Dr. Pedro Barata and Dr. Ravin Garg discuss strategies to increase trial representation, including leveraging trial navigators and prioritizing pragmatic trial models, as featured in the ASCO Educational Book article, "Practical Guide to Clinical Trial Accessibility: Making Trial Participation a Standard of Care."

TRANSCRIPT

Dr. Pedro Barata: Hello, and welcome to By the Book, a podcast from ASCO featuring compelling perspectives from authors and editors of the ASCO Educational Book. I'm Dr. Pedro Barata. I am a medical oncologist at University Hospital Seidman Cancer Center and an associate professor of medicine at Case Western Reserve University in Cleveland, Ohio. I am also the associate editor of the ASCO Educational Book.

We know that in recent years, the oncology community has increasingly prioritized the need to modernize clinical trial eligibility, reduce patient burden, and enhance diversity in trial participation. On that note, today we will be speaking about ways to enhance access to clinical trials with Dr. Ravin Garg. He is a hematologist oncologist at Maryland Oncology Hematology and also an assistant professor of oncology at Johns Hopkins Hospital in Baltimore. Dr. Garg is also the co-author of a fantastic paper in the ASCO Educational Book titled, "Practical Guide to Clinical Trial Accessibility: Making Trial Participation a Standard of Care." 

Dr. Garg, welcome. Thanks for being here, and congrats on your paper.

Dr. Ravin Garg: Thank you for having me, Pedro. I am excited to be here.

Dr. Pedro Barata: [KI1]  Your paper is a wonderful, multidisciplinary piece that actually features perspectives from the different stakeholders, right? The patient advocacy, industry, community practice, and academia about these challenges in making trials more available.

This podcast is a wonderful platform. It reaches out to a lot of folks within our community. So, I will start by asking you the obvious. Why do you think it is a must read for our community, for our listeners?

Dr. Ravin Garg: So Pedro, thanks again for inviting me. You do a great job with these podcasts. 

So, I think first and foremost, oncologists right now are under a lot of stress, just in terms of clinical volume. There is concern for research money, and how we get the best care for our patients. So I think this article is very important because it helps bring together, as you had mentioned, the stakeholders throughout academic to community practice and everywhere in between, and try to find how, as a team with different oncologists who partake in different aspects of oncology, can come together to streamline the process to try to get our patients on trials, or certainly have them have availability of trials, just if they are interested in going on them. Being in practice, we have had several challenges that we can talk about throughout this podcast, but I think it is a very important paper because it recognizes that at the end of the day, it takes a team effort for all of us in academics, community, industry, and pharmaceuticals to really come together as a team to really help put forth the trials for our patients.

Dr. Pedro Barata: So, from the perspective of a community oncologist, how do you put together, or maybe you can describe some of the challenges that you see to increase trial participation in the community?

Dr. Ravin Garg: Yes, Pedro, that is a great question, and it is something that I keep on thinking about and trying to find ways to be better at it myself. But I will say some of the challenges as a community doctor that I have seen for myself and talking to other colleagues. Number one, I do think there is a lot of stress on doctors in the community in general, Pedro. Oftentimes we are tasked to see a wide smorgasbord of patients, so we may not have the luxury of being a specialist in any particular tumor subtype. Like oftentimes, we will have to see lung cancer, the next one will be breast cancer, the next one could be CML, the next one could be thrombocytopenia. And as you know better than I do, Pedro, the field in each one of these disciplines is changing so rapidly: molecular genomics, radioligand treatments, different imaging tests, MRD testing for some of our hematologic malignancies. And I think one challenge we have in community is just keeping up with the basics of Oncology 101. In the process of doing that, it can be very difficult to sometimes remember that we have very exciting trials available for our patients. So, I think a lot of it is the day in and day out of being an oncologist is so taxing at times that oftentimes a research trial is not the first thing in our head space when we see a patient.

I think number two, Pedro, at least in the community, and perhaps this is with academics too, is that we are bombarded, I would say, by a lot of messaging these days. We have in-baskets to go through, labs to go through, things of that nature. And in the process of a patient visit, seeing them, doing an exam, taking a history, trying to go over the NCCN guidelines on best practice for how to manage their care, at least for me at times, it is very hard to remember, "Hey, there might be a great trial available, whether within our network or maybe partnering with an academic center." So getting through a day can be fraught with a lot of peril and just difficulties, I would say.

And I would say number three, Pedro, at least as, you know, I am in a private practice where I do see a wide range of benign and malignant hematology and solid tumors, so I would not call myself a specialist. And I think the challenge with that, at least for trials, Pedro, is that when you are a specialist or perhaps you are focusing on a couple of disease subtypes, you become more of an authoritative voice in those types of tumors, and you might be more aware of the trials within your network or perhaps in proxy with an academic center that you can offer your patient. So I think when sometimes we spread ourselves too thin, it can be very hard to be a thought leader, if you will, in a particular subtype of a malignancy, let's say, and maybe not be aware of a trial that could be really well-suited for your patient.

In terms of ideas that myself and colleagues have had in terms of helping mitigate against some of these, I would say, setbacks or issues in the practice for trial enrollment, some of the things we have talked about, Pedro, is, number one, is we do partner with academic centers. So we live here in Maryland. We have several really fantastic academic centers. So, you know, oftentimes, not just within our practice of Maryland Oncology Hematology, we have a lot of great trials available here too, for certain, but in addition to that, we will often times work with doctors at Georgetown, Johns Hopkins, and Maryland if they have a compelling trial that we do not have within our network. It is really of the patient's interest, Pedro, to reach out to them in a collaborative manner to see if they have a trial that might be really compelling for your patient. So I do find myself collaborating a lot with colleagues in, like talented like yourself in academics. You know, I think you do a lot of GU malignancies. So as an example, like partnering with colleagues who are GU experts and say, "Hey, we have a patient with stage IV renal cell. These are the standard options I know, but are there any trials that you might have available?"

I think the other thing that has been very helpful for us is having navigators within research, Pedro. Like as an example, what has really helped the uptake of trial enrollment for our center in Annapolis is having a research navigator because often times what they can do is, a priori, Pedro, before you see the patient and you are kind of formulating a standard of care treatment plan perhaps, they might tug you on the shirt and say, "Hey, we have a great trial here through Sarah Cannon, or there might be something else out there." And being aware of that when you go into a patient's room really provides a nice arena, if you will, to go and say, "The standard of care is here, but hey, we have a trial option that might be well suited for you, maybe perhaps even better, that we can talk about, too." So having research support in the community is really a huge boon, I think, Pedro, for us to really increase our enrollment for patients onto trials.

Dr. Pedro Barata: Yes, I really love that, Ravin. So, let me switch gears a bit. I would love for you to talk a little bit about patient advocacy because they do play a huge role in cancer, and they address many barriers. How do you think we should leverage the patient advocacy groups to reduce patient burden and maybe have them really leverage patient advocacies to improve representation in clinical trials? What do we think we can do more?

Dr. Ravin Garg: Oh, Pedro, I think they are very critically important. As a clinical oncologist now, and I would say this is for anyone in the field of medicine, you are exactly right. I think patients are bombarded by information. There are a lot of things online, whether it be TikTok, Facebook, Google, Yahoo, and people really just have a lot of information given to them. And some of it is fact driven, and some of it is not, Pedro. And oftentimes, I do think there can be at times a mistrust with some medical personnel. I think we are in an era where we are seeing that to some degree with some attributes of medicine. And I think of it as an opportunity for education for the patient and for myself as a physician.

And I think patient advocates, to your point, which was well taken, serve as a bridge to both. And what I mean is that, you know, patient advocates are wonderful. They are, I think, outstanding communicators. They almost are a neutral party, Pedro, where many patients feel that they are an independent source of information that is free of bias, if you will. They are there to provide support, emotional support, scientific support for patients so they can make an informed decision.

So, in terms of our practice right now, patient advocates is something that we are evolving in that capacity, I would say, Pedro. I think now more than ever, having more people as bridges of communication with care providers along with patients is of critical importance. And I would venture a guess, and I think this has been published, where patient advocates really can help tremendously in familiarizing patients with trials and what they are all about and maybe clear up some misconceptions of what trials, what the mission of trials are. Because I do think some patients, at least I have had a few over the years, where when they hear the term trial, they almost think they are being experimented upon, when, in point of fact, they could really help advance their care. That messaging along the way for some can may be mixed up a little bit. And so I think patient advocates is a really great way to offer more information for patients with a source they find very independent and trustworthy, if you will. And it can really help expedite, and I think make a more fruitful conversation for care providers, whether academic or community, and they might be more open-minded in terms of enrolling onto a trial.

Dr. Pedro Barata: Wonderful. Yes, I agree. I agree with you completely. 

So let's focus a little bit now on the folks designing the studies. We usually call them the sponsors. It might be an academic sponsorship, if you will, but we can also have pharma being the sponsor of a study. The angle from an academic design, it is not necessarily the same as what happens when we have pharma. And from that angle, how do you think a more inclusive research can be promoted?

Dr. Ravin Garg: Oftentimes with trials, I think keeping them simple, as simple as we can. And what I mean by that is, often times for trials, Pedro, even for care providers who are enrolling, it can be daunting when there are a lot of different things involved, particularly, let's say, for investigator sponsored, which are incredibly brilliant science, incredible, but it can be a little bit daunting for patients and even the referring physician to talk about getting translational specimens, imaging, traveling to certain centers to get scans and biopsies and even different diagnostic testing like PSMA testing for, you know, prostate cancer. And it can, I think, be very intimidating for patients in terms of what might be required of him or her to enter onto a trial. Like, "This is not what I signed up for. This is laborious. This is a full time job for me. Do I have to pay for parking to go to a city? Do I have to pay for these imaging tests? And do I have to stay in a place for my family to enroll onto a trial?" So I think keeping trials as simple as possible, but yet cull the data we need as investigators where we can really advance the care, hopefully get approval for a drug, but also learn more about the medication and how it works for our patients. So I think simplifying language for trial is very important. I know when I have gone over studies for patients, Pedro, if it is a voluminous amount of information, they can right away get very intimidated. "Like, oh my goodness, this is like a term paper for college again," you know? I am joking, but you know, keeping language simplified is very important, I think, number one.

And I feel that sometimes when they are asked to do a lot of different diagnostic testing, which is very important for translational work, I 100% understand, but I do think sometimes patients can get a little bit off put, if you will, and frustrated with the whole process of doing it.

The second thing for our patients, Pedro, that they have mentioned to us when we put them on trials, not just within our own site but elsewhere, is that it takes a lot of time in terms of collecting information, perhaps a washout period from their last standard of treatment prior to enrollment onto a study. Many patients, Pedro, as you know better than I do, are in maybe crisis in terms of their health and their cancer might be growing, promulgating out of control, and they worry about not being able to expeditiously start onto a treatment, onto a trial. So that can lead to a lot of frustration.

And one thing that you brought up, which was outstanding for me, is the enrollment criterion for some of our patients is felt to be somewhat strict. We have had some patients who may have had a remote history of a stage I malignancy that was by all accounts in remission, you know, let's say 4 or 5 years in the past, and the risk of recurrence at this point would be incredibly low, but they may not be able to enter onto a study because of some stringent criterion put forth. And that can be a little bit frustrating. In fact, I have had one or two patients who, as an example, with kidney issues, but the GFR was about 60, like right near a cutoff that oftentimes, as you know, we use where you can get into trial or not. And you know, if they are at 58, as an example, and otherwise they are a picture of health, a great candidate for a trial that will likely advance their care, and if the entry criterion is too stringent, that might be a lost opportunity for all parties involved, all stakeholders, if you will.

I do appreciate the criterion for entry onto studies cannot be too liberalized. You have to have a certain baseline, but there is a little bit of a gray area and tension, of sorts, if you will, where the patient has a comorbid illness that is a disqualifying offense, but in practicality, perhaps it shouldn't be, especially if they are motivated and there is an opportunity to really advance their care. We have run into, not often, but sometimes in the past, I should say, where patients have been very off put because we try to get them onto a study and there may have been a particular feature or attribute in their underlying care that they couldn't get onto it. So I think having a little bit more thoughtfulness, perhaps, in terms of entry criterion and practicality, if you will, I think would really help enrollment onto studies.

Dr. Pedro Barata: Really well said. Is there anything else that you would like to tell our listeners before we wrap up the podcast today?

Dr. Ravin Garg: I would say just macroscopically speaking, it is really an honor to be an oncologist. I think I speak for both of us. Anyone listening who is thinking about the field, it is tremendous. Just the research, the bravery of our patients, and the thoughtfulness of our scientists like Pedro and translationalists and clinical trialists is really awe inspiring. So I have really loved this field.

I will say from a trial perspective, we really need to enter as many patients as we can onto trials because the science is so brilliant now, the genomic underpinnings of the tumor, we are making great strides as a team of clinicians and scientists, translationalists. So the more that we can get people onto trials and get approved drugs, it is going to help them out in the end. So I think it is such an important time for all of us to come together as a community, find the best way to help our patients out. And clinical trials have to be at the forefront of how we can continue to advance care for our patients.

Dr. Pedro Barata: Yeah, no Ravin, I really agree with you. We really need to increase access to clinical studies, and actually your paper is a great step in that direction by raising awareness, bringing up solutions, and again, collaboration, collaboration, collaboration is really a multidisciplinary effort to accomplish that. 

Thank you so much for sharing your fantastic thoughts and insights with us.

Dr. Ravin Garg: Thank you, Pedro. I am- you do a wonderful job with these podcasts. I am really honored to meet you and to be part of this.

Dr. Pedro Barata: And thank you to our listeners for your time today. I encourage you to check out Dr. Garg's article in the 2025 ASCO Educational Book. We will post a link to the paper in our show notes. And please join us again next month on By the Book for more insights on key advances and innovations that are shaping modern oncology. Thank you for your attention.

Disclaimer:

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. 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.

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Disclosures:      

Dr. Pedro Barata:  

Stock and Other Ownership Interests: Luminate Medical  

Honoraria: UroToday  

Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Merck, Ipson, Astellas Medivation, Novartis, Dendreon  

Speakers' Bureau: AstraZeneca, Merck, Caris Life Sciences, Bayer, Pfizer/Astellas  

Research Funding (Inst.): Exelixis, Blue Earth, AVEO, Pfizer, Merck   

Dr. Ravin Garg:

Patents, Royalties, Other Intellectual Property: Creator, editor, and writer of hemeoncquestions.com

Dr. Pedro Barata and Dr. Aditya Bagrodia discuss the evolving landscape of testicular cancer survivorship, the impact of treatment-related complications, and management strategies to optimize long-term outcomes and quality of life.

TRANSCRIPT: 

Dr. Pedro Barata: Hello and welcome to By the Book, a podcast series from ASCO that features engaging conversations between editors and authors of the ASCO Educational Book. I'm Dr. Pedro Barata. I'm a medical oncologist at University Hospitals Seidman Cancer Center and associate professor of medicine at Case Western Reserve University in Cleveland, Ohio. I'm also an associate editor of the ASCO Educational Book.

We all know that testicular cancer is a rare but highly curable malignancy that mainly affects young men. Multimodal advances in therapy have resulted in excellent cancer specific survival, but testicular cancer survivors face significant long term treatment related toxicities which affect their quality of life and require surveillance and management. With that, I'm very happy today to be joined by Dr. Aditya Bagrodia, a urologic oncologist, professor, and the GU Disease Team lead at UC San Diego[KI1]  Health, and also the lead author of the recently published paper in the ASCO Educational Book titled, "Key Updates in Testicular Cancer: Optimizing Survivorship and Survival." And he's also the host of the world-renowned BackTable Urology Podcast.

Dr. Bagrodia, I'm so happy that you're joining us today. Welcome.

Dr. Aditya Bagrodia: Thanks, Pedro. Absolutely a pleasure to be here. Really appreciate the opportunity.

Dr. Pedro Barata: Absolutely. 

So, just to say that our full disclosures are available in the transcript of this episode. 

Let's get things started. I'm really excited to talk about this. I'm biased, I do treat testicular cancer among other GU malignancies and so it's a really, really important topic that we face every day, right? Fortunately, for most of these patients, we're able to cure them. But it always comes up the question, "What now? You know, scans, management, cardio oncology, what survivorship programs we have in place? Are we addressing the different survivorship piece, psychology, fertility, et cetera?" So, we'll try to capture all of that today.

Aditya, congrats again, you did a fantastic job putting together the insights and thoughts and what we know today about this important topic. And so, let's get focused specifically about what happens when patients get cured. So, many of us, in many centers, were fortunate enough to have these survivorship programs together, but I find that sometimes from talking to colleagues, they're not exactly the same thing and they don't mean the same thing to different people, to different institutions, right?

So, first things first. What do you tell a patient perhaps when they ask you, "What can happen to me now that I'm done with treatment for testicular cancer?" Whether it's chemotherapy or just surgery or even radiation therapy? "So, what about the long term? What should I expect, Doctor, that might happen to me in the long run?"

Dr. Aditya Bagrodia: Totally. I mean, I think that question's really front and center, Pedro, and really appreciate you all highlighting this topic. It was an absolute honor to work with true thought leaders and the survivorship bit of it is front and center, in my opinion.

It's really the focus, you know, we, generally speaking should be able to cure these young men, but it's the 10, 15, 20 years down the way that they're going to largely contend with. The conversation really begins at diagnosis, pre-education. Fortunately, the bulk of patients that present are those with stage one disease, and even very basic things like before orchiectomy, talking about a prosthetic; we know that that can impact body image and self esteem, whether or not they decide to receive it or not. Actually, just being offered a prosthetic is important and this is something, you know, for any urologist, it's kind of critical. To discussing fertility elements to this, taking your time to examine the contralateral testicle, ask about fertility problems, issues, concerns, offer sperm banking, even in the context of a completely normal contralateral testicle, I think these things are quite important. 

So if it's somebody with stage one disease, you know, without going too far down discussing adjuvant therapy and so forth, I will start the conversation with, "You know, the testes do largely two things. They make testosterone and they make sperm." By and large, patients are going to be able to have acceptable levels of testosterone, adequate sperm parameters to maintain kind of a normal gonadal state and to naturally conceive, should that be something they're interested in. However, there's still going to be, depending on what resource you look at, somewhere in the order of 10-30% that are going to have issues.

Where I think for the stage one patients, it's really incumbent upon us is actually to not wait for them to discuss their concerns, particularly with testosterone, which many times can be a little bit vague, but to proactively ask about it every time. Libido, erectile quality, muscle mass maintenance, energy, fatigue. All of these are kind of associated symptoms of hypogonadism. But for a lot of kids 18-20 years old, it's going to be something insidious that they don't think about. So, for the stage one patients, it absolutely starts with gonadal function.

If they are stage two getting surgery, I think the counseling really needs to center around a possibility for ejaculatory dysfunction. Now, for a chemotherapy-naive, nerve-sparing RPLND, generally these days we should be able to preserve ejaculatory function at high volume centers, but you still want to bring that up and again kind of touch base on thinking about sperm banking and so forth before the operation, scars, those are things I think worth talking about, small risk of ascites.

Then, I think the intensity of potential long term adverse effects really ramps up when we're talking about systemic therapy, chemotherapy. And then there's of course some radiation therapy specific elements that come up. So, for the chemotherapy bits of it, I really think this is going to be something that can be a complete multi-system affected intervention. So, anxiety, depression, our group has actually shown using some population resources that even suicidality can be increased among patients that have been treated for germ cell tumor.

You know, really from the top down, tinnitus, hearing changes, those are things that we need to ask about at every appointment. Neuropathy, sexual health, that we kind of talked about, including ED (erectile dysfunction), vertigo, dizziness, Raynaud's phenomenon, these are kind of more the symptoms that I think we need to inquire about every time. And what we do here and I think at a lot of survivorship programs is use kind of a battery of validated instruments, germ cell tumor specific, platinum treated patient specific. So we use a combination of EORTC questions and PROMIS questions, which actually serves as like a review of systems for the patient, also as a research element. We review that and then depending on what might be going on, we can dig into that further, get them over to colleagues in audiology or psychology, et cetera. 

And then of course, screening for the hypertension, hyperlipidemia, metabolic syndrome with basically you or myself or somebody kind of like us serving, many times it's the role of the PCP, just making sure we're checking out, you know, CBC, CMP, et cetera, lipid parameters to screen for those kind of cardiac associated issues along with secondary malignancies.

Dr. Pedro Barata: So that's super comprehensive and thorough. Thank you so much. Actually, I love how you break it down in a simple way. Two functions of the testes, produce testosterone and then, you know, the problem related to that is the hypogonadism, and then the second, as you mentioned, produce sperm and of course related to the fertility issues with that. 

So, let's start with the first one that you mentioned. So, you do cite that in your paper, around 5-10% of men end up getting, developing hypogonadism, maybe clinical when they present with symptoms, maybe subclinical. So, I'm wondering, for our audience, what kind of recommendations we would give for addressing that or kind of thinking of that? How often are you ordering those tests? And then, when you're thinking about testosterone replacement therapy, is that something you do immediately or are there any guidelines into context that? How do you approach that?

