as Dr. Ha mentioned, this is primarily a surgical disease. So most of the recommendations regarding radiotherapy involve the post-operative setting. But if you look at the guideline, we have actually laid out 10 recommendations regarding radiation, and they're dependent on various factors with each cancer, so the histology of the disease, other tumor pathologic factors, such as T-stage, vascular, lymphatic invasion, margin status, perineural invasion-- all of that goes into the recommendation here. There's also considerations for what nodal basins to cover, based on where the tumor is, and even the type of radiation, and, of course, the timing of radiation. All of that is important to be considered, and all of those specific features are mentioned within the recommendations.

BRITTANY HARVEY: Great. And then in addition to those radiotherapy recommendations, what's the role of systemic therapy for patients with salivary gland malignancy?

DR. JESSICA GEIGER: Well, unlike the radiation section, where I said we have 10 specific recommendations, we're limited with the evidence for the use of systemic therapy in the curative setting of these diseases. So one point that I will make is, again, we're very limited based on evidence, and this is what is driving such a guideline-- is evidence, evidence, evidence. And we just don't have it.

There are several large studies that are ongoing, but until those results flesh out, we were limited. And so our recommendations are based on the lack thereof, and often are considered low quality or moderate strength of recommendation at best, based on our expert panel.

Basically, outside of a clinical trial, we're not recommending the addition of radiosensitizing chemotherapy with post-op radiotherapy. Again, that can be contentious, especially in the clinical realm, where there's a wide variety of biologic behavior. So some of the more aggressive diseases, we know that oncologists are advocating for the use of chemotherapy. But again, the evidence is not there yet, and so we weren't able to make that informative within this guideline.

And then we also addressed tumors that are expressing different markers, like androgen receptor, HER2, and make a recommendation for the use of targeted therapy, again noting a lack of evidence for it outside of a clinical trial currently.

BRITTANY HARVEY: OK, thank you for explaining the reasoning and the evidence behind those particular recommendations. So then for patients who have then completed treatment for salivary gland malignancy, Dr. Ha, what are the timelines and recommendations for follow up for these patients?

DR. PATRICK HA: Well, so again, this is where the data are really not strong. And so you'll notice that pretty much all of these recommendations were informal in consensus. But similar to the NCCN guidelines for general cancer follow up was believed by the panel that early follow up more frequently and just sort of spaced out over time was important.

And then there was an emphasis on some form of imaging often, whether that be CT or MRI, it's sort of up to the practitioner. And then perhaps for a couple of years after treatment, that might be important.

It was also felt that, as everyone probably knows, that one of the areas where this may spread to distantly is in the lung. So getting some sort of chest imaging between years 2 and 5 would be important as well, just in case one can detect an asymptomatic yet potentially treatable metastasis.

So again, a lot of informal consensus. The idea is that we feel it's important to continue to follow these patients to look for signs of recurrence, whether that's with imaging or physical exam. We thought that either would be an option.

BRITTANY HARVEY: Definitely. And the last section of recommendations for this guideline is on recurrent or metastatic salivary gland malignancies. So what are those treatment options, Dr. Geiger?

DR. JESSICA GEIGER: Well like before, when we're talking about systemic therapy, again, informal consensus is sort of driving the majority of these recommendations, again highlighting lack of strong evidence. That said, there are several different clinical situations that we address within these recommendations.

So whether a patient presents with diffusely metastatic disease with a large tumor burden or oligometastatic disease, where maybe just one or two local or regional areas have recurred. And so in that latter case, you could discuss with the patient is it worthwhile to do some locally ablative therapy, such as SBRT, or possibly a resection versus, for more widely metastatic disease, starting systemic therapy.

Now, there's also a recommendation specifically for the histology adenoid cystic carcinoma. And that is based on studies that have been done with tyrosine kinase inhibitors. And so there's some evidence for that outside of cytotoxic chemotherapy.

And then we also make a mention, which is very important, again on checkpoint inhibitors, but also on some of the targeted therapies-- doing next generation sequencing, looking for molecular markers that drive the progression of these diseases, and then in subsequent targeted therapies for this.

So we really try to encompass any and all particular situations that an oncologist may encounter with these diseases and offer some guidelines and recommendations regarding the appropriate management.

BRITTANY HARVEY: Great. Thank you both for reviewing those key points of the recommendations. This guideline goes through a lot of content, and so it's interesting to hear more about what kind of those details are for each section. So Dr. Ha, in your view, what is the importance of this guideline, and how will it impact clinicians?

DR. PATRICK HA: Well, I think that we realized we had a lot to cover in just a short amount of time. And I think that we felt that while the data may not be as strong with-- full of randomized clinical trials as perhaps other disease subgroups, we felt it was important to organize what the current state of the data are, because these are rare cancers, and there are some nuances between some of the histologies even that it may be difficult to keep up to date all the time. So organizing it into one document where it we have clearly delineated what areas we feel are common practice amongst experts and what areas actually do have some studies and perhaps some deeper level of understanding and depth of studies would be important, so that clinicians understood where it was that they have to be a little more creative and areas where they felt like hey, we feel like this is important to do.

So I think that that would be useful for clinicians. And I think also it provides a framework for future studies, meaning that we hope that whenever these get updated and 5 or 10 years that there will be more studies. But it also does, I think, help for those of us who are in the field to organize where those gaps are so you can look at the guidelines and really understand OK, these are the areas that we need better understanding of how to treat patients.

BRITTANY HARVEY: Definitely. It's helpful to understand both where there is evidence and where there is no evidence and where informal consensus takes rule. So then finally, Dr. Geiger, how will these guideline recommendations affect patients?

DR. JESSICA GEIGER: Well, when it comes to cancer treatment, there is a lot of fear in the unknown. And I feel that patients are always asking am I doing the right things? Am I looking to make sure that I'm getting the best of care? And I think with any guideline-- this one included-- patients can rest assured that they don't have to make the trip and travel to a large academic center necessarily-- that they can feel comfortable knowing that their providers are following the data and following such guidelines that have been brought forth in one single document. Even though the patients aren't going to necessarily have this document at hand, they can have confidence within their oncology team.

And then I think they'll also benefit from, as Dr. Ha was saying, as medical professionals being able to identify gaps and bring forth clinical trials. That's the only way that we're going to be able to move this field forward, particularly in such a rare disease that many histologies as salivary gland malignancies. And so while being treated in a regional oncology office or a community oncology office, maybe their provider will then recommend clinical trials that are open and have that additional opportunity for patients, if they so desire. So knowing that they're getting great standard of care based on evidence, but then also the opportunity to create new evidence for us to better treat patients in the future.

BRITTANY HARVEY: Definitely. Well, I want to thank you both so much for your work on developing these evidence-based guidelines and for taking the time to speak with me today on the podcast, Dr. Geiger and Dr. Ha.

DR. JESSICA GEIGER: Thanks.

DR. PATRICK HA: Thank you.

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

An interview with Dr. David Hui from MD Anderson Cancer Center and Dr. Margaret L. Campbell from Wayne State University, co-chairs on "Management of Dyspnea in Advanced Cancer: ASCO Guideline." This guideline outlines a hierarchical approach to dyspnea management, beginning with identifying and managing potentially reversible causes, followed by the use of non-pharmacologic interventions, and then pharmacologic interventions. Read the full guideline at www.asco.org/supportive-care-guidelines

TRANSCRIPT

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm interviewing Dr. David Hui from MD Anderson Cancer Center in Houston, Texas, and Dr. Margaret Campbell from Wayne State University in Detroit, Michigan, co-chairs on "Management of Dyspnea in Advanced Cancer: ASCO Guideline." Thank you for being here, Dr. Hui and Dr. Campbell.

DR. DAVID HUI: Thank you. It's wonderful to be here.

DR. MARGARET CAMPBELL: Yeah, it's my pleasure.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Hui, do you have any relevant disclosures that are directly related to this guideline topic?

DR. DAVID HUI: I have no relevant disclosures.

BRITTANY HARVEY: Thank you. And Dr. Campbell, do you have any relevant disclosures that are related to this guideline topic?

DR. MARGARET CAMPBELL: No, I do not have any relevant disclosures.

BRITTANY HARVEY: Thank you. Then let's get into some of the guideline content. So first, Dr. Hui, can you give us a general overview of the purpose of this clinical practice guideline?

DR. DAVID HUI: Yeah. This clinical practice guideline is on dyspnea in patients with advanced cancer. And this symptom of shortness of breath, or dyspnea, is very common in our patients and extremely distressing. And the evidence base is rapidly evolving, so the purpose of this guideline is then to summarize the up-to-date information and provide some recommendations for clinical practice to help alleviate this very challenging symptom.

BRITTANY HARVEY: Great. Then let's review some of those key recommendations of this guideline. So Dr. Campbell, what is recommended for screening and assessment of dyspnea in patients with advanced cancer?

DR. MARGARET CAMPBELL: Well, as David mentioned, this is a highly prevalent symptom. But we know that in clinical practice, sometimes patients won't disclose their symptom unless they're asked. And it gives us an opportunity to be certain that we don't overlook the symptom, particularly when it's in the early stages, mild or moderate stages, where we can intervene rapidly.

So in order to treat a symptom, we have to know that the symptom exists. So in the guideline, we recommend at every clinical encounter that there be an assessment for dyspnea. So every clinical encounter could be every time the patient presents in the outpatient clinic, or it could be every day if the patient is an inpatient. Every day on rounds, or every time vital signs are obtained, there would be an assessment of the patient's dyspnea.

BRITTANY HARVEY: Great. Then, reading through this guideline, it takes a hierarchical approach to the management of dyspnea, addressing first potentially reversible causes, then the use of non-pharmacologic interventions, and finally pharmacologic interventions. So first, what does the guideline state regarding addressing those potentially reversible causes of dyspnea?

DR. DAVID HUI: Yeah, well, this is a very important aspect that you highlighted is that we really want clinicians to remember that it's not just about treating this symptom. It's ideally identifying what are the causes of shortness of breath that we could reverse. And in many patients, there may be multiple factors contributing to the shortness of breath.

Some patients may have some effusion, perifusion contributing to it. They may also have underlying emphysema. And other times they may have some complications, such as blood clots. And so it's important to kind of identify the issues that may be at stake. And some of them are very treatable, and patients may have significant improvement in their shortness of breath right away.

So I think it's a combination of identifying the complications and comorbidities in those patients. And of course that along with treating the cancer if the cancer is the cause of the dyspnea as well.

BRITTANY HARVEY: Great. Then so after addressing those potentially reversible causes, Dr. Campbell, what are the recommended non-pharmacologic interventions?

DR. MARGARET CAMPBELL: Well, in the case of a patient whose dyspnea is not severe but is a difficult to tolerate symptom, we propose that the clinician begin with a hierarchical approach from the easiest, simplest interventions that are non-pharmacologic that may actually help improve the symptom experience. So that might be as simple as changing the patient's position.

And depending on where their cancer is located, they may find that they are more comfortable sitting up straight propped with pillows, for example. In addition, circulating air around the face has a fairly strong evidence base. And that can be accomplished, weather permitting, by putting the patient's chair near an open window. Or it can be accomplished with a small handheld fan blowing on the face.

For some patients whose blood oxygen levels are low, then the application of supplemental oxygen may be helpful to correct the low blood oxygen. Those are the major interventions that we would suggest, but there could be others. If the patient is still ambulatory, then perhaps a walking aid, avoiding stairs. And some of that comes back to our comprehensive assessment. If we could determine what triggers the patient's shortness of breath, then perhaps we can suggest interventions to minimize that, like pacing activity.

So similarly, if the patient's in the hospital but has dyspnea, we would want to pace their clinical activity. We wouldn't want them to have their bed, bath, their breakfast, their linen change, their physical therapy all in the same short period of time. We would want to see those interventions staggered through the day.

BRITTANY HARVEY: Definitely. That makes a lot of sense. So then, Dr. Hui, what pharmacologic interventions are recommended for patients with advanced cancer and dyspnea?

DR. DAVID HUI: Yeah, and so building on Dr. Campbell's discussion of the non-pharmacologic interventions, sometimes patients will continue to have quite a bit of shortness of breath. Or it's a very acute or severe presentation, such as in the hospital setting, then we do recommend some pharmacologic interventions.

So the front line measure for that would be systemic opioids. And I recognize that, nowadays, opioids, there's still a lot of stigma around the use of it and concerns. But it is after careful review by the committee and based on the existing evidence that we do recommend this as the main pharmacologic agent. For patients, of course, the use of opioids need to be carefully monitored, and patients should be educated very carefully on how to use them properly for shortness of breath.

There are a number of other pharmacologic agents that may be considered for selected populations, other than opioids. So if patients have a higher level of anxiety, then a short-acting benzodiazepine may be considered for those individuals. And for patients with more structural causes of shortness of breath, such as airway obstruction, systemic corticosteroids may be considered. And for patients with airway obstruction, then bronchodilators may be helpful as well, although the evidence around that is still on the weaker side.

And there are some patients who, despite very active intervention with many of these non-pharmacologic and pharmacologic measures, who continue to have very severe shortness of breath. And for those who are, let's say, in a palliative care unit setting and have refractory dyspnea, palliative sedation is mentioned as an option for patients as a last resort.

BRITTANY HARVEY: OK, thank you both for reviewing those interventions for patients. So Dr. Campbell, in your view, why is this guideline important? And how will it change practice?

DR. MARGARET CAMPBELL: Well, for a busy oncologic clinician who may not have a lot of time to search the literature because of a busy practice, what this puts in one place is an opportunity to do a quick guideline that could suggest a treatment course. For a palliative care provider, who may have more experience with non-cancer diagnoses, this guideline focuses on the patient with advanced cancer.

So I think there's an opportunity for clinicians in both of those fields who would be taking care of advanced cancer patients to find a benefit.

BRITTANY HARVEY: Definitely. And then finally, Dr. Hui, how will these guideline recommendations impact patients with advanced cancer?

DR. DAVID HUI: Yeah, well, I'd like to echo what Dr. Campbell said. I would also say that perhaps one of the strongest recommendations of this guideline is actually for patients with dyspnea and advanced cancer to be referred to palliative care. Because dyspnea is such a multi-dimensional symptom and often just the tip of the iceberg in terms of what patients are going through.

So just the very presence of it really highlights that there is likely a high supportive care burden, and it would be a good idea for a team specializing in relieving of this symptom to be there to work with the oncology team to help patients. So we hope that with this guideline, that there will be more patients who will have access to palliative care teams. And I think that will be one important impact. And there is a lot of evidence that palliative care can help our patients.

And other, maybe, impacts, I think, down the road for maybe future patients would be that we highlighted that more research is really needed in this field. The guideline clearly highlighted some areas we need to work on for further research. And it is not easy to do research in dyspnea and cancer patients because these patients are so sick. And yet these are the very patients who need to have better interventions.

And so with this guideline, we hope that it can stimulate further research and to support some patients in the future as well.

BRITTANY HARVEY: Great. Well, it definitely sounds like these will have a positive impact for both researchers and for patients with advanced cancer. So I want to thank you both for your work on these guidelines. And thank you for taking the time to talk with me today, Dr. Campbell, and Dr. Hui.

DR. DAVID HUI: It's my pleasure.

DR. MARGARET CAMPBELL: Mine also.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store.

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

An interview with Dr. Natasha Leighl, Dr. Andrew Robinson, and Dr. Gregory Riely on "Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO and OH (CCO) Guideline Update." This guideline provides recommendations on systemic therapy for patients with stage IV NSCLC whose cancer has driver alterations, focusing on seven targets - EGFR, ALK, ROS-1, BRAF V600e, RET, MET exon 14 skipping mutations, and NTRK. Read the full guideline at asco.org.

TRANSCRIPT

PRESENTER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcasts.asco.org.

My name is Brittany Harvey, and today, I'm interviewing Dr. Natasha Leighl from Princess Margaret Cancer Center in Toronto, Ontario, Dr. Andrew Robinson from Queen's University in Kingston, Ontario, and Dr. Gregory Riely from Memorial Sloan Kettering Cancer Center in New York, New York, authors on Therapy for Stage IV Non-Small-Cell Lung Cancer with Driver Alterations: American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) Guideline Update. Thank you for joining me today, Drs. Leighl, Robinson, Riely.

DR. ANDREW ROBINSON: Thank you for having us.

DR. NATASHA LEIGHL: Thanks for having us, Brittany.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Leighl, do you have any relevant disclosures that are related to this guideline topic?

DR. NATASHA LEIGHL: I don't have relevant disclosures, but I do have institutional research funding from a number of companies, including Amgen, ARRAY, AstraZeneca, EMD Serono, Guardant Health, Eli Lilly, Merck, Pfizer, Roche, and Takeda, and personal fees from Bristol-Myers and MSD, which are unrelated. Thanks.

BRITTANY HARVEY: Thank you. And Dr. Robinson, do you have any relevant disclosures that are related to this guideline?

DR. ANDREW ROBINSON: I do not have any relevant disclosures related to this guideline. My institutional list of research funding is not as extensive as Dr. Leighl's, but is still fairly extensive and includes many of those companies.

BRITTANY HARVEY: And Dr. Riely, do you have any relevant disclosures?

DR. GREGORY RIELY: I receive institutional research funding from Novartis, Roche, Genentech, GlaxoSmithKline, Pfizer, Moradi, Merck, and Takeda. But those are my only disclosures.

BRITTANY HARVEY: Thank you all. Then let's get into some of the content of this guideline update. So this guideline is an update of an earlier ASCO guideline on the systemic treatment of patients with stage IV non-small cell lung cancer, which was then divided into two companion guidelines, one on systemic therapy treatment options for patients without driver alterations, which was published in 2020, and then this one for patients whose cancer has driver alterations.

So Dr. Robinson, can you give us a general overview of what this particular guideline covers?

DR. ANDREW ROBINSON: Thank you, Brittany. It was a great experience to be part of this important guideline and an honor. As you mentioned, this guideline is on treatment of stage IV non-small cell lung cancer patients with driver mutations. And it's a companion guideline to the earlier guideline published on treatment of stage IV non-small-cell lung cancer without driver mutations. The guideline followed a robust evidence gathering and evaluation process as a standard for ASCO-Ontario Health guidelines. In this case, we ended up reviewing several phase III trials, as well as many earlier phase studies and specific driver mutation groups.

If we look back to 2017, there were four driver mutation group recommendations included in the guideline. We now have recommendations for seven different oncogenes, as well as some recommendations that are specific not only for the oncogene involved, but also the specific mutation within that gene. The non-driver mutation guideline is referenced as well frequently in this guideline, as many of the treatment options that are recommended in that guideline are also appropriate for patients with driver mutations, with the exception of a couple of key mutation groups such as EGFR.

Recommendations in the guideline are qualified as weak, moderate, or strong, and the level of evidence for each recommendation is given. For many of these novel agents, the evidence is relatively low in comparison to what we are used to with recommendations based on phase II trials without comparator arms, and with surrogate endpoints for patient benefits such as response rates and duration of response, as opposed to quality of life and overall survival. Nonetheless, it was felt appropriate to include many of these agents in the recommendations, with the caveat that the level of evidence is weak or non-evidence-based.

One of the recommendations in the introduction to these guidelines is to continue with studies such as phase III clinical trials in many of these settings, in order to move from an informal consensus-based recommendation, to a recommendation based on moderate to high quality evidence. We hope oncologists and their patients will find these guidelines useful.

BRITTANY HARVEY: Great. Then, as you just mentioned, this guideline focuses on seven targets, EGFR, ALK, ROS1, BRAF, RET, MET, and NTRK. I'd like to review those key recommendations for each of those targets. So first, Dr. Robinson, what is recommended for patients with stage IV non-small-cell lung cancer and an epidermal growth factor receptor mutation?

DR. ANDREW ROBINSON: Thank you. In terms of stage IV EGFR mutation positive lung cancer, the recommendations in the 2017 guidelines were to use tyrosine kinase inhibitors upfront, such as gefitinib, afatinib, or erlotinib, and to follow that with osimertinib if a mutation was found in T790M, or chemotherapy depending on what was available. In the current treatment guideline, we have recommendations not only for first and second line treatment, but also some acknowledgment and recommendations for treatment of patients with EGFR mutations other than the classical exon 19 deletion mutation or LA58R.

For patients with a classical EGFR mutation, several strategies have been shown to be superior to first generation tyrosine kinase inhibitors in the first line setting. And the panel strongly recommended osimertinib to be used as first line therapy with a high level of evidence, based on the FLAURA clinical trial. This demonstrated not only an overall survival benefit, but a quality-of-life benefit.

Other strategies that have been shown to benefit include dacomitinib as first line therapy, gefitinib plus chemotherapy as first line therapy. Erlotinib/bevacizumab and erlotinib/ramucirumab are also options with a lower level of evidence, as they have not been shown yet to be associated with improved overall survival. But they are associated with improved progression-free survival.

Most of the recommendations, other than osimertinib, are really recommendations for what to pursue if osimertinib is not available. If we move to patients with sensitizing but non-classical EGFR mutations, the evidence is certainly much more sparse, as are these patients. And the recommendation was for afatinib first line or osimertinib was also considered an option based on phase II data.

For patients with EGFR exon 20 insertion mutations, recommendation at this time was not to use a targeted agent first line, but to default to the non-driver mutation guidelines. For second line therapy, after tyrosine kinase inhibition stops benefiting, the recommendation was to use doublet platinum chemotherapy with or without bevacizumab.

The atezolizumab/bevacizumab/carboplatin/paclitaxel combination was acknowledged as an option based on an exploratory analysis of the phase III EMPOWER trial, but this was considered exploratory and this regimen was not strongly recommended until further evidence accrues.

BRITTANY HARVEY: OK, thank you. Then Dr. Leighl, what is recommended for patients with stage IV non-small-cell lung cancer and ALK rearrangement?

DR. NATASHA LEIGHL: So for patients with ALK rearranged stage IV lung cancer, in the first line setting, next generation ALK inhibitors alectinib or brigatinib should be offered to patients. This is based on randomized trials comparing these to first generation inhibitors, crizotinib specifically, demonstrating better outcomes including progression-free survival and better intracranial activity.

If you live in a region where alectinib and brigatinib are not available, earlier inhibitors like crizotinib or ceritinib should be offered again based on high quality evidence randomized trials demonstrating that these are better than chemotherapy. In the second line setting, if your patient has received alectinib or brigatinib first line, lorlatinib may be offered. If your patient received an earlier generation inhibitor crizotinib, they should be offered alectinib, brigatinib, or ceritinib, again based on randomized trials. And later, lorlatinib third line may be offered.

It's also important to remember that in this group of patients, chemotherapy, especially pemetrexed-based chemotherapy, is very active. And we would refer you to the ASCO-Ontario Health non-driver mutation guidelines for chemotherapy recommendations when targeted therapy is no longer an option. I should also note that when we drafted these guidelines, we did not yet have results of the first line lorlatinib study, the CROWN study, where we found that lorlatinib was also superior to crizotinib, the first generation inhibitor. This is currently under review by the US FDA. So while it's not recommended in our guideline, we may see this added to future guidelines in our next guideline update.