Dr. Aditya Bagrodia: So, just a bit more on digging into it even in terms of the questions to ask, you know, "Do you have any decrease in sexual drive? Any erectile dysfunction? Are your morning erections still taking place? Has the ejaculate volume changed? Physically, muscle mass, strength? Have you been putting on weight? Have you noticed increase in body fat?" And sometimes this is complicated because there's some anxiety that comes along with a cancer diagnosis when you're 20, 30 years old, multifactorial, hair loss, hot flashes, irritability. Sometimes they'll, you know, literally they'll say, "You know, my significant other or partners noticed that I'm really just a little bit labile."

So I think, you know, there's the symptoms and then checking, usually kind of a gonadal panel, FSH, LH, free and total testosterone, sex hormone binding globulin, that's going to be typically pretty comprehensive. So if you've got symptoms plus some laboratory work, and ideally that pre-orchiectomy testosterone gives you some delta. If they started out at an 800, 900, now they're 400, that might be a big change for them.

And then, when you talk about TRT (Testosterone Replacement Therapy) recommendations, you know, Pedro, yourself, myself, we're kind of lucky to be at academic centers and we've got men's health colleagues that are ultra experts, but at a high level, I would say that a lot of the TRT options center around fertility goals. Exogenous testosterone treats the low T, but it does suppress gonadal function, including spermatogenesis.

So if that's not a priority, they can just get TRT. It should be done under the care of a urologist, a men's health, an endocrinologist, where we're checking liver chemistries and CBCs and a PSA and so forth. If they're interested in fertility preservation, then I would say engaging an endocrinologist, men's health expert is important. There's medications even like hCG, Clomid, which works centrally and stimulate the gonadal access. Niche scenarios where they might want standard TRT now, and then down the way, 5, 7 years, they're thinking about coming off of that for fertility purposes, I think that's really where you want to have an expert involved because there's quite a bit of nuance there in recovery of actual spermatogenesis and so forth. 

To kind of summarize, you got to ask about it. Checking it is, is not overly complicated. We do a baseline pre-orchiectomy and at least once annually, you can tag it in with the tumor markers, so it's not an extra blood draw. And if they have symptoms of course, kind of developed, then we'll move that up in the evaluation.

Dr. Pedro Barata: Got it. And you also touch base on the fertility angle, which is truly important. And I'm just curious, you know, a lot of times many of us might see one, two patients a year, right, and we forget these protocols and what we've got to do about that. 

And so I'm interested to hear your thoughts about when you think about fertility, and how proactive you get. In other words, who do you refer for the fertility clinic, for a fertility preservation program? You know, do all cases despite getting through orchiectomy or just the cases that you're going to, you know you're going to seek chemotherapy at some point? What kind of selection or it depends on the chemo, like how do you do that assessment about the referral for preservation program that you might have available at UCSD?

Dr. Aditya Bagrodia: Yeah, I mean I feel really fortunate to sit on the NCCN Testis Cancer Guidelines. It's in there that fertility counseling should be discussed prior to orchiectomy. So 100% bring it up. If there are risk factors, undescended testicles, previous history of fertility concerns, atrophic contralateral testicle, anything on the ultrasound like microlithiasis in the contralateral testicle, you kind of wanna get it there. And then again, there's kind of niche scenarios where you're really worried, maybe get a semen analysis and it doesn't look that good, arrange for the time of orchiectomy to have onco-testicular sperm extraction from the, quote unquote, "normal" testis parenchyma. You know, I think you have to be kind of prepared to go that route and really make sure you're doing this completely comprehensively. 

So pre-orchiectomy all patients. Don't really push for it too hard if they've got a contralateral testicle, if they've had no issues having children. There's some cost associated with this, sperm banking still isn't kind of covered even in the context of men with cancer. If they've got risk factors, absolutely pre-orchiectomy.

Pre-RPLND, even though the rates of ejaculatory dysfunction at a high-volume center should be low single digits, I'll still offer it. That'd be a real catastrophe if they were in that small proportion of patients and now they're going to be reliant on things like intrauterine insemination, where it becomes quite expensive. 

Pre-chemo, everybody. That's basically a standard these days where it should be discussed and it's kind of amazing currently, even if you don't have an accessible men's health fertility clinic, there are actually companies, I have no vested interest, Fellow is one such company where you can actually create an account, receive a FedEx semen analysis and cryopreservation kit, send it back in, and all CLIA certified, it's based out of California. The gentleman that runs it, is a urologist and very, very bright guy who's done a lot of great stuff for testis cancer. So, even for patients that are kind of in extremis at the hospital that kind of need to get going like yesterday, we still discuss it. We've got some mechanisms in place to either have them take a semen analysis over to our Men's Health clinic or send it off to Fellow, which I think is pretty cool and that even extends to some of our younger adolescent patients where going to a clinic and providing a sample might be tricky. 

So, I think bringing it up every stage, anytime there's an intervention that might be offered, orchiectomy, chemo, surgery, radiation, it's kind of incumbent on us to discuss it.

Dr. Pedro Barata: Gotcha. That's super helpful. And you also touch base on another angle, which is the psychosocial angle around this. You mentioned suicidal rates, you mentioned anxiety, perhaps depression in some cases as well as chronic fatigue, not necessarily just because of the low testosterone that you can get, but also from a psychological perspective. I'm curious, what do the recommendations look like for that? Do these patients need to see a social worker or a psychologist, or do they need to answer a screening test every time they come to see us and then based on that, we kind of escalate, take the next steps according to that? Do they see a psychologist perhaps every so often? How should that be managed and addressed?

Dr. Aditya Bagrodia: It's an excellent question and again, these can be rather insidious symptoms where if you don't really dig in and inquire, they can be glossed over. I mean, how easy to say, "Your markers look okay, your scans look okay. See you in six months," and keep it kind of brief. First off, I think bringing it up proactively and normalizing it, that, "This may be something that you experience. Many people do, you're not alone, there's nothing kind of wrong with you."

I also think that this is an area where support groups can be incredibly useful. We host the Testicular Cancer Awareness Foundation support group here. They'll talk about chemo brain or just like a little bit of an adjustment disorder after their diagnosis. Support groups, I think are critical. As I mentioned, we have a survivorship program that's led by a combination of our med oncs, myself on the uro-onc side, as well as APPs, where we are systematically asking about essentially the whole litany of issues that may arise, including psychosocial, anxiety, depression, suicidality. And we've got a nice kind of fast path into our cancer center support services for these young men to meet with a psychologist. If that isn't going to be sufficient, they can actually see a psychiatrist to discuss medications and so forth.

I do think that we've got to screen for these because, as anticipated from diagnosis, those first 2 years, we see a rise. But even 10, 15 years out, we note, compared to controls, that there is an increased level of anxiety, depression, suicidality that might not just take place at that initial acute period of diagnosis and treatment.

Dr. Pedro Barata: Really well said. Super important. 

So I guess if I were to put all these together, with these really amazing advances in technology, we all know AI, some of us might be more or less aware of biomarkers coming up, including microRNA for example, and others, like as I think of all these potential long term complications for these patients, look at the future, I guess, can we use this as a way to deescalate treatment where it's not really necessary, as a way to actually prevent some of these complications? Like, how do we see where we're heading? As we manage testicular cancer, let's say, within the next 5 or 10 years, do you think there's something coming up that's going to be different from what we're doing things today?

Dr. Aditya Bagrodia: Totally. I mean, I think it's as exciting as a time as there's ever been, you know, maybe notwithstanding circa 1970s when platinum was discovered. So microRNAs, which you mentioned, you know, there's a new candidate biomarker, microRNA-371. We are super excited here at UCSD. We actually have it CLIA-certified available in our lab and are ordering these tests for patients kind of in their acute stage, you know, stage one and surveillance, stage two, post-RPLND, receiving chemotherapy. And essentially this is a universal germ cell tumor specific biomarker, except for teratoma, suffice it to say 90% sensitive and specific. And I think it's going to change the way that we diagnose and manage patients. You know, pre-orchiectomy, that's pretty straightforward. Post-orchiectomy, maybe we can really decrease the number of CT scans that are done. Maybe we can identify those patients that basically have occult disease where we can intervene early, either with RPLND or single cycle chemo. Post-RPLND, identify the patients who are at higher risk of relapse that may benefit from some adjuvant therapy. In the advanced setting, look at marker decline for patients in addition to standard tumor markers. Can we modulate their systemic therapy? 

So, the international interest is largely on modifying things. There's really cool clinical trials that we have for stage one patients, that treatment would be prescribed based on a post-orchiectomy microRNA. I think the microRNAs are really exciting. Teratoma remains an outstanding question. I think this is where maybe ctDNA, perhaps some radiomics and advanced imaging processing and incorporating AI may allow us to safely avoid a lot of these post-chemo RPLNDs. And then identification using SNPs and so forth of who might be most susceptible to some of the cardiac toxicity, autotoxicity and personalizing things in that way as well.

Dr. Pedro Barata: Super exciting, right, what's about to come? And I agree with you, I think it's going to change dramatically how we manage this disease. 

This has been a pleasure sitting down with you. I guess before letting you go, anything else you'd like to add before we wrap it up?

Dr. Aditya Bagrodia: Yeah, first off, again, just want to thank you and ASCO for the opportunity. And it's easy enough to, I think, approach a patient with the testicular germ cell tumor as, "This is an easy case. We're just going to do whatever we've done. Go to the guidelines that says do X, Y, or Z." But there's so much more nuance to it than that. Getting it done perfectly, I think, is mandatory. Whatever we do is an impact on them for the next 50, 60, 70 years of their life. And I found the germ cell tumor community, people are really passionate about it. If you're ever uncertain, there's experts throughout the country and internationally. Ask somebody before you do something that you can't undo. I think we owe it to them to get it perfect so that we can really maximize the survivorship and the survival like we've been talking about.

Dr. Pedro Barata: Aditya, thanks for sharing your fantastic insights with us on this podcast.

Dr. Aditya Bagrodia: All right, Pedro. Fantastic. Appreciate the opportunity.

Dr. Pedro Barata: And also, thank you to our listeners for your time today. I actually encourage you to check out Dr. Bagrodia's article in the 2025 ASCO Educational Book. We'll post a link to the paper in the show notes. Remember, it's free access online, and you can actually download it as well as a PDF. You can also find on the website a wealth of other great papers from the ASCO Educational Book on key advances and novel approaches that are shaping modern oncology. 

So with that, thank you everyone. Thank you, Aditya, one more time, for joining us. Thank you, have a good day.

Disclaimer:

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. 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.

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Disclosures:     

Dr. Pedro Barata: 

Stock and Other Ownership Interests: Luminate Medical 

Honoraria: UroToday 

Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Merck, Ipson, Astellas Medivation, Novartis, Dendreon 

Speakers' Bureau: AstraZeneca, Merck, Caris Life Sciences, Bayer, Pfizer/Astellas 

Research Funding (Inst.): Exelixis, Blue Earth, AVEO, Pfizer, Merck  

Dr. Aditya Bagrodia:

Consulting or Advisory Role: Veracyte, Ferring

People who live in major cities in the US and abroad tend to benefit from better cancer care due to having access to more doctors, facilities and equipment. In contrast, those who live in rural areas face many challenges accessing consistent and quality care. 

In Part Two of this ASCO Education Podcast Dr. Jack Hensold, a hematologist/oncologist in Bozeman, Montana and Chair of the ASCO Rural Cancer Care Task Force, Dr. Chris Prakash, Medical Oncologist in Paris, Texas and Medical Director of Texas Oncology and President of the Texas Society of Clinical Oncology, and Professor Sabe Sabesan, a Medical Oncologist in Townsville, Australia and the President-Elect of the Clinical Oncology Society of Australia will examine the realities of practicing oncology in rural areas. 
They will discuss the need for rural populations to access clinical trials (1:42), using telemedicine for chemotherapy and clinical trials (3:00) and using political advocacy to improve cancer care in rural areas (13:00).

Speaker Disclosures
Sabe Sabesan: Speakers Bureau - Merck
Sucharu Prakash: Speakers Bureau - Myriad Genetics  
Jack Hensold:  Consulting or Advisory Role Company - Vibliome Therapeutics

Resources
Policy Recommendations for Improving Rural Cancer Services in the United States
                              

If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org.

TRANSCRIPT

Disclosures for this podcast are listed on the podcast page. 

Dr. Jack Hensold:  Hello and welcome to this two-part episode of the ASCO Education podcast. Today we will explore some real-time and real-world issues that oncologists face while practicing in rural areas in the US and abroad. I'm Dr. Jack Hensold, a Methodologist Oncologist in Bozeman, Montana, and chair of the ASCO Rural Cancer Care Task Force. I also serve as Medical Director of Regional Outreach at Bozeman Health. Joining me is Dr. Chris Prakash, an Oncologist and Medical Director of Texas Oncology and the President of the Texas Society of Clinical Oncology. Chris is also the Director of Quality Services for the statewide group and leads Texas Oncologist Precision Medicine Initiative. 

Also joining me is Professor Sabe Sabesan, a Medical Oncologist in Regional, Australia. He's the President-elect of the Clinical Oncology Society of Australia and the Clinical Director of the Australian Teledyne Health Program, led by the Queensland State Department of Health. Professor Sabazin is an internationally recognized expert in the area of teleoncology and has developed and evaluated various oncology models to deliver cancer care closer to home. 

In part one, our guests were explaining what got them into rural practice and the issues they face in patient transportation, telehealth, getting access to the latest information on treatments, and connecting with other colleagues to get insight on patient cases. Here, I ask Dr. Prakash about one issue that does not get talked about very often.

Dr. Chris Prakash: I think we don't talk enough about access to clinical trials for rural populations. And that's a hard problem. These are regulated. But I wonder about real-world trials. Those are a little easier to do. Maybe we can put more patients on those, the hub-and-spoke model, that would be helpful in that. And I know people are trying and many societies are trying to enroll more rural populations in trials, but it continues to be a challenge.

Dr. Jack Hensold: Correct. And actually, ASCO has a workforce right now that's trying to address this problem. That includes patient representatives, as well as, I think, people from National Cancer Institute and people from the pharmaceutical industry who've been on that task force and really is trying to address what are the barriers that keep us from getting trials out to our patients in rural areas because it is identified as a real problem. I think, as we all know, excellent cancer care requires access to clinical trials, and limited access means quality of care is going to be less. 

Dr. Sabesan, you've been working on improving chemotherapy access in rural parts of Australia. Do you think your programs like tele-chemotherapy could be implemented in other regions and even in this country, the United States, and can they be applied to clinical trials and teletrials essentially?

Dr. Sabe Sabesan: This is where I get really excited because the use of telemedicine, beyond providing consultations and then using it for chemotherapy and clinical trials, actually that's what keeps me up in the morning and keeps me awake at night as well. What I see these things as they are system solutions for a chronic problem. In tele-chemotherapy, it's simple, really. It's rural nurses. They are not chemotherapy nurses, they are general nurses. They administer selected chemotherapy regimens under the direct supervision of doctors, nurses, and pharmacies from larger centers through telemedicine, tele-nursing, and tele-pharmacy. So all we need for tele-chemotherapy to happen, if you have a larger center willing to supervise a smaller center or a larger center is now expected to do that through Health System directives, then I think we can implement that throughout the system. 

And what we have done in Queensland, we got the Queensland State Government to implement that because we got a governance document called "Queensland Remote Chemotherapy Supervision Model and Guide for Implementation." Basically, that articulates how to set up these services safely. But we already published that in the Journal of Oncology Practice in 2018, so that was a rewarding experience. But then what we found, we could do immunotherapy infusions, toxic chemotherapy like that and all those things in smaller centers, but we couldn't do clinical trials because, as Chris said, it's highly regulated. So then we said, "How come you can do toxic intensive chemotherapy but not clinical trials?" So that's how the Australasian teletrial model was born. 

So we thought we will use the teletrial model to connect larger centers with smaller centers to create trial clusters so that you can really distribute the clinical trials activity to the regional, rural, and remote areas. So now we have an Australian teletrial model and a national teletrial principle as a government policy to enable that. Through some pilots we published in the Journal of Telemedicine & Telecare, the Australian government actually funded $125 million to transform the Australian clinical trial sector as a network and a national system, so that patients from regional, remote, and rural areas can access clinical trials, some or all aspects of clinical trials closer to home. So that is exciting because it's about one year into the program and already we could see the narrative is changing, and we are saying clinical trials need to be offered as networks, not as silos anymore, because of social justice and equity. So that's been becoming powerful. 

And also, we've been now pushing the Ethics Committee to mandate that clinical trials need to be done as clusters because it is an ethical social justice issue. So I think if you have good governance and government support, I feel that we can actually implement these models in larger parts of the rural sector. Not all of them, but in larger parts. But I just wanted to highlight before I finish that the decentralized trials becoming popular and I feel like the decentralized trials are kind of hijacking the rural narrative here because they are not decentralized trials in my observation, they should be decentralized trial systems. And rather than bypassing hospitals and directly dealing with patients at home, in a lot of the trials, it seems that most of those patients are actually metropolitan patients. And I think any decentralized trial systems have to focus on partnerships with rural sectors, capability or capacity building of rural sectors so that you could really deliver clinical trials in a distributed network system to really fix this problem once and for all.

Dr. Jack Hensold: Sabe, it sounds like there's much that we can learn from paying attention to what's going on in Australia. It seems like your group is well ahead of the curve in terms of what needs to happen in rural areas. Chris, comments about that as well?

Dr. Chris Prakash: Yeah, I was going to say, I think excellent job, Sabe. Kudos to you for doing this in Australia. It's a clinical dilemma. It's an ethical dilemma. Sometimes clinical trials are fundamental to providing good quality care for our patients. But the American healthcare system is complex. Clinical trials, sad to say, I mean, that they're money makers for a lot of big institutions or pharmaceutical companies for sure. So what these companies are looking for is if they have a new drug, they want to get a trial done as quickly as possible, get positive data, and then get it approved. It's really hard to find a good phase III, randomized, placebo-controlled trial anymore. They're just nonexistent. They're all phase I, II, quick one year, get the data, and file for approval with the FDA. So I get your point. I think I would love to have a good trial where we can put patients on, rural patients on, but I don't know if that's going to be possible. 

Now, what I'm doing in Texas Oncology, I'm the director of Quality Services, so that is my goal; is to give quality care to the whole state population wherever we can. And clinical trials is the most difficult task, I'm finding. I can make testing consistent, I can make treatment protocols consistent, but getting patients on clinical trials is a very difficult task. So, kudos to you, Sabe. You're doing an excellent job.

Dr. Jack Hensold: It's actually the main enabler for us is actually the government intervention, because what we felt was the rural sector has been left in the hands of clinicians and local health managers for far too long, but no one was in charge of that gap. So now, by the governments coming to the party and trying to implement some policies and funding mechanisms, things are changing. But really still, I found the advocacy hasn't stopped and there's still a long way to go, even in Australia, but it's pure advocacy from rural oncologists like us.

Dr. Chris Prakash: Yeah, I think that kind of highlights the difference in American and Australian healthcare systems probably. I know the American healthcare system is still very private. I mean, we have a big Medicare part of the equation, but again, a lot of health care is really delivered by private companies, hospital systems that are for profit, pharmaceutical companies really have strong lobbying systems. So it's a complex situation here.

Dr. Jack Hensold: Yeah, I would agree with that fully in that, when I was hearing Sabe talk about things and comparing it to our experience in this country, we are very fragmented in terms of our care delivery systems, and trying to get a coordinated approach to how we address this rural health problem is difficult because we're bringing so many different people to the table who all have different points of view in terms of how they look at this. So, again, this may be a much harder piece to try to achieve just simply because of the fragmentation of the way we provide care in this country. 

So, Dr. Prakash, you're a member of several groups that address the needs for rural cancer care in the United States including ASCO's Rural Cancer Care Task Force, as well as the work you do with the Texas Oncology Society. Can you be a little bit more specific about those efforts? 

Dr. Chris Prakash: Thanks, Jack. As you know, I was a member of the ASCO Task Force on Rural Cancer Care. This was put together in 2019, and then the pandemic happened. The timing was just right. But we were tasked with finding and really defining what the challenges of rural cancer care are and what are the solutions that we can come up with. It was a very hard job, but we did come up with some solutions on that, mainly increasing provider education, workforce enhancement. We have talked about a few of these things already - telehealth, promotion, and of course, research. But as you know, these solutions are easier said than done, and work continues on these fronts. And thank you, Jack, for taking the lead on many of these issues in the US. 

So currently, as you know, I'm the President of the Texas Society of Clinical Oncology, and I'm doing a lot of advocacy work at the state capitol in Austin regarding various bills and provisions, but especially to garner support on a new biomarker bill. So this bill, if passed, will help pay for all biomarker testing in cancer. So there are disparities and rural disparities in cancer care. So if this bill is passed with the biomarker testing, this may go a long way in removing some of the disparities that our patients face in terms of testing biomarkers and payment for those tests as well. And I firmly believe that quality of care should be consistent no matter where a patient lives. I'm the Director of Quality Services for Texas Oncology. I'm leading the Precision Medicine initiative for the state, and I'm developing protocols for consistent biomarker testing, mutational analysis, and tumors and treatment protocols. So efforts continue, and please stay tuned.

Dr. Jack Hensold: Thank you for that and all the work you do, Chris. I think it's an important point, and I've been involved through the Montana State Oncology Society, which is our society in terms of doing advocacy at the state level as well. And I think that's very important, particularly for states that have large rural populations, because I'm not sure nationally, people fully understand some of the difficulties that those patients face. And advocating for improved health care across the board is critical. And the rural patient needs to be considered. As we think about any changes to how we invest in healthcare in this country, the laws are regulated.

Dr. Chris Prakash: You're exactly right. I mean, advocacy is very, very important. And our Congressmen and representatives, they do listen. As a physician, you go and talk to them and express concerns about what the constituents are going through and the hurdles they're facing in their care. They will listen and you can make a change. And that's what fascinates me about practicing in a rural setting, is that I can make a difference. I can see a change. Just over the last 20 years that I've been here, things have changed. Not all for the better, but you can be a part of the whole process.

Dr. Jack Hensold: Yes, I would completely concur. I think our legislators nationally and statewide are very responsive to our voices. If there's something that's impacting their constituents in terms of the care that they're receiving, they're going to want to know about that. And they're happy to look like the champions, I think, to support improving their care. It's something we all can do a better job at nationally. Sabe, not to leave you out of that conversation, any thoughts about that?

Dr. Sabe Sabesan: I mean, the advocacy is the key. That is also one of our jobs as doctors. But the main thing about advocacy is actually self-care, I found. As long as we don't burn out and we keep our energy level going and focus on recharging and minimizing energy discharge, we stay strong and take our colleagues with us. I think that's what I learned in advocacy is to make sure we don't drain our energy in that process.

Dr. Jack Hensold: The quality of care should be the same for every patient, no matter where they live. And that really is kind of one of the driving principles for me in terms of why I got into this rural cancer care task force and the initiatives that we're taking on. And I'd like to describe a project right now that I've undertaken with ASCO and with our local regional health center and a medium-sized hospital in our area. Actually not in our area, it's 125 miles away, but an area that we service, and patients regularly come to our regional center for their cancer care, I think, was the appreciation that this 250-mile round trip, particularly to receive things like chemotherapy, was just a tremendous burden for patients from that area. 

And in addition to the problems with the financial aspects of traveling long distances to receive that care, there was also the issue that we were sending patients back to fairly distant sites to experience the toxicities associated with our treatments without sufficient support in those sites locally in terms of understanding what needed to be done. That really led to this initiative with ASCO and Barrett Health in Montana, as well as Bozeman Health. And we've now been funded as part of a multi-year pilot program to increase high-quality and equitable cancer care at this site in rural Montana. And the work in this area was based on, again, the prior work on the task force that Dr. Prakash talked about in terms of identifying what barriers were in place to getting care to patients in their own community and how we could overcome these barriers. 

And really, the concept of this program is to enable patients to receive care in their own community through what's described as a hub-and-spoke care delivery model. This is an established method for extending access to cancer care in remote rural areas. In fact, I think, as Dr. Sabesan talked about, I think much of the published work in this area has actually come out of Australia. So again, kudos again to that health system in terms of taking the initiative on these things. 

And the initiative that we were talking about aims again to keep patients in their own community for as much of their cancer care as feasible, not to rely on that long drive to our regional site to get care. We understand this will require education and training of primary care physicians, advanced practice providers, pharmacists, and nurses at what we would refer to as the spoke site. And specifically, this needs to focus on education regarding how to properly administer infusion services and also how do we provide adequate supportive care for the cancer patients. 

We do appreciate that those providers at that distant site, we can never really expect them to have full knowledge to appreciate what treatment cancer patients will need at any given point in time. But that really is where the expertise of the oncologist comes in. And oversight from the hub site will be provided by oncologists both by telehealth and supplemented, by regularly scheduled onsite visits by the oncologist to ensure just a seamless integration of care at both the hub and the spoke site and also to ensure the shared culture of cancer care between those two sites. 

So that is the intent of the pilot that we're setting up. As we achieve function of that site, we will be doing quality measures to ensure that the care that's being administered at the spoke is really equivalent to what they would be receiving at the hub. So hopefully this will become a model for how we can deliver care to more remote rural areas in this country. I'd like to give Dr. Sabesan and Dr. Prakash an opportunity to make further comments regarding that model and any suggestions they may have; I'm willing to take in terms of how we can achieve this end.

Dr. Chris Prakash: Yeah. Thank you, Jack. And again, kudos to you for being so passionate about taking care of patients in rural areas with their cancer care. But I think you highlighted the most important thing: we've got to be passionate, we've got to care, we have to do everything possible, find solutions. There are many challenges in this realm. So the hub-and-spoke model, that's very helpful, but again, we may need more multi-hub models or regional hubs, so to say on that. Education, keep developing the workforce, retain the workforce that we have, provide access to research, promote telehealth as much as possible. I think these are all pieces to the puzzle. Keep doing advocacy and just work and hopefully not get burnt out. So yeah, it's a work in progress, but again, that's why I'm doing this because I'm passionate about this, and thank you so much for having me as a part of this conversation.

Dr. Jack Hensold: Well, thank you for participating. Sabe, any comments?

Dr. Sabe Sabesan: Yeah, thank you. I really enjoyed being part of this conversation and I think it looks like it's almost good to have a community of international rural practice like this so that we can share and implement within our sector. And I'm really looking forward to seeing how your pilot project evolves, Jack, and how that can become a model for the whole of the country. Good luck to you.

Dr. Jack Hensold: Thank you very much for that. And again, just a comment about the international working on this. We do have someone from Romania on our current task force. There's a group there that's very interested in providing kind of hub-and-spoke model care. So these are topics that I think are really getting on everyone's radar internationally. Again, I think the more buy-in we get internationally as well as nationally, the more wind we will have at our backs in making some improvements in this. Thank you, Dr. Prakash, for your insight into this topic and also to Professor Sabesan for his perspective from his practice in Australia.

I'm Dr. Hensold and I would like to thank all of our listeners of Cancer Topics and ASCO Education Podcast. This is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncologist well-being and professional development. If you have an idea for a topic or a guest you'd like to hear on the show, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, visit education.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. 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.

Click here to learn more about ASCO Voices speaking sessions from ASCO Annual Meeting 2019.

Monica Morrow, MD, FASCO
Surgery Is Never Elegant When Women Are in the Operating Room

An interview with Dr. Fabrice Andre from Institute Gustave Roussy, Paris Sud University, in Paris, France on "Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update: Integration of Results from TAILORx." This update provides updated recommendations on chemoendocrine therapy for patients who present with a hormone receptor positive, HER2 not overexpressed, axillary node negative early breast cancer.

TRANSCRIPT

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Hello, and welcome to the ASCO Guidelines Podcast Series. My name is Shannon McKernin, and today I'm interviewing Dr. Fabrice André from the Institute Gustave Roussy in Paris, France, lead author on "Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Early Stage Invasive Breast Cancer. ASCO Clinical Practice Guideline Update: Integration of Results from TAILORx." Thank you for being here today, Dr. André.
Thank you.
So based on the title of this guideline, we know that this update was prompted by the results of the TAILORx trial. So can you tell us more about that trial and what its results were?
Yes. So the TAILORx trial was a trial that randomized two treatment modalities, endocrine therapy versus chemotherapy endocrine therapy in patients who presented what we call an intermediate recurrence cohort. So before moving to the results, maybe we can discuss a little bit the background. What we knew from the past is the fact that patients who present a recurrence score below 11 should be treated with endocrine therapy alone, because they have the good outcomes. And patients who present recurrence score that is high, 31 but also can be more on 25, should receive chemotherapy.
And we are talking about patients with hormone-receptor receptor positive, HER2-negative early breast cancer without lymph node involvement. And this is extremely important. So to summarize, it's a clinical trial that includes patients with hormone-receptor positive HER2-negative lymph node negative in early breast cancer, who present with recurrence score between 11 and 25. And the question is whether we can avoid adjuvant chemotherapy in these patients who present this intermediate score. So this is the general design and the question.
In terms of research, what we have learned. We have learned that for patients above 50 years old, there is no difference between endocrine therapy and chemotherapy followed by endocrine therapy. So it means that this patient or these patients, we would consider endocrine therapy alone. Then, for patients below 50 years old, there was some difference. And I think we go further into the detail. There was some difference favoring the use of chemotherapy in the group of patients who presented with recurrence score from 16 to 25.
And so what changes were made to the recommendations in this update of the guideline?
So first, what were [INAUDIBLE] the previous guidelines. The previous guidelines were telling the clinician which genetic tests they could use in patients with hormone-receptor positive, HER2-negative early breast cancer. Now, the big change is that we are making guideline to explain how to use the test. And what is new is that we have made three important decisions.
So first, for the patient is at the age above 50, now it is recommended clinician may recommend endocrine therapy alone for women older than 50 who present a recurrence score below 26. Before, the recommendation to use endocrine therapy alone was for patient's who present with low recurrence score.
So it means now we have broadened-- we have increased the number of patients who could receive endocrine therapy alone and not receive chemotherapy. Then, for patients who present a recurrence score between 16 to 25 and who are below 50 years old, the clinician may offer chemotherapy followed by endocrine therapy, meaning that we are moving from [INAUDIBLE]. This intermediate score between 11 to 25 was what we call a [INAUDIBLE].
There was no recommendation on how to use the recurrence score. So right now, the update from the ASCO guideline is to provide recommendation on which treatment to administer in case a patient presents with intermediate recurrence score, and there are two different situations above 50 years old and below 50 years old.
So why are these changes so important and how will they affect practice?
So they will affect practice because for many reasons, I will say. In the US, they would affect practice because they increase the number of patients who will not receive adjuvant chemotherapy, because right now, we have an answer from randomized trial that we can avoid chemotherapy in women above 50 and from 11 to 25 recurrence score. So the impact in terms of public health would be that we could have a decrease in the use of chemotherapy or at least a better precision about who should receive adjuvant chemotherapy.
Globally, this trial is going to provide an incentive and increase the level of evidence supporting the use of genetic tests. So it's important to remember that in a large number of countries, genetic tests are not reimbursed. But now, because lack of evidence, and here we have a randomized trial showing a level 1 evidence supporting the use of genetic tests.
So we have two direct impacts of this trial. The first, inside US, where [INAUDIBLE] colleagues already use genetic tests, it provides better precision on who will receive adjuvant chemotherapy. And it's going to broaden the number of patients who will not receive. And globally, it's prospective randomized trial that we hope is going to incite payers to reimburse the genetic test in patients with early breast cancer.
And so what does this all mean for patients with early stage invasive breast cancer? And what should they talk to their doctors about?
So for patients with early breast cancer, so what are the messages for the patient? I think for the patient, the key message is that we are moving to precision medicine. We need a medicine that is extremely precise in terms of who should receive which treatments. And now, thanks to this trial, we are going to decrease the number of patients who receive chemotherapy, but also for the ones who will receive adjuvant chemotherapy, the value of the treatment, we need what the treatment provides to the patient is going to be very, very high.
So what is important for patients is to understand that because of this trial, when we give them chemotherapy, we will know that the value of this treatment and the expected benefit is going to be higher than what we used to do in the past. So it's really fast forward and more precise medicine that consists in using molecular tests in order to provide or administer treatment with very high value.
Great. Thank you Dr. André for your overview of this guideline update. This has been very informative. It's really good to hear that the expert panel has incorporated the latest research into the guideline and has carefully considered the implications for the patients. So thank you for coming on the podcast to discuss the "Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update: Integration of Results from TAILORx"
Thank you. What people don't realize is we did hard work that ASCO doing with all these guidelines, and people are very committed, and they are [INAUDIBLE]. I mean, it's very reassuring for ASCO member to know that there are highly professional people who provide guidelines and it is also reassuring for the patients, for everyone.
And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast, and refer the show to a colleague.

Dr. Timothy Price, medical oncologist in Adelaide, Australia, presents the ASCO Guideline on HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma, originally published in the Journal of Clinical Oncology in February 2017.

Dr. Steve Braunstein, radiation oncologist and assistant professor at the UCSF Medical Center at Mission Bay, presents the ASCO Guideline on Radiation Therapy for Glioblastoma, originally published in the Journal of Clinical Oncology in November 2016.

TRANSCRIPT

An interview with Dr. David Adelstein of the Cleveland Clinic on the ASCO PCO which provides statements on the role of treatment deintensification in the management of p16+ oropharyngeal cancer. Read the full PCO at www.asco.org/head-neck-cancer-guidelines

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

Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today I'm interviewing Dr. David Adelstein from the Cleveland Clinic Taussig Cancer Institute. Lead author on "Role of Treatment Deintensification in the Management of p16 Positive Oropharyngeal Cancer: ASCO Provisional Clinical Opinion." 

Thank you for being here today, Dr. Adelstein.

Thank you, Shannon. Before we get started, I'd like to first note the contributions of my panel co-chair, Drew Ridge, and those of all of the other panel members. And I'd like to extend a special thank you to ASCO for their support in allowing us to put this together and specifically Nofisat Ismaila who did a tremendous amount of work in allowing us to complete this provisional clinical opinion.

First, can you give us an overview of the clinical issue for this PCO?
Sure. So this really came out of the implications of human papillomavirus mediated oropharynx cancer. I think as most of the listeners know, over the last several decades we've recognized the fact that oropharynx cancer has a second ideology, that not all of it is caused by tobacco use, but that the human papillomavirus is now the major ideologic factor in North American and northern Europe.
The importance of this is that the human papillomavirus-induced oropharynx cancer is a different disease. It has a number of different characteristics from the kinds of head and neck cancer we've seen in the past. It's a disease that tends to occur in younger patients, patients who are otherwise generally more healthy. It is unassociated with smoking, although it can occur in smokers. But it's much more frequent in nonsmokers.

And I think most importantly, it's a disease that has a dramatically better prognosis than the tobacco related disease. Now over the last several decades, our ability to treat advanced head and neck cancer has improved significantly, because we've begun to incorporate non-operative treatments-- chemotherapy and radiation-- and have been more aggressive in our utilization of chemotherapy and radiation with significantly greater success than we had in the past. The problem with this kind of treatment is that it is quite rigorous. And there's a good deal of acute and, more importantly, late toxicity that patients experience from these kinds of approaches.
Now as we became more familiar with the importance of HPV associated oropharynx cancer, we realized that there are subgroups of these patients who have cure rates that are in excess of 90%. And the question arose whether the kinds of rigorous chemotherapy and radiation therapy treatments that we were utilizing were really necessary. Was it necessary to cause this much acute and late toxicity in patients who in vast majority of cases were going to be cured of the disease.

And it's important, because these are younger patients. And the late toxicities are going to have a major impact on their quality of life for a number of years.

What came about was the notion of treatment deintensification, the idea that perhaps it would be possible to deintensify the kinds of treatments we were giving in select patients. It's a very compelling hypothesis for medical oncologists and radiation oncologists.
But there are a number of problems as we try to test this hypothesis. The first problem is how do we identify the good risk patients? There are patients with HPV-positive disease who do not do so well-- the heavy smokers and patients with very advanced tumors. And we need to be careful if we're going to be talking about giving less treatment that we don't give less treatment to the patients who have a worse prognosis. We pick the best prognosis patients.

There have been a number of what we call risk stratification schemes that have been developed looking at trying to identify the very good prognosis patients-- those patients who are HPV positive who don't smoke and who have relatively limited disease extent. There's not universal agreement on how best to define these patients. All we know is that they do exist, that you can look at patients with these characteristics and see very good outcomes.
One of the issues that has come up is how do we utilize the American Joint Committee staging system-- AJCC the 8th edition. One of the things that AJCC 8 did which is new is that it defined a separate staging system for patients with HPV-positive oropharynx cancer, a system which is entirely different than the staging system that we've used for head and neck cancers for many years.
This was based on the recognition that the prognosis of patients with HPV-positive disease is so good so that many patients who we would previously have considered to have stage 4 disease are now classified as having stage 1 tumors, because their prognosis is so good. And that can be confusing, because the typical thought process for an oncologist is that a patient with stage 1 disease should be treated with single modality therapy.

The reason that the HPV-positive patients have such a good prognosis, however, is that many of them have been treated with combined modality therapies. And to make the assumption that because now they're classified as stage 1 is incorrect. It is they shouldn't be treated with less intensive treatments and can be confusing. AJCC 8th edition is a prognostic robust staging system, but it really doesn't help us in defining treatment.

First problem is how best to define patients who are appropriate for deintensification. Second problem is, what do you do to deintensify? What constitutes meaningful deintensification?

Well, over the last 10 or 20 years there have been some significant advances in our standard treatments for all head and neck cancers that weren't developed the idea of deintensification. We now have tremendous experience using transoral surgical techniques, which are generally minimally morbid, much less morbid than the former open techniques that previously were used, which allows consideration of surgery for many of these patients where we wouldn't have considered it before.

Similarly, intensity modulated radiation therapy has been widely adopted, and d clearly an approach using radiation, which is far less difficult, far less toxic than the former 2D or 3D radiation planning techniques that used to be used.

But if we talk about intensification, what kinds of things can we do to deintensify our treatments? Well, one thought is to reduce the radiation dose. Then the question is, how much reduction is reasonable? And how much reduction is going to actually impact on this toxicity? And are our toxicity measuring tools adequate to even detect the difference in reduction of a radiation dose? Many of our toxicity tools are very crude. Perhaps we should be using some of the patient-reported outcome quality of life instruments that are available.

Other thoughts are, perhaps one can reduce the size of the radiation therapy field. Can we reduce the dose of the chemotherapy? Can we eliminate chemotherapy? Can we even use less intensive chemotherapy? Generally, the other treatments for this disease have employed high doses of cisplatin, which is a toxic agent.

And then there the question has been asked as to whether we can reincorporate minimally morbid transoral surgical techniques in an effort to better pathologically stage patients and define more appropriate adjuvant treatment. Perhaps not all patients need adjuvant radiation or chemotherapy and radiation.

All of these approaches are interesting. They're exciting. They're being tested. But all of the experiences is preliminary.

And that really brings us to the third and the biggest problem in any deintensification approach. And that's the need to be certain that if we deintensify our therapy, we're not going to compromise outcomes. It would not be acceptable to give less treatment or less intensive treatment if our survival were compromised. And we have to be certain that we don't do this.

So what has evolved over the past decade is a whole number of treatment approaches that have some very enthusiastic early results. But these are generally single arm phase 2 reports where there is no comparison to conventional treatment. And they become difficult to interpret, because the results in general are very good.
I think what really raised a red flag for us and that really caused us to take notice was the results of the RTOG 1016 trial that we reported last year. And at the same time, the European de-escalate trial, both of which had a similar design. These were studies that were designed in an effort to see if treatment deintensification would be possible by randomly comparing the standard treatment radiation and cisplatin with what was felt to be a less intensive approach-- radiation and concurrent cetuximab. And cetuximab is an accepted agent in the United States for treating head and neck cancer.

The assumption here is that the survival would be equivalent when these two arms were compared, but that the toxicity would be improved by giving the less intensive systemic agent-- the cetuximab. The surprise when the study was analyzed was that that assumption was incorrect, that the radiation and cetuximab arm-- the deintensified arm-- actually proved inferior in terms of survival.
And this was in both trials-- both the RTOG trial and the trial from Europe. And that was a big note of caution, because it was somewhat unexpected. I think we learned from that kind of a study, from a good randomized-- a large randomized trial-- that even though the outcomes may appear to be good, we need to be very careful about deintensifying our treatment until we're sure that the survival is equivalent.

So although it's tempting for the clinician to see these very exciting reports about administering less treatment with the idea of producing less toxicity, the guideline advisory committee for ASCO really thought it was important that we get the message out that this kind of approach is not a treatment standard. This remains an investigational approach, and that the treatment standards for this disease really haven't changed.

So what are the provisional clinical opinions that were made by the expert panel?

They made several statements. The first was to acknowledge that the idea of treatment deintensification is a very compelling hypothesis, and it does require careful and appropriate testing. The second was that even though we are now better at identifying good prognosis patients, and we've seen some very promising early results, and even though we're now reclassifying patients with previously advanced stage HPV-positive disease as stage 1 or stage 2 tumors, the treatment recommendations for this disease have not changed. And they're based on the results achieved using AJCC 6 and 7.

Standard of non-operated management to patients who are eligible to receive cisplatin remains high concurrent radiation and high dose cisplatin given every three weeks. If patients undergoing a surgical resection, then adjuvant chemotherapy and radiation with radiation and high dose cisplatin every three weeks is recommended in those patients with high risk factors of positive surgical margins or external tumor extension.

And most importantly, deintensification, though it's a compelling hypothesis, is something that should only be undertaken on a clinical trial.

Why is this guidance so important? And how will it affect practice?
Well, I think the important thing about this guideline is that it shouldn't affect practice. The practice shouldn't change. The standards of care are not altered. And that for the clinician, this remains something that is exciting, something that should encourage enrollment on a clinical trial, but that we haven't changed treatment standards.

And finally, how will this guidance affect patients?

So from a patient's point of view, I think there is continued reason for optimism. A patient with the diagnosis of an HPV-positive oropharynx cancer is a patient with a very good prognosis. Patients are increasingly sophisticated. They read about the potential for treatment deintensification, and recognize that this is not something which is an accepted standard. But it should encourage their participation in clinical trials if [INAUDIBLE] is offered.

I think ultimately it's a remarkable thing when oncologists can consider the possibility of reducing treatment intensity because the treatment results have been so good.