BRITTANY HARVEY: Great. Thank you. And then, what is recommended for patients with ROS1 rearrangement?

DR. NATASHA LEIGHL: So for patients with ROS1 rearranged stage IV lung cancer, in the first line setting, specific ROS1 inhibitors, crizotinib or entrectinib may be offered. Because this is based on very impressive response rates and prolonged duration of response and patient benefit, in single arm studies, we have to recognize that alternatives may also include standard treatment based on the ASCO non-driver mutation guidelines, as well as other target agents, such as ceritinib or lorlatinib, that may be offered.

If, though, your patient has progressive disease and previously received non-targeted therapy, targeted therapy with crizotinib, ceritinib, or entrectinib, can certainly be offered. Also, if your patient has received ROS1 targeted therapy in the first line setting, standard treatment based on the ASCO non-driver mutation guidelines should be offered also with consideration of clinical trials.

BRITTANY HARVEY: And then additionally, what is recommended for patients with stage IV non-small-cell lung cancer and an NTRK fusion?

DR. NATASHA LEIGHL: Thanks, Brittany. For patients with stage IV disease and an activating NTRK fusion, entrectinib or larotrectinib may be offered in the first line setting based on single arm studies, including patients with lung cancer and very dramatic response rates and prolonged duration of response. However, standard treatment based on the non-driver mutation guideline chemotherapy-based may also be offered in the second line setting. If NTRK targeted therapy was given first line, standard treatment with chemotherapy-based options may be offered second line based on the non-driver mutation guideline. If NTRK targeted therapy, though, was not given in the first line setting, entrectinib or larotrectinib may be offered to your patient.

And I think at this point, we really don't know what the optimal sequence is for these patients. But I think it's very clear from the data that we do have, that we want to try and identify this target and get patients on targeted therapy as soon as possible in the course of their disease.

BRITTANY HARVEY: Great. Then Dr. Riely, can you review what the guideline recommends for patients with stage IV non-small cell lung cancer and a BRAF mutation?

DR. GREGORY RIELY: Thank you, Brittany. I'll highlight that the BRAF mutation guideline pertains specifically to those patients with BRAF V600E mutations. The other BRAF mutations that we observed, we don't have sufficient data to make recommendations. But for those patients with BRAF V600E alterations, again, based on the quality of the data and the type of data available, the guidelines recommend consideration of first line use of dabrafenib with trametinib. This is a consideration rather than a should recommendation, given the absence of randomized clinical trial evidence.

But nonetheless, we recommend that they be considered in the first line setting. If, in fact, you choose to use a non-targeted approach in the first line setting, then the guidelines do recommend consideration of dabrafenib with trametinib in the second line setting. So it's, again, the first line setting, dabrafenib/trametinib combination. Or, if not used in the first line setting, then recommendation dabrafenib/trametinib in the second line setting.

BRITTANY HARVEY: OK, then, what is recommended for patients with stage IV non-small-cell lung cancer and a MET mutation?

DR. GREGORY RIELY: Again, specific for MET, we're talking about MET exon 14 alterations rather than MET amplification with other mutations, which we might call emerging targets. So for patients with metastatic exon 14 altered non-small cell lung cancer, the recommendation is for the use of capmatinib or tepotinib. These are newer MET inhibitors that have recently been approved. And again, the guidelines recommend that they should be considered in the first line setting. If, however, you choose to use non-targeted therapies in the first line setting, then MET directed therapy such as capmatinib or tepotinib should be considered in the second line setting.

BRITTANY HARVEY: And then the final target addressed in this guideline, what is recommended for patients with stage IV non-small cell lung cancer and RET rearrangement?

DR. GREGORY RIELY: RET rearrangements are relatively uncommon, but important in a subset of patients with non-small cell lung cancer. And we have MET targeted agents that are available. The current guidelines recommend that in the first line setting, we consider the use of selpercatinib. And in the second line setting, if patients have not previously received a RET inhibitor, one should consider selpercatinib in that context.

Patients who have received a targeted therapy in the first line then conventional chemotherapy with or without immunotherapy or bevacizumab should be considered. I will note that the guidelines were finalized prior to the approval of pralsetinib, and pralsetinib is another RET inhibitor with similar data in this context.

BRITTANY HARVEY: Great. Thank you all for reviewing those recommendations. So Dr. Robinson alluded to this earlier, but Dr. Riely, could you describe what emerging targets the panel reviewed but were unable to make recommendations for at this time?

DR. GREGORY RIELY: The development of treatments in patients with non-small cell lung cancer has really proceeded at a breakneck pace over the past 10 years. We've seen newer alterations identified, new drugs tested in those populations, and new drugs approved in relatively rapid succession. We have a number of targets that are currently being studied with new drugs, but we don't quite have enough data yet and the drugs aren't yet approved, so they can't be included in the guidelines.

Some of these targets include KRAS G12C, recently seen a number of direct KRAS inhibitors that have been developed and seem to have activity in that group of patients. And that's a hot area to look forward to. We've also seen that patients with EGFR exon 20 insertions don't seem to benefit from currently available EGFR TKIs at the standard recommended dose. And so we don't have recommendations for their utilization here, but there are new drugs that are being developed to target this group of patients.

Similarly, patients with HER2 mutations seem to not benefit from available therapies, but there are drugs that are being developed, and we look forward to seeing more data in that context. Finally, patients with NRG1 fusions are another emerging target, but we don't have good recommendations yet or good drugs yet.

BRITTANY HARVEY: Great. Understood. So then, Dr. Robinson, in your view, why is this guideline important, and how will it impact clinical practice?

DR. ANDREW ROBINSON: Well, this guideline is important because it's taking a problem that we see in the real world, which is patients with lung cancer with an ever-expanding number of driver mutations, and trying to give recommendations for the integration of new therapies with standard clinical practice.

It's important that I've highlighted that for most of these mutations, without phase III evidence, the recommendations were to consider the targeted agent as first line therapy. But also, if it's not given first line, to use it in subsequent lines. And I think we need to recognize that these targeted agents, it's most important that patients get these drugs at some point in their care, even if we don't know exactly what the optimal point in their care is.

The guideline was sort of the first one in lung cancer, where we've taken a number of these rare mutations and examined the phase II data, and will likely be the template for what is going forward with an ever-expanding number of medications. So hopefully, we get a bit of standardization out of it. Hopefully, we've highlighted some of the areas that are still unclear and can be a template for the next round of targeted therapy guidelines.

BRITTANY HARVEY: Definitely, it's an ever-changing landscape. So finally, Dr. Leighl, what do these updated guideline recommendations mean for patients with stage IV non-small-cell lung cancer?

DR. NATASHA LEIGHL: So this is really great news. And as Dr. Riely and Dr. Robinson have highlighted, in just a very short number of years since 2017, we've made tremendous progress. We have at least three new targets, many new treatments for almost every class of targeted therapy indication in lung cancer. And most of these new targets are their oral therapies or pills. And many of them should now be offered to patients as first or second line treatment instead of chemotherapy.

So for patients, this really means many more will be able to enjoy a chemotherapy-free world, or at least a chemotherapy-free period for a time. I think it's really important for patients and the oncology team to remember that genomic testing is essential. And it's an essential part of the stage IV non-squamous, non-small-cell lung cancer diagnostic process, and in some places, you know, any non-small-cell lung cancer. And this may be a very important part of the process. And it really doesn't depend on clinical factors like smoking. It's really about your pathologic diagnosis or in your tumor sample.

So it's really key that we make sure that patients get their samples tested as soon as possible in their lung cancer journey, preferably with comprehensive profiling so we can identify any of these targets, if our patients have them, and then get them onto the right treatment as fast as possible. If there isn't enough tissue for testing, liquid biopsy has emerged as a potential alternative. And I think it's so important for patients and oncology professionals to remember that PD-L1 expression, which is an important marker for immune therapy, is not enough.

At least a quarter of our patients with PD-L1 expression that suggests immunotherapy should be an option, in fact, have these actionable genomic targets. And we do know that in these patients, targeted therapy should come first. So again, tremendous progress, many exciting opportunities for our patients to be chemo-free for much longer. And again, important to get the right test as soon as possible so we can get you onto the right treatment as soon as possible.

BRITTANY HARVEY: Great. Well, thank you all for reviewing the extensive literature associated with this guideline and developing these recommendations, and for taking the time to speak with me today, Dr. Leighl, Dr. Riely, and Dr. Robinson.

DR. GREGORY RIELY: Thank you.

DR. ANDREW ROBINSON: You're welcome, and thanks a lot to the ASCO staff for doing all of the work in sort of herding the cats that are oncologists, as well as getting all the references and the deep literature searches for us.

DR. NATASHA LEIGHL: Agreed. Thanks so much.

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

An interview from Dr. Larissa A. Korde from the National Cancer Institute and Dr. Dawn L. Hershman from Columbia University on "Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline." This guideline covers the optimal use of neoadjuvant therapy for women with invasive, non-metastatic breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one podcast.asco.org.

My name is Brittany Harvey, and today I am joined by Dr. Larissa Korde from the clinical investigations Branch of the Cancer Therapy Evaluation Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute in Bethesda, Maryland, and Dr. Dawn Hershman from the Herbert Irving Comprehensive Cancer Center at Columbia University in New York, New York, co-chairs on Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline. Thank you for being here Dr. Korde and Dr. Hershman.

DR. LARISSA KORDE: Thank you for having us.

DR. DAWN HERSHMAN: Yes, thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available on-line with the publication of the guideline in the Journal of Clinical Oncology. Dr. Korde, do you have any relevant disclosures that are related to this guideline topic?

DR. LARISSA KORDE: I do not.

BRITTANY HARVEY: And Dr. Hershman, do you have any relevant disclosures that are related to this guideline topic?

DR. DAWN HERSHMAN: No, I do not.

BRITTANY HARVEY: Great, thank you both. Then, Dr. Hershman, to kick off the content of the guideline, first, can you give us a general overview of the scope and the purpose of this guideline?

DR. DAWN HERSHMAN: Yeah, sure. In breast cancer, we have seen a plethora of studies looking at neoadjuvant therapy for breast cancer. And as we've learned over time, that neoadjuvant therapy has focused on the role of, really, response as a predictive marker and whether or not the improvement in a pathologic complete response rate translates into benefit in terms of long-term outcome. And the fact that several studies have shown that has really increased our interest in looking at pathologic complete response rate and its predictive value.

So part of the guideline is really to help us really elucidate as the understanding of biology of breast cancer has evolved over time, what scenarios where neoadjuvant therapy is the best choice for patients, and what the real purpose of neoadjuvant therapy is. So the guidelines' purpose is really to help us develop recommendations concerning the optimal use of neoadjuvant therapy, whether it be chemotherapy, endocrine therapy, or targeted therapy for a variety of different biologic subtypes. And I think the overarching principle is that the expert panel strongly advocated for a multidisciplinary team in the management of these patients. Specific guidelines really go into details about each of the scenarios where we would use this therapy.

BRITTANY HARVEY: Great. Then I'd like to review some of those key recommendations that you just mentioned for our listeners. So Dr. Korde, which patients with breast cancer are appropriate candidates for neoadjuvant systemic therapy?

DR. LARISSA KORDE: So when we sat down to write this guideline, we thought through this question in many different ways. But we basically ended up sort of dividing patients by breast cancer subtype and then coming up with recommendations separately for each subtype. So broadly speaking for triple negative breast cancer patients and for HER2-positive breast cancer patients, we felt that the kind of most important triage point is that in both those diseases, there are effective treatments that can be used in the adjuvant setting in patients who do not have a pathologic complete response to neoadjuvant therapy. And so broadly speaking, it's those patients where there would be an adjuvant therapy decision point, or recommendation in whom the neoadjuvant response is important. Those would be the patients in whom we would most strongly recommend neoadjuvant chemotherapy.

In ER-positive disease, we looked at both chemotherapy and endocrine therapy in the neoadjuvant setting. And we know that both of these can improve response. Pathologic complete response is less common in patients with ER-positive disease. But there are also benefits to neoadjuvant treatment in those patients in terms of being able to reduce the size of the surgery, reduce potentially morbidity from surgery, and then also in terms of being able to convert patients who were not lumpectomy candidates from mastectomy to lumpectomy. And so in the guideline we outline the scenarios for ER-positive patients in which neoadjuvant therapy would be recommended as well.

BRITTANY HARVEY: Great, got it. Then Dr. Hershman, what do the guidelines say about how clinicians should measure response in patients receiving neoadjuvant chemotherapy?

DR. DAWN HERSHMAN: Yes, so patients undergoing neoadjuvant therapy should really be monitored by their provider at each visit with a clinical examination at regular intervals. And we really felt that the role of breast imaging was really for patients where there was some clinical suspicion of progression during that therapy to ensure that patients were not progressing during treatment. And ultimately, the best modality for imaging was the modality that was most effective at the point of diagnosis, whether it be mammogram, ultrasound, or MRI, that should be the imaging modality used at follow up.

We did not feel that there were any specific blood markers or tissue based markers at this time that should be used for monitoring patients undergoing neoadjuvant therapy. Much of that is done for clinical trial purposes, but not so much in the clinic. And that when patients had completed their treatment, pathologic complete response rate is the most important outcome and would be really assessed at the time of surgery as the absence of any invasive disease in either the breast or the lymph nodes.

But in order for that to be good for clinical decision making, it's really imperative that the clinician and the surgeons make sure that the tissue is removed that is suspect to begin with, so to make sure that the clips that defined where the tumor was evaluated and that the tumor bed is clear of any evidence of disease.

BRITTANY HARVEY: Great, that's helpful information. So then, Dr. Korde, you mentioned that the recommendations are divided up by biologic subtypes. So what are those neoadjuvant systemic therapy regimens recommended for the following patient population-- so first, those with triple negative breast cancer, second, those with HER2-negative hormone receptor positive breast cancer, and then finally, for those with HER2-positive disease?

DR. LARISSA KORDE: So maybe we can divide this up a little. Let's start with the triple negatives. For triple negative breast cancer patients who are embarking on neoadjuvant chemotherapy, and that would be patients with clinically node positive disease, and/or at least T1C disease, and again, with the thought that the goal is really to think about whether adjuvant therapy recommendations would be altered based on PAP CR. But in that setting, we recommended that patients be offered an anthracyclines and taxane containing regimen.

We also found data supporting the use of carboplatin with neoadjuvant therapy for the purpose of increasing the likelihood of PCR. So we noted that while there is good data showing that PCRs increase with carboplatin, there is more conflicting data regarding the effect of carboplatin on long-term outcomes. Although, hopefully, new clinical trials that are ongoing now or that are in follow up may clarify this question a little bit more.

We felt at the time that we wrote the guideline, and certainly, this is potentially an evolving topic. But at this point, we felt that there was insufficient evidence to recommend routinely adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early stage breast cancer. And again, there may be more data on this upcoming in the next few years. So maybe Dawn can take the next category, the HER2-negative hormone receptor positive patients.

BRITTANY HARVEY: Yeah, that would be great.

DR. DAWN HERSHMAN: Absolutely. So we felt for this population of patients that neoadjuvant chemotherapy could be used instead of adjuvant chemotherapy in any patient where the chemotherapy decision could be made without the benefit of having the results from the surgical pathology data, or any results from the specific genomic testing. So if the decision was made that the patient was going to need chemotherapy regardless, that would be a patient that could get it neoadjuvantly.

We felt that for postmenopausal patients with hormone receptor positive HER2 negative breast cancer that neoadjuvant endocrine therapy with an aromatase inhibitor could be offered to either increase local regional treatment options, if there was no intent for surgery, endocrine therapy could be used for Disease Control. So in a patient where they really were not a good surgical candidate, we could offer this therapy to try to control their disease. For premenopausal patients with hormone receptor positive HER2-negative disease, we did really not feel that neoadjuvant endocrine therapy should be routinely offered outside of a clinical trial. Because in this scenario, there really wasn't enough evidence to offer this approach.

BRITTANY HARVEY: And then Dr. Korde, do want to finally address those patients with HER2-positive disease?

DR. LARISSA KORDE: Absolutely. So in patients with HER2-positive disease that is either node positive or high risk node negative, we felt it would be appropriate to offer neoadjuvant therapy with either an anthracycline and taxane containing regimen, or a non-anthracycline-based regimen in combination with targeted therapy. And we did feel that targeted therapy should include trastuzumab and may also include pertuzumab. For patients with smaller tumors, really those in whom it's unclear whether the more aggressive for on-chemotherapy regimens or even any chemotherapy at all is needed, for example, those with very small tumors, T1A and T1B, we did not feel that neoadjuvant should be routinely offered. And we did note that in those patients with smaller tumors, an alternative regimen, the APT regimen of paclitaxel and Trastuzumab is something that has been studied in the adjuvant setting. But again those patients with these very small node negative tumors, in general, would not be routinely offered neoadjuvant chemotherapy.

BRITTANY HARVEY: Great, thank you both for reviewing those neoadjuvant systemic therapy approaches for those specific patient populations. So Dr. Hershman, in your view, what is the importance of this guideline? And how will it impact clinical practice?

DR. DAWN HERSHMAN: Yeah, that's an excellent question. I think as our data has shown more and more studies where there's a benefit to giving adjuvant treatment based on the response of patients in the neoadjuvant setting to get additional benefit long-term amongst patients with residual disease, I think that these guidelines really can help clinicians to understand those scenarios where we know we can maximize treatment.

I think ultimately the goal of neoadjuvant therapy is that it gives us opportunities to both escalate treatment in patients that are at high risk that don't have great responses, and de-escalate therapy in patients that have outstanding responses. And so I think this will help clinicians understand what those benefits are.

BRITTANY HARVEY: Definitely. It seems like it will provide some clarity for those scenarios. So finally, Dr. Korde, how do you envision that these guideline recommendations will affect patients with non-metastatic breast cancer?

DR. LARISSA KORDE: Well, I think building on Dr. Hershman's answer to the previous question, really, the key here is to be able to personalize or tailor the therapy for individual patients. So in those patients whose disease is very high risk, or did not respond to initial therapy, patients can be given appropriate escalation of treatment. And for patients who have an excellent response to treatment in the neoadjuvant setting can potentially be spared other treatments. And so I think that the main use of neoadjuvant treatment and the use of this guideline in terms of how it affects patients is being able to offer the most appropriate therapy for each patient.

BRITTANY HARVEY: Great, well, thank you both for your work on this guideline on neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer. Appreciate your leadership on this guideline. And I want to thank you also for taking the time to speak with me today, Dr. Korde and Dr. Hershman.

DR. DAWN HERSHMAN: Thank you.

DR. LARISSA KORDE: Happy to be here. Thanks so much.

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

An interview with Dr. Megan E. Daly from the University of California, Davis on "Radiation Therapy for Small Cell Lung Cancer: ASCO Guideline Endorsement of an ASTRO Guideline." An ASCO Expert Panel reviewed an ASTRO guideline on radiation therapy for SCLC and determined it was clear, thorough, and evidence based. ASCO endorsed the ASTRO guideline with a few discussion points, which Dr. Daly reviews in this podcast. Read the full guideline endorsement at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

PRESENTER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today, I'm interviewing Dr. Megan Daly from the University of California Davis, Co-Chair and lead author on "Radiation Therapy for Small Cell Lung Cancer: ASCO Guideline Endorsement of an ASTRO Guideline."

Thank you for being here, Dr. Daly.

DR. MEGAN DALY: Thank you. Glad to be here.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Daly, do you have any relevant disclosures that are directly related to this guideline topic?

DR. MEGAN DALY: I do not.

BRITTANY HARVEY: Great. Thanks so much. So generally, can you give us an overview of what this guideline endorsement addresses and how the ASCO guideline endorsement process works?

DR. MEGAN DALY: This guideline was designed to provide an endorsement of a very comprehensive guideline provided by the American Society of Radiation Oncology addressing the use of radiation therapy for small cell lung cancer. The guideline endorsement process involved us developing a team of physicians, both medical oncologists and radiation oncologists, to review and assess the ASTRO guideline and make recommendations and clarifications for the ASCO audience.

So our guideline panel met several times by teleconference. We carefully reviewed the guidelines with assistance from the ASCO staff. We reviewed each individual recommendation within the ASTRO guideline, including the supporting evidence and the final recommendations, and provided clarifying comments, when necessary.

The entire guideline panel had to vote and reach a consensus on each individual recommendation from the ASTRO guideline to form a final consensus. And ultimately in the case of this guideline, we largely agreed with the excellent ASTRO guideline that had already been produced. So this was largely a process of confirming and endorsing ASTRO's guideline product. We also, then, provided a written paper that provides some additional clarification in context for ASCO's audience.

BRITTANY HARVEY: Great. So you just touched on some of the recommendations of the guidelines. So what were those key recommendations of this guideline?

DR. MEGAN DALY: So this guideline was specifically addressing the use of radiation therapy for small cell lung cancer, both limited-stage and extensive-stage small cell lung cancer. So the key recommendations that came out of both the ASTRO guideline and ASCO's recommendation of ASTRO's guidelines were first that radiation therapy should be used for most patients with limited-stage small cell lung cancer, confirming standard practice, and that doses of 45 gray in twice daily fractionation remain the standard of care, but alternative schedules delivering 60 to 70 gray over a single fraction are also reasonable.

The guideline also addressed that stereotactic radiation is an appropriate consideration for early-stage node-negative limited-stage small cell lung cancer. The guideline also addresses the use of prophylactic cranial irradiation and continues to recommend the use of prophylactic cranial irradiation for fit patients with limited-stage small cell lung cancer while recommending shared decision making for other patients, including those with extensive-stage disease or patients who might have contraindications to PCI for limited-stage small cell lung cancer. And finally, the guideline also addressed the use of consolidated thoracic radiation in extensive-stage small cell lung cancer, providing a recommendation that it be considered for well-selected patients with extensive-stage disease.

BRITTANY HARVEY: OK, and then you mentioned earlier that there were select scenarios in which the panel offered clarifying comments. So in which sections did the ASCO expert panel decide to offer those clarifying comments?

DR. MEGAN DALY: Our clarifying comments were largely simply to provide clarification in several of the recommendations. For example, in recommendation 1.2, where ASTRO recommends that it's important to maintain the dosage and timing of chemotherapy with radiation and that timing is more critical for accelerated dose intensive radiation, we clarified that dose intensive radiation would be referring to twice daily hyper-fractionated regimens.

We also provided clarification that ultracentral tumors refer to those where a planning target volume is overlapping or touching the proximal bronchial tree, the esophagus, and trachea within the recommendation that those tumors, even when early stage might better be addressed by fractionated, rather than a stereotactic radiation.

And finally, for recommendation 4.4, it states for patients with extensive-stage small cell with a response to chemotherapy and immunotherapy and residual disease in the thorax, thoracic radiation to 30 gray and 10 fractions within six to eight weeks can be considered. And we provided clarification that that would be six to eight weeks of completion of the chemotherapy and prior to maintenance immunotherapy.