Great. Thank you for your overview of this PCO. And thank you for your time today, Dr. Adelstein.

And thank you, Shannon. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full PCO, go to www.asco.org/head-neck-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

TRANSCRIPT

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

Hello, and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today, I'm interviewing Dr. Nancy Baxter from St. Michael's Hospital in Toronto, senior author on "Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline." Thank you for being here today, Dr. Baxter.

Thanks very much, Shannon, for speaking with me. I'm happy to share our work developing this guideline.

So first, can you give us a general overview of what this guideline covers and the studies which provide the evidence?

Absolutely. So use of adjuvant therapy for patients with stage III colon cancer is common, and it's effective. We know that these patients are at substantial risk of recurrence of their disease and that adjuvant therapy can reduce that risk.
But we also know that comes with a cost. The most effective adjuvant therapy is FOLFOX or oxaliplatin-containing chemotherapy regimens. And we know that a really substantial number of people will end up with neurotoxicity, with peripheral sensory neurotoxicity, that can be long lasting and certainly affects their quality of life.
So the whole question was whether the duration of oxaliplatin-containing chemotherapeutic regimens could be shortened when they're used for adjuvant therapy, so if we could give three months instead of six months. Because we know that if we give three months of therapy, the risk of neurotoxicity is much lower. So if we had the same effectiveness with the shorter duration, then we could spare patients the negative consequences of the agent given for a longer period of time.
So in developing these guidelines, we looked at the results of international group of trials, the six trials from the IDEA collaboration. So these were six randomized trials in various jurisdictions that tried to look at this question, so three months of an oxaliplatin-based chemotherapeutic regimen for adjuvant therapy for stage III cancer versus six months duration of therapy. And so there was a planned analysis to bring all of these data together to develop the evidence base to make this recommendation.
So our guideline and our systematic review basically identified this is the key piece of literature to base our recommendations and guidelines on. That's essentially the main study, so the meta-analysis of these six randomized controlled trials that formed the basis of the IDEA collaboration.
So the IDEA collaboration studies-- there were six individual randomized trials that formed part of the IDEA collaboration. And they were conducted in Italy, Greece, Japan, North America, through CALGB/SWOG, the UK, Denmark, Spain, Australia, Sweden, and New Zealand, as well as France. So data came from, really, around the world.
The median age of people in the studies was 64 years of age. And these people had a really good performance status, so almost all of these patients had an ECOG performance status of 0 or 1. So they were healthy patients that were in the study.
And so some patients received CAPOX, and some received FOLFOX. That wasn't part of the randomization scheme. Other than the CALGB/SWOG study, this was up to the discretion of the investigator or patient. In the SWOG/CALGB study, only FOLFOX was given.
And the authors planned a prespecified subgroup analysis to look at differences between CAPOX and FOLFOX. There was also a prespecified analysis to look at differences based on stage.
What they found when they looked at the results was that, overall, the difference between groups in terms of the three months versus six months was that the hazard ratio between these two was 1.07, meaning a small difference between the groups in terms of recurrence or death between three months and six months overall. But because the prespecified confidence interval, noninferiority interval, for the difference in outcome was 1.12, the 95% confidence interval for the hazard ratio was above this. So it was 1.15, indicating that this prespecified noninferiority margin was exceeded.
And so the study did not prove noninferiority of the three-month regimen. So we're left with an inconclusive result. So that's why our guidelines don't have a strong recommendation for the three months, because we can't rule out a small but potentially important difference between the two groups in terms of recurrence or death.
Now, interestingly, when they looked at the prespecified subgroup analysis, which was looking at CAPOX versus FOLFOX, a difference was found. So they actually found that for FOLFOX chemotherapy, three months of therapy was inferior to six months of therapy, while for CAPOX, actually, three months and six months were the same. So it met the criteria of noninferiority. So these are kind of two different conclusions based on which type of chemotherapy was used.
This was surprising to the investigators and was not expected. And certainly, it was not consistent with the randomized trials that we have comparing these regimens. So we therefore did not make any conclusions in our recommendations about CAPOX versus FOLFOX. But this is certainly something that requires further investigation in the future.
In terms of stage, we did not find that there was an interaction between T stage or end stage when you looked at the differences between the three and the six month. And that was the prespecified analysis. But in non-prespecified analysis, which was the higher risk versus lower risk categories, you did find this difference where the patients with high-risk disease had inferior disease-free survival with three months versus six months of therapy, while those at low risk of disease, it seemed quite safe to give three months versus six months.
So that's a long story. But essentially, because the high risk versus low risk analysis was not prespecified, there's a limitation to how strong our recommendations can be to have three months of therapy. However, given that the hazard ratio associated with three months versus six months of therapy for this lower risk group was only 1.01, indicating they were the same, and the risk of neuropathy was substantially higher with six months, this has led to us making recommendations that the three months of therapy is adequate for patients with low-risk disease after discussion with patients about the possible pros and cons.

And what are the key recommendations of this guideline?

Well, so the recommendations of this guideline do depend on the pathology, so how high risk the patient is. So based on the evidence from the IDEA collaboration, the researchers found that patients who had a high risk of recurrence-- so had T4 disease or heavily node-positive disease, N2 disease-- the six-month duration of therapy was better than the three-month duration of therapy.
These studies and the meta-analysis were designed as noninferiority meta-analyses. But it was clear from the results that the three-month duration was inferior when compared to three months for these high-risk patients. So that seems clear, although we know that those patients will also be at more risk of neuropathy. And so that needs to be discussed with patients, as well.
So for the second group, which are patients who are at lower risk of recurrence, what we found was there was less of a clear benefit of six months of therapy. The recommendation was that patients who are in this low-risk category-- so T1, T2, or T3 cancers that are N1, so not heavily node-positive-- clinicians can offer three months versus six months of therapy after having a discussion with their patients about the pros and cons of that. So the clinicians can go ahead and offer that to patients and still be within the common guidelines based on evidence for treatment of stage III colon cancer.
So because there's some uncertainty after analysis of the IDEA collaboration, one of the really important recommendations that we make is about this shared decision-making approach. So the third recommendation that we make is that oncologists should discuss these factors with their patients who have stage III resected colon cancer and that the duration of therapy needs to take into account the tumor characteristics-- the surgical resection, the number of lymph nodes examined, the comorbidities, the patient functional status, all of these various things-- and there needs to be a discussion of the potential for benefit and the risk of harm based on the duration of therapy.
And oncologists definitely discuss these things with their patients. And this just emphasizes how this is yet another component of the discussion that needs to be included, particularly when speaking with low-risk patients who are at substantial risk of harm from neuropathy and are unlikely to benefit greatly by extending chemotherapy to six months.

So why is this guideline so important? And how will it change practice?

Well, I think, until now, the standard recommendation has been six months of FOLFOX or six months of oxaliplatin-based chemotherapy. And again, there are many patients who have quality of life-affecting neuropathy because of this. So for a substantial proportion of patients who present to us with stage III cancer-- so those that are low risk-- I think this provides some options to them.
So they can opt for a shorter duration of chemotherapy with a lower risk of toxicity. This saves time. This saves cost to the patient and to the system and potentially improves their quality of life without a great impact on outcome in terms of disease recurrence.
So that's a substantial number, a substantial proportion of our patients, who can be treated in this way. So I think that this is a real benefit. Again, oncologists need to have a conversation with their patients about the pros and cons. But this is an option for their patients, whereas from an evidence-based perspective, it wasn't before the publication of the IDEA collaboration.

Finally, how will these guideline recommendations affect patients?

So for patients who have heavily node-positive disease-- so high-risk patients with T4 or N2 disease-- it's not going to affect care. So the expectation would be those patients would be treated with six months of therapy, similar to previous recommendations.
So this will be for people who are at lower risk of disease recurrence, so patients with T1 to 3 tumors that are N1 positive, so not heavily node positive. So these patients will have the opportunity to opt for a shorter duration of therapy. So that's a major benefit to patients.
Again, it's important that there's a discussion and that patients understand the pros and cons. But this is now an option for them, which is excellent.

Thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, please go to www.asco.org/gastrointestinal-cancer-guidelines.
And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

TRANSCRIPT

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

Hello and welcome to the ASCO Guidelines Podcast Series. My name is Shannon McKernin, and today I'm interviewing Dr. Alejandro Lazo-Langner from Western University in London, Ontario, senior author on Management of Cancer-Associated Anemia with Erythropoeiesis-stimulating Agents, ASCO/ASH Clinical Practice Guidelines Update. Thank you for being here today, Dr. Lazo-Langner.

Thank you very much for the invitation to present the new guidelines.

So this guideline has been updated now three times since its original publication in 2002. So how has this guideline changed over time?

Since initial publication in 2002, this guideline has undergone a number of different changes. If you look at the initial series of recommendations in the 2002 guideline, it was really limited and it was fairly upfront recommending the use of erythropoiesis-stimulating agents in this setting.
But during the last two updates in 2007 and 2010, that has changed significantly. And in the current guidelines, we have added some additional evidence that has been published in the last eight years. And now, in general, what we can tell is that the use of erythropoiesis-stimulating agents is now more restrictive than in the original guideline and is basically recommended for only one or two situations.
There has been some other updates in the last iteration of the guideline that I can certainly discuss in more detail later. But basically, in general, the guideline has now, in the last iterations, restricted the recommendations that were much more general during the first edition of this guideline, almost all of them based on available and emerging evidence regarding the onset of their side effects with these medications.
And can you give us a general overview of what this new guideline update covers, especially that new evidence that's emerged?
Yeah. So the new guideline has changed a few items. And indeed, we-- the committee did a little bit of an overhaul in the recommendations that are not in the same order as they were in the previous editions. We can say that there is a couple of important updates.
The first one would be addressing the use of biosimilars, which were not available in the previous guidelines. And we have addressed that in the current edition. The biosimilars have not been extensively studied in cancer, but they have. And so far, the committee considered that they were equivalent in terms of effectiveness and safety to the originator agents, both epoetin and erythropoietin.
And the second most important update on the guideline is the recommendation of the concurrent use of iron supplementation in patients who are receiving erythropoietin-stimulating agents. The previous versions of the guideline just recommended the use of iron supplementation in patients with documented iron deficiency. However, in the last eight years, there's been a number of studies that have suggested that the concurrent use of iron supplementation, irrespective of the baseline iron status, does increase the efficacy of the agents.
Third point is that, although this is not new, there's been more emerging evidence supporting the notion that all of the erythropoietin-stimluating agents increase the risk of thromboembolism. And this has been very consistent across all studies, and in particular derive from Julia Bohlius's systematic review and meta-analysis that was published a few years ago. And she's the lead author on these guidelines now. This has been confirmed, and I think that at this point this is probably the main limiting factor on the use of these medications.
And the final minor update was that regarding the use of erythropoietin in patients with myelodysplastic syndrome. This guideline now suggests baseline serum erythropoietin level cut-off that might actually increase the chances of the erythropoietin-stimluating agents of being effective. This has been updated from the previous guidelines based on recent research.

And what are the key takeaways of this guideline update?

Well, the key takeaways is that if a clinician is deciding to use erythropoietin-stimluating agents, in agreement with the previous guidelines, the first thing that you have to consider is that you should not use these agents in patients that are receiving chemotherapy with a curative intent.
And it should be reserved to patients in whom the chemotherapy is being given with a palliative intent. It should be only used to decrease the use of red blood cell transfusions. And if a clinician is to make a decision as to whether to use these agents or not, they should consider concurrent use of iron supplementation.
But basically, the other consideration that needs to be made is that because of the confirmed increase in the risk of thromboembolic complications, in the last eight years, there's been a myriad of new treatments that may potential increase the risk of these complications, specifically and most importantly in patients with myeloma in whom the use of immunomodulators such as lenalidomide or thalidomide does increase the risk of thromboembolic events per se.
And in those patients, if they were to be considered for treatment with erythropoietin-stimluating agents, that should be done in a very, very careful fashion. The risk of thrombosis is significantly high in these patients, and the concurrent use of erythropoietin-stimluating agents is probably not a very good idea.
So if one were to summarize the guidelines, I would say that, one, consider very carefully whether your patient actually needs these agents, and if they do need the agents, whether they should be receiving them, specifically if they are only being given chemotherapy with palliative intent with a short time life expectancy. Some patients would be considered to be in palliative.
However, in conditions such as myeloma, for instance, although they are not curable, the patients may go on living for many years. So that's probably not a very good idea to use these agents if they increase the risk of complications. And if one is going to be considering these, they should consider also the concurrent use of iron to improve the efficacy of these agents.

And finally, how will these guideline recommendations affect patients?

Well, the guideline recommendations won't have a particularly high impact on patients. The most important thing is that, if patients require ongoing transfusional support due to the palliative chemotherapy or the nature of the disease they have, the use of erythropoietin-stimluating agents might decrease the need for these transfusions at the cost of increasing the risk of complications.
The new updated guidelines are probably going to result in-- if they are considered when a clinician is using these agents, they are probably going to result in lower complications for patients due to the more restrictive nature of the recommendations.
And in general, the only other consideration would be that under special circumstances related to, for instance, access to transfusional support or other personal considerations from certain patients and groups, these guidelines might actually help to overcome those barriers for transfusional support. But those were the two major impact points that would be considered based on this updated guideline.

Great. Thank you for your work on this important guideline and thank you for your time today, Dr. Lazo-Langner.

Thank you for the invitation.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague. 

Dr. James Harding (Memorial Sloan Kettering) is a board-certified medical oncologist specializes in caring for people with liver cancer, gallbladder cancer, and bile duct cancer, as well as other gastrointestinal cancers. In this week's episode, he discusses a new checkpoint inhibitor with monoclonal antibodies to programmed death receptor 1 (PD-1) for patients with Hepatocellular Carcinoma (HCC). He presents a clinical case and to highlight several aspects of immunotherapy for liver cancer.

There was time during the early 70's when the field of oncology began to take hold where the singular focus was to extend the patient's life. In this ASCO Education podcast, our guest was one of the first to challenge that notion and rethink methods that focused the patient's QUALITY of life. Dr. Patricia Ganz joins us to describe her transition from cardiology to oncology (6:00), the moment she went beyond treating the disease and began thinking about treating the WHOLE patient (10:06) and the joy of the increasing numbers of patients who survive cancer (21:47). 

Speaker Disclosures
Dr. David Johnson: Consulting or Advisory Role – Merck, Pfizer, Aileron Therapeutics, Boston University
Dr. Patrick Loehrer: Research Funding – Novartis, Lilly Foundation, Taiho Pharmaceutical
Dr. Patricia Ganz: Leadership - Intrinsic LifeSciences 
Stock and Other Ownership Interests - xenon pharma,  Intrinsic LifeSciences, Silarus Therapeutics, Disc Medicine, Teva,  Novartis, Merck. Johnson & Johnson, Pfizer, GlaxoSmithKline, Abbott Laboratories
Consulting or Advisory Role - Global Blood Therapeutics, GSK, Ionis, akebia, Rockwell Medical Technologies, Disc Medicine, InformedDNA, Blue Note Therapeutics, Grail
Patents, Royalties, Other Intellectual Property - related to iron metabolism and the anemia of chronic disease, Up-to-Date royalties for section editor on survivorship

Resources 
If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org.

TRANSCRIPT 

Disclosures for this podcast are listed on the podcast page.  

Pat Loehrer: Welcome to Oncology, Etc., an ASCO Education Podcast. I'm Pat Loehrer, Director of Global Oncology and Health Equity at Indiana University. 

Dave Johnson: And I'm Dave Johnson, a Medical Oncologist at the University of Texas Southwestern in Dallas. If you're a regular listener to our podcast, welcome back. If you're new to Oncology, Etc., the purpose of the podcast is to introduce listeners to interesting and inspirational people and topics in and outside the world of oncology.

Pat Loehrer: The field of oncology is relatively new. The first person treated with chemotherapy was in the 1940s. Medical oncology was just recognized as a specialty during the 1970s. And while cancer was considered by most people to be a death sentence, a steady growth of researchers sought to find cures. And they did for many cancers. But sometimes these treatments came at a cost. Our next guest challenged the notion that the singular focus of oncology is to extend the patient's duration of life. She asked whether an oncologist should also focus on addressing the patient's quality of life. 

Dave Johnson: The doctor asking that question went to UCLA Medical School, initially planning to study cardiology. However, a chance encounter with a young, dynamic oncologist who had started a clinical cancer ward sparked her interest in the nascent field of oncology. She witnessed advances in cancer treatment that seemingly took it from that inevitable death sentence to a potentially curable disease. She also recognized early on that when it came to cancer, a doctor must take care of the whole patient and not just the disease. 

From that point forward, our guest has had a storied career and an incredible impact on the world of cancer care. When initially offered a position at the West LA VA Medical Center, she saw it as an opportunity to advance the field of palliative care for patients with cancer. This proved to be one of her first opportunities to develop a program that incorporated a focus on quality of life into the management of cancer. Her work also focused on mental, dietary, physical, and emotional services to the long-term survivors of cancer. 

That career path has led to many accomplishments and numerous accolades for our guest. She is a founding member of the National Coalition for Cancer Survivorship, served as the 2004 Co-chair of ASCO's Survivorship Task Force, and currently directs UCLA's Cancer Survivorship Center of Excellence, funded in part from a grant from Livestrong. Our guest is Dr. Patricia Ganz.

Dr. Patricia Ganz: It's great to be with both of you today.

Dave Johnson: We always like to ask our guests a little about their background, where they grew up, a little about their family.

Dr. Patricia Ganz: Yes. I grew up in the city of Beverly Hills where my parents moved when I was about five years old because of the educational system. Unlike parts of the East Coast, we didn't have very many private schools in Los Angeles, and so public education was very good in California at that time. So I had a good launch and had a wonderful opportunity that many people didn't have at that time to grow up in a comfortable setting.

Dave Johnson: Tell us about your mom. I understand she was a businesswoman, correct?

Dr. Patricia Ganz: Yes, actually, my parents got married when my mom was 19 and my dad was 21. He was in medical school at the University of Michigan. His father and mother weren't too happy with him getting married before he could support a wife. But she worked in a family business in the wholesale produce business in Detroit. One of six children, she was very involved with her family in the business. And they were married, and then World War II started, my father was a physician in the military, so she worked in the family business during the war. After finally having children and growing up and being in Beverly Hills, she sat back and was a homemaker, but she was always a bit restless and was always looking for something to do. So wound up several years later, when I was in my early teens, starting a business with one of my uncles, an automobile parts business. They ultimately sold it out to a big company that bought it out. 

Pat Loehrer: Where did your father serve in World War II?

Dr. Patricia Ganz: He was actually D-Day Plus 21. He was in Wales during the war. They had to be stationed and moved down into the south before he was deployed. I have my parents' correspondence and letters from the war. He liberated some of the camps. Actually, as I have learned about the trauma of cancer and post-traumatic stress that happens in so many people, our military veterans, most recently, I think he had post-traumatic stress. He didn't talk very much about it, but I think liberating the camps, being overseas during that time, as it was for that silent generation, was very profound in terms of their activities.  

He wound up practicing medicine, and Los Angeles had a practice in industrial medicine, and it was a comfortable life. He would work early in the morning till maybe three or four in the afternoon and then go to the gym, there were moonlighting physicians who worked in the practice. But I kind of saw an easy kind of medicine, and he was always very encouraging and wanted me to go into medicine -- that I could be an ophthalmologist or a radiologist, good job for a woman. But I didn't really see the tough life of some of the internists and other people who were really working more 24/7, taking care of patients in the way medicine used to be practiced.

Dave Johnson: Yeah. So you were interested in, early in your career, in cardiology. Could you tell us about that, and then a little bit more about the transition to oncology? 

Dr. Patricia Ganz: I went away to college, I went to Harvard Radcliffe and I came home during the summers. And was interested in doing something during the summer so I actually in a pediatric cardiology research laboratory as a volunteer at UCLA for a couple of summers between my freshman and sophomore year then my sophomore and junior year. And then I actually got a California Heart Association Fellowship between my junior and senior year in college. 

And this pediatric cardiology lab was very interesting. They were starting to give ketamine, it had an identification number, it wasn't called ketamine. But they were giving it to children in the cardiac cath lab and then were very worried about whether it would interfere with measuring the pressures in the heart. So we had intact dogs that had catheters implanted in the heart, and the drug would be given to the animals and we would then measure their pressures in the heart. 

That cardiology experience in 1970, the summer between my first and second year of medical school, the Swan-Ganz catheter was being tested. I worked at Cedars that summer and was watching them do the various studies to show the value of the catheter. And so by the time I was kind of finishing up medical school, I'd already invested all this time as an undergraduate. And then a little bit when I was in medical school and I kind of understood the physiology of the heart, very exciting. So that's kind of where I was headed until we started my internship. And I don't know if any of you remembered Marty Cline, but he was the oncologist who moved from UCSF to Los Angeles to start our hem-onc division. And very exciting, a wonderful bedside teacher.  

And so all of a sudden, I've never been exposed to oncology and this was very interesting. But at the same time, I was rotating through the CCU, and in came two full-arrest patients, one of whom was a campus cop who was very obese, had arrested at his desk in the police station. And we didn't have emergency vehicles to help people get on campus at that time. This was 1973 or 1974, something like that. And he came in full arrest, vegetable. And then another man had been going out of his apartment to walk his dog and go downstairs, and then all of a sudden his wife saw him out on the street being resuscitated by people. And he came in also in full arrest.  

So those two experiences, having to deal with those patients, not being able to kind of comfort the families, to do anything about it. As well as taking care of patients in my old clinic who had very bad vascular disease. One man, extremely depressed with claudication and angina, all of a sudden made me feel, "Well, you know what? I'm not sure I really want to be a cardiologist. I'm not sure I like the acute arrest that I had to deal with and the families. And also, the fact that people were depressed and you couldn't really talk to them about how serious their disease was." Whereas I had patients with advanced cancer who came in, who had equally difficult prognoses, but because of the way people understood cancer, you could really talk about the problems that they would be facing and the end-of-life concerns that they would have. 

So it was all of those things together that made me say, "Hmm." And then also, Pat, you'll appreciate this, being from Indiana, we were giving phase II platinum to advanced testicular cancer patients, and it was miraculous. And so I thought, "Oh my gosh, in my lifetime, maybe cancer is going to be cured! Heart disease, well, that's not going to happen." So that was really the turning point.  

Pat Loehrer: When many of us started, we were just hoping that we could get patients to live a little bit longer and improve the response rate. But you took a different tack. You really looked at treating the whole patient, not just the disease. That was really a novel approach at the time. What influenced you to take that step forward?

Dr. Patricia Ganz: Well, it was actually my starting– it was thought to be in a hospice ward. It would turn out it was a Sepulveda VA, not the West LA VA, but in any case, we have two VAs that are affiliated with UCLA. And it was an intermediate care ward, and there was an idea that we would in fact put our cancer patients there who had to have inpatient chemotherapy so they wouldn't be in the acute setting as well as patients who needed to travel for radiation. Actually, the West LA VA had a hospice demonstration project. This is 1978. It's really the beginning of the hospice movement in England, then in Canada, Balfour Mount at Montreal and McGill was doing this. And so I was very much influenced by, number one, most of our patients didn't live very long. And if you were at a VA Hospital, as I was at that time, you were treating patients with advanced lung cancer, advanced colon cancer, advanced prostate cancer, other GI malignancies, and lung cancer, of course. So it was really the rare patient who you would treat for curative intent. 

In fact, small cell lung cancer was so exciting to be treating in a particularly limited small cell. Again, I had a lot of people who survived. We gave them chemo, radiation, whole brain radiation, etc. So that was exciting. This was before cisplatin and others were used in the treatment of lung cancer. But really, as I began to develop this ward, which I kind of thought, "Well, why should we wait just to give all the goodies to somebody in the last few weeks of life here? I'm treating some patients for cure, they're getting radiation. Some of them are getting radiation and chemo for palliation." But it was a mixed cancer ward. And it was wonderful because I had a team that would make rounds with me every week: a pharmacist, a physiatrist, a psychologist, a social worker, a dietitian. This was in 1978 or '79, and the nurses were wonderful. They were really available to the patients. It wasn't a busy acute ward. If they were in pain, they would get their medication as soon as possible. I gave methadone. It was before the days of some of the newer medications, but it was long-acting. I learned how to give that. We gave Dilaudid in between if necessary. And then we had Brompton solution, that was before there was really oral morphine. 

And so the idea was all of these kinds of services should really be available to patients from the time of diagnosis until death. We never knew who was going to be leaving us the next few days or who was going to be living longer and receiving curative intent. We had support groups for the patients and their families. It was a wonderful infrastructure, something that I didn't actually have at UCLA, so it was a real luxury. And if you know the VA system, the rehabilitation services are wonderful. They had dental services for patients. We had mostly World War II veterans, some Korean, and for many of these individuals, they had worked and lived a good life, and then they were going to retire and then they got cancer. So this was kind of the sadness. And it was a suburban VA, so we had a lot of patients who were in the San Fernando Valley, had a lot of family support, and it was a wonderful opportunity for me to learn how to do good quality care for patients along the continuum. 

Dave Johnson: How did you assemble this team? Or was it in place in part when you arrived, or what? Nobody was thinking about this multidisciplinary approach? 

Dr. Patricia Ganz: I just designed it because these were kind of the elements that were in a hospice kind of program. And I actually worked with the visiting nurses and I was part of their boards and so forth. And UCLA didn't have any kind of hospice or palliative care program at that time. But because the VA infrastructure had these staff already, I didn't have to hire them, you didn't have to bill for anything. They just became part of the team. Plus there was a psychiatrist who I ultimately began doing research with. He hired a psychologist for the research project. And so there was kind of this infrastructure of interest in providing good supportive care to cancer patients. A wonderful social worker, a wonderful psychologist, and they all saw this patient population as very needy, deserving, and they were glad to be part of a team. 

We didn't call it a hospice, we called it a palliative care unit. These were just regular staff members who, as part of their job, their mission was to serve that patient population and be available. I had never been exposed to a physiatrist before. I trained at UCLA, trained and did my residency and fellowship. We didn't have physiatry. For whatever reason, our former deans never thought it was an important physical medicine, it wasn't, and still isn't, part of our system.

Pat Loehrer: Many decisions we make in terms of our careers are based on singular people. Your dad, maybe, suggesting going into medicine, but was there a patient that clicked with you that said, "Listen, I want to take this different direction?" Or was it just a collection of patients that you were seeing at the VA? Is there one that you can reflect back on?

Dr. Patricia Ganz: I don't know if you all remember, but there was something called Consultation Liaison Psychiatry where, in that time, the psychiatrist really felt that they had to see medical patients because there were psychological and sometimes psychiatric problems that occurred on the medical ward, such as delirium. That was very common with patients who were very sick and very toxic, which was again due to the medical condition affecting the brain. And so I was exposed to these psychiatrists who were very behaviorally oriented when I was a resident and a fellow, and they often attended our team meetings in oncology on our service, they were on the transplant service, all those kinds of things. So they were kind of like right by our side. 

And when I went to the VA, the psychiatry service there also had a couple of really excellent psychiatrists who, again, were more behaviorally focused. Again, you have to really remember, bless her heart, Jimmie Holland was wonderful as a psychiatrist. She and Barrie Cassileth were the kind of early people we would see at our meetings who were kind of on the leading edge of psychosocial oncology, but particularly, Jimmie was more in a psychiatric mode, and there was a lot of focus on coping. But the people that I began to work with were more behaviorally focused, and they were kind of interested in the impact of the disease and the treatment on the patient's life and, backwards, how could managing those kinds of problems affect the well-being of the patient.

And this one psychiatrist, Richard Heinrich, had gotten money from the VA, had written a grant to do an intervention study with the oncology patients who I was serving to do a group intervention for the patients and their families. But, in order to even get this grant going, he hired a project manager who was a psychologist, a fresh graduate whose name was Anne Coscarelli, and her name was Cindie Schag at that time. But she said, "I don't know much about cancer. I've got to interview patients. I've got to understand what's going on." And they really, really showed me that, by talking to the patient, by understanding what they were experiencing, they could get a better handle on what they were dealing with and then, potentially, do interventions. So we have a wonderful paper if you want to look it up. It's called the "Karnofsky Performance Status Revisited." It's in the second issue of JCO, which we published; I think it was 1984. 

Dave Johnson: In the early 90s, you relocated back to UCLA. Why would you leave what sounds like the perfect situation to go back to a site that didn't have it?

Dr. Patricia Ganz: Okay, over that 13 years that I was at the VA, I became Chief of the Division of Hem-Onc. We were actually combined with a county hospital. It was a wonderful training program, it was a wonderful patient population at both places. And we think that there are troubles in financing health care now, well, there were lots of problems then. Medicaid came and went. We had Reagan as our governor, then he became president, and there were a lot of problems with people being cared for. So it was great to be at the VA in the county, and I always felt privileged. I always had a practice at UCLA, which was a half-day practice, so I continued there, and I just felt great that I could practice the same wherever I was, whether it was in a public system, veteran system, or in the private system.  

But what happened was, I took a sabbatical in Switzerland, '88 to '89. I worked with the Swiss International Breast Cancer Consortium group there, but it was really a time for me to take off and really learn about quality of life assessment, measurement, and so forth. When I came back, I basically said, "I want to make a difference. I want to do something at a bigger arena." If I just continue working where I am, it's kind of a midlife crisis. I was in my early 40s, and my office was in the San Fernando Valley at the VA, but my home was in West Los Angeles. One day I was in UCLA, one day I was at the VA, one day I was at the county, it was like, "Can I practice like this the next 20 years? I don't know that I can do this. And I really want to have some bigger impact."

So I went to Ellen Gritz who was my predecessor in my current position, and I was doing my NCI-funded research at UCLA still, and I said, "Ellen, I really would like to be able to do research full time. I really want to make a difference. Is there anything available? Do you know of anything?" And she said, "Well, you know, we're actually recruiting for a position that's joint between the School of Public Health and the Cancer Center. And oh my goodness, maybe I can compete for that, so that's what I did. And it was in what was then the department called Health Services, it's now called Health Policy and Management. I applied, I was competing against another person who I won't name, but I got the position and made that move. 

But again, it was quite a transition because I had never done anything in public health, even though UCLA had a school of public health that was right adjacent to the medical school. I had had interactions with the former dean, Lester Breslow, who I actually took an elective with when I was a first-year medical student on Community Medicine. So it kind of had some inklings that, of what I was interested in. I had actually attendings in my medical clinic, Bob Brook, a very famous health policy researcher, Sheldon Greenfield. So I'd been exposed to a lot of these people and I kind of had the instinctive fundamentals, if you will, of that kind of research, but hadn't really been trained in it. And so it was a great opportunity for me to take that job and really learn a lot and teach with that. 

And then took, part of my time was in the cancer center with funding from the core grant. And then, within a year of my taking this position, Ellen left and went to MD Anderson, so all of a sudden I became director of that whole population science research group. And it was in the early '90s, had to scramble to get funding, extramural funding. Everybody said to me, "How could you leave a nearly full-time position at the VA for a soft money position?" But, nevertheless, it worked out. And it was an exciting time to be able to go into a new career and really do things that were not only going to be in front and center beneficial to patients, but to a much larger group of patients and people around the world. 

Pat Loehrer: Of all the work that you have done, what one or two things are you most proud of in terms of this field?

Dr. Patricia Ganz: Recognizing the large number of people who are surviving cancer. And I think today we even have a more exciting part of that. I mean, clearly, many people are living long-term disease-free with and without sequelae of the disease. But we also have this new group of survivors who are living on chronic therapy. And I think the CML patients are kind of the poster children for this, being on imatinib or other newer, targeted agents over time, living with cancer under control, but not necessarily completely gone. And then melanoma with the immunotherapy, lung cancer, all of these diseases now being converted to ones that were really fatal, that are now enjoying long-term treatment.  

But along with that, we all know, is the financial toxicity, the burdens, and even the ongoing symptoms that patients have. So the fact that we all call people survivors and think about people from the time of diagnosis as potentially being survivors, I think was very important. And I would say that, from the clinical side, that's been very important to me. But all of the work that I was able to do with the Institute of Medicine, now the National Academy of Medicine, the 2013 report that we wrote on was a revisit of Joe Simone's quality of care report, and to me was actually a very pivotal report. Because in 2013, it looked like our health care system was in crisis and the delivery of care. We're now actually doing a National Cancer Policy Forum ten-year follow-up of that report, and many of the things that we recommended, surprisingly, have been implemented and are working on. But the healthcare context now is so much more complicated. 

Again, with the many diseases now becoming rare diseases, the cost of drugs, the huge disparities, even though we have access through the Affordable Care Act and so forth, there's still huge disparities in who gets care and treatment. And so we have so many challenges. So for me, being able to engage in the policy arena and have some impact, I think has been also very important to me.

Dave Johnson: 20 years ago, the topic of survivorship was not that common within ASCO, and you led a 2004 task force to really strengthen that involvement by that organization, and you also were a founding member of the National Coalition for Cancer Survivorship. I wonder if you might reflect on those two activities for us for a moment.

Dr. Patricia Ganz: In 1986, Fitzhugh Mullen, who in 1985 had written a really interesting special article for the New England Journal called "Seasons of Survivorship" - he was a young physician when he was found to have a mediastinal germ cell tumor and got very intensive chemotherapy and radiation therapy and survived that, but realized that there was no place in the healthcare system where he could turn to to get his questions answered, nor get the kind of medical care that was needed, and really wrote this very important article. He then, being somebody who was also kind of policy-oriented and wanting to change the world, and I would say this was a group of us who, I think went to college during the Vietnam era - so did Fitz - and we were all kind of restless, trying to see how we could make a difference in the world and where it was going.  

And so he had this vision that he was going to almost develop an army of survivors around the country who were going to stand up and have their voices heard about what was going on. Of course, most people didn't even know they were a survivor. They had cancer treatment, but they didn't think about themselves as a survivor. And so he decided to get some people together in Albuquerque, New Mexico, through a support group that he had worked with when he was in the Indian Health Service in New Mexico. And there were various people from the American Cancer Society, from other support organizations, social workers, and a couple of us who are physicians who came to this meeting, some Hodgkin survivors who had been treated at Stanford and were now, including a lawyer, who were starting to do long term late effects work. And we gathered together, and it was a day and a half, really, just kind of trying to figure out how could a movement or anything get oriented to try and help patients move forward. 

So that's how this was founded. And they passed the hat. I put in a check for $100, and that was probably a lot of money at that time, but I thought, well, this is a good investment. I'll help this organization get started. And that was the start. And they kind of ran it out of Living Beyond Cancer in Albuquerque for a few years. But then Fitz, who was in the Washington, DC. area decided they weren't going to be able to get organizations all over the country organized to do this, and they were going to have to do some lobbying. So Ellen Stovall, who was a Hodgkins survivor living in the Washington area, beginning to do policy work in this area, then became the executive director and took the organization forward for many years and championed this, got the Office of Cancer Survivors established at the NCI in the 1990s, and really did a lot of other wonderful work, including a lot of the work at the Institute of Medicine. She was very involved with the first Quality of Care report and then ultimately the survivorship report, the Lost and Transition report in 2005, 2006, I was on that committee. So that was really how things were evolving. 

And by that time, I was also on the ASCO board, 2003 to 2006. And so all of these things were kind of coming together. We had 10 million survivors. That was kind of an important note and a lot of diseases now - lymphoma, breast cancer, multi-agent therapy had certain benefits, but obviously toxicities. We lived through the horrible time of high-dose chemotherapy and transplant for breast cancer in the '90s, which was a problem, but we saw a lot of toxicities after that. And so there were people living after cancer who now had sequelae, and the children obviously had been leading the way in terms of the large number of childhood cancer survivors. So this was this idea that the children were kind of the canary in the coal mine. We saw them living 20, 30 years later after their cancer diagnosis, and we were now beginning to see adults living 10, 15, 20 years later, and we needed to think about these long-term and late effects for them as well.

Dave Johnson: I'm glad you mentioned Fitz's article in the New England Journal that still resonates today, and if listeners have not read it, "Seasons of Survivorship" is a worthwhile five-minute read. 

What do you think the most pressing issues and challenges in cancer survivorship care today?

 Dr. Patricia Ganz: Many people are cured with very little impact. You can think of somebody with T1 breast cancer maybe needing endocrine therapy for five years, and lumpectomy radiation. That person's probably not going to have a lot that they're going to be worried about. But if they're a young breast cancer patient, say they're 35 or 40, you're going to get five years of ovarian suppression therapy. You're going to be put into acute menopause. You're going to lose bone density. You're going to have cardiac risk acceleration. You may have cognitive changes. You may have also problems with cognitive decline later. I mean, all of these things, the more intense treatments are associated, what we're really thinking about is accelerated aging. And so a lot of what I've been studying the last 20-25 years in terms of fatigue and cognitive difficulties are related to neuroinflammation and what happens when somebody has intensive systemic therapy and that accelerated process that's, again, not everyone, but small numbers of patients, could be 10-15-20%. So I worry a lot about the young patients. So I've been very focused on the young adult population who are treated intensively for lymphoma, leukemia, and breast. And that's, I think, something that we need to be looking out for. 

The other thing is with the newer therapies, whether it's immunotherapy or some of the targeted therapies, we just don't know what the late effects are going to be. Where we're very schooled now in what the late effects of radiation, chemo, and surgery could be for patients, we just don't know. And another wonderful part of my career has been to be able to do quality-of-life studies within the Clinical Trials Network. I've been affiliated with NSABP, I was SWOG previously, but NSABP is now NRG Oncology doing patient-reported outcomes and looking at long-term outcomes in clinical trials. And I think we're going to need this for all of these new agents because we have no idea what the long-term toxicities are going to be. And even though it's amazing to have people surviving where they wouldn't have been, we don't know what the off-target long-term effects might be. So that's a real challenge right now for survivorship. 

And the primary care doctors who we would want to really be there to orchestrate the coordinated care for patients to specialists, they are a vanishing breed. You could read the New England Journal that I just read about the challenges of the primary care physician right now and the overfilled inbox and low level of esteem that they're given in health systems. Where are we going to take care of people who really shouldn't be still seeing the oncologist? The oncologist is going to be overburdened with new patients because of the aging of the population and the many new diagnoses. So this is our new crisis, and that's why I'm very interested in what we're going to be looking at in terms of a ten-year follow-up report to the 2013 IOM report.

Dave Johnson: The industry-based trials now are actually looking at longer-term treatment. And the trials in which interest is cancer, we cut it down from two years of therapy down to nine weeks of therapy, looking at minimizing therapy. Those are difficult trials to do in this climate today, whereas the industry would just as soon have patients on for three to five years worth of therapy as opposed to three to five months. Talk a little about those pressures and what we should be doing as a society to investigate those kinds of therapies and minimizing treatments.

Dr. Patricia Ganz: Minimizing treatments, this is the place where the government has to be, because we will not be able to do these de-escalation studies. Otherwise, there will be countries like the UK, they will be able to do these studies, or other countries that have national health systems where they have a dual purpose, if you will, in terms of both financing health care and also doing good science. But I think, as I've seen it, we have a couple of de-escalation trials for breast cancer now in NRG Oncology, which is, again, I think, the role that the NCTN needs to be playing. But it's difficult for patients. We all know that patients come in several breeds, ones who want everything, even if there's a 1% difference in benefit, and others who, "Gee, only 1 out of 100 are going to benefit? I don't want that." I think that's also the challenge. And people don't want to be denied things, but it's terrible to watch people go through very prolonged treatments when we don't know that they really need it for so long. 

Dave Johnson: Pat and I both like to read. I'm wondering if there's something you've read recently that you could recommend to us.

Dr. Patricia Ganz: It's called A Gentleman in Moscow by Amor Towles. I do like to read historical fiction. This one is about a count at the time of the Bolshevik Revolution who then gets imprisoned in a hotel in Moscow and how constrained his life becomes, but how enriched it is and follows him over really a 50-year period of time and what was happening in the Soviet Union during that time. And of course, with the war in Ukraine going on, very interesting. Of course, I knew the history, but when you see it through the drama of a personal story, which is fictional, obviously it was so interesting.  

My husband escaped from Czechoslovakia. He left in '66, so I had exposure to his family and what it was like for them living under communism. So a lot of that was interesting to me as well. 

Dave Johnson: Thank you for joining us. It's been a wonderful interview and you're to be congratulated on your accomplishments and the influence you've had on the oncology world. 

We also want to thank our listeners of Oncology, Etc., and ASCO Educational Podcast where we will talk about oncology, medicine and beyond. So if you have an idea for a topic or a guest you'd like us to interview, by all means, email us at education@asco.org. To stay up to date with the latest episodes and explore other ASCO educational content, please visit education.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. 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.

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The ASCO eLearning Weekly Podcast is an educational series focused on helping learners identify knowledge gaps and stay up-to-date with the latest in new drug developments, cancer treatments and patient care approaches. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO eLearning. Subscribe to the podcast through a mobile device by clicking the Apple Podcasts link (iOS devices) or the Google Play Music link (Android devices). We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO eLearning Weekly Podcast, email elearning@asco.org for more information.

Dr. Daniel George is Professor of Medicine and Surgery, Director of GU Oncology for the Duke Cancer Institute, and Co-Chair of the DCI Center for Prostate and Urologic Cancers. Dr George's primary areas of interest are in drug development and optimizing care for patients with GU cancers, particularly prostate and kidney cancers. In this episode, Dr. George reviews disparities in prostate care.

The ASCO eLearning Weekly Podcast is an educational series focused on helping learners identify knowledge gaps and stay up-to-date with the latest in new drug developments, cancer treatments and patient care approaches. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO eLearning. Subscribe to the podcast through a mobile device by clicking the Apple Podcasts link (iOS devices) or the Google Play Music link (Android devices). We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO eLearning Weekly Podcast, email elearning@asco.org for more information.

Alexander Menzies, a Medical Oncologist and Associate Professor of Melanoma Medical Oncology at Melanoma Institute Australia (MIA), The University of Sydney, and Royal North Shore and Mater Hospitals discusses appropriate biomarkers and treatments for Stage IV Melanoma.

Lora Black, RN, MPH, OCN, CCRP, Senior Director of Clinical Research at Sanford Health highlights two key points for building a sustainable oncology research program in an oncology-based setting.