BRITTANY HARVEY: Great. Then it sounds like those notes will be key for the ASCO audience in interpreting and implementing these recommendations. So in your view, what is the importance of this guideline endorsement? And how will it affect ASCO members?

DR. MEGAN DALY: So I believe this guideline endorsement and the initial ASTRO guideline are both very important in providing guidance to both radiation oncologists and medical oncologists who routinely treat small cell lung cancer patients in their practice. The small cell lung cancer space is constantly changing, and there have been some major developments in small cell lung cancer within the last 5 to 10 years, most notably surrounding the use of prophylactic cranial irradiation and extensive-stage disease.

There's also a number of interesting ongoing clinical trials looking at the use of consolidated thoracic radiation in extensive-stage disease. And many practitioners have questions about how to use radiation in the landscape of changing systemic therapies, for example, the integration of immunotherapy into extensive-stage disease, as well as how to integrate newer irradiation technologies like stereotactic radiation into the treatment of small cell lung cancer. So I believe that this guideline endorsement, as well as the original guidelines, can provide valuable guidance to the ASCO community in how to treat these patients in their daily practice.

BRITTANY HARVEY: Great. And then finally, how do these guideline recommendations impact patients with small cell lung cancer?

DR. MEGAN DALY: Hopefully, these guideline recommendations will help patients with small cell lung cancer receive standard of care latest treatments incorporating radiation. And there's a number of areas where radiation has been shown to improve survival in small cell lung cancer. So we absolutely want to make sure that our patients are receiving the best possible care that incorporates all available treatment modalities and incorporates all the latest data.

BRITTANY HARVEY: Great. Well, thank you so much for your work on this guideline endorsement, and thank you for taking the time to speak with me today, Dr. Daly.

DR. MEGAN DALY: Yeah, Brittany, thank you so much. Glad to be here.

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

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.

An interview with Dr. Katherine S. Virgo from Emory University in Atlanta, GA on "Initial Management of Non-Castrate Advanced, Recurrent or Metastatic Prostate Cancer: ASCO Guideline Update." This guideline updates recommendations for initial hormonal management of non-castrate advanced, recurrent, or metastatic prostate cancer. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

PRESENTER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Katherine Virgo from Emory University, lead author and co-chair on initial management of non-castrate advanced, recurrent, or metastatic prostate cancer, ASCO guideline update. Thank you for being here, Dr. Virgo.

DR. KATHERINE VIRGO: Thank you, Brittany.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Virgo, do you have any relevant disclosures that are directly related to this guideline topic?

DR. KATHERINE VIRGO: No, I do not.

BRITTANY HARVEY: OK, thanks. Then let's delve into some of the guideline content. What prompted this update of the initial management of non-castrate advanced, recurrent, or metastatic prostate cancer guideline, and what is the scope of the update?

DR. KATHERINE VIRGO: Well, the update of the 2007 version of the guideline was largely prompted by the many Phase III randomized clinical trials that had been completed or were nearly complete in the non-castrate space. It was believed that the results of these trials might permit revisiting previous recommendations regarding intermittent versus continuous androgen deprivation therapy and early or immediate versus deferred androgen deprivation therapy.

As you might imagine, it took quite some time to gather and review 13 years of literature for each of the study questions from the original 2007 guideline. So in the interim, a sufficient number of randomized clinical trials reached completion to also inform recommendations regarding the use of newer therapies in combination with androgen deprivation therapy as initial therapy for men with metastatic disease, such as docetaxel, abiraterone, enzalutamide, and apalutamide, and thereby also update another existing ASCO guideline authored by Morris et al in 2018, which previously only provided guidance on the use of docetaxel and abiraterone for men with metastatic disease.

BRITTANY HARVEY: Great, yeah, definitely a large volume of literature to review there. So then you talked about the recommendations. So I'd like to go through some of those. For men with metastatic non-castrate prostate cancer, what are the recommended standard initial treatment options?

DR. KATHERINE VIRGO: So docetaxel, abiraterone, enzalutamide, and apalutamide, each when administered with androgen deprivation therapy, represent four separate standards of care for non-castrate metastatic prostate cancer. The use of any of these agents in any particular combination or in any particular series cannot yet be recommended. That said, we were able to make a recommendation for each agent individually. So I'll go through those recommendations now, first for docetaxel.

So for men with metastatic non-castrate prostate cancer with high-volume disease who are candidates for treatment with chemotherapy, the addition of docetaxel to androgen deprivation therapy should be offered. Here, high-volume disease is defined per the charted trial as four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or the presence of any visceral disease.

Second, for abiraterone, for men with high-risk de novo metastatic non-castrate prostate cancer, the addition of abiraterone to androgen deprivation therapy should be offered per the latitude trial. For men who are considered low-risk, androgen deprivation therapy plus abiraterone may be offered for the STAMPEDE trial.

Third, for enzalutamide, androgen deprivation therapy plus enzalutamide should be offered to men with metastatic non-castrate prostate cancer, including those with de novo metastatic disease and those who have received prior therapies, such as radical prostatectomy or radiation therapy for localized disease. Enzalutamide plus ADT has demonstrated short-term survival benefits, such as PSA progression-free, clinical progression free, and overall survival when compared to androgen deprivation therapy alone for men with metastatic non-castrate prostate cancer per the ENZAMET trial.

And finally, fourth, androgen deprivation therapy plus apalutamide should be offered to men with metastatic non-castrate prostate cancer, including those with de novo metastatic disease or those who have received prior therapy, such as radical prostatectomy or radiation therapy for localized disease, per the TITAN trial. Thus in summary, to your initial question, all of the recommendations were phrased as "should be offered" except in the case of androgen deprivation therapy plus abiraterone for men with low-risk de novo metastatic non-castrate prostate cancer, for which the recommendation was phrased as "may be offered," as the evidence was not as strong as for the other recommendations.

BRITTANY HARVEY: Great, thank you for reviewing those standard initial treatment options for men with metastatic non-castrate prostate cancer. So then what does the guideline say regarding combination therapy for men with non-castrate locally advanced non metastatic prostate cancer?

DR. KATHERINE VIRGO: So here, androgen deprivation therapy plus abiraterone and prednisolone should be considered for men with non-castrate locally advanced non-metastatic prostate cancer, rather than castration monotherapy, due to the failure-free survival benefit for the STAMPEDE trial. We were unable to make a recommendation for men with high-risk non-metastatic prostate cancer progressing after radical prostatectomy or radiotherapy or both, as it's currently unclear whether enzalutamide in the 160-milligram dose plus leuprolide improved metastasis-free survival compared to enzalutamide monotherapy or placebo. The recruitment is complete for the ongoing Phase III EMBARK trial, which is designed to answer this question. The results are not available yet.

BRITTANY HARVEY: Great. Then how does the guideline address early or immediate androgen deprivation therapy versus deferred therapy for men with non-castrate locally advanced non-metastatic prostate cancer?

DR. KATHERINE VIRGO: So here, early or immediate androgen deprivation therapy may be offered to men who initially present with non-castrate locally advanced non-metastatic disease who have not undergone previous local treatment, and are either unwilling or unable to undergo radiotherapy, based on evidence in one meta-analysis of a modest but statistically significant benefit in terms of both overall survival and cancer-specific survival among the larger population of men with locally advanced non-metastatic disease. Unfortunately, we were unable to make a recommendation for men with PSA relapse after local treatment. Though existing studies suggest a potential overall survival benefit, additional research is needed, as such studies were underpowered.

BRITTANY HARVEY: And then finally, for men with biochemically recurrent non-metastatic disease, what are the recommendations for intermittent androgen deprivation therapy versus continuous androgen deprivation therapy?

DR. KATHERINE VIRGO: So intermittent therapy may be offered to men with high-risk, biochemically recurrent non-metastatic prostate cancer after radical prostatectomy and/or radiotherapy, based on evidence and meta-analyses of the non-inferiority of intermittent androgen deprivation therapy when compared to continuous androgen deprivation therapy, with respect to overall survival. This is further supported by evidence from four meta-analyses testing superiority. And here, high-risk biochemical recurrence after radical prostatectomy is defined as a PSA doubling time less than one year or a pathologic Gleason score of 8 to 10. High-risk biochemical recurrence after radiation therapy has a different definition, here defined as an interval to biochemical recurrence of less than 18 months or a clinical Gleason score of 8 to 10.

BRITTANY HARVEY: Thank you for reviewing all those recommendations and the evidence supporting them. It's very interesting to hear where you were able to make recommendations and where you weren't. So in your view, what is the importance of this guideline, and how will it change practice?

DR. KATHERINE VIRGO: As mentioned earlier, the previous version of the guideline was 13 years old. And practice, as you might imagine, has changed considerably in the interim. Though consensus documents have been issued by other organizations since that time, it was important, given ASCO's global audience, to provide up-to-date, evidence-based guidance for the organization's worldwide membership.

Practice patterns of most clinicians based at large university medical centers likely approximate the guidance provided in the ASCO guideline update, at least with respect to the treatment of men with de novo metastatic high-risk or high-volume disease. Some may be surprised by the current lack of evidence for the use of docetaxel among patients with de novo metastatic low-volume disease. The new guidelines should be particularly useful for community-based clinicians, who may not be as actively involved in clinical trial enrollment.

BRITTANY HARVEY: Definitely. And then finally, how will these guideline recommendations impact patients with prostate cancer?

DR. KATHERINE VIRGO: So patients will be impacted in three ways. First, the guidelines should be helpful to patients in understanding the various treatment options available to them, depending on the extent of their disease and any previous treatment they may have already received. The guidelines also highlight treatment options that should not be offered to patients who have certain characteristics and hopefully assist patients with adjusting their treatment expectations.

Second, the cost table in the guidelines should also be helpful to patients, as it provides some idea of how costs vary by the type of treatment received, while also indicating when a less costly generic equivalent is available. And finally, third, the guidelines suggest that patients be counseled about the potential side effects associated with androgen deprivation therapy, such as depression, dementia, stroke, myocardial infarction, deep venous thrombosis, hot flush, fatigue, and nausea. Side effects vary by type of androgen deprivation therapy, as well as by age and patient comorbidities. Knowing up-front that such side effects are possible can assist patients in having more informed conversations with their physician when treatment discussions are underway.

BRITTANY HARVEY: Great. Then it sounds like these guidelines have a real impact for both community oncologists and for patients. So I want to thank you for your leadership on the development of these evidence-based guidelines, and thank you for taking the time to speak with me today, Dr. Virgo.

DR. KATHERINE VIRGO: Thank you, Brittany.

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

A preview of the interview by ASCO in Action podcast host ASCO CEO Dr. Clifford A. Hudis with retiring ASCO Chief Medical Officer Dr. Richard L. Schilsky examining Dr. Schilsky's trailblazing medical career, his leadership in ASCO and indelible mark on its research enterprise, and what he sees for the future of oncology. Dr. Hudis also shares what Dr. Schilsky's friendship and mentorship has meant to him and suggests that he will still be supporting ASCO on critical priorities. Find all nine of ASCO's podcasts and subscribe at podcast.asco.org.

TRANSCRIPT

Dr. Clifford Hudis: Hello, I'm Dr. Clifford Hudis, CEO of ASCO, dropping into your feed to let you know about a special episode of the ASCO in Action podcast featuring the extraordinary career of Dr. Richard Schilsky, ASCO's Chief Medical Officer. Rich and I discuss the advances that have revolutionized cancer care over the last 50 years and much, much more. Here's a preview of the episode.

Dr. Richard Schilsky: The 1980s in many respects were the doldrums of progress in clinical oncology. There really was not a lot of innovation in the clinic. But what was happening and what was invisible to many of us, of course, was that was the decade of discovery of the fundamental biology of cancer. That's when oncogenes were discovered, when tumor suppressor genes were discovered, when it became clear that cancer was really a genetic disease. And that is what transformed the field and put us on the path to targeted therapy and precision medicine as we think of it today.

Dr. Clifford Hudis: You can find the ASCO in Action Podcast on Apple Podcasts or wherever you are listening to this show. And you can find all nine of ASCO's podcasts which cover a wide range of educational and scientific content and offer enriching insight of the world of cancer care at podcast.asco.org.

An interview with Dr. Jun Ma from Sun Yat-sen University Cancer Center in Guangzhou and the Chinese Society of Clinical Oncology on "Chemotherapy in Combination with Radiotherapy for Definitive-intent Treatment of Stage II to IVA Nasopharyngeal Carcinoma: Chinese Society of Clinical Oncology and American Society of Clinical Oncology Guideline." Read the full guideline at www.asco.org/head-neck-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm interviewing Dr. Jun Ma from Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy in Guangzhou, and the Chinese Society of Clinical Oncology, author on Chemotherapy in Combination with Radiotherapy for Definitive-intent Treatment of Stage II to IVA Nasopharyngeal Carcinoma, Chinese Society of Clinical Oncology and American Society of Clinical Oncology Guideline. Thank you for being here today, Dr. Ma.

JUN MA: Yes.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict-of-interest policy is followed for each guideline. The full conflict-of-interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Ma, do you have any relevant disclosures that are directly related to this guideline topic?

JUN MA: Thank you, Brittany. Hi, everyone. I'm Dr. Jun Ma from the Sun Yat-sen University Cancer Center in China. And I don't have any potential conflicts of interest related to this guideline topic.

BRITTANY HARVEY: Great. Thank you. Then can you give us a general overview of what this guideline covers?

JUN MA: Yes. This guideline aims to highlight significant clinical questions about the chemotherapy in combination with the radiotherapy for the definitive treatment of stage II to stage IVA NPC, nasopharyngeal carcinoma, It will clarify the fundamental principles of the radiotherapy planning and how to combine chemo with radiotherapy for a patient's success.

BRITTANY HARVEY: Great. Then this guideline covers five clinical questions. I'd like to review those key recommendations for our listeners. First, what does the guideline state regarding radiotherapy for patients with stage II to IVA nasopharyngeal carcinoma?

JUN MA: Yes. For all nasopharyngeal carcinoma patients, we support the use of IMRT summarized in the current evidence. We don't recommend the use of other techniques, such as 2D or even 3D radiotherapy. If IMRT is not available at that spot, patients should be transferred to the institution that could that could implement IMRT whenever possible.

For all NPC patients, a prescribed dose of 70 Gy in 33 or 35 fractions delivered over seven weeks should be offered. It should be noted that the radiation dose may be adjusted according to the tumor volume and its response to the chemoradiotherapy. In terms of the target delineation, we recommend you to follow several existing consensus guidelines. Thank you.

BRITTANY HARVEY: OK. Then what is recommended regarding chemotherapy sequence in addition to radiotherapy?

JUN MA: OK, generally speaking, patients with low disease burden, such as the lower end category of clinical stage, could receive lower intensity of chemotherapy. For T2, and if not negative of patients, chemotherapy is not routinely recommended, while for T1 or 2, N1 patients concurrent chemotherapy may be offered, particularly for T2 N1 patients.

For locoregional advanced disease, except the T3 lymph node negative patients, we recommend the use after concurrent chemotherapy with induction or adjuvant chemotherapy. It should be noted that there is a lack of head-to-head trials comparing induction chemo plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy plus adjuvant chemo. Thus, which sequence performs better in the contemporary era remains uncertain.

Finally, for T3 lymph node-negative patients, concurrent chemoradiotherapy should be offered. Adjuvant or induction chemotherapy may also be offered if there are adverse features, such as the bulky tumor volumes or high EBV DNA copy numbers.

BRITTANY HARVEY: Great. Then you just mentioned some chemoradiotherapy regimens. So for patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy, what are the recommended chemotherapy options?

JUN MA: OK, for all NPC patient without contraindications, concurrent cisplatin should be offered along with radiotherapy. Weekly use after suspending with 48 milligrams per square meter or three weekly with eight or 200 milligram per square meter is acceptable. We recommended the cisplatin dose should be attempted to achieve a cumulative dose of at least 200 milligrams per square meter.

For patients with contraindications to cisplatin, nedaplatin, carboplatin, or oxaliplatin may be alternative choice. For patients with contraindications to cisplatin-based chemotherapy, Fluoropyrimidines such as 5FU with concurrent chemotherapy also may be offered. Thank you.

BRITTANY HARVEY: Great. And then for patients with nasopharyngeal carcinoma receiving induction chemotherapy, what are those recommended options?

JUN MA: Yes. For all patients receiving induction or adjuvant chemotherapy, platinum-based induction regimens should be offered in terms of induction chemo, such as GP, TPF, TP, PF, and the PX regimens are recommended. So induction regimens should be administered every three weeks for a total of three cycles, or at least the minimum two cycles. If the patients receive induction chemotherapy, chemoradiotherapy should be commenced within 21 to 28 days from the first day of the last cycle of induction chemotherapy.

BRITTANY HARVEY: Great. And then for the final set of recommendations for patients with nasopharyngeal carcinoma receiving adjuvant chemotherapy, what are those recommended chemotherapy options?

JUN MA: Considering that adjuvant chemotherapy is a choice of adjuvant regimens were much fewer than those of induction chemotherapy, according to current evidence. PF regimen administered every four weeks for a total of three cycles is recommended. If with contraindication to cisplatin, carboplatin may be combined with 5-FU.

It should be noted that for all patients receiving adjuvant chemotherapy and with contraindications to platinum-containing chemotherapy, the use of non-platinum based regimens remain experimental at this time and should not be offered routinely outside of the context of a clinical trial. The main difference between the recommendation for the induction and adjuvant chemotherapy are primarily due to the number of the randomized trials in which there are few studies regarding the adjuvant chemotherapy in nasopharyngeal carcinoma. Thank you.

BRITTANY HARVEY: Thank you for reviewing each of those recommendations. So then, what is the importance of this guideline? And how will it impact clinical practice in patients with nasopharyngeal carcinoma?

JUN MA: For nasopharyngeal carcinoma, it has extremely uneven geographically global distribution. More than 70 percent of this new diagnosis worldwide in the 2018 year, occurred in the East and Southeast Asia. Therefore, nasopharyngeal carcinoma remains a significant public health problem in these regions, which emphasize the significance of this guideline for providers and patients from the endemic area.

From my point of view, one of the novel features of this joint deadline is that it was developed through the international collaboration with the regional groups. Experts from the CSCO and ASCO shared interpretation of the evidence while accounting for the organizing national or cultural diversity of different regions. In brief, the guideline provides the guidelines on how to plan radiotherapy and when and how to add chemotherapy. Through the interpretation protecting the guideline, care providers can avoid over or under-treatment. And providing the most suitable chemoradiotherapy for NPC patients.

Besides, for the patients, they could receive the most suitable treatment, which is the balance of the efficiency as a quantity of the life. Thank you.

BRITTANY HARVEY: Great. Definitely, we appreciate the collaboration between the American Society of Clinical Oncology and the Chinese Society of Clinical Oncology. So thank you so much for your work on these guidelines. And thank you for your time today, Dr. Ma.

JUN MA: Thank you.

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

An interview with Dr. John D. Gordan from the University of California, San Francisco, and Dr. Michal G. Rose from Yale Cancer Center and VA Connecticut Healthcare System on "Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline." This guideline addresses first-line and subsequent systemic therapy options for patients with unresectable hepatocellular carcinoma that is not amenable to local therapies. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network. A collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org

My name is Brittany Harvey, and today I'm interviewing Dr. John D. Gordon from the University of California, San Francisco, and Dr. Michal G. Rose from Yale Cancer Center, and VA Connecticut Health Care System, co-chairs on "Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline." Thank you for being here Dr. Gordon and Dr. Rose.

DR. MICHAL G. ROSE: Thank you.

DR. JOHN D. GORDON: Thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Gordon, do you have any relevant disclosures that are related to this guideline topic?

DR. JOHN D. GORDON: I do not.

BRITTANY HARVEY: Thank you. And Dr. Rose, do you have any relevant disclosures that are related to this guideline topic?

DR. MICHAL G. ROSE: I do not, either.

BRITTANY HARVEY: OK, then thank you. Then Dr. Rose, can you first explain the general purpose and the scope of this guideline?

DR. MICHAL G. ROSE: Of course. Thank you for this opportunity. As people know, the incidence of liver cancer, hepatocellular carcinoma, is rising rapidly in the United States and worldwide. And although there are multiple local and potentially curable treatments for early stage disease, the medical oncologist does get involved when these fail or if the patient presents with metastatic disease. And over the last three years, or bit more than three years, we've gone from having only one agent for advanced disease, which is sorafenib, to having nine agents approved for either first or subsequent lines of treatment. So this has created a really good problem for medical oncologists, how to choose between these multiple options. So the purpose of our guideline is to help us select the best treatment for the individual patient based on the best current evidence.

BRITTANY HARVEY: Great. Then this guideline covers both first line and subsequent systemic therapy options for patients with advanced hepatocellular carcinoma. Dr. Gordon, what are the key recommendations for first line therapy?

DR. JOHN D. GORDON: Thanks, and it's also a great pleasure for me to be on this podcast and I appreciate the entire process of putting together this guideline. In the front line setting, a lot of what motivates the completion of this guideline is the approval of the first front line combination for advanced HCC, which is the combination of bevacizumab and atezolizumab. So this was approved based on a report in the New England Journal of Medicine back in May that specifically studied a first line population of patients with advanced HCC and relatively preserved liver function. And the key recommendation of this guideline is that the combination of atezolizumab and bevacizumab be adopted for patients that meet this description. Particular caution is recommended for patients who are at risk of specific side effects or adverse events with these agents.

So for patients receiving bevacizumab, there is a particular risk of bleeding complications and MI or other ischemic complications. And so for patients with a recent MI or with uncontrolled esophageal varices, we recommend either management of these or not using this combination. Similarly, there are a range of contraindications to use of PD1, PDL1 inhibitors, such as atezolizumab, including history of various autoimmune diseases. And so we do not recommend this combination for patients with those co-morbidities. For patients with either more advanced liver failure or the specific risks that I just outlined, we're recommending continuation when safe and appropriate, of what was the previous standard of care. Which is front line treatment with either the oral TKI lenvatinib or the oral TKI sorafenib.

BRITTANY HARVEY: Great. Thank you for that overview of the first line recommendations. And Dr. Rose, what are the recommendations for second line therapy?

DR. MICHAL G. ROSE: So our team had a harder time with second line recommendations. And mainly because there's a lack, currently, of published data on treatment outcomes in patients who've received atezolizumab plus bevacizumab front line or lenvatinib front line. So we debated a lot in our group, which was a very multidisciplinary and collaborative group. And we did agree that patients who are well enough to receive second line therapy, that is their Child-Pugh was still A, and they had a good performance status, they should be considered for sorafenib, oral lenvatinib, if they had received atezolizumab plus bevacizumab in the front line setting. But of course other options for the second line would be cabozantinib or regorafinib, are reasonable in the evidence based options.