Komal Jhaveri, MD, FACP, is a breast medical oncologist with dual appointments in the breast medicine and early drug development services at Memorial Sloan Kettering Center in New York. In this special Annual Meeting 2019 episode, Dr. Jhaveri discusses two patient cases that relate to adjuvant treatment for breast cancer.

Click here to visit ASCO's Annual Meeting website to learn more about the education session. Come back after the meeting for more videos, links and information from relevant sessions.

Providing high-quality cancer care to patients is the goal for any oncologist, yet there are many places across the globe that face multiple hurdles in achieving that goal. In this ASCO Education podcast we explore how one group is making a positive impact in the state of Surawak in Malaysia via the efforts of ASCO's International Cancer Corp Program (ICC). 
Dr. Roselle de Guzman, past chair of the Asia Pacific Regional Council of ASCO, Dr Voon Pei Jaye medical oncologist and onsite director of the ICC Program at Sarawak and Dr. Evangelia D. Razis medical oncologist focused on neuro-oncology from Athens, Greece and ASCO volunteer of the ICC Malaysia Program describe the benefits of implementing the efforts of Project ECHO (Extension of Community Healthcare Outcomes) (3:38), the challenges in providing quality cancer care in Sarawak (8:31) and details on how to volunteer for the ICC program (19:45). 

Speaker Disclosures
Dr. Roselle de Guzman: 
Honoraria - Roche Oncology (Philippines); AstraZeneca; Merck Serono, MSD Oncology Recipient, Boehringer Ingelheim, Zuellig Pharma
Consulting or Advisory Role - Roche Recipient, Novartis, Boehringer Ingelheim, AstraZeneca, Zuellig Pharma (ZP) Therapeutics, Eisai Recipient, MSD Oncology
Research Funding - Centus Biotherapeutics
Travel, Accommodations, Expenses - Hospira (Philippines), Roche (Philippines), Merck Sharp & Dohme, Eisai, Boehringer Ingelheim, AstraZeneca, Pfizer

Dr. Evangelia D. Razis:
Honoraria Company - Servier pharmaceuticals. ESMO
Research Funding – Tesaro, IQvia, AstraZeneca, Exelixis, PPD Global, MSD
Travel, Accommodations, Expenses - Genesis Pharmaceuticals, Roche, Pfizer, Karyo

Dr. Pei Jye Voon:
Research Funding - Novartis Recipient, Boehringer Ingelheim, Viracta Therapeutics Inc,  ROCHE, Merck KGaA, Merck Sharp & Dohme, BeiGene, AstraZeneca, Janssen-Cilag, Johnson & Johnson

Resources 
If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org.

TRANSCRIPT

Disclosures for this podcast are listed in the podcast page. 

Dr. Roselle De Guzman: Providing high-quality cancer care to patients is the goal for any oncologist, yet there are many places across the globe that face multiple hurdles in achieving that goal. One such location has limited trained personnel, financial constraints, geographical challenges, and limited access to healthcare service in rural areas. The location, the state of Sarawak, located in the eastern part of Malaysia. The population is almost evenly split between urban and rural areas, which are the most dispersed in Malaysia. 

The major challenge in Sarawak is the inadequate connectivity in the rural area and limited access to healthcare service. To address these issues, in 2020, a collaboration was formed between Sarawak General Hospital, University of Malaysia Sarawak and ASCO through ASCO's International Cancer Corp Program, or ICC for short. The ICC program is focused on three basic goals: incorporating a multidisciplinary approach into cancer care, integration of palliative care into oncology care, and quality improvement through ASCO's Quality Oncology Practice Initiative, or COPI program. This podcast will spotlight all the planning, activities, and results thus far of the ASCO ICC program in Malaysia.

Hello, I'm Dr. Roselle de Guzman, past chair of the Asia Pacific Regional Council of ASCO. I am pleased to spotlight one of ASCO's collaborations with a lower-resource country to improve the quality of cancer care through a multifaceted approach. This year, we are focusing on Malaysia, where, through the ICC program, ASCO has been providing training in multidisciplinary care, palliative care, and quality measurement. Joining us later in the podcast will be medical oncologist Dr. Voon Pei Jye, who serves as the Onsite Coordinator for the ICC program at Sarawak.  

First, we will speak to an ASCO volunteer of the ICC Malaysia Program, a medical oncologist focused on neuro-oncology, Dr. Evangelia Razis from Athens, Greece. 

Welcome, Dr. Razis. 

Dr. Evangelia Razis: Thank you. Thank you for the opportunity.

Dr. Roselle De Guzman: First of all, Dr. Razis, what made you want to volunteer for the ICC Malaysia program, and what has been the most rewarding aspect of this service for you?

Dr. Evangelia Razis: So, I've been actually collaborating with ICC for many years through ASCO and other programs as well, such as Honduras, and I find volunteering an extremely rewarding experience because you share and interact with colleagues from all over the world, you offer to those less fortunate, and you actually learn a lot through this process as well. So, volunteering is a very rewarding process for me, and I've been involved in it for many years. Plus, the opportunity to do something in neuro-oncology, which is very close to my heart, is very important, because this is a new field. I feel it needs to be exposed in all countries because it has many intricacies. 

Dr. Roselle De Guzman: Well, that's really rewarding and must be really fulfilling work for you, Dr. Razis.  

Dr. Razis, you also serve as a lead facilitator of the Project ECHO Neuro-Oncology Mock Tumor Board series, which delivers monthly online training to physicians from Malaysia. Can you tell us more about this project? What are mock tumor boards?

Dr. Evangelia Razis: So, Project ECHO, the word stands for Extension of Community Healthcare Outcomes, and it's a project that has attempted to be near community healthcare delivered in low and middle-income countries through virtual media to support the healthcare in these areas. And in this particular effort, we are holding a neuro-oncology tumor board once a month since September with the Malaysia team. It's mock because we don't actually deliver specific patient advice for the purpose of patient care. We actually do it for educational purposes. So, we present cases and then discuss a topic.  

The program has been set up for several months now by the Malaysia team based on their needs, which neuro-oncology topics they want to highlight. And we have a once a month, one-and-a-half-hour session, whereby cases are presented, and then an invited speaker from several places around the world, as I'll tell you in a minute, highlights this topic and then discusses the cases and discusses the questions that the group from Malaysia has. 

And not only have we been able to be joined very regularly by the Sarawak team, but other parts of Malaysia have joined in, other centers in Malaysia have joined in different occasions. Now, the speakers have been experts from Europe and the United States based on their expertise in particular neuro-oncology topics. 

Dr. Roselle De Guzman: So, Project ECHO is one of those innovative ways of delivering healthcare to extraordinarily challenging environments, those which are extremely remote or under-resourced areas. So to your knowledge, Dr. Razis, what improvements have been made since the implementation of Project ECHO?

Dr. Evangelia Razis: Over the last nine months, I have noticed more insightful questions that show that some understanding of the standard neuro-oncology way of thinking, if you will, has come through to the colleagues that are joining us, though I must say that they were very knowledgeable from the beginning. I also hope that certain intricacies of neuro-oncology, such as, for example, the way to read scans and evaluate the fact that there may be pseudo progression or pseudoresponse, the way to integrate molecular parameters into the decision-making process, has now become part of the way they think about patients. And ultimately, the most important aspect has been the multidisciplinary approach to neuro-oncology and the constant use of all specialties to make a decision. Surgery, radiotherapy, radiology, pathology, all of these specialists need to come together to produce an appropriate decision for the patient.

Dr. Roselle De Guzman: So one thing that's interesting as well is in 2013, Dr. Razis, your institution, HYGEIA Hospital in Athens, Greece, was one of the first outside the United States to join the Quality Oncology Practice Initiative or COPI program of ASCO. And your program was also the one to be accredited. So, Sarawak General Hospital in Malaysia is collaborating with ASCO as well for the COPI program that focuses on quality improvement. So, based on your experience, what benefits does the COPI program bring to an institution?

Dr. Evangelia Razis: So, COPI, in fact, is an extremely useful way to streamline one's work and increase patient safety and patient satisfaction. I would also say that it helps reduce waste of resources, which is particularly important in resource-limited settings. And we do have a COPI version that is for limited resource settings. It's amazing, but just doing one's work lege artis does result not only in better outcomes but less waste. And that I think is extremely important for Sarawak. So, I think they will find it very useful to be streamlining their work through COPI.

Dr. Roselle De Guzman: Thank you, Dr. Razis, for sharing your experience, your expertise, and your insights. Now, at this point, I would also like to introduce medical oncologist Dr. Pei Jye Voon, who serves as the Onsite Coordinator for the ICC program at Sarawak. 

Dr. Voon, Welcome.

Dr. Pei Jye Voon: Thank you so much.  

Dr. Roselle De Guzman: Dr. Voon, can you describe what cancer care was like in this area of Malaysia for the past few years and what are the main challenges in providing quality cancer care?

Dr. Pei Jye Voon: Yes, of course. So first of all, I would like to give a brief introduction of Sarawak, which is situated at the Borneo island of Malaysia and is the largest state in Malaysia with a very large land area populated by only 2.9 million people, meaning it is very sparsely populated. And for information, newly diagnosed cancer cases in our state is about 2300 cases a year, and the common cancer include breast cancer, followed by colorectal and lung cancer, as well as a cancer that is peculiar to our setting here: nasopharyngeal cancer.  

Half of our 2.9 million population, as mentioned before, are residing outside the urban area, which causes the issue of accessibility of health care, particularly good cancer care, for this rural population. It has always been a great challenge as we have only one public comprehensive cancer center, and thus inequity of access to cancer care is one of the major hurdles in providing good quality cancer care in our state here. In addition, inadequate formally trained, for example, oncologists and palliative care physicians, as well as other healthcare personnel, like oncology nurses, perioperative nurses, which has also negatively impacted the quality of care that we are providing here.  

Furthermore, limited availability of good, top-notch cancer infrastructures, especially at the district hospitals outside our capital city of Kuching, also poses a great challenge to us in developing good quality cancer care across the whole state. Moreover, similar to many parts of the world, the ever-increasing cost of cancer treatment, especially on the expensive new anti-cancer drugs, is another pressing issue for us as well. 

In summary, I can say that inequity of access due to the geographical barrier, lack of human resources, inadequate infrastructure, and also the ever-increasing cost of cancer, are the major challenges that we are facing here in Sarawak. 

Dr. Roselle De Guzman: Thank you, Dr. Voon. I'm sure the situation in Sarawak resonates with other countries, low- and middle-income countries. Of course, there are truly challenges, but of course, with the challenges come opportunities. So what benefits or changes have taken place through this collaborative ICC program?

Dr. Pei Jye Voon: I have to say that participating in the ASCO ICC program is one of the greatest things that has happened to our radiotherapy oncology and palliative care department at Sarawak General Hospital. We have gained tremendously, definitely from that. And for instance, we have been actively participating in a highly personalized palliative care education program which is one of the highlights of this collaboration. Various projects have been successfully conducted, including the ASCO Palliative Care e-Course course, which subsequently led to the Train the Trainer's program. This program benefited not only the Sarawak team, but also healthcare providers across Malaysia as well. And this aspect of human development in palliative care was further consolidated with the in-person training by Dr. Frank Ferris as well as Dr Shannon Moore in November last year when they came to visit us physically. We are very grateful for that. 

And in addition to enhancing palliative care, another very interesting project that is actively ongoing is the project ECHO Neuro-oncology Tumor Board Series, which delivers online monthly training to physicians across Malaysia on neuro-oncology care. This was discussed by Dr. Razis earlier on in the podcast, so I'm not going to elaborate at length here. But essentially, the idea of this project was conceived initially in view of the gap that we noted in our neuro-oncology management in our hospital, as compared to those of common cancers that we are actually treating. So through the diverse lectures and many case discussions of the recent in-person visit by the ASCO team that we saw, the management of our neuro-oncology cases has definitely been enhanced and we are looking forward to Dr. Razis coming to visit us physically as well.  

At the same time, we are also looking forward to the incoming multidisciplinary board project under the ASCO ICC program on breast cancer management in August this year. I believe that Dr. Guzman is going to come to visit us, and we are looking very much forward for this as well. And at the same time, this exciting project is under active planning now. Furthermore, we are also eagerly awaiting the improvement of quality cancer care programs using evidence-based quality measures via the COPI project in the near future.

Dr. Roselle De Guzman: Dr. Voon, it seems there is a lot of things happening with Sarawak General Hospital, and we know that there are so many patients globally that do not get the comforts and benefits of palliative care program. You have mentioned palliative care program. Has the ICC Sarawak program made a difference in patient quality of life thus far? 

Dr. Pei Jye Voon: Again, the answer is yes. Definitely yes. So the ASCO Sarawak Palliative Care program has definitely made a great difference in the patient's quality of life. This collaborative work between SarGenHospital, our university, UNIMAS, and ASCO has been in its third year. And many important palliative care milestones in Sarawak have been accomplished. This specially designed program—I would say that this is a specially design program that fits us, that fits our needs—has been mentioned before and includes the ASCO e-course, Train the Trainer program, the mentorship program through the International Development and Education Awards through the Conquer Cancer Foundation, and last but not least is the translation of the ASCO Palliative Care Interdisciplinary Curriculum Resources to our national language to reduce the language barrier in training and education for our people here.  

All these innovative programs have provided a fundamental framework of palliative care  education that is invaluable in equipping our oncologists as well as oncology trainees with the necessary knowledge and skill set to better identify and also meet the palliative care needs amongst our patients. It also ensures a more competent and timely palliative care provision at a general level by the oncology team of our hospital. I think that is extremely important. And it enables the team to incorporate the best palliative care management early in the course of the disease. We call this early introduction through palliative care in our hospital. And in some ways, actually, the ASCO collaboration has enhanced the teamwork and helped the oncology team to recognize our own limitations while providing general palliative care, thereby encouraging the timely palliative care referral whenever appropriate to ensure that patients with more complex physical, psychosocial, and spiritual needs have the necessary input and support from our palliative care team throughout the course of their illnesses. 

Dr. Roselle De Guzman: So we have been discussing important points on the ICC program focusing on multidisciplinary cancer care management, palliative care program, and the COPI program. What do you think are other solutions? Are there others that exist to overcome hurdles to provide quality cancer care to people in Malaysia? Dr. Voon?

Dr. Pei Jye Voon: Yes. Definitely yes as we have discussed in our conversation. So besides the ASCO ICC program, various existing and some projects which are in planning now to overcome hurdles to provide quality care to the people in Sarawak have been implemented or are currently in a very active planning phase. So in terms of inequity of access to good cancer care due to the geographical barrier, we have actually undertaken decentralization efforts of cancer care here in Sarawak. One of the actual efforts around initiatives is to host our senior long-term oncology liaison medical officers with adequate oncology experience to other district hospitals in Sarawak so that better cancer care could be delivered to patients closer to their homes. This was also consolidated with our regular visiting oncologists to these district hospitals as part of decentralization efforts as well. There is also a nursing training program for systemic treatment administration being conducted since last year in all major district hospitals, with the aim of credentialing all our nurses in the state managing cancer care patients with this essential nursing skill of administering systemic therapy in their own hospital.  

In addition to that, weekly oncology and palliative care continuous medical education program across the state has been conducted since the fourth quarter of last year, to disseminate oncology knowledge rapidly to healthcare providers, especially those outside our capital city, who have inadequate exposure in oncology care. And upgrading of our cancer care infrastructure has also been actively planned and we are actually looking forward to a new comprehensive cancer center in our city in the next few years.  

Besides that, our center is also robustly developing our clinical trial capacity in the hope that we can provide additional treatment options to our patients who have limited optional treatment due to cost constraints. In summary, I can say that various initiatives have been implemented to enhance the cancer care in Sarawak, and one thing for sure is the ASCO ICC program has been facilitating all this positive development.

Dr. Roselle De Guzman: So many things are happening, so many things are being done. And with all your efforts, knowledge, and expertise, of course, nothing is impossible. And it's always helpful if you have a very dedicated and committed team, right?

Dr. Pei Jye Voon: Yeah, definitely. We have a very dedicated team, that's for sure.

Dr. Roselle De Guzman: So Dr. Voon, thank you for being with us today and for your onsite coordination of the program. And Dr. Evangelia Razis, thank you for volunteering your time and insights to the ICC program and to our podcast. 

Malaysia is not the only location that the ICC program has been implemented in. There are currently nine sites in Asia, Africa, and South America currently accepting volunteers. Now I would like to give a brief information for volunteers wanting to participate. ASCO pairs eligible oncology professionals with a medical center whose needs match the expertise of the volunteer. Volunteers must be appropriately trained and credentialed medical professionals who specialize in oncology. This includes physicians specializing in medical, radiation, and surgical oncology, laboratory professionals, and nurses. Final-year oncology fellows may also participate if paired with an experienced volunteer.

Volunteers spend one to four weeks on site. During that time, they teach and train staff, residents, and students, and gain insight into cancer management needs and challenges at that institution. As an added benefit, the program enables volunteers to form long-term supportive relationships with clinicians in participating countries. If you are interested in volunteering for the ASCO ICC program, please go to volunteer.asco.org - that's volunteer.asco.org - to apply. I'm Dr. Roselle De Guzman, past Chair of Asia Pacific Regional Council of ASCO.  

Thank you for listening to this ASCO Education Podcast. The ASCO Education Podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncology well-being and professional development. If you have an idea for a topic or guest you would like to see on the show, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, visit education.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. 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 Celano from the greater Baltimore Medical Center, lead author on "Safe Handling of Hazardous Drugs: ASCO Standards."

TRANSCRIPT

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

Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin. And today I'm interviewing Dr. Paul Celano from the greater Baltimore Medical Center, lead author on "Safe Handling of Hazardous Drugs: ASCO Standards." Thank you for being here today, Dr. Celano.

Thank you for having me. I'm certainly glad to talk about these standards. They're very important to our employees and our patients.

So first I want to make the distinction that this publication is not a guideline like we usually cover on this podcast. So can you tell us what standards are and how they differ from guidelines?

Well, guidelines really are intended to guide practitioners around recommended care options. They give obviously a lot of latitude to clinical judgment and circumstances. Standards, on the other hand, are really meant primarily for the organization of care and are intended to have a higher level of obligation to help drive either practice or policy or even legislative efforts. So that's really the distinction.

And what are the standard statements that are made by ASCO in this publication?

The publication really is about safe handling of hazardous drugs. This all came about is because recently there have been a number of national guidelines or standards that have been offered by other organizations, but not specifically oncology or certainly ASCO or the ASCO organization. We felt a need to address the standards that have been put out on the basis of the evidence, so that best practices can be offered.

Initially, we did collaborate with other societies, such as the Oncology Nursing Society and the Hematology Oncology Pharmacy Association. That was really the impetus behind making sure that we are, in a sense, congruent with standards that are already being published and discussed, but also to also place in our interpretation of these standards so that they're based on the best evidence that's available.

And what qualifying statements are there to note about these standards?

Well, I think the best way to look at these standards is there has been recently published or offered what's been called the UST 800 standards, which really incorporate other previous standards by the Pharmacy Association as well as OSHA, the Occupational Safety and Health Association, as well as NIOSH, the American Society of Hospital Pharmacists, Oncology Nursing, etc. So there's a lot of standards that have been offered.

And in fact, the ASCO review of this really in a sense agrees with many of the standards that have already been published and offered-- types of exposures, the responsibilities of personnel handling the drugs, the personal protective equipment, how we communicate the hazardous drugs, the training of compounding personnel, how the drugs are dispensed and even transported. So there's lots of things that we really do agree with.

I think it's also important to understand that the objectives of this is really to protect personnel and the environment to make sure the standards apply to all personnel who compound hazardous drugs and preparations, all places where hazardous drugs are prepared and stored, transported and administered. So that's really a key part of this. These are a comprehensive program really to prevent worker environmental exposure and to provide the most practical safety environment for all involved.

So finally, why are these standards so important? And how will they affect practice?

Well, they effect practice in many ways. I mean, the key thing is making sure that our employees, meaning the nurses, pharmacy, the technicians, really everyone involved that they're not unduly exposed to these hazardous drugs. And so that's really the key thing that we're all trying to achieve by this.

Now, what really makes the sort of ASCO standards somewhat different or the things that we came into a contention with has to do with the differences that ASCO has come up with in contrast to some of the other standards. And these have to do with really four main areas within these standards. They have to do with medical surveillance, external ventilation, closed system transfer devices, and also proper assignment of our personnel while they may have either trying to conceive or pregnant or nursing.

So those areas that in our review, the ASCO review, have come under some question. As an example, medical surveillance, there in some of the standards offered-- not ASCO's-- that there's a number of medical surveillance procedures that have been elucidated, that really we find, number one, have really not any proven value for our employees and generate a lot of confusion in terms of how this process is supposed to be done. Obviously, if one of our employees has some undue exposure, such as a spill of chemotherapy or even just have flat out a concern, then obviously those things will be clearly investigated. But to have general medical surveillance of all employees, really we did not feel was of great value.

But also further, we really feel that this is an area where more research needs to be done to better elucidate really what should this process look like and what value are we providing to our employees.

Another aspect of this is the use of what are called closed system transfer devices. Currently, there are a number of these devices available that there is interestingly no standard way that these devices have been evaluated. And so it's hard to recommend one device over another, because there is no standards for which they're really being compared. And there certainly have been no studies looking at really any form of health outcome that really help us to direct this to how best to use these devices. And so really, a lot of these objections are more around let's do things in an evidence-based way so we can better know how to best direct our practices.

Another area of concern in terms of ASCO standards have been the implementation of external ventilation in either containment secondary engineering controls or other situations. And the challenges is that HEPA filters are probably appropriate for collecting solid or aerosolized particles, but don't capture vaporized drugs. But there's little data available on the ability of hazardous drugs to vaporize within the workplace environment and what those hazards really are. And so again, it's is a call for more research to have an optimal environment for preparing these drugs and without having to place undue burdens in terms of external ventilation.

Another area is options for alternative duties for workers who are actively trying to conceive or are pregnant or breastfeeding. And these we recognize can be special burdens to small practices looking to implement alternative duty programs. There is a lot of controversy regarding the potential level of risk that really these workers really have. And basically our stance has been that we should have a policy that identifies alternative work options for workers who are trying to conceive, are pregnant or are breastfeeding, and that this information needs to be conveyed to these employees at the time of their hire so they understand what their risks are and what their options are within the workplace.

Again, trying to make sure everyone is well informed and aware of what the work environment they're in and as their life circumstances change what they can do to change with this. I think the key is that we all feel that this is an area that we should have continued research on. And our standard, certainly ASCO's standards will continue to evolve as more and more research and evidence becomes available.

Thank you so much for taking the time to explain these standards to us today, Dr. Celano.

You're welcome.

And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague

Dr. Noelle LoConte, associate professor of medicine at the University of Wisconsin, presents two patient cases regarding cancer prevention.

TRANSCRIPT

Hello. My name is Noelle LoConte. I am a physician and associate professor at the University of Wisconsin Carbone Cancer Center in Madison. I am a GI medical oncologist in my clinical practice, and also the principal investigator of my state's Comprehensive Cancer Control program, and an implementation science researcher in cancer prevention and screening. 

Today, we will compare two patient cases that relate to cancer prevention. These two cases have similarities yet the recommended treatments may be different. Let's look at our cases. 

Patient case number one is Harold. Harold is a 55-year-old man with a history of head and neck cancer treated with curative intent with chemotherapy and radiation, which was completed about six months ago. He is seeing you for a follow-up surveillance visit. He reports he is currently drinking three to four beers per day, most days of the week. He had quit smoking at diagnosis, but prior to diagnosis had a 45 pack-year history. He recently reports that he started vaping or using e-cigarettes. 

Our second patient case is Susan. Susan is a 44-year-old woman with node-negative, ER-positive, PR-positive, HER2 neu-negative breast cancer. She has also been treated with curative intent with surgery, chemotherapy, and radiation, and has completed her treatments about six months ago. She is seeing you for a routine follow-up visit and reports no new symptoms. She tells you she is drinking two glasses of wine per day, and she denies any history of smoking. 

As you can see, both cases are very similar, but there are some differences. How would you counsel each patient about their use of alcohol? And in the case of Harold, about his use of e-cigarettes? Do either of these affect the risk of recurrence for the patient? And what are the alcohol-associated cancers? 

For background, the cancer burden attributable to alcohol is significant. In 2012, an estimated 5.6 percent of worldwide cancer deaths were attributable to alcohol-associated cancers. In the United States, alcohol accounted for about 3.5 percent of cancer deaths in 2009. Both of these numbers are increasing over time as alcohol use is becoming more common both in the US and globally. 

Upper airway and squamous cell esophageal cancers accounted for the majority of alcohol-attributable deaths among men. Breast cancer accounted for the majority among women. Additional cancers causally linked to alcohol include hepatocellular carcinoma and colorectal cancer. Cancer risk correlates with increasing alcohol consumption for cancers in which alcohol is implicated. 

E-cigarettes are currently approved for adults as a way to decrease the harms from combustible tobacco products, but much about their risk remains unknown, particularly for cancer survivors. Although the risk appears to be lessened with e-cigarette use, they are not proven to be safe and can often serve as a gateway product for youth and nonsmokers to more traditional combustible smoking products. 

In both cases, each patient has an alcohol-associated cancer. However, it is unclear for all but head and neck cancers and esophageal squamous cell carcinoma if cutting down on alcohol intake after cancer diagnosis reduces the risk of recurrence. E-cigarette use among cancer survivors is an emerging issue for clinicians, who often do not know how to counsel their patients about these products. 

For Harold, with his head and neck cancer, there is clear data that supports that patients with that diagnosis who continue to drink do have higher rates of recurrence and also secondary head and neck cancers. Thus, the oncologists should counsel him to stop, or at least cut down on his alcohol drinking. 
The current guidelines recommend no more than two servings of alcohol a day for men and no more than one per day for women. As a reminder, a serving of alcohol varies dependent on the product being consumed. It is roughly one 12 ounce bottle of regular beer, five ounces of wine, or 1 1/2 ounces of distilled spirits. 

For Susan, who has an estrogen and progesterone receptor-positive breast cancer, the data is less clear. There is a suggestion in some studies that ongoing alcohol use for hormone receptor-positive patients may increase the recurrence rates. However, the data is not definitive. It would be prudent for all health risks related to alcohol to counsel her to stick to the recommended amounts of alcohol use, however. So for her, this would be one drink per day for women. 

For e-cigarette use, a 2015 ASCO and AACR statement on ENDS, or electronic nicotine delivery systems, concludes that oncologists should not recommend e-cigarettes to their patients as first-line treatment for quitting smoking. Oncologists should also be aware that more and more cancer survivors are using e-cigarettes and similar products, and they should ask about use at each visit. The unclear health risks of e-cigarettes should be discussed with patients. 

Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. For more information on cancer prevention, including additional patient cases and opportunities for self-evaluation, visit the comprehensive eLearning center at elearning.asco.org. 

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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. 

TRANSCRIPT

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Hello, and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin, and I'm interviewing Dr. Joe Mikhael from the City of Hope Cancer Center and International Myeloma Foundation, lead author on "Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline." Thank you for being here today, Dr. Mikhael.
It's a pleasure to be with you.
So first, can you give us some context as to why this guideline was developed?
Well, we had a lot of ideas when we put together this guideline, but most importantly, multiple myeloma continues to be a rare disease in the cancer world. It really only accounts for about 1% to 2% of cancers. So for the practicing oncologist, they spend perhaps 3-ish percent of their time doing multiple myeloma.
And when you add to that there has been really a revolution in myeloma with new drugs approved, new treatments, new approaches, it really leaves the general oncologist with a complexity of how to treat this disease. And so we wanted to create a very practical guideline that would give very precise advice to walk through how one would care for a multiple myeloma patient, right from their diagnosis to indeed relapse disease.
We felt this approach was so important now, more than ever, because of the fact that myeloma has really changed so much, and now, thankfully, we're seeing our patients live so much longer that the treatment options can become a little bit more complicated over time. Furthermore, we partnered with Cancer Care Ontario, because this was really felt to be not just an American phenomenon, but really a full North American phenomenon of how we could work together to really give practical advice as to how to treat this disease.
So what are the key recommendations of this guideline?
In this guideline, we focused really on the treatment of the disease itself. There have been other guidelines that have focused on supportive care and bone disease and multiple myeloma, but we really focused on the treatment of patients really from induction therapy through to relapse.
So we spend time helping guide the decision around whether or not a patient is transplant eligible or ineligible, because that's really the first dividing marker in myeloma, because we know that transplant still has a role in myeloma, and eligible patients should have a transplant, or at least have access to a transplant. And historically, this was really done on the basis of age.
But the guidelines helps the clinician see that it's really not just an age phenomena. It's really a decision based on comorbidities and really what's best for the patient. So we spend time helping making that decision, and then provide very practical advice as to how to treat a patient who's going to transplant versus a patient who's not going to transplant.
We also, then, after the transplant, or in lieu of a transplant, we discuss the importance of continuous therapy, or sometimes called, maintenance therapy in myeloma. Again, we've seen maintenance therapy, now, have an impact on both progression free and overall survival. And so we felt it was really important to be very practical in giving advice as to what maintenance therapy agents to use and how to use them.
And then lastly, the guideline provides a lot of practical advice as to a patient who has relapsed with multiple myeloma. We have so many choices now with three major classes of drugs of proteasome inhibitors, immuno-modulatory drugs, and now newer monoclonal antibodies, it can be difficult sometimes to know which combination to use.
We know that triplet combinations tend to be preferred. So we walk through a number of those triplets and provide advice as how to explicitly use them. We do emphasize the importance of supportive care and of risk factor analysis throughout the guideline, so that we can understand the difference between high risk and low risk myeloma, so that we can understand how important a patient's comorbidities, especially in a disease that primarily affects older patients, can be managed.
And so we try to do so in a comprehensive way, but one that really distills down to the critical pieces to allow the practicing clinician some real advice.
So why is this guideline so important, and how will it change practice?
There are several kinds of guidelines for multiple myeloma, but I really think this is a critical guideline because it is so clinical and practical in its essence. It's really designed to not just give the utopian view or the clinical trial view of a disease, but practically in the trenches, how do we use the drugs that we know are going to benefit our patients.
Myeloma is one of the few cancers where we have seen a doubling, if not a tripling of survival in the last decade, because of so many of these new agents. And so making sure that our patients are treated optimally really is important. And we want to be able to ensure that they receive the best therapy possible, so they can live a longer life, but also live it with a greater quality of life.
And so finally, how will these guideline recommendations affect patients?
Well, we really hope that this is going to help patients all across North America and the whole world, because it will give very concrete advice to the practicing clinician in how to approach the disease. And one of the things I think will directly impact patients, if you will, right away is one of the themes of these guidelines, which is that you don't treat a patient simply based on the biopsy or simply based on their age, but that it is really a complex network of comorbidities, risk factors from the disease itself, the potential side effects of certain drugs, and a patient's own very personal history.
It really fits in with the ASCO modality that we have of ensuring that we bring personalized medicine to our patients. And so this will allow the person who's reading it and who's applying it to their patient to recognize the importance of general guidelines, but also of applying it to the specific patient they care for. Because as I like to say, we don't treat multiple myeloma, we treat people. And so hopefully, this will allow the clinician to have that precision to care for their patient in the best way possible.
Great. Thank you for that overview of this guideline, and thank you for your time today Dr. Mikhael.
It's been a real pleasure. Thank you very 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/hematologic-malignancies-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast, and refer the show to a colleague.

TRANSCRIPT

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

Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Susan Chang from the University of California San Francisco, lead author on "Anticonvulsant Prophylaxis and Steroid Use in Adults with Metastatic Brain Tumors: ASCO and SNO Joint Endorsement of the CNS Guidelines." Thank you for being here today, Dr. Chang.

Thank you so much for this opportunity.

So first, can you give us the general overview of what this guideline covers and about the endorsement process?

Absolutely. So one of the things we've noticed, of course, is that the incidence of newly diagnosed adult patients with brain metastases is now estimated to be in the range of about 20,000 to 40,000 per year. And this has really been increasing because of several factors. This includes improved imaging tools, the fact that there's an increase in the number of cancers that are prone to spread to the brain, and the improved survival of patients with cancer.
And so the Congress of Neurological Surgeons have developed a series of guidelines on the treatment of adults with metastatic brain tumors. That includes systemic therapy, as well as supportive care. There are two guidelines that address the role of anti-convulsant abuse and steroids in the care of patients with brain tumors.
Specifically, the guideline questions were do prophylactic anti-epileptic drugs decrease the risk of seizures in both non-surgical and post-surgical patients, who are otherwise seizure free? So these are patients who have never had a seizure, does it make any sense to use these drugs? The second is do steroids, which are commonly used in patients when there is increased mass effect and cerebral edema, could that help to improve neurological functioning or quality of life, compared to supportive care or other treatments? And if they are used, what sort of dose should be used?
So the process of endorsing these guidelines included an initial assessment by content evaluators from ASCO and members of the Society of Neuro Oncology, or SNO guidelines committee. And subsequently, it was determined that a detailed review of the guidelines should be pursued.
So in this joint effort of both ASCO and SNO, a multidisciplinary expert panel of medical and radiation oncologists and neurosurgeons, neurologists, and others providing care for adults with metastatic brain tumors reviewed the content to determine the appropriateness for endorsement by the two professional societies.

So what are the key recommendations of this guideline?

The key recommendations of this guidelines include the fact that routine use of prophylactic anti-epileptic drugs is not recommended for patients who are seizure free, either in the non-surgical and post-surgical settings, and that steroids could be used when patients had mild, moderate, or severe symptoms that were related to mass effect in the brain.
This choice of steroids that was recommended was dexamethasone, and the doses was about 4 to 16 milligrams, depending on the severity of the symptoms. Now, what they found was that there was insufficient evidence to recommend steroid use in asymptomatic patients, when they didn't have any mass effect.
And one of the additional aspects that the panel provided was that the minimal effective dose should be used, and that nighttime doses should be avoided. And this is because of the known side effect of insomnia that a lot of our patients experience when taking this medication right before they go to sleep.

So why is this guideline so important, and how will it change practice?

Well, these guidelines provide a basis for oncologists to avoid the over prescription of anti-epileptics and steroids in patients with brain metastases, particularly in those who are asymptomatic and those without signs of mass effect. It also highlights that if steroids are going to be administered, that clinicians should be very familiar with both the short and long term sequelae of steroid therapy, and they should have a plan to taper the steroids as fast as can be clinically tolerated.

So finally, how will these guideline recommendations affect patients?

Well, both anti-epileptics and steroids have a wide range of toxicities that can adversely affect a patient's quality of life. And so the routine use of these drugs in patients with incidentally discovered or asymptomatic brain metastases is not supported by the available medical literature. For patients with symptoms related to mass effect, the best evidence supports the temporary use of steroids are the lowest effective dose with the intent to taper them off, and if tolerated, and after a definitive treatment of brain metastases has been initiated.
And because of the well known side effects of insomnia and agitation, nighttime doses of steroids should be avoided. So the hope is that this will have a direct effect on how we care for our patients.

Great. Thank you for your work on these important guidelines, and thank you for your time today, Dr. Chang.

You're very welcome. It's such a pleasure to be able to provide this for patients and families.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, please go to www.asco.org/neurooncology-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

TRANSCRIPT

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

Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Rachna Shroff from the University of Arizona Cancer Center, lead author on "Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline." Thank you for being here today, Dr. Shroff.

Thank you so much for having me.

So what does this guideline recommend?

This is a guideline that is basically looking at the role of post-operative therapy in patients who undergo surgical resection for biliary tract cancers. Biliary tract cancers are a somewhat heterogeneous group of malignancies that include intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gall bladder cancer.
And so the question always in most cancers are, if you are able to undergo surgical and curative treatment, is there a role for post-operative chemotherapy or radiation therapy to help improve the chance of cure and decrease the risk of recurrence? So that is exactly what we investigated as an expert panel.
So our recommendations are actually twofold. The first one is that we are clearly recommending that patients with resected biliary tract cancer should be offered adjuvant chemotherapy with capecitabine for a total of six months. Within that recommendation, we do acknowledge that this is based on the BILCAP phase III randomized controlled trial and that there was a specific dosing and treatment schedule that was done in that study, but that we are allowing for institutional and regional variances that we've noted in terms of dosing of capecitabine. And so as a result, we're recommending adjuvant capecitabine, and we're allowing practitioners to determine what the best and safest dosing would be, based on their experience.
The second recommendation is more specifically for patients with extrahepatic cholangiocarcinoma or gallbladder cancer who undergo resection and have a microscopically positive surgical margin, which is an R1 resection. And in those patients, we are recommending that we could consider offering these patients chemoradiation therapy.
Now, again, this is not as strong of a recommendation, because we do not have prospective randomized phase III data to support it. This was based more on a prospective single-arm study out of the Southwest Oncology Group, as well as some other retrospective studies. And so we do go on to qualify that that recommendation should really be made in a shared decision-making approach, with a multidisciplinary conversation to decide the risks and benefits of radiation in these patients-- and that we acknowledge that a prospective study would really help clarify that question a little bit more.

So can you tell us about the research that informed these recommendations?

There have been a number of studies that have looked at the role of adjuvant therapy in biliary cancers. And up until very recently, a lot of these studies were small retrospective series, single-institution or multi-institution, but everything in retrospect-- no prospective or randomized data. And so I think a lot of the reasons that we decided to have these guidelines come out now is that in the last two to three years we do finally have prospective randomized data that helps guide the recommendations.
And the majority of the recommendations that we made are based on one randomized phase III, which is BILCAP study. This was a study that was done in the UK and was presented at ASCO in 2018 and is currently in press. And it is basically a randomized controlled trial that compares adjuvant capecitabine by itself versus surveillance alone in patients who undergo surgery for biliary tract cancers.
And so our recommendations, which include that study as well as a couple others, is primarily hinged on that, since that is the largest prospective data we have so far. And based on that study, we did in fact recommend that there was a role for adjuvant chemotherapy with capecitabine after complete resection for biliary tract cancers.
And based on that research that was done in that trial that was completed, we do believe that the role for capecitabine for six months is pretty strong and that the data supports that now.

So why is this guideline so important, and how will it change practice?

Well, I think it's going to be practice-changing because up until now there has not been a clear consensus on how we approach these patients. And I will say that even now, it's really just this one study that has helped guiding these recommendations. There were a number of other studies that we looked at as part of the expert panel. And these were all prospective studies as well that looked at things like gemcitabine and oxaliplatin in the adjuvant setting, or single-arm phase II studies that came out of the Southwest Oncology Group that also explored the role of radiation. But really, nothing was a positive study other than the BILCAP study.
And so up until now, I would say it was a little bit all over the place in terms of how medical oncologists approached resected biliary cancers. I think the majority of us felt that there was probably a role for adjuvant chemotherapy or perhaps chemoradiation. But there was no rules that we could follow, and there was no clear study that we could turn to that would tell us what we should give, how long we should give it for, and whether it should be a combination of chemotherapy or chemoradiation.
And so I think it will be practice-changing because now, as part of the expert panel, we are making a very clear recommendation that patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a total of six months, hopefully eliminating that kind of regional or specialist-based variation that has been happening up until this point.

And finally, how will these guideline recommendations affect patients?

Again, I think that the main way it's going to affect them is that there's going to be a little bit less gray area, in terms of medical oncologists having conversations with the patients and saying, well, you know, I think that there's probably a role for agent therapy here, but I can't show you the data that supports why I think that.
And as a result, I would hope that patients will have a little bit more faith and confidence in knowing that there is a large study that has looked at and proven the benefit of adjuvant capecitabine and that that decreases the chance of recurrence and improves overall survival. The improvement in overall survival was dramatic in this study. And we had not seen a survival of 51 months, which is what we saw in this study, in a very long time.
So for patients, not only does it make clear what they should be doing after surgery, but I would hope it also gives them additional hope that we have really changed the bar by doing this adjuvant capecitabine, and that the chance for cure is even higher when we can offer adjuvant chemotherapy.
I think the only other thing that may still be a gray area, and that is kind of what we allude to in our second recommendation, and that is in patients who undergo resection and have a microscopically positive margin or an R1 resection. And that's typically patients with extrahepatic cholangiocarcinoma or gall bladder cancer.
In those patients, we suggest that they could be offered chemoradiation therapy, but the evidence is not as strong there. Again, it's more retrospective studies that we looked at. There is no prospective study that answers the question of whether or not there's a role for radiation. And so as a result for patients, I think that is still the one area that's a little bit of a gray zone in terms of knowing whether chemoradiation would benefit them if they undergo surgery and have a microscopically positive resection.
But I do think that there is a definitive benefit to giving adjuvant chemotherapy, and that, hopefully, will clarify things not only from the physician perspective but also from the patient perspective.
Great.

Thank you for your work on these important guidelines, and thank you for your time today, Dr. Shroff.

Thank you.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

Wendy Vogel is a Nurse Practitioner and President of APSHO, the Advanced Practitioner Society for Hematology and Oncology. In this week's episode, she presents a self-evaluation question about the correct chemotherapy treatment of obese patients and provides an explanation of the correct choice.

Increasing diversity in the field of oncology is an ongoing task. Our next guest has made it her mission to increase those ranks as well as becoming the first African American woman to be a Brigadier General in the US Air Force. Dr. Edith Mitchell describes her early years growing up in rural Tennessee (2:52), the motivation for joining the Air Force in the 70's (7:33) and strategizing to increase ethnic diversity in medicine and oncology (16:53).

Speaker Disclosures
Dr. David Johnson: Consulting or Advisory Role – Merck, Pfizer, Aileron Therapeutics, Boston University
Dr. Patrick Loehrer: Research Funding – Novartis, Lilly Foundation, Taiho Pharmaceutical

Dr. Edith Mitchell: Leadership – Corvus; Honoraria - Sanofi, Exelixis; Consulting or Advisory Role Company - Genentech, Novartis, Merck, Bristol Myers Squib; Speakers' Bureau – Ipsen; Research Funding Company - Genentech, Sanofi 
Resources (related podcasts, courses or articles)

If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org.

TRANSCRIPT 

Disclosures for this podcast are listed on the podcast page.  