In patients who received sorafenib oral lenvatinib front line, we also discussed that it was reasonable to treat them with atezo bev because we presume that these patients did not have access to that combination in the front line. Of course if they meet the criteria that John outlined in the discussion of front line treatment. In patients who received sorafenib or lenvatinib front line, of course that we have data on using other tyrosine kinase inhibitors, such as cabozantinib or regorafinib. We also have data on using ramucirumab in patients who have an alpha fetoprotein greater than 400. And those were the recommendations that we made.

The other discussion that we had in these guidelines was the use of the immune checkpoint inhibitors second line. And we made the recommendation that they should be considered for patients who received sorafenib or lenvatinib in the front line setting, especially if they have contraindications to the use of further tyrosine kinase inhibitors. Or if they could not tolerate tyrosine kinase inhibitors.

BRITTANY HARVEY: Got it. Thank you for reviewing those second line systemic therapy options. Then Dr. Gordon finally, what is the importance of this guideline and how will it impact clinical practice and affect patients with advanced hepatocellular carcinoma?

DR. JOHN D. GORDON: Thanks. And so I think this very much follows on Michal's initial introduction about the purpose of this guideline, which was to address the dramatic proliferation of approved agents for advanced HCC. And what we were attempting to do, and I think achieved to the best that the evidence would support, was provide some degree of guidance on how providers could select both their first line agent and then later lines of therapy to the extent that patients are able to receive it. We think that the availability of these multiple agents for HCC, as Michal alluded to, is really an embarrassment of riches and now we need to think about how to use them wisely.

And we hope that actually as these new combinations and just a greater set of options enter clinical practice, it will be possible to actually do some of the studies that would address the questions that right now remain unanswered around treatments sequencing and the like. I think that there remain some interesting questions in the management of HCC, both for patients with more impaired liver function and for patients at the threshold between localized HCC who are still candidates for local regional therapies such as TACE or selective internal radiotherapy, and requiring systemic therapy as the outcomes from systemic therapy are becoming more positive. But in aggregate we think that these guidelines now provide something of a sequence for the treatment of patients who do require systemic therapy and hopefully an outline for further development.

BRITTANY HARVEY: Great. Thanks. It sounds like this will be important for both practitioners, and patients. So I want to thank you both for joining me on the podcast today and for your leadership on the development of these guidelines, Dr. Rose and Dr. Gordon.

DR. MICHAL G. ROSE: Thank you. And thank you for the opportunity to discuss them.

DR. JOHN D. GORDON: Yeah, thanks as well. And thanks to the amazing team at ASCO and to the entire expert panel, which put in quite a bit of time over the several years that we developed this guideline as more and more data became available.

BRITTANY HARVEY: Great. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

An interview with Dr. Neelima Denduluri from Virginia Cancer Specialists, U.S. Oncology in Arlington, VA and Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, TX on "Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update." This update addresses the use of adjuvant trastuzumab emtansine and the use of biosimilar forms of trastuzumab. Read the full guideline at www.asco.org/breast-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Neelima Denduluri from Virginia Cancer Specialists, US Oncology in Arlington, Virginia, and Dr. Sharon Giordano from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, co-chairs on "Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update."

Thank you for being here, Dr. Denduluri and Dr. Giordano.

Dr. Neelima Denduluri: Thanks for having us.

Dr. Sharon Giordano: Yeah, we're delighted to be here. Thank you.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Denduluri, do you have any relevant disclosures that are related to this guideline topic?

Dr. Neelima Denduluri: Our institution has received research funding from companies including Genentech.

Brittany Harvey: Thank you. And Dr. Giordano, do you have any relevant disclosures that are related to this guideline topic?

Dr. Sharon Giordano: No, I don't have any relevant disclosures. Thank you.

Brittany Harvey: Thank you. Then let's get into the guideline content. Dr. Denduluri, what prompted this focused update of the selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer guideline?

Dr. Neelima Denduluri: There was an FDA meta analysis and several other studies that showed that patients that did not receive a pathologic complete response after preoperative therapy in the HER2-positive setting had a worse prognosis. In the past, we didn't have actionable findings to improve their outcome.

But there was a trial, the KATHERINE trial, that randomized patients that received chemotherapy and trastuzumab, plus or minus pertuzumab, that did not achieve a pathologic complete response to receive standard of care trastuzumab or 14 cycles of trastuzumab emtansine. And the patients that received trastuzumab emtansine had a significantly improved outcome over those that received standard of care trastuzumab. These were very impactful findings that changed care for women with early breast cancer. Therefore, we wanted to update the guideline.

Brittany Harvey: So Dr. Giordano, there are two new recommendations in this guideline update. First, what does the guideline say regarding the use of adjuvant trastuzumab emtansine following standard preoperative chemotherapy and HER2-targeted therapy for patients with HER2-positive breast cancer with residual invasive cancer in the breast or lymph nodes at surgery?

Dr. Sharon Giordano: So the first recommendation was based on the data from the KATHERINE trial that Dr. Denduluri just mentioned. And so their recommendation is that patients with HER2-positive breast cancer who have pathologic invasive residual disease at surgery to either in the breast or the lymph node after standard pre-op chemo with HER2-targeted therapy should be offered 14 cycles of adjuvant trastuzumab emtansine unless there's a recurrence or unworkable toxicity. So basically stating, based on the data from KATHERINE, that if patients have residual disease after their chemotherapy for HER2-positive breast cancer, they should get adjuvant trastuzumab emtansine. And the panel overall felt that the evidence behind this-- the quality of the evidence was very high, and it had a strong recommendation for this treatment.

Brittany Harvey: And then second, Dr. Denduluri, how does this guideline address the use of biosimilar forms of trastuzumab?

Dr. Neelima Denduluri: So biosimilars are increasingly being incorporated into clinical practice, and the guidance that we have from the FDA is that the efficacy of biosimilars compares well with standard trastuzumab. So, we said that patients that would receive trastuzumab are allowed to receive trastuzumab biosimilar without what we think will negatively impact their outcome.

Dr. Sharon Giordano: For that recommendation, we also had input from the Breast Cancer Guideline Advisory Group that helped us decide to expand the update to include the biosimilars. We think that at least five biosimilars have been approved by the FDA, and based on similar efficacy and similar safety data felt that it was appropriate to use them or trastuzumab in a setting where previously we had just used trastuzumab.

Brittany Harvey: Great. And then how will this guideline update impact clinical practice?

Dr. Sharon Giordano: I think that many practitioners have already adapted clinical practice to start to use adjuvant trastuzumab emtansine based on the KATHERINE data, but we certainly hope that this guideline update will reinforce the practice of providing adjuvant trastuzumab emtansine for patients with HER2-positive breast cancer with residual disease after preoperative treatment. The improvement in outcomes was really clinically meaningful for patients, so this does seem to be a significant step forward in the treatment of HER2-positive breast cancer.

Dr. Neelima Denduluri: Additionally, I think that it's important to remember, as clinicians, that we should think about preoperative therapy in those patients with higher-risk HER2-positive disease, because we know that we can impact their outcomes if they don't achieve a pathologic complete response. And hopefully this guideline will heighten the awareness that we need to do that. The other question that we commonly are asked is, even if there is a small amount of residual invasive carcinoma, should we switch to trastuzumab emtansine instead of trastuzumab plus or minus pertuzumab. And what the KATHERINE data did show is that patients that-- even if they had a small amount of residual cancer burden, they still derived benefit.

Obviously, we have to think about the safety, and we also wanted to outline that in this guideline that trastuzumab emtansine is associated with a higher risk of neuropathy and thrombocytopenia and liver function abnormalities. So we certainly need to worry about that. And those patients that do have poor tolerance, we can go back to their HER2-targeted backbone they received in the preoperative setting.

Dr. Sharon Giordano: Yeah, those are great additional points.

Brittany Harvey: Definitely. And you've both already touched on a bit of how adjuvant therapy impacts patients, but how will these guideline recommendations affect patients?

Dr. Neelima Denduluri: I think that really, as Dr. Giordano stated, this is an overwhelming benefit that we don't normally see in terms of impacting outcomes. So the addition of trastuzumab emtansine potentially has good efficacy for them and improves their outcomes.

Dr. Sharon Giordano: Yeah, I agree. I think this trial was associated with a really meaningful reduction in risk of recurrence and better outcomes. So this really is a step forward for treating HER2-positive breast cancer.

Dr. Neelima Denduluri: The other interesting thing about this trial is that it did not delay their local therapy. They allowed concurrent trastuzumab emtansine with radiation therapy. And they also, in terms of systemic therapy, allowed endocrine therapy with trastuzumab emtansine, similar to what we do with trastuzumab plus or minus pertuzumab in the adjuvant setting. So as Dr. Giordano stated, really impactful in terms of efficacy, well-tolerated in most situations, and pragmatic in terms of not holding up the local therapy and the systemic therapy that they may need additionally.

Brittany Harvey: Great, thank you so much for sharing that information about how it impacts patients. I appreciate you both coming on the podcast today and for all your work that you put into updating these guidelines. And thank you for your time today Dr. Giordano and Dr. Denduluri.

Dr. Sharon Giordano: Thank you so much. It was a pleasure.

Dr. Neelima Denduluri: Thank you both, and thank you Brittany for always working so hard to make sure that these guidelines help our patients.

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

An interview with Dr. Felasfa Wodajo from Virginia Cancer Specialists on "The Treatment of Metastatic Carcinoma and Myeloma of the Femur: Joint MSTS/ASTRO/ASCO Guideline." This guideline covers medical oncology, radiation oncology, and surgical recommendations regarding the management of patients with metastatic or myelomatous lesions of the femur. Read the full guideline at www.asco.org/supportive-care-guidelines.

Transcript

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

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

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world's cancer care. You can find all the shows, including this one, at podcast.asco.org

My name is Brittany Harvey and today I'm interviewing Dr. Felasfa Wodajo from Virginia Cancer Specialists in Fairfax, Virginia, co-chair on the treatment of metastatic carcinoma and myeloma of the femur, joint Musculoskeletal Tumor Society, American Society for Radiation Oncology, and American Society of Clinical Oncology Guideline. Thank you for being here Dr. Wodajo.

Dr. Felasfa Wodajo: Thank you so much Brittany, I really appreciate the opportunity to talk about our joint guideline that is being published as we speak. It's a great opportunity to share the information with your members as well as hopefully patients and members of other societies.

Brittany Harvey: Great. Then first I'd like to note that ASCO takes care in the development of its guidelines in ensuring that the conflicts of interest are managed for each guideline. This guideline expert panel was assembled in accordance with the American Association of Orthopedic Surgeons conflict of interest policy implementation for clinical practice guidelines. And the full conflict of interest information for this guideline panel is available online in the full text of the joint guideline on the MSTS website.

Dr. Wodajo, do you have any relevant disclosures that are related to this guideline topic?

Dr. Felasfa Wodajo: There's one relevant, but not directly conflicting. I'm a consultant for ONKOS Surgical. That's a maker of implants, but mostly for patients who need sarcoma surgery, and they don't make implants for the types of conditions that are in the guideline.

Brittany Harvey: OK, well thanks for letting us know. First, can you give us a general overview of what this guideline covers?

Dr. Felasfa Wodajo: Sure. The guideline is focused on the effects of metastatic carcinoma or myeloma on the femur. And, as all medical oncologists are aware, metastatic disease to the bone and myeloma are often associated with skeletal pain and sometimes skeletal fractures. Those fractures can occur in any part of the body, spine, of course long bones, and ribs, and so on.

But in our world of orthopedic surgery-- I'm a representative from the Musculoskeletal Tumor Society-- the bones and then added complication are not all equal, and some areas have greater morbidity and effect on patient's outcome than others, the femur being a very important one. And we wanted to focus our efforts on discussing the causes and potential treatments of metastatic disease to the femur.

Brittany Harvey: And then what are the key recommendations of this guideline?

Dr. Felasfa Wodajo: Sure, I'm looking forward to discussing those. I do want to, of course, take a second to acknowledge the hard work that was done by my co-chairs, Dr. Patrick Getty, also from the MSTS, Dr. John Charlson, who was an ASCO co-chair, and Dr. Josh Petit, who is the ASTRO co-chair. And also this gives me a chance to say that this guideline was a joint effort between those three organizations which you already mentioned.

The initiative was led by our organization-- the Musculoskeletal Tumor Society, MSTS-- which is a mostly North American, but also international, society of musculoskeletal tumor surgeons, also known as orthopedic oncologists. And therefore, in almost every place that members of our group work, they're working in close association with medical oncologists and radiation oncologists.

So we wanted to make sure that the guideline reflects the input of all three specialties since all three specialists are often treating the same patients. And in developing the PICO questions-- which are the underlying questions in developing a guideline-- we made sure that we had co-chairs-- one from each of the societies-- agree on which PICO questions to include in the final literature search.

And then finally, the guideline as written, roughly breaks the recommendations down by specialty. It starts off with medical oncology topics, then radiation oncology topics, and then surgical topics. So that's a little bit of background that might be helpful.

I also wanted to mention that one of the meta level findings was the paucity or the dirth of literature that directly addressed the question at hand which is, what kinds of treatments can prevent femur fractures, and then which therapies are best for patients with disease in the femur that may or may not lead to fractures. And we started off with a fairly broad net. But as we focused down on the questions, our initial literature search-- which resulted in over 4,000 journal articles-- was winnowed down to a total of 23 papers which had the high enough level of evidence to be included in our guideline production. And therefore, that inevitably a good number of our questions-- not having strong enough evidence to make a strong evidence based recommendation-- and therefore more than half of our recommendations in the end had to be consensus or expert opinion.

So let me continue with your original question which is, what are the key recommendations. Well, questions that we were interested in were number one, to what extent can non-surgical treatments of metastatic disease to the femur, or myeloma in the femur, will reduce the risk of fracture.

So almost everybody listening to this podcast will know well that bone targeted agents such as the bisphosphonates and denosumab have a strong effect validated in multiple high level randomized and prospective studies in reducing Skeletal Related Events, SREs. As you know, as the listeners also know, Skeletal Related Events is a fairly broad umbrella term, and it includes fracture of any bone as well as hypercalcemia and need for surgery.

But like I said earlier on, a compression fracture of a vertebral body which causes back pain but is treated conservatively, and a fracture of the rib, which also causes pain, treated conservatively or nonoperatively, is a very different matter from a femur fracture which always requires surgery in order to allow the patient to ambulate and regain function.

Having said that, we were disappointed to find that in much of the literature around bone targeted agents-- of which there is plenty-- there's really very little of it that you can find where they stratify, or at least retort, which bones were fractured. So even though there is a strong literature base supporting reduction skeletal events, we can't really say for sure that the risk of a fracture of a femoral lesion is diminished by both targeted agents.

That came out as a consensus statement because this seems to reduce fractures overall, so we left this as a consensus and agreed that BMAs may assist in reducing the incidence of femur fractures.

The next item, number three, in our final report recommended that clinicians consider decreasing the frequency of zoledronic acid dosing to 12 weeks instead of the usual, and most common, four week interval.

There's actually a fair amount of literature supporting quarterly injections as equally efficacious. That's mostly focused on zoledronic acid. It may be true for [INAUDIBLE]. It may also even be true for denosumab, but the literature didn't support that as yet.

But we did make this strong recommendation on our part that clinicians consider reducing the frequency of dosing. If nothing else, because in addition to reducing costs to the patient and time of the patient, we think there may be-- and we put this in our rationale-- there's some chance that some of the unintended side effects of long-term treatment with these bisphosphonate and bismuth therapies such as aseptic necrosis of the jaw and atypical fractures, or brittle bone fractures, of the femur may be reduced with decreased frequency.

Extrapolating from the finding that the longer patients are treated, the higher the incidence of these conditions are, especially atypical fractures. So it could be that less frequent dosing is analogous to less length of treatment. So that was an evidence based and strong recommendation.

We also then looked at the effect of radiation on bone lesions and whether or not it does reduce risk of fracture. We found, not surprisingly, that the radiation oncology literature really focuses on pain. And it's been proven many times and in multiple studies across many decades that radiation therapy does reduce pain at 80% to 90%. And even re-treatment will reduce pain in up to 50% to 70% of patients. But surprisingly, there's actually very little data out there whether it reduces the risk of fracture.

Now we would presume that fracture risk is correlated to bone loss, and that would be radiolucency or loss of calcification on the X-ray. And there are some studies out there which attempt to measure density of bone before and after radiation therapy. And there seems to be some validation, or at least some measurement out there that radiodensity does increase with radiation therapy, and again, we went from that and extrapolated that fracture risk would best be reduced.

But that ended up being a consensus statement. And it's actually a fairly important topic. And hope that more studies would be forthcoming on this, because it would be very helpful for us to predict ahead of time whether this patient can avoid a fracture with radiation alone or do they need to go to surgery.

Next we talked about how effective or beneficial is radiation after somebody's had surgery. So whether or not they've had a fracture, is there a further benefit to radiation. And here the amount of data was even more disappointing.

There's really only two studies that attempt to address this question-- is there a benefit to additional radiation following surgery-- neither one of which was well controlled. They're way out of date and the criteria themselves used in measuring the benefit were not validated.

Now we felt, as a work group-- again consisting of medical oncologists, radiation oncologists, and surgical oncologists, in this case orthopedic oncologists-- that the additional morbidity from radiation after surgery is fairly low. So we left that recommendation as that it has some benefit, but that was the consensus only.

One item that we elevated from consensus to a moderate strength was the benefit of using multifraction radiotherapy to reduce the risk. There is some data-- again, it may be biased-- that patients who undergo single dose radiotherapy as opposed to multifraction radiotherapy for metastatic lesions have an increased risk of fracture. And it may be associated and it may be that those patients getting single dose radiation were at higher risk or had more rapidly progressing disease. But there may be some signal in that noise, and after evaluating the papers and with the help of our experts in radiation oncology, we elevated that to a moderate strength of recommendation.

Then there was a series of questions we tried to address, various surgical techniques and the management of pathology of fractures in the femur and prevention of, and those questions are really more about surgical technique. And these were addressed to our surgical colleagues in large part. I don't know, and I would suspect that the audience of this podcast probably won't be as interested in these questions as the ones we just discussed, so I'll leave those for another time. But I will say a large number of these ended up being also consensus driven evidence.

Brittany Harvey: Got it. Well, thank you so much for reviewing those highlights from the multidisciplinary group and the supporting level of evidence. That's very helpful. So in your view, why is this guideline so important and how will it impact clinical practice?

Dr. Felasfa Wodajo: So, thank you for the question. I'll answer that in two ways. I think the two items that might be of immediate clinical relevance, and therefore of help to patients and their physicians, is number one, further promulgation of the idea of less frequent dosing of bone targeted agents is equally efficacious.

We felt that, if based on our common experiences in our various practices and institutions, that still was not widespread practice. In other words, most patients were still receiving monthly injections of these medications. So we do believe that there is some net patient benefit available to us if those are reduced to quarterly injections for the reasons I mentioned above. So that's one potential immediate release and early improvement that we can expect for patients.

I think the other one, to some extent, may be that what I discussed a little while ago about and multifraction versus single fraction therapy. Again, we don't have nationwide survey data to tell us how often those techniques are used. Again, based on this sort of experience of the workup we thought that that may not be widely understood. So those are two immediate clinical benefits that may be there for patients.

The other way I would look at is at a meta level. Number one was that this is a cooperative venture in which the design and implementation of the guideline was across three organizations. And many times guidelines do incorporate the viewpoints of people of multiple specialties, and sometimes even patient representatives. But it's also, I think, further valuable to have multiple organizations involved because there's some cross-fertilization opportunities there, other products may arise from that, and then also you get what we hope is promulgation of that information to people of different specialties. In other words, these recommendations don't stay inside the ecosphere of one association.

Now when you have multiple organizations working on one project, necessarily it gets more complicated. And there is certainly a heavier administrative burden in getting this project initiated and completed. But hopefully the benefits of that will accrue.

The other thing which I'd like to mention is that I think the paucity of high level evidence for the questions we ask-- which we believe are important questions for physicians and patients-- I think hopefully should stimulate the researchers in these fields to accrue more data so that future researchers and clinicians have access to these information.

For example, I suspect that in future prospective studies of bone targeted agents-- those studies are ongoing-- new agents will be coming out. Pharma will be looking at how those work for their patients in the future. And we would like to ask that those future researchers include, at a minimum, anatomic data for fractures. In other words, they should unbundle Skeletal Related Events and tabulate fractures as occurring in which part of the bone, and if that resulted in surgery.

Those data are there in the records, but if they don't collate them as they go forward, they will not be available to us, and so therefore won't be as efficacious in helping our patients in the future.

Brittany Harvey: Definitely. Those are some important points and I like that you touched on the collaboration of the societies. We find that very important at ASCO to one, reduce the duplication of efforts, and then also to improve the clarity of the recommendations. So, I guess then, finally-- and you've addressed this a bit in terms of dosing of bone modifying agents-- what do these guideline recommendations mean for patients?

Dr. Felasfa Wodajo: Well, for the bone targeting agents, as I said, that might mean fewer doctors visits and maybe less expense, hopefully fewer side effects. For the hyperfractionated radiation, it may not be immediately apparent. I mean a lot of times when a patient's getting single fraction radiation they are fairly advanced in their cancer. But of course they'll get more fractions which means more time in the machine. But hopefully maybe some benefit If they survive longer, which of course, patients are now doing. So those are two potential patient benefits.

Brittany Harvey: Great. Well thank you for your work on these guidelines and for joining me on the podcast today Dr. Wodajo.

Dr. Felasfa Wodajo: I very much appreciate your invitation, and thank you.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store.

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

An interview with Dr. William P. Tew from Memorial Sloan Kettering Cancer Center on "PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline." This guideline provides recommendations on the use of poly (ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer. Read the full guideline at www.asco.org/gynecologic-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Brittany Harvey: Hello, and welcome to the ASCO guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today, I'm interviewing Dr. William P. Tew from Memorial Sloan Kettering Cancer Center in New York, New York, lead author on PARP inhibitors and the management of ovarian cancer. Thank you for being here, Dr. Tew.

Dr. William Tew: Thank you, Brittany, for having me.

Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Tew, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. William Tew: No, I do not.

Brittany Harvey: OK, thank you. Then, can you give us a general overview of what this guideline covers?

Dr. William Tew: Sure. So my co-chair, Elise Kohn, and panel members, and ASCO staff put together a very comprehensive guideline on the use of PARP inhibitors in the management of women with ovarian cancer. And as many of your listeners may know, there has been a rapid speed of phase 3 practice changing trials that have been published and FDA approvals within the last year, and what we wanted to do was to put that all in one document and give guidance on how and when and which PARP inhibitor to use in your specific patient and at what point during the lifecycle of ovarian cancer of when to use it.

So we broke up the guideline into five sections. One is the use of PARP inhibitors as maintenance therapy after first line platinum based treatment in women with stage 3 and 4 ovarian cancer. Second, we looked at maintenance therapy after a second or higher platinum based treatment. Three, the use of PARP inhibitors as treatment for patients with recurrent epithelial ovarian cancer.

We then looked at different combinations of PARP inhibitors, whether it's with chemotherapy or biologics and the data that we have presently on those combinations. And then lastly, we looked at common side effects with PARP inhibitors and offering guidance on how to manage those toxicities.

Brittany Harvey: Great. Then you just mentioned that this covers several different sections, so I'd like to go through each of those sections and review those recommendations for our listeners. So first, what are the recommendations for PARP inhibitors for patients with newly diagnosed epithelial ovarian cancer?

Dr. William Tew: So for women with newly diagnosed ovarian cancer, there's been several studies that have been published in the last year and a half, and we broke this up into the different studies and the different patient populations. First and foremost, we wanted to stress that PARP inhibitors are not recommended for the use in the initial treatment of patients with early stage, meaning stage 1 or 2 ovarian cancer, because there really isn't sufficient evidence to support the use in this population. All of the trials looked at patients with stage 3 or 4 epithelial ovarian cancer and used primarily in the main setting, and what that basically means is that women that have had a complete or partial response to first line platinum based chemotherapy and have response by CT scan or CM 125, when do you use a PARP inhibitor?

Which are the women that you would say PARP inhibitor is going to benefit you with long-term outcome? So our first recommendation is based on a trial-- looking at a drug called olaparib. Olaparib was the first PARP inhibitor published in this population, and in that study, they included women with both germline or somatic pathogenic or likely pathogenic variants in the BRCA1 or BRCA2 gene. And so this is a group of women that you could offer olaparib for.

And generally, that is given at a dosage of 300 milligrams once every 12 hours for up to two years. The second study looked at a drug called niraparib, and in this trial, they included population of all women, regardless of BRCA status. And they offered it to women with high-grade serous or endometrial ovarian cancer. And the FDA has given approval for the use of niraparib for all patients, and that is at a dosage of 200 to 300 milligrams oral daily for three years, with the lower dose given for patients who have a low platelet count or low body weight to prevent the common toxicity of thrombocytopenia.

Then you could consider longer durations in select individuals, but generally, these drugs are given for a limited period of time and continued unless a patient has significant toxicity or progression. The other two studies in the newly diagnosed ovarian cancer population was a study that looked at olaparib with bevacizumab maintenance. This was a study that included patients with germline or somatic mutations and BRCA 1 or 2 and/or genomic instability or homologous repair deficiency, as determined by the myriad my choice test.

And again, this population, a partial or complete response to chemotherapy and their first line therapy should have included bevacizumab. And so if one is on bevacizumab with their platinum based therapy, they should have a response to treatment, one could continue bevacizumab and add the addition of olaparib as a PARP inhibitor. And then the final study that we addressed was called switch therapy, and that we don't really have enough data to support its use, specifically that's with the drug called veliparib, and veliparib was given in addition to the chemotherapy and then continued as a maintenance therapy.

We don't really have sufficient data to suggest this was superior, equal, or less toxic than the approaches discussed above, which is single agent PARP inhibitor or bevacizumab with PARP inhibitor. And it should be noted, also, veliparib is not yet an FDA approved drug and not commercially available.

Brittany Harvey: OK, then what are the recommendations for PARP inhibitors for patients with recurrent epithelial ovarian cancer?

Dr. William Tew: Yeah, and this data has been around a little bit longer, and I think any oncologists that treat them with ovarian cancer are more comfortable with the evidence with these studies. So what we're talking about here is that patients who were in clinical remission and then their ovarian cancer recurs. And the first group of women that we look at is patients that are then retreated with platinum based therapy. Those women that have platinum sensitive disease, and then whether to offer PARP maintenance in the second line or more remission settings.

And there is very good data to support the use of PARP monotherapy in second or greater maintenance. This has been shown with all three commercially available PARP inhibitors, olaparib, rucaparib, and niraparib. We do know that women who have a germline or somatic pathogenic or likely pathogenic variant in the BRCA 1 or 2 genes have the highest benefit of maintenance PARP inhibition, and those patients have the strongest evidence to receive those drug.

So the only other point I wanted to make with current ovarian cancer is if a patient has received a PARP inhibitor in the past, there is no evidence to give a second exposure to PARP inhibitor. Those studies are being developed now, but PARP inhibitor use once in the life cycle is what's recommended. And then there's also evidence to use PARP inhibitor as an actual treatment. So not in the maintenance setting, and the drug most commonly used as one called niraparib or olaparib, and these are patients that have measurable disease or generally have platinum sensitive disease, and those women that have homologous repair deficiency, as determined by the Myriad myChoice test, and again, have platinum sensitive to disease do have benefit for treatment with PARP inhibitors.

Brittany Harvey: OK, then, so you just mentioned this, but is it correct that PARPi therapy for epithelial ovarian cancer should not be repeated over the course of treatment?

Dr. William Tew: Right now, that is what we recommend. All of the studies that looked at the use of PARP inhibitors disqualified women who have had prior PARP inhibitors. So as of now, we don't have any evidence to support the use of repeated PARP inhibition.

Brittany Harvey: And what does the guidelines say about using PARP inhibitors in combination with chemotherapy or other targeted agents?

Dr. William Tew: There are many studies going on currently looking at the use of PARP inhibitors in combination with immunotherapy, chemotherapy, and other targeted agents, but currently, at least in the recurrent setting, there is no data to support its use in combination with another anti-cancer treatment. Now, of course, in the context of a clinical trial, this would be very reasonable, and we encourage clinical trial participation.

The only studies that looked at PARP in combination with other anti-cancer treatments are in the first line setting, as I discussed earlier, including PARP inhibitors with bevacizumab, as in the case with olaparib or PARP inhibitors with chemotherapy, as is often the case with veliparib.

Brittany Harvey: OK, thank you. And then how should clinicians manage the adverse effects associated with PARP inhibitors?

Dr. William Tew: I think the first and foremost thing is to be aware of the specific side effect profile of each PARP inhibitor, because they can vary slightly between parts. The most common side effects include fatigue, nausea, change in appetite, and effects on the blood counts, and we gave guidance on each of those specific side effects. As far as the effects on the blood counts, anemia, I'd say, is one of the more common side effects across all PARPi's, and the use of blood transfusions is generally recommended if patients are symptomatic and their hemoglobin is below 8 to 7.

And then for neutropenia, usually, this requires hold of dosing, and we did not encourage the use of growth support, although it may be used in certain settings when the drugs on hold. And then the final cytopenia issue is the issue with platelets, and this is unfortunately very common side effect with niraparib. And we discussed earlier about starting at a lower dose, 200 milligrams of niraparib based on a weight and platelet count to help temper the degree of thrombocytopenia. But with thrombocytopenia, clearly, the drugs sometimes need to be held or discontinued if it's significant.

And with cytopenias, we do recommend close observation of laboratory blood work, particularly in the first month of use of PARP inhibitors, and then always being mindful if patients are on PARP inhibitors for prolonged periods of time that there has been reports of treatment related myelodysplastic syndromes and leukemias and that should be further worked up if there is any evidence of dysplasia.

Brittany Harvey: So then, what is the importance of this guideline in your view, and how will its implementation affect clinical practice?

Dr. William Tew: Well, I think this is the most up-to-date and comprehensive guideline on PARP inhibitors and will help, both clinicians and patients, understand all the practice changing studies, the populations, and the settings they will use, and all these studies that were published over the last five years. I think this last year we've seen such a rapid growth of clinical trial results and FDA approvals that this manuscript, I think, successfully puts them all together in table form and brief recommendations to better treat and provide proper management to your patients with ovarian cancer.

Brittany Harvey: And then finally, how will these guideline recommendations impact patients with ovarian cancer?

Dr. William Tew: We were very fortunate to have two patient advocates as part of our panel, and what they told us was that these recommendations will help them understand the scientific trials, will put in context when to use PARP inhibitors, and also to prepare them for those conversations that they have with their clinicians in discussing if they're a good candidate for a PARP inhibitor now or in the future. So we're really proud of that, that we were able to get our patients perspective in developing these guidelines.

Brittany Harvey: Definitely. Well, thank you for your work on these important and timely guidelines and for taking the time to join me on the podcast today, Dr. Tew.

Dr. William Tew: My pleasure. Thank you so much, Brittany, for having me.

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

An interview with Dr. Davendra Sohal from the University of Cincinnati, and Dr. Daniel Laheru from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins on "Metastatic Pancreatic Cancer: ASCO Guideline Update." This update covers new information on targeted therapies for metastatic pancreatic cancer. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines

Transcript

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello, and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm interviewing Dr. Davendra Sohal from the University of Cincinnati, and Dr. Daniel Laheru from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, co-chairs on Metastatic Pancreatic Cancer, ASCO Guideline update. Thank you for being here, Dr. Sohal and Dr. Laheru.

Hi, Brittany. Thank you for inviting us.

Happy to be here. Thanks.

First, I'd like to note that ASCO takes great care in development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. But Doctor Sohal, do you have any relevant disclosures that are directly related to this guideline topic?

No, I do not have anything directly in conflict. Thank you.

And Dr. Laheru, do you have any relevant disclosures that are related to this guideline topic?

Thank you, Brittany. I do not either.

Great. Than delving into the guideline content, Dr. Laheru, can you tell us what prompted an update to this guideline?

Yeah, sure. So what has been seen in almost every cancer is that with careful understanding of the molecular alterations of individual cancers, that targeted therapies have been developed for almost every cancer. And so for pancreas cancer, we have not had an opportunity in the past to use targeted therapies. Because for pancreas cancer, many of the genetic alterations that are found in other cancers are not seen in pancreas cancer. And so the guidelines were updated based on new evidence of the use of certain targeted therapies for pancreas cancer.

Then Dr. Sohal, what are the key updates that were made to the recommendations in this guideline iteration?

So the key updates relate to the so-called targeted therapies, the genomic-driven therapies that have now come up with evidence that pertains to pancreatic cancer as well. The overarching update is that every patient with metastatic pancreatic cancer who is a candidate for treatment should have tumor or somatic, the so-called somatic genomic profiling, as well as germline genomic testing, because these can lead to treatment recommendations.

And those treatment recommendations include PD-1 checkpoint inhibitor therapies for microsat light instability high tumors, track the TRK fusion inhibitors, such as larotrectinib and entrectinib for track fusions in tumors. And PARP inhibitors, such as olaparib for germline BRCA1 or BRCA2 mutations to be used as maintenance therapy after stable disease on platinum-based therapy.

Then Dr. Laheru, can you speak to the importance of this guideline and how it will drive changes to clinical practice?

Yes. So as Dr. Sohal said, these specific genetic alterations, the mismatch repair deficiency, the use of PARP inhibitors for BRCA1, BRCA2 germline mutations or somatic mutations that are pathologically significant, and for the NTRK fusion transcripts, even though these mutations for pancreas cancer are quite unusual, less than 5%, for example, for NTRK fusion transcripts, 5% to 10% for BRCA1, BRCA2 germline mutations, and probably 1% or 2% for a mismatch repair deficient pancreas cancer, the committee felt that we should inform the larger cancer community that even though these mutations are uncommon, if they are found, they could be very important for individual treatment for pancreas cancer.

And so this is why we really felt that it was time to provide an update, because of the recent information with the olaparib maintenance and with the NTRK inhibitors for the NTRK fusion transcripts.

Great. And then finally, Dr. Sohal, how do you envision that this guideline update will affect patients?

I think it expands our armamentarium for pancreas cancer patient management. It affords opportunities for better treatments, targeted therapies, which have hopefully higher efficacy and lower toxicity than standard chemotherapy, even though, as Dr. Laheru said, the proportion of patients being eligible for these therapies may be only around 5%. Still, in a disease where there are not many options, every 1 in 20 patients can get these therapies based on tumor genomic profiling and/or germline testing.

And the other slightly different but associated topic is that if germline testing finds something in the patient, a bad gene, then obviously, that patient's blood relatives can be tested for that germline finding, and there may be implications for further testing and surveillance of family members.

Well, thank you both for your work on this metastatic pancreatic cancer guideline update. And thanks for taking the time to speak with me today, Dr. Sohal and Dr. Laheru.

It's our pleasure, Brittany. Thank you very much.

Certainly. Thank you so much.

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

An interview with Dr. Jessica Hwang from MD Anderson Cancer Center and Dr. Andrew Artz from City of Hope Cancer Center on "Hepatitis B Virus Screening and Management for Patients with Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update." This update presents a clinically pragmatic approach to HBV screening and management that calls for universal HBV serological testing of patients at the onset of anticancer therapy. Read the full PCO at www.asco.org/supportive-care-guidelines

Transcript

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at podcast.asco.org.

My name is Brittany Harvey. And today, I'm interviewing Dr. Jessica Hwang from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, and Dr. Andrew Artz from the City of Hope Comprehensive Cancer Center in Duarte, California, co-chairs on hepatitis B screening and management for patients with cancer prior to therapy, ASCO provisional clinical opinion update. Thank you for being here, Dr. Hwang and Dr. Artz.

Thank you for inviting us.

Thank you so much.

First, I'd like to note that ASCO takes great care in the development of its guideline products and ensuring that the ASCO conflict of interest policy is followed. The full conflict of interest information for this provisional clinical opinion panel is available online with the publication in the Journal of Clinical Oncology. Dr. Hwang, do you have any relevant disclosures that are related to this topic?

Well, I have received some research funding from Gilead, a maker of a hepatitis drug in the past.

And, Dr. Artz, do you have any relevant disclosures?

I have no relevant disclosures.

OK, then so, Dr. Artz, so this provisional clinical opinion, or PCO, on hepatitis B screening and management for patients with cancer prior to therapy was first published in 2010 and then last updated in 2015. What prompted this update to the PCO?

This PCO guidance, more broadly, is necessary because the hepatitis B status for most patients is actually unknown at the time they're starting cancer therapy. In 2015, the PCO though suggested that we limit hepatitis B screening to patients who were at most risk for hepatitis B reactivation, if they were hepatitis B carriers, so those receiving anti-CD20 antibodies, such as rituximab or stem cell transplant. But for the remaining patients, most patients receiving cancer therapy, the guidance was to survey patients about their close contacts or exposures to hepatitis B and determine if formal hepatitis testing should ensue.

This 2020 PCO represents an evolution in our understanding of hepatitis B screening and the dangers of hepatitis B after anticancer therapy. We've learned from studies, including those done by my colleague, Dr. Hwang, that questionnaires to detect hepatitis B are not very effective or practical. We also have accumulating information that many of our anticancer therapies pose a significant danger for hepatitis B related complications in hepatitis B infected patients. We believe appropriate monitoring and treatment, as outlined in the PCO, will reduce these dangers.

So given that new information, I'd like to discuss the updated statements for the PCO. So first, Dr. Hwang, for patients who will receive systemic anticancer therapy, who should be tested for HBV and how should they be tested?

That's a great question, Brittany. Thanks. I think that the data is really clear now that all patients with cancer anticipating systemic anticancer therapy should be tested for hepatitis B virus. That includes all solid tumor patients, as well as hematologic malignancy patients.

And they can be tested with a simple blood test. The hepatitis B virus can be tested by three blood tests for hepatitis. It's the hepatitis B surface antigen, HBsAG, or the hepatitis B core antibody. There are two types of this. It's either the IgG or the total IG, which shows, if positive, could indicate a patient has past infection. There is a IgM version of that core antibody test. And that tells, if positive, tells whether a patient has acute infection. So for our purposes, it's recommended that the IgG or total IG is used and not the IgM, because we are interested in whether a patient has past infection.

So the third test is a hepatitis B surface antibody. And this is a protective antibody. So if positive, it shows that a patient has had some exposure in the past or perhaps a vaccination in the past. And so this is a good test to have positive.

So then what does the PCO state for patients with chronic HBV infection?

Patients with chronic HBV infection, that is those patients with a positive hepatitis B surface antigen test, these patients really should have very close monitoring during as well as after anticancer therapy. These patients will need antiviral therapy prophylactically prior to enduring as well as after the cancer treatment. They should also see a clinician experienced in the management of hepatitis B, whether it's a hepatologist, a gastroenterologist, an infectious disease specialist, or maybe a primary care doctor who's experienced in treating and caring and monitoring for patients with hepatitis B. That's really important for these patients with a chronic hepatitis B, because they are at high risk of developing complications during and as well as perhaps even shortly thereafter of receiving systemic anticancer therapy.

And then what does the PCO state for patients with past HBV infection?

This is a really good question. The patients with past HBV infection are those who have a negative hepatitis B surface antigen and a positive hepatitis B core antibody. This represents maybe some 6% at least of the US population. It could be much higher. So this is a sizable group of patients. And it's really important to know that it is sort of a tailored approach.

So patients with past HBV infection who are anticipated to receive one of the high risk anticancer therapies that Dr. Artz mentioned just a few moments ago, namely stem cell transplantation or maybe one of the anti-CD20 monoclonal antibodies, these patients are at really high risk of reactivation. So these patients would need a very close monitoring plan. They would need their hepatitis B and liver test monitored during their anticancer therapy. And most often they would need antiviral prophylaxis before, during, and even after their immunosuppressive therapy ends.

So there are patients, of course, who don't receive these high-risk therapies. So that is patients with past HBV infection who are receiving anticancer therapy that's not a stem cell transplant and not an anti-CD20 monoclonal antibody. These patients could be monitored carefully. They could have hepatitis B and/or liver testing monitoring during anticancer therapy. And if they have any elevations in their surface antigen or their ALT, then they could have further hepatitis B testing to see if they have any evidence of complications from their hepatitis B. So that's in general what the PCO recommends for these two groups.

Well, thank you for reviewing those highlights from the PCO. So Dr. Artz, what is the importance of this PCO and how will its implementation impact practice?

Thank you for the question. This PCO I feel dramatically simplifies the challenge of hepatitis B screening by proposing universal hepatitis B testing, as Dr. Hwang outlined, at a defined point in time. That is at the initiation of therapy.

And clinicians have really struggled with hepatitis B testing for lots of different reasons. They're difficulties in knowing who to screen, how to screen, in part because the data have started to emerge that many of the therapies may pose some risks and the prior suggestion that we use questionnaires, but there wasn't a standard set of questionnaires that we could use if we wanted to identify people based on risk factors of acquiring hepatitis B. So this led to a lot of confusion on testing.

I think by standardizing this makes it considerably easier. And also, the guidance from the PCO is better harmonized with other organizations, such as the Centers for Disease Control and our Liver Society colleagues who actually participated in the panel. And so now the guidance clinicians receive are more consistent across organizations. So I think this will allow doctors and health care systems overall to now invest in the implementation of hepatitis B screening, rather than the question about who should we do it and can we do it and when should we do it, but rather more on the implementation to help patients.

Great. And then finally, what is the impact of this updated PCO for patients?

Well, I'll take the first part of that. I believe that the implementation should permit safer systemic anticancer therapy by reducing hepatitis B related complications. Whenever patients have complications or there's even uncertainty about whether hepatitis might be contributing, this also can lead to delays in our treatments. If we know in advance and we appropriately manage and monitor this, we should have fewer treatment delays as well. Dr. Hwang, I know, might also have some comments on this.

Thanks. I do have a few general comments beyond the cancer care implications. And I'd like to say I think that hepatitis B testing and then the results of that and sharing that information with patients is really important. Letting patients know their hepatitis B status, especially if they're positive, empowers them to seek further care, get connected with a hepatitis B specialist person who's experienced in managing hepatitis B, and also to look around the local environment to their household and close contacts because hepatitis B is a virus that is transmitted from person to person through blood-borne sexual transmission and close family or household contact.

So I think it's important for patients to know their status to protect themselves during cancer therapy, as Dr. Artz mentioned, but just in general for good health care for themselves and for those around them. And in addition, I think that it's important for the family members and those close contacts to then get screened and perhaps even consider getting vaccinated if they haven't been vaccinated.

Well, thank you both for your hard work on updating this PTO and for taking the time to speak with me today, Dr. Hwang and Dr. Artz.

Thank you, Brittany.

Thank you, Brittany.

And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full provisional clinical opinion go to www.asco.org/supportive-care-guidelines. This PCO also has a companion cancer.net podcast episode. Cancer.net is the patient information website of ASCO. And we encourage you to learn more by tuning into their episode. You can find their podcast and all ASCO podcasts at podcast.asco.org.

You can also find many of our guidelines, PCOs, and interactive resources in the free ASCO Guidelines app, available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

An interview with Dr. Charles Loprinzi from Mayo Clinic in Rochester, MN on "Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update." This update incorporates new evidence into recommendations for the prevention and treatment of chemotherapy-induced peripheral neuropathy in adults with a history of cancer. Read the full guideline at www.asco.org/survivorship-guidelines

TRANSCRIPT

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm interviewing Dr. Charles Loprinzi from the Mayo Clinic in Rochester, Minnesota, lead author on prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers, ASCO guideline update. Thank you for being here, Dr. Loprinzi.

It's my pleasure to participate.

First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each of our guidelines. The full conflict of interest information for this guideline panel is available online with the publication in the Journal of Clinical Oncology. Dr. Loprinzi, do you have any relevant disclosures that are related to this guideline topic?

Well, that's always the perception, I think. Let me mention a couple of things. I've been intimately involved with research with chemotherapy-induced neuropathy for about 20 years or so, and have looked at a lot of the different drugs and treatments that we considered in this guideline.

I consulted for companies that have interest in neuropathy, including Asahi Kasei Pharma, Disarm Therapeutics, Metis Pharmaceuticals, PledPharma, and NKMax America. But other than that, I do not have anything else to note there.

Great, thanks. So first, what prompted an update to this guideline on the prevention of management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers?

Well, it's been about five years since we did the initial guideline. It is a very prominent problem-- I think probably one of the most prominent chronic problems we get associate with chemotherapy. You get acute problems like nausea and vomiting, but those go away. But this can be a prominent problem that can last for years.

There have been about 40 new trials for looking at prevention of neuropathy while you're giving chemotherapy, or treatment of neuropathy after you receive the chemotherapy and looking at ways to try to treat that. About 40 new trials have been published since we did the last guideline. So it was decided that it's time to look at this again to see what's new, what's not new, and sort things out.

So with that new information that the guideline panel looked at, what are the recommendations for prevention of chemotherapy-induced peripheral neuropathy?

OK. So for prevention-- and we're talking about you're about to give chemotherapy that has neurotoxic properties, if you will. Not all chemotherapies cause neurotoxicity. And by neurotoxicity, I'm talking about numbness, tingling, pain, usually in distal extremities. Hands and feet is where it usually starts. But that's what we're talking about here.

And the bottom line answer, which is similar to what it was five years ago, is that there is no proven means for being able to prevent this problem other than not giving the chemotherapy that can cause the problem. And we usually want to give the chemotherapy to try to kill the cancer process. So there is no proven means.

There is, however, suggestive evidence for a few things. And each of these need more research to really clarify the risks of doing them and that benefits from. One of these things is something called cryotherapy or cold therapy. And you put cold therapy on hands and feet, causes less blood flow, and slows the metabolism somewhat while the person is getting chemotherapy. And there's suggestive evidence that helps, although not proof.

There is another thing that's somewhat related to that, and it's called compression therapy, where if you put tight surgical gloves on a hand while you're getting the chemotherapy, decreasing blood flow when there's a lot of chemotherapy in the blood-- again, suggestive evidence. But there is things where they've actually combined these things with both doing cryotherapy and some compression.

And the third thing is exercise. There are data suggestion that exercise can decrease the amount of neuropathy that patients get. Again, no proof for any of those three things, but more research is needed in that area.

Thanks for reviewing those recommendations for prevention. What are the recommendations for treatment approaches for chemotherapy-induced peripheral neuropathy?

So I think we have two things in here. One of them is what about when you're giving chemotherapy to a patient-- neurotoxic chemotherapy-- and you're planning to give, let's say, 12 cycles of paclitaxel, a common drug that we give for 12 cycles once a week-- one-week cycles, so dose once a week for 12 weeks, and it causes neurotoxicity. And you might be six or seven or eight doses in, and the patient's getting fairly significant neuropathy. And you're worried about giving more of that chemotherapy because it might cause more neuropathy, which may not go away for months or years after it is finished.

So in that setting, the decision, the recommendation, is for the doctor to think about how much additional benefit are we going to get from continuing onto the 12 cycles from the 8 cycles or 6 cycles wherever we are, and decide how much, if this is given in the adjuvant setting where you're trying to cure a person.

They've had surgery. They've had-- the cancer has been removed, and you can see that there's a risk of recurrence, and you're giving chemotherapy to try to decrease the risk of recurrence, what percentage benefit will it get if you go on to 12 cycles? Is that 1% additional benefit that the patient wouldn't get recurrence? Or is it 10%? Is it 5%? Is a 15%? So helping to sort that through, and then talking to the patient about that, and then making a decision. Do I continue on with the planned full dose of their chemotherapy?

The other aspect is what about treatment of a patient who is finished with their chemotherapy, and now they have the neuropathy? And, again, for some types of chemotherapy drugs, their neuropathy continues to get worse for about three months after you've did the last dose of chemotherapy. It's not because you stop the chemotherapy that it makes the neuropathy get worse. But it's rather, in my mind, that it takes three months to get full manifestations of the neuropathy for drugs such as oxaliplatin.

So in that setting, there is one drug that is a winner, if you will, called duloxetine. It does improve things statistically significantly. It doesn't improve them a whole lot. But it does work, and it's been shown in repetitive studies for that. So that's the one recommended approach there.

There are three things where there is suggestive evidence of benefit. And, again, exercise fits in that category. There is some suggestion that patients who exercise will get benefit and get improvement. There are some data that acupuncture will cause some improvement. And there are some data that something called scrambler therapy, a type of cutaneous neuro stimulation process will help decrease neuropathy in those situations. Again, for all three of them, the committee was unable to say yes, we-- was unable to say that we have scientific proof that these work. But there's suggestive evidence that they might provide some benefit.

So with these updated recommendations, in your view, what is the importance of this guideline and its relevance for practicing clinicians?

I think it's-- again, it's a big problem in practice for patients-- oncologists as they're seeing patients, and for the patients themselves, and to find what we do know works, and what we know doesn't work, and what we think might be helpful is helpful for patients. It's helpful for patients to hear this and know this.

It's helpful for physicians to be able to say, yes, we looked at all the data. There were 42 more studies, and most of them didn't show benefit, unfortunately. Here's the ones that did show benefit, and here's the ones that are suggestive evidence, or some things like exercise is probably a reasonable thing to go with. Even though it needs more study, it's probably a reasonable thing for people to do, because we don't exercise enough in this country.

And then finally, you've touched on this a bit, but how will these guideline recommendations impact patients?

I think that just kind of as we said. You know, whatever the doctors can understand better about it, the clinicians there, and then relate that back to the patients themselves is the best way. Is it possible for the patients, and there are some very bright patients out there who could read the medical literature and take a look at this and read it on their own? Yes. Sure. Why not? But that's how I think. Understanding-- getting the physicians to-- scientists to understand what we do know, and then getting that word on to the patients and their families in this setting.

Great. Well thank you for your work on this important guideline update and for taking the time to speak with me today, Dr. Loprinzi.

You're welcome.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/survivorship-guidelines. This guideline also has a companion cancer.net podcast episode. Cancer.net is a patient information website of ASCO, and we encourage you to learn more by tuning into their episode.

You can find their podcast and all ASCO podcasts at podcast.asco.org. You can also find more ASCO guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

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.

An interview with Dr. Paul J. Hesketh from Lahey Hospital and Medical Center in Burlington, MA on "Antiemetics: ASCO Guideline Update." This update addresses antiemetic prophylaxis in patients treated with checkpoint inhibitors and incorporates new data since the last guideline publication. Read the full guideline at www.asco.org/supportive-care-guidelines

TRANSCRIPT

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello, and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey. And today, I'm interviewing Dr. Paul Hesketh from Lahey Hospital and Medical Center in Burlington, Massachusetts, co-chair of antiemetics, ASCO Guideline update. Thanks for joining me, Dr. Kesketh.

Hello, Brittany. I'm very happy to have the opportunity to join in today's podcast.

First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Hesketh, do you have any relevant disclosures directly related to this guideline topic?

No, I do not have any relevant disclosures.

So, Dr. Hesketh, what prompted an update to this an antiemetics guideline, which was last published in 2017?

Well, as you know, Brittany, each guideline panel is instructed by ASCO to regularly review the evolving literature and other information, looking for any significant developments that are relevant to that specific guideline. And since our last update in 2017, there has been a tremendous expansion in the use of checkpoint inhibitors for a variety of different neoplastic diseases. Although they're often used alone, increasingly, the checkpoint inhibitors were being added to a variety of chemotherapy regimens. And as this was occurring, concerns were being expressed by some oncologists that corticosteroids, a critical component of many antiemetic regimens, might be contraindicated when checkpoint inhibitors were being added to chemotherapy regimens given the potential immunosuppressive possibility for corticosteroids. So the panel felt that an update was indicated to try to address this issue as well as providing information on new antiemetics, antiemetic regimens, and to try to categorize the medic potential of the many new anticancer agents that have been approved since our last update.

Great. So you touched on a couple things there. So first, how does the guideline address antiemetic prophylaxis in patients treated with checkpoint inhibitors?

Well, the search that we conducted for this guideline found 10 relevant publication on checkpoint inhibitors. The search reaffirmed the panel's conclusion that all currently available checkpoint inhibitors really have minimal emetic potential when used as monotherapy. And really, no prophylactic antiemetics are required when an individual checkpoint inhibitor is used.

When used in combination with chemotherapy, two phase III trials were particularly instructive in helping to formulate our guidelines. Both trials were conducted in adult patients with non-small cell lung cancers treated with a platinum based doublet with or without the Program Death 1, PD-1 inhibitor pembrolizumab. And they recommended in both those studies that all patients receive dexamethasone as a component of the prophylactic antiemetic regiment. And of note, in both studies, superior efficacy outcomes were noted in the PD-1 inhibitor containing harms. Therefore, the panel feels that there is really no clinical evidence at present to warrant emission of dexamethasone from guideline compliant prophylactic antiemetic regiments when checkpoint inhibitors are administered to adults in combination with chemotherapy.

And then you touched on also antiemetic regimens that were updated. Given the new information about olanzapine, what recommendations were updated?

Well, olanzapine is a very interesting drug. It's a second generation antipsychotic which, very interestingly, has significant antiemetic properties. And the updated guidelines reaffirms the role of olanzapine as part of antiemetic prophylaxis when one administers highly emetogenic chemotherapy regimens. And it also can be very useful as a rescue agent in patients developing emesis despite appropriate prophylaxis.

So the new studies that were published since our last update have demonstrated the value of adding olanzapine to a 5-HT3 receptor antagonist, dexamethasone, and an NK-1 receptor antagonist used in the setting of high dose chemotherapy when used with hematopoietic stem cell transplantation. In addition, the prior recommendations only specified a 10 milligram dose of olanzapine as the only option. We now have data from an updated study that a 5 milligram dose is an acceptable alternative to the 10 milligram dose when used in the setting of highly emetogenic chemotherapy.

Great. Thanks for reviewing that information. So what in your view is the importance of this guideline for clinical practice?

Well, we have made really enormous progress in developing effective means to prevent treatment induced nausea and vomiting in patients with cancer. Each update of the guidelines, the current version included, have provided additional valuable insight for clinicians to help further limit the frequency of this potential side effect of cancer treatment. The most important aspect of the current update will be providing reassurance to clinicians that effective antiemetic prophylactic regimens do not need to be compromised when the new checkpoint inhibitors are administered in combination with emetogenic chemotherapy regiments. In addition to the new information on olanzapine, the update also notes the addition of useful new IV formulations of aprepitant and the combination agent netupitant and palonosetron. In addition, we have information on the use of fosaprepitant and as an option when an NK-1 receptor antagonist is indicated in the pediatric setting.

And then finally, how do you view that these recommendations will impact patients?

Well, we know from many patient surveys that treatment induced nausea and vomiting are among the most dreaded potential side effects that patients worry about when they think about starting cancer treatment, especially if they're going to be receiving chemotherapy. So fortunately, we now have extremely effective and well tolerated antiemetic regiments for all treatment settings. However, patients will only benefit if these evidence-based regimens are utilized in a manner consistent with the ASCO guidelines. So we hope that this guideline update will provide useful information for ecology providers to really optimize the prevention of nausea and vomiting in patients receiving various emetogenic type of treatment regimens.

Well, thank you so much for your work on this ASCO guideline update on antiemetics and for taking the time to speak with me today, Dr. Hesketh.

Thanks very much, Brittany. Happy to do so.

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

An interview with Dr. Manish Shah from New York Hospital Weill Cornell Medical Center on "Treatment of Locally Advanced Esophageal Carcinoma: ASCO Guideline." This guideline provides evidence-based recommendations on treatment options for patients with locally advanced esophageal adenocarcinoma and squamous cell carcinoma. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines

Transcript

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey. And today, I'm interviewing Dr. Manish Shah from New York Hospital Weill Cornell Medical Center, lead author on "Treatment of Locally Advanced Esophageal Carcinoma," ASCO guideline. Thank you for being here, Dr. Shah.

I'm so pleased to be here on this podcast for ASCO with you, Brittany. I'm very pleased to talk about this guideline and its significance to the oncologic community and to our patients.

First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. But Dr. Shah, do you have any relevant disclosures that are directly related to this guideline topic?

No, I have no conflicts as it relates to this topic. I do have research funding from Merck, Boston Biomedical, Oncolys, BMS, and Acelis, and no other conflicts and nothing specific to locally advanced esophageal cancer.

Thank you. Then let's dive into this guideline. First, can you give us an overview of what this guideline covers?

Sure. This guideline covers the management of locally advanced esophageal cancer, both adenocarcinoma and squamous cell cancer, because management of these diseases is very complicated, primarily as the epidemiology of this disease has shifted over the past several decades. About 20 to 30 years ago, squamous cell cancers of the esophagus was the predominant disease subtype. About 90% of patients that we would see with esophageal cancer were of squamous cell histology.

However, with the rise in Barrett's esophagus and adenocarcinoma of the distal esophagus and GE junction, now, about 50% of esophageal cancers are adenocarcinoma histology. This distinction is important because, while the two diseases have significant overlap and treatment options, there are differences in sensitivity to various therapies. The guideline attempts to tease out these distinctions to provide the best evidence-based practice recommendations for the community.

Great. So you mentioned that this covers both adenocarcinoma and squamous cell carcinoma. So what are the key recommendations of this guideline for patients with locally advanced esophageal adenocarcinoma?

Sure. So for both squamous cell cancer and adenocarcinoma of the esophagus, locally advanced disease, the first and key recommendation is that multimodality therapy is considered and offered to both disease histologies. It's very important that these patients are treated through a multidisciplinary approach that involves a surgeon, typically a thoracic surgeon, but sometimes a general surgical oncologist as well, as well as a radiation oncologist and a medical oncologist.

For adenocarcinoma of the esophagus, which is really becoming the most common type, the primary recommendation is that patients with locally advanced esophageal adenocarcinoma receive either preoperative chemotherapy with radiation or perioperative chemotherapy. Because there is no comparative study for these two options, we also provide a clinical vignette to help readers understand some of the key features that may sway one to one treatment versus another.

For example, large bulky tumors where an R1 resection is more likely may be better suited for chemoradiotherapy, followed by surgery. An R1 resection, of course, is where the microscopic margin might still be positive. Additionally, patients who may not have a three-hole or a thoracic surgery as part of their surgical plan may not have an adequate lymph node dissection. That might be another reason to consider chemoradiotherapy, followed by surgery.

And what is recommended for patients diagnosed with locally advanced esophageal squamous cell carcinoma?

Yes. For squamous cell cancer, we recognize that these tumors are much more sensitive to radiotherapy. So the options that are recommended here, based on the evidence available, is that patients who receive preoperative chemotherapy and radiation or definitive chemotherapy and radiation, meaning chemotherapy and radiation with or without surgery. These are the recommendations for squamous cell cancer.

So why is this guideline important, and how will it change practice?

So we hope that our guideline will provide some clarity on a very murky field. The study suggests that there are several options available for patients with locally advanced esophageal squamous cell cancer and adenocarcinoma. And the guideline helps us frame the question and frame how we think about these options in offering patients the best practice that we can with regard to the available data. Additionally, the guideline may help define future research questions as well, as the gaps in knowledge are clear based on the guideline.

For example, there are patients, a significant number of patients, who have a complete response to chemotherapy and radiation. Should all of these patients have immediate surgery, or can surgery safely be delayed? That's an ongoing question that is being examined in rectal cancers. And also, there is some data in esophageal cancer as well. And that might be an important question to ask, moving forward, for example.

Great. And then finally, how will these guideline recommendations affect patients?

We hope that through the guideline process and understanding the nuances of how to treat patients with locally advanced esophageal cancer, that based on histology, based on the size and bulk of the tumor, based on the likelihood of an R1 resection, or based on even the surgical approach, that patients will receive more uniform therapy and therapy that is more tailored to their particular condition and situation. In the end, we hope that patients will receive the right care and ultimately have better outcomes because their care is more uniform.

It sounds like these guidelines could have a real impact for patients. So thank you for your work on these treatment of locally advanced esophageal carcinoma guidelines and for taking the time today to speak with me, Dr. Shah.

Thank you. It's a pleasure to be here.

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

An interview with Dr. Eric Roeland from Massachusetts General Hospital Cancer Center on "Management of Cancer Cachexia: ASCO Guideline." This guideline provides evidence-based recommendations on the clinical management of cancer cachexia in adult patients with advanced cancer. Recommendations are made on both pharmacologic and nutritional interventions. Read the full guideline at www.asco.org/supportive-care-guidelines

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm speaking with Dr. Eric Roland from Massachusetts General Hospital Cancer Center. Lead author on Management of Cancer Cachexia, ASCO Guideline. Thank you for being here, Dr. Roland.

Well thank you very much.

Before we get into the content of this guideline, I want to note that all conflict of interest disclosure information for the expert panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Roland, do you have any conflicts of interest to disclose?

Yes, within the last two years, I've served as a consultant for Asahi Kasei Pharmaceuticals, DIG Consulting, Napo Pharmaceuticals, American Imaging Management, Immuneering Corporation, and Prime Oncology. I've also served on advisory boards for Herron Pharmaceuticals and Vector Oncology. And I serve as a member on the Data Safety Monitoring Boards for Oragenics, Kalyra Pharmaceuticals, and [INAUDIBLE] Life Sciences Pharmaceutical Company.

Thank you. Then first, can you give us a general overview of what this guideline covers?

Sure. We performed a systematic review of the literature regarding available evidence for nutritional and pharmacologic interventions for cancer cachexia. Specifically, we searched PubMed and the Cochrane Library for randomized controlled trials and systematic reviews published between 1966 in 2019. We focused our review on adult patients with advanced or incurable cancer. And given the highly variable nature of cancer cachexia, we specifically evaluated the endpoints of loss of appetite or anorexia, body weight, and lean body mass, or skeletal muscle. Our targeted audience included clinicians as well as patients and caregivers.

Can you provide us with a little background on cancer cachexia?

Yes, first I think it's incredibly important for us to define cancer cachexia, especially given its prevalence in cancer care. Traditionally, cancer cachexia has been defined as a certain amount of weight loss over a defined time period. However, cachexia is much more complicated than weight loss alone. It is a multifactorial syndrome characterized by loss of appetite, weight, and skeletal muscle, which leads to fatigue, functional impairment, increased treatment related toxicity, poor quality of life, and even reduced survival. And as clinicians, we need to try to identify any reversible causes contributing to cachexia and treat them. This of course, includes treating the underlying cancer when possible.

Additionally, it's essential for patients to receive optimal palliation of all symptoms that may be interfering with the intake of calories, such as pain, nausea, vomiting, constipation, diarrhea, and depression. Therefore, as clinicians, we need to work in teams of experts that might include expertise in pain, palliative care, nutrition, physical occupational therapy, and mental health where available.

We also need to introduce and discuss the term, cachexia, with our patients and their caregivers, who often have never heard of it before. They may not understand that this term is unique and very different from weight loss alone. I personally have found that describing the unique nature of cachexia and providing the information to patients and caregivers can be very helpful.

Additionally, we need to recognize that food is a very complicated issue. And when we engage patients and caregivers around issues of food, we need to recognize that there are informational needs, but there are also emotional needs. And as clinicians, we help patients and caregivers gain access to evidence based information and interventions, but we equally need to ensure that they receive emotional support. Food represents hope and control in an uncontrollable situation. And not being able to eat or feed a loved one can cause severe distress.

Therefore, we need to engage patients and caregivers regarding these emotional issues and make sure they feel heard. We can also reach out to our mental health colleagues, such as social workers and psychologists, who may help us support patients and caregivers in this difficult issue.

Then, what are the key recommendations covered in this guideline?

With regard to our systematic review, we identified 20 systematic reviews and 13 additional randomized controlled trials. And from this data, we made the following recommendations. First, we found limited data supporting the integration of dietary counseling with or without oral nutritional supplements. However, given the lack of harm and the critical role of educating patients and caregivers, we felt it was important to support referring patients with incurable cancer and loss of appetite and/or body weight to registered dietitian for assessment and counseling.

It's critical for patients and caregivers to learn about practical and safe approaches to feeding. Specifically, registered dietitians may help develop strategies, such as shifting away from three larger meals per day towards frequent high protein, high calorie, nutrient dense snacks. Dietitians can also address questions regarding specific diets, including fad diets and unproven or extreme diets.

Moreover, clinicians should not routinely offer enteral tube feeding or parenteral nutrition to manage cachexia in patients with incurable cancer. A short term trial of parenteral nutrition may be offered to a very select group of patients, such as patients with a reversible bowel obstruction, or short gut, or issues with malabsorption, but otherwise reasonably fit. We also can consider discontinuing previously initiated enteral parenteral nutrition near the end of life, as it is associated with net harm at that time.

With regard to pharmacologic interventions, there are no FDA approved drugs to treat cancer cachexia. Yet there is sufficient data to support two pharmacologic interventions associated with improvements in appetite and/or body weight. And these include progesterone analogs, such as megestrol acetate and corticosteroids. The optimal dose and timing of each drug remains unknown.

Regarding megestrol acetate, data support its role in improving appetite, modest weight gain, and improvement in quality of life. However, the weight gain associated with megestrol acetate is primarily fat and not skeletal muscle. We also need to be aware of side effects of megestrol acetate, including an increased risk of thromboembolic events, edema, adrenal insufficiency, and even an increased risk of death.

As for corticosteroids, the first published double-blind randomized study dates back all the way to 1974, which showed an improvement in appetite and sense of well-being. However, clinicians are aware of the multiple side effects associated with corticosteroid use, that often limit initiation and timing of their use. Additionally, the weight gain associated with corticosteroids is not skeletal muscle.

As important as it is to know what drugs are evidence based, it is also important to note what pharmacologic approaches are not supported by evidence. There are many agents that have been evaluated in clinical trials without any evidence to support an improvement in cancer cachexia outcomes.

One such drug that frequently is asked about is dronabinol or the general class of cannabinoids. Insufficient data was available to recommend dronabinol or medical cannabis, and they have notable side effects, including altered mental status and a higher risk of falls. Especially in the elderly.

Why is this guideline important? And how will it impact practice?

Cachexia is a very common clinical entity and causes lots of distress for patients and caregivers. Oftentimes, the issues regarding nutrition and weight loss can be the central focus of clinical appointments and conversations with oncologists. We need to ensure that patients and caregivers have access to evidence based information and recognize that some interventions may be associated with more harm than benefit.

And finally, you've just spoken to this a bit, but how will these guideline recommendations affect patients?

Primarily, I think these cancer cachexia guidelines will serve as a great educational resource. They will also allow patients to better understand the risks associated with some of the pharmacologic interventions. I also think it's critical to define the current state of evidence in cancer cachexia, as we have many new exciting clinical trials evaluating novel agents in the setting.

Furthermore, as a cancer community, we need to ensure that interventional trials are focused on clinically meaningful endpoints, such as improvements in appetite, muscle mass, and quality of life. We also need to encourage a rigorous but expedited approval of these agents, given the lack of any FDA approved drugs in this setting.

Lastly, we need to recognize this is a multi-modal syndrome that requires the help and expertise of our interdisciplinary colleagues. Supporting our patients and their caregivers with this very difficult syndrome requires as much help as possible.

Great. Thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Roland.

Thank you so much, Brittany. I would also like to recognize and thank ASCO for its support of these guidelines, the talented ASCO staff, and the experts who contributed. Most of all, I'd like to recognize our patients and their caregivers.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/supportive-care-cancer-guidelines.

This guideline also has a companion, cancer.net podcast episode. Cancer.net is the patient information website of ASCO. And we encourage you to learn more by tuning into their episode. You can find their podcast and all ASCO podcasts at podcast.asco.org. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe, so you never miss an episode.

An interview with Dr. Benjamin Levy from Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital on "Lung Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline." This guideline provides recommendations to clinicians on radiographic imaging and biomarker surveillance strategies after definitive curative-intent therapy in patients with stage I-III non–small-cell lung cancer and small-cell lung cancer. Read the full guideline at www.asco.org/thoracic-cancer-guidelines

Transcript

Hi. My name is Clifford Hudis, and I am the CEO of the American Society of Clinical Oncology, as well as the host of the ASCO in Action podcast. About twice a month, I interview thought leaders in health care and experts in oncology, and we provide analysis and commentary on a wide range of cancer policy and practice issues. You can find the ASCO in Action podcast on Apple Podcasts or wherever you are listening to this show, and you can find all nine of ASCO's podcasts which cover a wide range of educational and scientific content, and offer enriching insight into the world of cancer care at podcast.asco.org.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Benjamin Levy from Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, author on "Lung Surveillance After Definitive Curative Intent Therapy ASCO Guideline." Thank you for being here, Dr. Levy.

Thanks for having me.

So first, can you give us a general overview of what this guideline covers?

Yeah, I think that the general broad stroke intent of this consensus paper was to provide evidence-based guidelines and recommendations for practicing clinicians on what the optimal radiographic imaging and biomarker surveillance strategy should be for patients who received definitive curative intent therapy, and specifically for patients with stage I through III non-small-cell lung cancer, or patients who have received curative intent therapy for a limited-stage small-cell lung cancer.

And importantly, this expert panel comprised a multidisciplinary team, and this included not only medical oncologists, but surgical oncologists, pulmonologists, radiologists, a general internist, a patient representative. So we had, I think, the relevant stakeholders to make the best recommendations we could based on the evidence. And we really framed our recommendations by answering five questions, and I think we can get to the five questions at a later time during this cast, but we try to answer these five questions in a systematic way. And really looked at the type-- was an evidence-based or was it informal consensus? What was the evidence quality? Was it low, was it intermediate, or was it high? And then finally, the strength of the recommendation.

And importantly, we tried to answer these questions based on the evidence. We did a literature search, which culminated in a systematic review of more than-- close to 1,200 studies of which 14 studies were identified, and these 14 studies included meta-analysis, randomized control trials, case-controlled trials, and retrospective studies, and really by doing this, we wanted to come up with important guidelines. I think these guidelines are coming on the heels of a lot of confusion about what is the optimal surveillance strategies post-curative intent therapy for our lung cancer patients? So we recognize this confusion and tried our best to create guidelines that were reasonable to follow, and hopefully it can change practice.

Great. So you just mentioned that there were five key questions that you looked at for this guideline.

Yeah.

Could you elaborate on what those questions are and the key recommendations of the guideline?

Sure. So the crux of our recommendations, again, come on these five questions, and just a summary of these questions. One, what should be the frequency of surveillance imaging post-curative intent therapy? Two, what is the optimal imaging modality? Three, are there any patient factors such as performance status or age limits that would preclude surveillance? Four, is there a role for circulating biomarkers and surveillance? And then five, is there-- or what is the role of brain MRI imaging for surveillance of curative intent patients both non-small cell and small-cell?

And just briefly in terms of-- I'll maybe go over briefly just the answers to these questions that we tried to hash out in this consensus work-- for the question, what should be the frequency of surveillance imaging? We recommended that patients should undergo surveillance imaging for recurrence every six months for two years. We then recommend that patients should undergo surveillance imaging for detection of new primary lung cancers annually after the first two years.

And in question 2, what is the optimal imaging modality? We recommended a diagnostic chest CT that included the adrenals with contrast, that's preferred, or without contrast when conducting surveillance for recurrence during the first two years post-treatment. We did state that there was no evidence of any added benefit for CT of the abdomen and pelvis over a chest CT through the adrenals, that surveillance. We then, again, similar answer to recommendation 1, we do recommend a low dose screening for chest CT when conducting surveillance for new lung primaries after those first two years. And then I think importantly, we take a hard stand on PET scans as part of the answer to question 2, where we really should not be using PET scans as a surveillance tool in the surveillance starting post-curative intent therapy.

Question 3, are there any patient factors such as performance status or age limits that would preclude surveillance? And for us, we make the recommendation that surveillance imaging may be permitted in some patients who are clinically unsuitable, have multiple medical comorbidities, or unwilling to undergo further treatment. Doesn't make a lot of sense to offer surveillance imaging if patients are stating that they're not going to undergo any further treatment. We also state that age should not preclude surveillance imaging, but there needs to be a consideration for overall health status and chronic medical conditions and patient preferences.

Question 4 was, is there a role for circulating biomarkers in surveillance? And this is probably one of the more confusing parts of surveillance. Many physicians are still using CEA to monitor for a recurrence, and we really take a hard stand and say that clinicians should not be using circulating biomarkers as surveillance strategy for the detection of recurrence in patients who've undergone curative intent treatment, but we also do state that there is emerging data looking at ctDNA that may change this over the next four or five years, but we're certainly not there yet. So standard of care should not be-- to be using anything like that.

And then question 5 is, are there-- or what is the role for brain MRI for surveillance in patients with both non-small-cell and small-cell? And our recommendations are a little nuanced here. We did say for patients with stage I through III non-small-cell lung cancer, clinicians should not be using a brain MRI for routine surveillance after curative intent therapy, and patients who have undergone curative intent treatment for small-cell and did not receive prophylactic cranial radiation, this is where we do say clinicians should offer a brain MRI every three months for the first year and then every six months for the second year for surveillance. So a little bit different surveillance strategies for patients whether you're small-cell or non-small-cell.

So those are the broad stroke overviews of the recommendations that we put together in this consensus statement.

And then can you speak to the importance of this guideline and these recommendations and how they will impact practice?

I think that ASCO recognized how much confusion there was post-curative intent therapy. So I think this is the reason why these guidelines are so important. We need to keep in mind that health care resources that are utilized and be mindful of that. There's no real role for routine imaging less than the intervals that we're describing as they may obviously not be in touch with health care utilization and cost.

The other thing is this idea that patients are getting scans so frequently that we're picking up on a lot of false positive information that can't be used, and so we recognize that as well. So I think that on the heels of the confusion coupled with cost considerations, as well as what we're picking up on frequent scans, we do have to make recommendations that will hopefully unify and harmonize practice across the country to better suit patients and also evidence-based practice. I think that's really important.

And finally, how will these guideline recommendations affect patients?

Yeah, I think patients hopefully, if physicians follow these guidelines, will be receiving the appropriate interval. I mean, look, we understand that two-thirds of patients with lung cancer who relapse will present with metastatic disease and that there have been limited data thus far on what should be the optimal interval for scans. But we understand also that patients who do relapse could present with potentially curable lung cancer, and in addition, there's been recent data to suggest that even patients with limited metastatic disease who was detected on recurrence may be cured or may have improved survival with certain strategies like local ablative therapy.

So we hope that these guidelines can be firmly cemented into the practice for clinicians so that the appropriate interval is selected, but that also patients can benefit from these appropriately timed-out scans to improve outcomes for them.

Great. Thank you for your work on these guidelines, and thank you for taking the time today to give an overview to our listeners, Dr. Levy.

Thank you so much.

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

An interview with Dr. Jessica Geiger from Cleveland Clinic on "Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline." This guideline provides evidence-based recommendations addressing diagnosis, surgery, radiation therapy, and systemic therapy for patients with squamous cell carcinoma of unknown primary in the head and neck. Read the full guideline at www.asco.org/head-neck-cancer-guidelines.

Transcript

[MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at podcasts.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Jessica Geiger from Cleveland Clinic, author on Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck ASCO guideline. Thank you for being here, Dr. Geiger.
Thanks, Brittany, for the invitation and the opportunity.

First, can you tell our listeners what is squamous cell carcinoma of unknown primary in the head and neck and what this guideline generally covers?

Sure. So cancer of unknown primary or carcinoma of unknown primary in the head and neck is metastatic squamous cell carcinoma found in cervical lymph nodes. And importantly, there's a lack of a primary mucosal tumor that's identified. So these patients comprise about 5% of all head and neck cancers. And it poses a challenge for all members of the treatment team, both from a diagnostic perspective but as well as treatment management; what is the best way to proceed for treatment with these patients? Now this guideline provides an up-to-date and evidence-based management for recommendations. And these recommendations are based on published literature. But where the data is lacking in the literature, expert panel consensus was utilized to provide recommendations.
I'd like to discuss some of the key recommendations of this guideline. First, with regard to diagnosis of squamous cell carcinoma of unknown primary in the head and neck, what are the challenges, and what are the recommendations from the guideline?

The diagnostic challenges come about when a patient presents with a neck mass. They often have imaging, a clinical exam. But again, about 3 to 5 percent of patients, we will be unable to locate where this tumor started. Squamous cells don't show up in the lymph nodes by themselves. They came from somewhere else. And part of the reason that this makes a diagnostic challenge if we're not able to readily see where the primary tumor is, oftentimes, it's very small in size. And so it's not picked up by imaging or by a physical exam. Also, these are sometimes difficult anatomic locations to evaluate. So all of this can pose a challenge to coming up with the right diagnosis. Now some of the recommendations for diagnosing these patients, obviously, we need to have a complete history and physical exam. And this physical exam should include a fiberoptic laryngoscopy, so a good lab endoscopy exam looking at all of the mucosal tissues, trying to find abnormalities, trying to see where exactly this cancer started.
Now in order to make the diagnosis of squamous cell carcinoma, obviously, a biopsy needs to be done, and that is in the neck, where these suspicious nodes are. Either a fine needle aspiration or a core needle biopsy is recommended within these guidelines. The guidelines also indicate when to do additional pathologic testing. So this is for high-risk HPV, especially in neck nodes that are in level two or three. If high risk HPV testing is negative, then we give recommendations regarding Epstein-Barr virus testing, so looking to find is this nasopharynx primary cancer and then, of course, imaging guidelines. So the image modality of choice is a contrast enhanced CT of the neck, not just to elucidate and better evaluate the nodal burden of disease, which the patient presents with, but also to investigate for evidence of a mucosal primary. Now if that fails to produce a primary then we give recommendations regarding PET scans.

And then what are the recommendations for surgery for a squamous cell carcinoma of unknown primary in the head and neck?

There are many recommendations that we go into to address the surgical approach to a cancer with unknown primary. Now the previous question asked about diagnosis included in the surgical recommendations in our guidelines for diagnostic surgical interventions. So we can sort of branch point or divide recommendations for surgery, whether it's a diagnostic or a therapeutic procedure. And then in the therapeutic procedures, we can look more in detail at what surgery is recommended for a primary or the mucosal, and then how to how do we address the neck? So first, as part of diagnosis with surgery, all patients need a complete operative evaluation of the upper aerodigestive path. And this includes directed biopsies. So the surgeon goes in the operating room, gets a good look around. Any suspicion for any possible cancer is biopsied, as opposed to blind biopsies or random biopsies, which are not recommended.

Now the recommendations for surgery also include when to do tonsillectomies and what tonsillectomies to do. So are these palatine tonsillectomies or lingual tonsillectomies? Do we perform them or recommend them on the ipsilateral side, or what is the role for a contralateral or even bilateral tonsillectomy? And I won't go into the specifics because they're all-- all the different scenarios are laid out within the guidelines, but the recommendations are based on the patient's nodal burden. So do they have bilateral lymph nodes; do they have lymph nodes just on one side; how big they are, that all plays a role into the recommendations regarding surgical intervention. Now if mucosal primary tumor is identified, there are clear recommendations and guidelines that every effort to clear the disease with negative margin is of paramount importance. So we're talking about a definitive oncologic surgery in this case. And the reason we want to stress that negative margins are the goal is because we're trying to avoid trimodal therapy. So we're trying to get to a good surgical resection. A positive margin left behind is likely going to lead to recommendations for postoperative radiation with the addition of radiosensitizing chemotherapy, which is what we do not want. We want to try to avoid toxicities with trimodal therapy.

That brings me to then surgical management of the neck and the guidelines set forth in this document. So recommendations for neck surgical management are broken into whether the patient has what we consider small volume disease versus large volume disease. So for small volume disease, small lymph nodes on one side of the neck, we recommend a multidisciplinary discussion whether or not the patient should be best served with a definitive surgery involving a neck dissection or if they should have definitive radiotherapy. Again, our goal is to avoid trimodal therapy. So if there's obvious gross extranodal extension seen on imaging, then they would be best served with a primary radiation approach, as opposed to surgical. Similarly, any large volume disease, obviously, gross extranodal or extracapsular extension, definitive chemo radiotherapy is favored. Now a comment on management of the neck, if you're suspecting an oropharynx primary, which is the majority of cancer of unknown primaries of the head and neck, we give specific recommendations regarding what levels to routinely surgically dissect, levels IIa, III, and IV in that instance.

In your discussion of the surgical recommendations, you began to touch on the radiation recommendations. Could you elaborate on those recommendations from ASCO on radiation therapy for this patient population?
Of course. And again, when you refer back to the guideline and the recommendations, there are even more specific recommendations regarding when and how to use primary radiotherapy or adjuvant radiotherapy in this setting. So I'm not going to go into great detail for every single recommendation that is provided, but a nice overview is, basically, if a patient is receiving radiotherapy as the primary definitive management of cancer of unknown primary, obviously, we recommend treatment should be given to gross nodal disease but also to neck regions and mucosal anatomic regions, which are considered at risk for containing microscopic disease. So it's not just good enough to radiate what we see on imaging but also to consider the areas around it, the nodal echelons and other mucosal areas where there could be cancer. So for example, an HPV-related disease where it's likely oropharynx unilateral disease, there are specific locations to include. And this is also the same for HPV-negative disease. Now if we're worried about a possible nasopharynx cancer in the setting of E-Barr or EBV-positive disease, the mucosal radiotherapy can be limited to just the nasopharynx, but you want to radiate bilateral necks, level II through IV, and include the retropharyngeal lymph nodes.

There are specific recommendations where unilateral versus bilateral neck irradiation is recommended. And again, I just encourage the listeners to refer back to the guideline itself for these specific instances. Also included within the radiotherapy guidelines and recommendations are specific doses. What doses do you use? Where do you use these doses? And these doses are extrapolated from known and well established evidence for traditional head and neck squamous cell carcinoma in which we know where the primary is, also, when to give post neck dissection kind of in the adjuvant setting, again, all extrapolated from known head and neck squamous cell carcinoma but very specific and laid out within the guidelines.

And what does the expert panel recommend for systemic therapy for squamous cell carcinoma of unknown primary in the head and neck?

Similarly, when we devised the recommendations for radiotherapy for this disease, the use of systemic therapy, when to use it, when to add it to radiation is also extrapolated from the head and neck guidelines and evidence for known head and neck cancer. So we recommend adding chemotherapy to definitive radiotherapy in advanced nodal disease, and we've defined what advanced nodal disease is based on the AJCC 8th Edition. So in HPV-negative disease, this is N2 or N3, in HPV-positive disease, multiple ipsilateral lymph nodes. If a lymph node is greater than three centimeters, we recommend adding chemotherapy to radiation in the definitive setting. Now, specifically, the chemotherapy that we recommend is cisplatin. Again, this is based on well-established studies and evidence in head and neck cancer. So patients who are medically fit and able to receive cisplatin, that is the treatment of choice. There are also recommendations regarding resected cancer of unknown primary. So with evidence of extranodal capsular extension, we recommend the addition of, again, cisplatin chemotherapy to postoperative radiotherapy, again, extrapolated from well-established head and neck studies. And then, again, if you are concerned that this is an Epstein-Barr-related nasopharynx cancer, stages II through IVA, again, AJCC 8th Edition, we recommend the addition of chemotherapy to radiation in those settings as well.

Great. This guideline covers a lot of ground and many recommendations. Can you speak to why this guideline is important and how you envision it will impact practice?
So this guideline is important because a fair amount of patients will be presenting with cancer of unknown primary. We stress through this guideline that this is very evidence-based recommendations and guidelines with a focus on a multidisciplinary approach to how to treat these patients.

And finally, how will these guideline recommendations affect patients?

Well, hopefully, this guideline will provide reassurance to patients that no matter where they are receiving treatment, they are receiving quality standard of care management, again, largely driven by evidence. And it doesn't matter whether they're treated by locally practicing experts and specialists or at a large institution, they're being treated by the standard of care that is accepted across the board.

Well, thank you for your time today, Dr. Geiger, and for working on these comprehensive guidelines.
You're very welcome. Thanks, Brittany.

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

An interview with Dr. Nadine Tung from Beth Israel Deaconess Medical Center in Boston, MA on "Management of Hereditary Breast Cancer: ASCO, ASTRO, and SSO Guideline." This guideline covers recommendations for the management of patients with breast cancer with germline mutations in breast cancer susceptibility genes. Read the full guideline at www.asco.org/breast-cancer-guidelines 

An interview with Dr. Pauline Funchain from Cleveland Clinic in Cleveland, OH on "Systemic Therapy for Melanoma: ASCO Guideline." This guideline provides recommendations on systemic therapy options for adult patients with cutaneous and noncutaneous melanoma. Read the full guideline at www.asco.org/melanoma-guidelines

An interview with Dr. Gabriela Chiorean from the University of Washington, Fred Hutchinson Cancer Research Center, Dr. Mary Chamberlin from Dartmouth-Hitchcock Medical Center, and Dr. Pritesh Lohar from the HCG Cancer Center, on "Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline." This guideline provides guidance for resource-constrained settings on the management of late-stage CRC. Read the full guideline at www.asco.org/resource-stratified-guidelines.

An interview with Dr. Sharon Giordano from MD Anderson Cancer Center and Dr. Michael Hassett from Dana-Farber Cancer Institute on "Management of Male Breast Cancer: ASCO Guideline". This guideline provides recommendations concerning the management of male breast cancer; addressing five main areas where treatment for men differs from the approach used for women with breast cancer: adjuvant endocrine therapy, endocrine therapy for advanced/metastatic cancer, adverse effects of endocrine therapy, germline genetic testing, and survivorship. Read the full guideline at www.asco.org/breast-cancer-guidelines. 

An interview with Dr. Nasser Hanna from Indiana University Simon Cancer Center and Dr. Gregory Masters from Helen F. Graham Cancer Center and Research Institute on "Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update." This guideline provides recommendations on systemic therapy treatment options for patients with stage IV non-small-cell lung cancer (NSCLC) without driver alterations in epidermal growth factor receptor or ALK, based on histology, PD-L1 status, and/or the presence or absence of contraindications. Read the full guideline at www.asco.org/thoracic-cancer-guidelines. 

Transcript

[MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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Hello, and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at podcasts.asco.org.

My name is Brittany Harvey. And today, I'm interviewing Dr. Nasser Hanna from Indiana University's Simon Cancer Center and Dr. Gregory Masters from Helen F. Graham Cancer Center and Research Institute, co-chairs on therapy for stage IV, non-small cell lung cancer without driver alterations, ASCO and CCO Joint Guideline Update. Thank you for being here today Dr. Hanna and Dr. Masters.

Thank you. Glad to be with you.

My pleasure. Thanks.

First, Dr. Hanna, can you give us a general overview of what this guideline covers?

Sure. So the ASCO guidelines for the treatment of patients with stage IV, non-small cell lung cancer were last updated in 2017. And since that time, there has been a tremendous amount of change that has taken place. The 2017 guidelines included recommendations for basically three subgroups-- those patients with non-small cell lung cancer who have certain targetable DNA mutations and those who do not have those mutations but have a PD-L1 score of 50% or higher and then everyone else.

But because of the rapid and vast changes that have taken place, we decided to make a separate guideline for those with targetable DNA mutations and to focus this current guideline on those without the targetable mutations. So within that context, this guideline categorizes patients by whether their tumors have a PD-L1 score of 0% to 49% or those who have a PD-L1 score or 50% or greater.

And within those categories, recommendations are characterized based upon whether the patient has squamous cell histology or non-squamous cell histology. And we also consider whether patients are candidates for chemotherapy or perhaps even those that decline chemotherapy and whether they have any contraindications for immunotherapy.

So what distinguishes these guidelines from other guidelines is our attempt to adhere to the strongest available evidence-based medicine. And while not every iteration of clinical management can be covered, these guidelines provide oncologists with a strong, evidence-based roadmap to treat the vast majority of patients with non-small cell lung cancer.

So as a result of this collective effort by ASCO staff and the guideline writing committee, this report offers a substantial amount of change to the recommendations from the clinical practices guidelines provided in 2017. In 2017, the only recommendations for the use of immunotherapy were in the first line setting for patients who had a PD-L1 score of greater than 50% and in the second line setting of patients progressing after first line chemo.

But these updated guidelines include the incorporation of immunotherapy in all subgroups of patients regardless of histology and PD-L1 score. So as a result, there are about three times the number of options to consider in the first line setting with these new guidelines compared to the 2017 guidelines. However, the 2020 guidelines provides a preferred treatment regimen for each situation to simplify the decision making process for most patients.

And what are those key recommendations of this guideline update for patients without driver alterations?

So the key changes for 2020 is the incorporation of immunotherapy into nearly all settings in the first line setting, regardless of tumor histology and regardless of PD-L1 score. For those patients who have a PD-L1 score of 50% or higher, single agent pembrolizumab remains the preferred treatment for most patients.

But new evidence does provide a rationale for giving select patients chemotherapy, either carbo and pemetrexed if they have non-squamous, or carbo plus paclitaxel or nab-paclitaxel for squamous plus the addition of pembrolizumab in this subgroup of patients. For those patients with PD-L1 scores of 0% to 49% who are eligible and willing to take chemotherapy, these new guidelines recommend chemotherapy plus pembrolizumab.

For those who have a PD-L1 score of 1% to 49% are not appropriate for chemo or decline chemotherapy, these guidelines suggest single agent pembrolizumab as a reasonable option. The guidelines also provide the option of alternative chemo immunotherapy regimens to be used in patients with non-squamous, non small-cell that were not included in the prior guidelines.

And while these are not necessarily preferred for most patients, select patients can be considered for these regimens, which include the immunotherapy drug, atezolizumab, and combination chemo with atezolizumab and bevacizumab. And the guidelines provide some commentary on potential scenarios in which these options should be considered.

Dr. Masters, why is this guideline important, and how will it change practice?

Well, the new ASCO CCO joint non-small cell lung cancer guideline update is important in that it clarifies recommendations for an international audience and is co-sponsored by the American Society for Clinical Oncology and Cancer Care Ontario. These guidelines were developed through a rigorous, evidence-based process with a broad range of experts, including a multidisciplinary team of clinicians, researchers, data specialists, and patient representatives.

The new guideline update provides a comprehensive review and analysis of the current literature on the treatment of advanced non-small cell lung cancer. The current update also includes a data supplement with evidence tables, slide sets, and links to patient information through cancer.net, ASCO's patient information website.

In an increasingly complicated environment for oncologists, managing patients with advanced cancer, we're learning how to incorporate molecular testing and other biomarkers. And this guideline will help change day-to-day practice for clinicians as they implement these recommendations. This guideline will help clarify the optimal treatment strategies for non-small cell lung cancer patients without driver gene mutations and allow individualization based on tumor histology and immunotherapy biomarkers, such as PD-L1 testing.

At the same time, the update allows clinicians to use their individual judgment and experience to incorporate unique, intangible characteristics of patients. It also emphasizes the importance of patient preferences in deciding the optimal care for an individual affected by advanced non-small cell lung cancer.

And finally, how will these guideline recommendations impact patients?

The broad range of experts who've contributed to these guidelines includes a multidisciplinary team, including clinicians, researchers, data specialists, and patient representatives. This assures patients of a consensus opinion based on the available clinical research on treating advanced non-small cell lung cancer. It provides clinicians with the best up-to-date distillation of the many complicated trials of chemotherapy and immune checkpoint inhibitor therapy in an area where patient-centered, precision medicine dictates the optimal treatment strategies.

We incorporate molecular testing in these guidelines, although this particular guideline is directed at patients without driver gene mutations. We include recommendations on implementation of chemotherapy and immunotherapy based on the best available data on biomarker testing for PD-L1.

We recognize, however, that new research continues into treatment strategies and molecular analysis to help guide incorporation of targeted therapy and immunotherapy. We recognize that new treatment options and combinations will become available, and new testing techniques will help guide the decision process in the future. We plan to continue to analyze the available research and update these guidelines as clinically indicated to provide the best options for our patients.

Most of our patients will still be treated with palliative intent. But a growing number of patients have sustained control of their cancer with recent studies and updates suggesting that up to 25% of patients may have control of their disease for five years or longer. Now that more patients can maintain their quality of life with prolonged survival, with the current therapy, it is also critical that we continue to look to patient reported outcomes as an important way of defining the best options for our patients.

Thank you both for your work on this ASCO CCO guideline update for therapy for stage IV, non-small cell lung cancer without driver alterations and for coming on the podcast today to provide an interview, Dr. Hanna and Dr. Masters.

Thanks for having us on the program. And we have enjoyed being part of the process.

Thank you.

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

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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.

An interview with Dr. Philip Saylor from Massachusetts General Hospital on "Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline." This guideline includes recommendations for management of osteoporotic fracture risk in nonmetastatic disease and interventions for men with castration-resistant prostate cancer metastatic to bone. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines. 

Transcript

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The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

Hello, and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.ASCO.org.

My name is Brittany Harvey, and today I'm interviewing Dr. Philip Saylor from Massachusetts General Hospital, lead author on "Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline." Thank you for being here today, Dr. Saylor.

Oh, it's my pleasure.

First, can you give us a general overview of what this guideline covers and about the endorsement process?

Yes. So the Cancer Care Ontario has a program in evidence-based medicine, and they periodically put out clinical practice guidelines for management of a whole variety of topics. And they relatively recently put out a publication on bone health and bone-targeted therapies in prostate cancer.

And so that's a really big topic because bone health is such a big part of prostate cancer care across the entire range of scenarios that patients can face. And their guideline addresses topics all the way from osteoporosis and fragility fractures and that risk as it relates to GnRH agonist, androgen deprivation therapy that men can get for really any prostate cancer scenario, goes all the way from that to improving quality of life in patients who have bone metastases that have progressed despite systemic therapy. So it's really a very broad series of topics that they addressed.

And so when they put out that guideline, ASCO identifies it as something that's very relevant to the ASCO community and goes through, then, a formal process of reviewing the methodology of those guidelines and then having an expert panel discuss the quality and evidence of the guidelines and really provide, if appropriate, an endorsement and some additional discussion of those topics.

So what are the key recommendations of this guideline?

They really have four sort of subtopics within this bone-themed guideline that are addressed and discussed in a fair amount of detail. And each one of those four topics deserves some of its own discussion. The first topic is osteoporosis and risk for just fragility fractures, like hip fracture and vertebral body compression fractures. That's one.

The second is potential prevention of bone metastases in a patient that does not yet have bone metastases. The third one is management of castration-resistant prostate cancer metastatic to bone. And the fourth one is symptomatic management of men with CRPC metastatic to bone. So it is probably worth discussing each one of those, in some detail, one by one.

So for the osteoporosis fracture risk question, Cancer Care Ontario, their recommendation really is that men with non-metastatic prostate cancer at high risk for fracture who are receiving ADT should be considered for the osteoporosis dosing of denosumab. And in situations or places where denosumab is not available, then patients can consider a bisphosphonate as an alternative.

So we had a fair amount of discussion of that recommendation. We endorsed that recommendation. And I guess my personal emphasis would be that osteoporotic fracture risk is really the biggest challenge to that is not forgetting about it.

So you can often have men who are in a good prostate cancer scenario, likely to be cured by their therapy. They're going to get some duration of ADT. And they look healthy as they sit there in clinic with you. They're likely to do well from a prostate cancer standpoint.

And it just would be so easy not to adequately screen for osteoporotic fracture risk, and just not to remember that because so many of our discussions together in clinic are focused on the prostate cancer more than the broader health questions. And so, I mean, to me, I think not forgetting about this issue is really one of the most important things to emphasize in any discussion of osteoporosis.

And so really, it's a fairly simple problem to screen for and manage. Most men should be, if they're going to be on any duration of ADT, should be tested with a bone density test, a DEXA scan. It's really a fairly inexpensive and easy test for getting a sense for where their bone health is as they begin.

And I usually tell my patients in clinic that most men don't need any new prescription medicines to manage that risk, but we'll never figure out the ones who need it unless we go through the very disciplined systematic work of doing that screening. And then among those who really do deserve treatment, it's really denosumab at the osteoporosis dosing or a bisphosphonate. Really, any of those choices really works well for improving bone mineral density.

One of the big ASCO discussion points is that denosumab is the only medicine that's been shown definitively to improve fracture risk in this setting. But that's really a product of denosumab being studied in a really large prospective randomized controlled trial. And so that's one where they required more than 1,000 patients in order to assess that fracture endpoint.

So the reason, perhaps-- probably the most important reason that bisphosphonates have not been shown to improve fractures is that none of them have been studied in such a big study. The bone mineral density trials that have studied bisphosphonates are all on the order of maybe 30 to 100 patients rather than 1,000. So really, in many clinical settings, cost and convenience are important considerations. And when those are factored in, it's often very reasonable to use a bisphosphonate rather than denosumab, though either one really could be considered a gold standard. So that's point number one from the guidelines.

Number two really discusses the issue of prevention of bone metastases. And so there are a couple of sub-recommendations from Cancer Care Ontario. But really, the most important point from that is that there is no bone-targeted drug that has been shown to prevent or delay the development of the first bone metastasis. So a number of different studies have tried to address this question in slightly different clinical scenarios.

But the bottom line is, we don't use bone-targeted medicines to prevent the first bone metastasis. And so there's always been sort of an attractive potential effectiveness there because you think if your bone-targeted therapy changes the bone microenvironment, could the natural history of prostate cancer play out differently? But the answer is that we really don't have any convincing evidence of effectiveness on that front using any drug, in any situation. So that's a pretty easy one to summarize.

For the third category of situation that's addressed in the guideline really relates to castration-resistant prostate cancer metastatic to bone. And so there are three sub-recommendations there. In that situation, either zoledronic acid or denosumab in monthly dosing at the skeletal event preventing dosing is a gold standard and reasonable to pursue. So that's one thing.

In men with symptomatic disease, radium-223 can be considered, both to prevent skeletal events and to improve health-related quality of life. And then, finally, all radiopharmaceuticals can be considered in that situation for palliation of bone pain. And so we endorsed those recommendations as well.

And we added a fair amount of discussion about how to optimally support men's health in those situations. For one thing, it's important to note that monthly zoledronic acid or monthly denosumab, whichever is pursued, is a fairly intensive osteoclast-targeted therapy. And so the studies that formally establish those as gold standards in that setting, they really only treated for about two years, plus or minus. So we don't know a lot about the safety of that intensity of therapy beyond two years.

And so that's an important consideration, because there are many men who do well, thankfully, for a lot longer than two years in the castration-resistant setting with bone metastases. And so we really do, as clinicians, need to respect the possibility of toxicities, especially osteonecrosis of the jaw seems to be a much, much more common phenomenon with longer durations of treatment and with these more intensive regimens. So that's one thing that deserves a lot of attention by clinicians.

The other thing is that dental evaluation and proactive dental care before and during any of these bone-targeted therapies is really an important issue not to miss. So the highest risk for having osteonecrosis of the jaw is in patients who are on one of these intensive regimens and then need to have invasive dental work when they're already been started on one of those regimens. Those are the jaws and mandibles that seem not to heal as well.

And so ideally, every patient that is going to go on intensive osteoclast-targeted therapy really should be evaluated by a dentist with the question of whether there's any dental work that really needs to be done proactively before the start of one of those medicines. And so I always say I have to be humble as a medical oncologist to say I really know little to nothing about teeth. And so I have to reach out to my colleagues in the dental field to tell me which are the patients that need to do something ahead of time and heal before they start one of these medicines. So those are a couple of important points.

And then the other thing that's really not a new piece of information but is important to emphasize is that it's really monthly therapy with denosumab or zoledronic acid should really be used only for patients with castration-resistant prostate cancer metastatic to bone. So the patients who are responding to their systemic therapy really seem not to benefit from the bone-targeted therapy. And that's likely because any systemic therapy that's controlling the prostate cancer, in general, that's active against the cancer, in general, is going to prevent skeletal complications. We just have a lot fewer of those events, thankfully, when the disease is under control.

And then, finally, the fourth category of recommendation addresses symptomatic castration-resistant prostate cancer metastatic to bone. And that's a situation where the radium-223 given in the typical once per month times six series of treatments is a gold standard, improves health-related quality of life and overall survival.

I think one of the important discussion points on that front relates to recent clinical trial data that examines the use of other secondary systemic therapies in addition to the radium. So we have a prospective randomized study that looked at abiraterone with or without radium. And what it really showed was that the combination of abiraterone and prednisone with radium resulted at a very high rate of fractures and worsened overall survival. So that's really a combination that should absolutely not be pursued outside of a clinical trial.

And so that's an important thing to know, but it's also sort of a cautionary tale that if we're tempted to combine other secondary medicines with our radium treatment, we really don't have a lot of evidence for the safety or efficacy of doing that. So that's the sort of thing that really should be reserved for clinical trials. And those are probably the most important-- those are the four main topics addressed by the guidelines. As you can tell, it really includes situations that are relevant to just about every man who receives systemic therapy for prostate cancer.

Absolutely. And thank you for that comprehensive overview and those considerations of the guideline endorsement panel. Why if this guideline important? And how will it impact practice?

So I think there's really sort of two main ways that it's important to the reader in 2020. I'd say, first of all, as a reminder and sort of educational promotion of awareness of the things that we already know but are easy to overlook. And I think the things that are really there are that it is easy to focus on the cancer therapy and easy to overlook the bone-targeted therapy.

So as we have an increasing number of systemic therapies that are active against the cancer itself, and as we have sort of, in the best possible way, more options and more molecular considerations for our prostate cancer patients, we really can't forget to do the fundamentals, like doing monthly zoledronic acid or monthly denosumab in men with castration-resistant disease that's metastatic to bone. So I think that's the kind of thing that would be easy to forget, but that we shouldn't.

And the second subtopic there would be screening for osteoporosis in any man who receives ADT. And again, that's something that-- osteoporosis or someone at high risk for fragility fracture, that's an asymptomatic situation until the fracture occurs. And then at that moment, you're really thinking back and saying, man, I wish I'd done something three years ago, or five years ago, or 10 years ago to improve bone health so that this wouldn't have happened in the first place.

So it really is up to us as the clinicians caring for these prostate cancer patients to advocate for their general health in a way that includes their bone health. We just have to really not forget to screen for osteoporotic fracture risk. So I think those reminders of things that we already know but are really easy to miss, I think that's one aspect of this.

And I think the other is just discussion of the data. It really adds some richness to the topics. And we do have these updates in an emerging field, particularly when it relates to radium-223. It seems like a drug really on, like, a drug strategy that could easily be paired with other drug strategies because it's reasonably well-tolerated.

But we learned, really especially from that clinical trial experience of radium with abiraterone, we really learned that freewheeling combinations are not necessarily safe and not necessarily effective. And so we have to just be mindful of recently emerging data and have an ear to the ground about ongoing clinical trials, sort of how to best combine and sequence all the different medicines that are sort of in our back pocket.

And finally, how will these guideline recommendations affect patients?

Yeah. I mean, I think bone health is really just so important to every patient with prostate cancer. And it's almost, for clinicians, it's almost an educational issue where we have to help our patients understand how important bone health is. When we talk in clinic about a DEXA scan to look at bone density, a lot of men really look at me a little bit blankly. They think of osteoporosis more as this sort of issue that women deal with more so than men.

But I always talk about, if you imagine having a hip fracture and needing hip surgery, or if you think about the pain and the postural changes that happen with vertebral body compression fractures, we really have to do something before any of those things occur. And most men agree with me if you put it in those practical terms. It's just the kind of thing that you have to take a couple of minutes out of your clinic visit to make sure that you address.

And the other thing really is, in men who have more challenging prostate cancer metastatic to bone, even life-threatening prostate cancer, all the complications that can happen later in the course of disease, we really need to do the best possible job not only to keep men living longer, but also to make sure their quality of life is the best it can possibly be.

And that's really-- and most of the time when prostate cancer starts to become a physical burden as it progresses, it's really a physical burden that's centered on bones and skeletal health. And that can have an effect on comfort. That can have an effect on mobility. And these things are hugely central to quality of life. So the impact on patients, all the way from osteoporosis to bone metastases, really, it's just such a central theme within the management of everybody who has to face prostate cancer.

Thank you for your work on this important guideline, and thank you for your time today Dr. Saylor.

Oh, it's my pleasure. We got to keep working to get the word out there and have the optimal management for all of our patients.

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

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An interview with Dr. Christina Annunziata from the National Cancer Institute on "Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline". This guideline provides recommendations for women diagnosed with epithelial ovarian cancer and their families on which individuals should receive risk evaluation, counseling, and genomic testing, and when they should be tested. Read the full guideline at www.asco.org/gynecologic-cancer-guidelines. 

Transcript

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The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at podcast.asco.org.

My name is Brittany Harvey. And today, I am interviewing Dr. Christina Annunziata from the National Cancer Institute, co-chair on Germline and Somatic Tumor Testing and Epithelial Ovarian Cancer: ASCO Guideline. Thank you for being here Dr. Annunziata.

Oh, it's my pleasure. Thank you.

First, can you give us a general overview of what this guideline covers?

Sure. So this guideline is covering the use of molecular testing in women diagnosed with ovarian cancer. And that's specifically what tests should be done and when to do them.

And what are the key recommendations of this guideline?

The key recommendations really are that all women diagnosed with ovarian cancer should be tested for certain gene mutations that are responsible for predisposing people to ovarian cancer and also that a genetic counselor should be involved in discussing the results of these tests with the person involved and with her family. In the guidelines, we go into specifics of which genes should be tested at what point in the course of the disease. And the guidelines mainly focus on the BRCA genes and mismatch repair genes because these are the ones with approved treatments for cancers with these mutations.

What are the clinical questions that you addressed in this guideline?

So we have three main questions when we started out. We wanted to know, first, in which individuals should risk evaluation counseling genomic testing for germline and somatic tumor alterations be performed. We also wanted to know, number two, which genomic alterations had actually demonstrated clinical utility to direct therapy for women with ovarian cancer. And third, what is the most appropriate sequence and timing of testing, meaning specifically at what point in the course of the diagnosis and the treatment of the women should we be performing this testing?

So we came up with specific answers to each of these questions. And just to briefly summarize, for the first questions in which individuals should we test, we did find evidence that all women diagnosed with ovarian cancer should be offered germline testing for, specifically, BRCA1 and BRCA2 cancer susceptibility genes, irrespective of whether or not they had a family history of the disease.

Also within that question, we found evidence that women who have non-high grade serous ovarian cancer, specifically clear cell endometrioid or mucinous ovarian cancer, should have somatic tumor testing for mismatch repair deficiency. And both of these recommendations are because there are FDA approved therapies for women with cancers with these particular genetic makeups.

In the second question, we asked, which genomic alterations have demonstrated clinical utility? This goes specifically into, which specific genes should be tested in the germline and the somatic setting? And in that recommendation, specifically, we focused on, again, the BRCA1 and 2 genes and the mismatch repair deficiency genes.

We did not make specific recommendations for the homologous recombination deficiency assays at this time. Those are still undergoing evaluation. And it's likely in the near future that we will amend this recommendation to specifically discuss those.

In the third question, what is the most appropriate sequence and timing of the testing? That goes into, when should we be doing this in the course of the disease? And we did want to emphasize that women with ovarian cancer should be tested at the time of diagnosis because of the specific implications for therapies. If they have not had testing at the time of initial diagnosis-- let's say they were diagnosed several years ago-- then they should be tested at the time of their first recurrence or subsequent recurrences if those have already happened. And again, these have implications for treatment.

Why is this guideline important, and how will it impact practice?

So one of the most important recommendations is that all women should be tested at the time of the initial diagnosis. In practice today, we estimate that only about 1/3 of women are actually being tested at the time of diagnosis. This testing is important, especially for the BRCA genes, because this has implications for the choice of treatment because of recent FDA approvals for PARP inhibitors in this setting.

And how will these guideline recommendations affect patients?

Our goal is to ensure that all women have access to the best treatments for their ovarian cancer. In order to achieve this goal, doctors need to be aware of best practices, and patients need to understand the results in the context of their disease.

This is why we recommend that the results of the gene testing be delivered to the patient in conjunction with a genetic counselor because this has been shown to increase understanding of the tests and follow through on the recommended treatments. In some settings, we know it may be difficult to arrange these discussions with a genetic counselor, so we hope that these guidelines will emphasize the importance of this step.

Well, thank you for your overview of these and for your work on these guidelines. And thank you for taking the time today to come on the show, Dr. Annunziata.

Oh, you're very welcome. And thank you for the opportunity to highlight these guidelines.

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

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An interview with Dr. Edouard Trabulsi from the Sidney Kimmel Medical College at Thomas Jefferson University on "Optimum Imaging Strategies for Advanced Prostate Cancer: ASCO Guideline." This guideline outlines techniques available and provides recommendations on appropriate use of imaging for specified patient subgroups. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

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

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

[MUSIC PLAYING]

Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org.

My name is Shannon McKernin, and today I'm interviewing Dr. Ed Trabulsi from the Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania, lead author on "Optimum Imaging Strategies for Advanced Prostate Cancer: ASCO Guideline." Thank you for being here today, Dr. Trabulsi.

Thanks, Shannon. Thanks for inviting me.

So first, can you give us a general overview of what this guideline covers?

Sure. So the purpose of this guideline, and it's fairly broad, is to try to come up with some recommendations and strategies for appropriate imaging for patients with advanced prostate cancer. Also, that includes patients that are newly diagnosed that are high or very high risk for having micrometastatic disease.

Also, patients that have been treated and are suffering recurrence of disease as indicated by rising PSA. And then also, patients with metastatic disease, either on initial diagnosis, or on treatment and who are contemplating changing treatments.

Also, it has a wide range of different patient populations that all fit in the category of advanced prostate cancer. And the idea is to try to figure out or make some recommendations on strategies for what imaging is appropriate for each of those groups of men.

So what are the key recommendations for this guideline?

Well, the big impetus for this guideline is the awareness of what we would consider next-generation imaging, meaning that there's a large group of new or novel imaging studies available and on the horizon. And we're trying to figure out the best way to fit them in in the context of traditional imaging in what we would call conventional imaging.

So that would be-- conventional imaging would be imaging tests like CAT scan, radionuclide bone scan, prostate MRI, that sort of thing. Next-generation imaging would include some of the newer PET imaging scans, using different tracers and isotopes, and some of the new SPECT imaging scans, as well as full body MRI.

And so how to interweave those different imaging tests is really what's proving to be not as straightforward as we'd like. And so we realized that we need to really approach this based on a clinical disease state model. So not just one monolithic category of advanced prostate cancer, but looking at specific scenarios.

And we developed this guideline as a scenario-based algorithm. So the initial diagnosis of prostate cancer of men that are at high risk, what images we think about there; for men that have been treated and their PSA is rising, and so forth.

And so we shouldn't jump to next-generation imaging across the board. We really should look very specifically at circumstances where these new, novel, and unfortunately, expensive imaging tests could have real clinical impact.

So patients that are newly diagnosed that are high risk who have suspicious or equivocal conventional imaging, so they have a CAT scan or a bone scan or something that we're really not sure if something that we're seeing there might be an indication of disease, that's a good spot where next-generation imaging might be very helpful.

For patients that have been treated and their PSA is rising, say, after surgery or, say, after radiation, and they get traditional, what we would call conventional imaging, and we don't see a source for the PSA, well, that is another scenario where a patient-- or a category where next-generation imaging should be considered.

In that specific space, there actually are two PET imaging studies that have been approved by FDA in the US with C-11 choline, as well as the fluorine-18 fluciclovine scans.

And then also overseas, or not yet approved in the US, there are other PET-based agents that are being used in that specific space.

Another important aspect of this is that it should have real clinical impact. So if you have a man who unfortunately may be suffering, or evidence of recurrence of disease after surgery or radiation, but because of their comorbidities or age or patient preference, they're not necessarily going to be aggressive with additional therapy, then we probably don't need to chase some of these next-generation imaging studies in that man.

In the confirmed metastatic patient population, that is a little more unclear in terms of what the benefit of next-generation imaging would be outside of the setting of a clinical trial. And in those patients, if it is thought that there would be a change in clinical treatment based on the results of the scan and of next-generation imaging, then that would be a scenario where those might be considered. But we wouldn't necessarily recommend them across the board.

And so why is this guideline so important? And how will it change practice?

Well, it's important and timely because of the tidal wave that we are expecting of novel, next-generation imaging that is going to become closer and closer to clinical practice. Patients are aware of these studies, and they're asking for them, even if they're not currently available or approved by an FDA or covered by a third-party insurance.

There's been a plethora of research studies and new imaging tracers in Europe, Southeast Asia, and Australia. And so trying to get ahead of where they might fit in, and which patients might benefit now and in the future, was really one of the main drivers to come out with a strong position statement on the appropriate use of imaging.

There's a lot of controversy about some of the implications of the next-generation imaging, such as the potential for false positives and the attendant prognostic tests, that that might trigger false negatives, and potentially offering clinicians or patients a more optimistic outlook than may be really present.

And so figuring out specific scenarios and specific patient populations that would benefit from next-generation imaging is the real goal of this guideline.

And so finally, how will these guideline recommendations affect patients?

Well, the ultimate goal is to improve patient care and improve patient outcomes. And so by coming up with some reasonable templates and framework of where some of the next-generation imaging will fit in on a patient's disease spectrum and disease course will help them both to potentially indicate when treatment changes may be necessary, or to isolate areas of disease, and to importantly and accurately give their correct stage. And then that will translate, or we hope and expect, with more information and more accuracy in diagnosis, in better treatment plans and better patient outcomes.

Great. Thank you for your work on this important guideline on Optimum Imaging Strategies for Advanced Prostate Cancer. And thank you so much for your time today, Dr. Trabulsi.

Thank you so much. Thanks for having me.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline and find additional resources, such as the guideline pocket card, go to www.asco.org/genitourinary-cancer-guidelines.

And you can find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. And if you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.