Pat Loehrer:  Welcome to Oncology, Etc., an ASCO Education Podcast. I'm Pat Loehrer, Director of Global Oncology and Health Equity at Indiana University. 

Dave Johnson: And I'm Dave Johnson, a Medical Oncologist at the University of Texas Southwestern in Dallas. If you're a regular listener to our podcast, welcome back. If you're new to Oncology, Etc., the purpose of the podcast is to introduce our listeners to interesting and inspirational people and topics in and outside the world of oncology.

Pat Loehrer: Imagine knowing in your heart what you wanted to be in life. It usually takes people decades to figure that out, but our next guest knew at age three that she wanted to be a doctor and, later in high school, to be an oncologist. She's achieved much in her lifetime and has incorporated the "pay it forward" by mentoring many others.

Dave Johnson: Our guest today is Dr. Edith Mitchell. I first met Edith over 40 years ago when we were both starting out our careers as junior faculty. She grew up in rural Tennessee, and as Pat mentioned, remarkably, she chose a career in oncology at a very early age in high school, despite the fact that oncology was barely a specialty at that time and the lack of role models, particularly role models of color, and women in particular. She received a Bachelor of Science degree in Biochemistry with distinction from Tennessee State University and a medical degree from the Medical College of Virginia and Richmond.  

In 1973, while still attending medical school, Edith joined the Air Force, receiving a commission through the Health Profession Scholarship Program, and eventually rose to the rank of Brigadier General. She completed a residency in internal medicine at Meharry Medical College in Nashville and a fellowship at Medical Oncology at Georgetown University. Her research interests are broad and involve new drug evaluation, development of new therapeutic regimens, combined modality therapy strategies, patient selection criteria, and supportive care for patients with gastrointestinal malignancies.

 She is the leader of the GI oncology program at Jefferson Medical College, Director of the Center to Eliminate Cancer Disparities, and Enterprise Vice President for Cancer Disparities at Jefferson's Sidney Kimmel Cancer Center. She's held a number of leadership positions, including those in ASCO, and she's a former president of the National Medical Association. I could go on forever. So, Edith, welcome, and thanks for joining us on Oncology, Etc. 

Dr. Edith Mitchell: And thank you so much for the invitation, Dave and Pat, it is a pleasure. 

Dave Johnson: You grew up on a farm, as I recall, in Tennessee. Perhaps you could tell us a little about your early life.

 Dr. Edith Mitchell: I grew up on a farm that my great grandfather's mother received about 1863 when the Emancipation Proclamation was made. I was the fifth child in my family. My parents were working, my older siblings were in school, so my great-grandparents were my babysitters, so I spent a lot of time with them. He was 89 at the time, became ill, and I overheard family members and neighbors say that they couldn't take him to the hospital because Blacks were not treated properly in the hospital, so they were going to take care of him at home. A physician made a house call. When he left, I told my great-grandfather, "Pa, when I grow up, I'll be a doctor just like Dr. Logan and I'll make sure you get good health care." 

So, at three years, I decided I would become a doctor and I would make sure that Blacks received good health care. My work in disparity started when I was three. So, after my sophomore year in high school, there was a National Science Foundation program in Memphis at LeMoyne-Owen College. So, I applied and was accepted. And part of the time in Memphis that year, we were given opportunities to go to St. Jude. So my time at St. Jude made the decision that I would become an oncologist. I became really fascinated by cancers and in pathology, use of the microscope, and how cancers were all different, how they varied from the normal tissue for areas such as the colon or the stomach or the pancreas.

Dave Johnson: It's amazing that that early in your life you made that kind of decision. 

Can I back up just one moment? I want to ask you briefly about the doctor that visited your great-grandfather, Dr. Logan. 

Dr. Edith Mitchell: Dr. Logan was a family physician, African American, and he had a great interest in Blacks being healthy. In fact, when the polio vaccine was made public, Blacks could only go one day per week because you couldn't go the times when whites were there. Dr. Logan obtained the vaccine and he would line the children up at his office. He gave me my first polio vaccine. He was a very handsome man. And, you know, Dave, I found out later that the medical school that he attended in Memphis was one of the ones closed as a result of the 1910 Flexner Report. So he had to go to Meharry in Nashville and take other courses to maintain his license to practice medicine. 

Pat Loehrer: Were you the first one to go into medicine? Tell me about that background and how your family influenced you personally. 

Dr. Edith Mitchell: Neither of my parents finished 8th grade, but they were very smart. They pushed their seven children to do well. They provided educational materials in our home and encouraged us to work and to take advantage of opportunities.

Dave Johnson: Let's move forward a little bit. I thought I knew a lot about you, Edith, but I didn't realize that you were a Brigadier General. What was the motivation for joining the service in the '70s when you were at med school? Was it scholarship funding, or was there just patriotic zeal or a little of both?

Dr. Edith Mitchell: My main objective was, for financial reasons - a scholarship covering all expenses of medical school, plus a monthly stipend. When I was in medical school, one of my laboratory instructors told me about this new scholarship program, and I said, "Okay, I just want to graduate from medical school." So he says, "Well, I know people in the surgeon general's office. I'll have them send you the information." He did, and I looked at it and didn't remember David, that my husband filled out the application. After my neurosciences final exam, I came home, and he says, "Your commission came in the mail today." So I said, "Okay." He says, "Well, I can swear you in. We can't do it at home because you have to have a witness. You take a nap, and then we're going out to job control, which was where all the aircraft controlled, the control room." We went there. We've got a picture of the swearing-in, and we then went to the officers club. It was Friday, and there were lots of people in his group from the Air Force Academy, from Citadel, Virginia Tech, and others. And they were all talking. "Yeah, Edith got a mail-order commission." 

So I owed the Air Force two years, and I practiced at Andrews Air Force Base, which was the presidential squadron. You hear the president always leaving Andrews Air Force Base. So I think I was 29 maybe, but I was young, and here I was taking care of senators and other important people in government, and these are people I'd only seen on TV before. So I had a really good experience. I received many accolades, but also many letters from people for whom I cared for. And I was therefore invited to stay on in the Air Force, either go to Walter Reed or to San Antonio. I said, "No, I'm going to Georgetown." So one of the VIPs, if I mentioned his name, you would know, said and wrote a letter for me that the Air Force should give me whatever I wanted and whatever I needed to continue in the Air Force. So I received my Air Force pay while I was a fellow at Georgetown. 

So I stayed on. I got promoted early and engaged in Air Force work. I loved it, and I did well in that atmosphere and stayed on. After my second child was born, I decided I could not continue active duty and take care of two kids. So I left the Air Force, went to the University of Missouri, and someone called me one day and said, "You know, I hear you are at the University of Missouri now. Would you consider joining the National Guard?" I went, " Joining the National Guard? Why would the National Guard want an oncologist?" And the information was, the Air National Guard wants good doctors, and you've got a great record. They invited me to St. Louis to just see the National Guard squadron there. I filled out the application while I was there and in a few days was appointed to the National Guard. 

So after being there for a few years, I was discussing with one of the higher-ranking people in the National Guard who was in Washington, but visiting St. Louis. He said to me, "You know, you've done great work." He had gone through my record, and he said, "And you know, you're one of the people being considered to be in a group for promotion. Promotion at that time meant that it was a higher rank." So he said, "There's one thing you don't have in your records, however, and other competitors in your group have." I said, "What's that?" "You haven't been to flight school." I said, "Okay." He said, "And everybody who is going to be competing with you will have gone to flight school, and having a flight record will be an important part." 

So I was in my 40s. My oldest child was 14. I went to flight school and I got my certification, and obviously, I got promoted. And I am the first woman doctor to become a General in the history of the Air Force. And it was really interesting. I'm a Brigadier General. I'm invited to give a talk someplace, and there were lots of people there. So the person introducing me said, "And she is the first African American woman to become a General in the history of the United States Air Force." So I get up to speak and I thank him for this introduction. And I said, "Yes, I was the first Black woman physician to become a General. I said, but, you know, my ancestry says that I'm 30% something white. So I guess I was the first white woman, too." There was a big roar. But I loved every opportunity, and I worked hard at every opportunity.

 So when I was in the active duty Air Force, I was chief of the cancer center at Travis Air Force Base. So I made my application for research with the Northern California Oncology group, got, they said, one of the highest ratings of the applicants at that time. And I received a phone call from Air Force administration saying "Congratulations, but the Air Force cannot accept this funding from the National Cancer Institute." There is a law saying you can't transfer money from one area of the government to the other, as they called it, a "gift," but it was a grant. So I call Phil Schein and I tell him about the situation. And he already knew that I had received a top report, and he knew that I had the grant before I knew. So he says, "Well, let's see what we can do."

 Now, remember, Vince DeVita was the NCI Chair at that time and Dr. Rosenberg. At every ASCO meeting Phil, Vince, and Dr. Rosenberg would get together and they would bring their fellows. And Bill said, "Let me see what I can do.'" So somebody at NCI made some things happen. And I got this call from Saul Rosenberg. "Edith, congratulations." So I said, "Well, thank you, but I didn't expect a phone call from you." And he says, "Well, there have been some changes. Your grant, the face sheet has been changed." I said, "Oh." 

Pat Loehrer: Your husband again.

Dr. Edith Mitchell: I can't say who or what, but it had Stanford on it. So my grant went to Stanford. I'm sure they appreciated the kick you get. But Dr. Rosenberg said, "Your grant is now Stanford. We're setting up an account for you at Stanford, and the funding goes to Stanford." So I had people working for me at the Air Force Cancer Center who were Stanford employees.

Dave Johnson: Edith, there are still too few African American and particularly African American men in medicine. What's your perspective on that? 

Dr. Edith Mitchell: I think that many people are not given opportunities, and I've been concerned about Blacks and other racial and ethnic minorities not entering medicine, and particularly regarding oncology. So fewer than 5% of all practicing physicians in this country identify as Black. Little more than 5% identify as Hispanic. And I've been trying to do something about that. So ECOG-ACRIN has been very good about allowing me, and I set up with others, but I was the lead, a program for individuals - they could either be medical students, residents, fellows, or early faculty - to attend ECOG-ACRIN. And as a result of that program, we identified 12 individuals for each of the two ECOG-ACRIN annual meetings. We bring people in, and that has been a success. There's one person I introduced when she was a resident, she then did a fellowship in oncology, and it is now in her first year as faculty. And we have students mainly from Tennessee State. I do maintain very close relationships with Tennessee State, and I have the first Tennessee State student who has just been admitted to medical school at Jefferson. So trying to work with them. 

As a result of my work with the National Medical Association and the International Myeloma Foundation, we have a group of medical students that have been mentored for oncology. Whether they will become oncologists, I don't know, but they all 12 are doing well in medical school, and with some anticipation they might select oncology as their area of specialty. We set them up with an individual mentor, various oncologists around the country, and they have conducted research with their mentor. 

So I'm doing things that I think will be helpful to individuals. And I think we're not giving Blacks enough opportunities. Even in entering medical school, the number of Blacks entering most majority medical schools is still very low. Somewhere nine or ten students per year, Blacks entering medical schools. And also there has been a study conducted by the ACGME, which is the Accreditation Council for Graduate Medical Education, looking at graduate studies in oncology. Do you know that most of the oncologists have been trained at a few medical schools? And there are, I think it was 109 programs did not have a single minority student in the fellowship program. And that's terrible. I think that all fellowship programs should have some racial or ethnic fellows in their programs.

Dave Johnson: Yeah. One of the disturbing statistics that I've read from the AAMC is that the number of African American men applying to medical school in 2023 and 2022 is actually less than the number that applied in the '70s. It's puzzling to me why we've not been able to attract young men into the medical profession, and perhaps it's because there's a sense of not being wanted or encouraged into the profession. More African American women are applying, but even that number is small, at least in terms of the increase in what we've seen.

Pat Loehrer: Edith. You're also the Associate Director of Diversity Affairs at the Sidney Kimmel Cancer Center. What does the recent Supreme Court decision against Harvard in terms of admissions policy, how are you viewing that now at Jefferson?

Dr. Edith Mitchell: So I think that the Supreme Court decision certainly was disappointing, but it is what it is, and we've got to deal with it. That is the Supreme Court. So my suggestion and what I am telling students that they have to do, you do have the essay. So when I applied to medical school, I did not talk about Dr. Logan, my growing up on the farm, or my parents not finishing 8th grade. But if I were applying to medical school now, I would use all of that background to include in my essay. And the Supreme Court didn't say that you couldn't include that information in your essay. It said the schools could not use your racial background as a part of the equation, but your letter is still there, and therefore, I would include all of that in the essay, so that you do have an advantage. We've just got to be able to do what we've got to do, not put the university or the medical school at risk because of the Supreme Court decision. But there's nothing in that decision that says you can't include that information in your letter.

Dave Johnson: I have one question. What career advice would you offer your younger self? If you could speak to your 30-year-old self based on your knowledge, experience, what career advice would you give yourself?

Dr. Edith Mitchell: So the one thing that I did not do when I was about 30 years old and I'm not sure I even knew about it, I think I could have done more in health policy, and the one thing that I have not done is become a White House fellow. And that's usually early in your career plan. But I think my research would have suffered had I done that. And I still say I don't know that I made bad choices.

Dave Johnson: No, you didn't make bad choices. Knowing you, you could have been a White House fellow and done everything else you did.

Pat Loehrer: And your husband did not make a bad choice either.

Dave Johnson: Evidently not.

Pat Loehrer: Edith, thank you so much for joining us. You've had such an incredible life, and it's so rich, and we deeply appreciate your spending time with us. 

I want to also thank all our listeners of Oncology, Etc, which is an ASCO Education Podcast. This is as you know, where we talk about oncology medicine and everything else. If you have an idea for a topic or guest you'd like to see on the show, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, visit education.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. 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. Sparano is Professor of Medicine & Obstetrics, Gynecology, and Women's Health at the Albert Einstein College of Medicine, Associate Chairman for Clinical Research in the Department of Oncology at Montefiore Medical Center, and Associate Director for Clinical Research at the Albert Einstein Cancer Center. He also serves as Vice Chair of the ECOG-ACRIN Research Group and Vice Chair of the AIDS Malignancy Consortium. He is former director of the Hematology-Oncology Fellowship Program at Einstein/Montefiore,  co-directs the ECOG-ACRIN Young Investigator Program, and is a faculty member of the Calabresi K12 Oncology Training Program.  He is co-principal investigator of the Montefiore-Einstein Minority/Underserved National Community Oncology Research Program (NCORP) grant (in conjunction with Dr. Bruce Rapkin), which funds multicenter, NCI-sponsored clinical trials in cancer therapeutics, cancer prevention/control, and cancer care delivery research.  He is also the recipient of funding from the Breast Cancer Research Foundation that is supporting creation of a biospecimen bank designed to identify determinants of late relapse.

Dr. Sparano is a practicing clinician who specializes in medical oncology and clinical and translational cancer research. His research has focused on developmental therapeutic approaches for breast cancer, lymphoma, and HIV-associated cancers, and therapeutic application of molecular profiling in cancer.

TRANSCRIPT

Welcome to the ASCO University Weekly Podcast. My name is Joseph Sparano, and I am Associate Director for Clinical Research at the Albert Einstein Cancer Center, and chief of the section of breast medical oncology at Montefiore Medical Center in New York. Today, we contrast two cases on adjuvant treatment of breast cancer.
The standard treatment for hormone receptor positive, HER2 negative, early stage breast cancer is surgery, followed by endocrine therapy. Since the early 2000s, adjuvant chemotherapy has also been recommended to the majority of these women, but the added benefit from chemotherapy is modest for most.
Many different gene expression assays have been developed to determine prognosis and identify which woman may be more likely to benefit from chemotherapy. One commercial test that is recommended in clinical practice guidelines is a 21 gene recurrence score assay. Based on the recently completed TAILORx study, it was known that woman with low recurrence scores on the 21 gene expression assay do well with adjuvant endocrine therapy alone. Whereas woman with high recurrence scores benefit from adjuvant endocrine therapy and chemotherapy.
The TAILORx study clarified the best treatment option for women with an intermediate recurrence score, which was defined as a recurrence score of 11 to 25 in the trial. This is particularly important because the majority of patients fall in this intermediate risk category, up to 70%, in fact.
Before we discuss the new evidence reported from this study, let's take a look at two intermediate risk cases. These two cases are very similar, yet the recommended treatments may be very different. Can you identify the key differences between these two cases?
We begin with the first case. Case 1 is a 55-year-old postmenopausal woman with a node negative, ER positive, PR positive, HER2 negative breast cancer. The size of the tumor is 1.6 sonometers. The 21-gene recurrence score is 24, which is in the upper range of the intermediate risk category.
Which option would you recommend as the best systemic treatment. The choices in this case include endocrine therapy alone or chemotherapy followed by endocrine therapy. The correct answer to this question is, A, endocrine therapy alone. We will discuss the rationale for this recommendation shortly, but first let's move on to the second case.
The second case is a 44-year-old premenopausal woman with node negative, ER positive, PR positive, HER2 negative breast cancer. Like case 1, the size of the tumor is 1.6 centimeters and the 21-gene recurrence score is 24. Which option would be the best adjuvant treatment in this case? The choices here include endocrine therapy alone or chemotherapy, followed by endocrine therapy.
The correct answer in this case is chemotherapy, followed by endocrine therapy. Both of these cases had nearly identical clinical presentations. That is, they presented with ER, PR positive, HER2 negative breast cancer, associated with negative axillary nodes, a primary tumor size of 1.6 sonometers, and a 21-gene recurrence score of 24.
However, the key difference was the age at presentation, with one patient being in her mid 50's and postmenopausal, and the other patient being in her mid 40's and premenopausal. The TAILORx trial found that endocrine therapy was not inferior to chemotherapy plus endocrine therapy in the overall population with a mid-range 21-gene recurrence score of 11 to 25. However, there was an interaction between age, chemotherapy treatment, and recurrence score.
About 1/3 of women who participated in the trial were 50 or younger. These women seem to have some chemotherapy benefit if the recurrence score was between 16 and 25. For those who had a recurrence score of 21 to 25, the absolute reduction in the risk of distant recurrence was approximately 7% at 9 years. For a woman who had a recurrence score of 16 to 20, the absolute reduction in distant recurrence by the addition of chemotherapy was about 2%.
It remains unclear as to whether the benefit from chemotherapy in younger woman was due to a true cytotoxic effect associated with chemotherapy in eradicating micrometastatic disease, or a castration effect in inducing early menopause. Nevertheless, the findings from the TAILORx trial provide the highest level of evidence supporting the greatest level of precision in using the 21-gene assay to guide the use of adjuvant chemotherapy in early stage breast cancer.
Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the adjuvant treatment of breast cancer, including additional patient cases and opportunities for self-evaluation, visit the comprehensive e-learning center at university.asco.org. Thank you for your attention.
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.

Dr. Arun Singh, Co-Clinical Director of UCLA Sarcoma Clinic and Assistant Professor of Hematology and Oncology at UCLA, presents a self-assessment question from an ASCO University course focusing on the treatment of non-small cell lung cancers.

TRANSCRIPT

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

Hello, and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Jennifer Griggs from the University of Michigan, senior author on "Adjuvant Endocrine Therapy for Women with Hormone Receptor Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update." Thank you for being here, Dr. Griggs.

And thank you for the opportunity to talk about this focused update to the guidelines on extended adjuvant therapy. I would, of course, like to thank all my co-authors in the ASCO guidelines team for their contribution to this effort.

So first, can you give us a general overview of what this guideline covers and their research which informed this focus update?

Yes. First of all, the goal of the guideline was to give an update to the previous guidelines on this topic. And we specifically focused on extended adjuvant therapy. In particular, the aromatase inhibitors in women who had completed five years of adjuvant endocrine therapy. And it goes without saying, but it's worth reminding our listeners that the guideline is restricted only to post-menopausal women with hormone receptor-positive breast cancer. And, of course, our guidelines are only as good as the data upon which we rely. So for this guideline, six phase III randomized controlled trials met the pre-specified eligibility criteria for the updated systematic review and provide the evidence base for the guideline recommendations on the duration of aromatase inhibitor therapy. Each of the trials used the standard doses of the drugs that we use in practice today. So I'm not going to say the doses of each of the medications. So I'm going to go briefly over those six trials and just describe them so everybody's up to date with how the studies were designed.

So briefly, the first trial I'll describe is MA17R, which compares letrozole to placebo for five years in over 1,900 women who had already received 4.5 to six years of adjuvant therapy with an AI, proceeded in most women by treatment with tamoxifen. The second study is NSABP B-42. And this also compares letrozole to placebo in nearly 4,000 women who'd completed five years of endocrine therapy with either five years of an aromatase inhibitor or up to three years of tamoxifen followed by an aromatase inhibitor, for a total of five years.

The third study that we looked at is the DATA trial, which stands for the Different Durations of Adjuvant Anastrozole Therapy. This trial compared six years of adjuvant anastrozole with three years of adjuvant anastrozole in over 1,600 women after two to three years of adjuvant tamoxifen. The fourth trial out of the six is the IDEAL trial, the Investigation on the Duration of Extended Adjuvant Letrozole. This study randomized over 1,800 women to either 2 and 1/2 or five years of letrazole after five years of tamoxifen, an AI, or a combination in sequence of tamoxifen and an AI. So very similar study designs.

The fifth study is the ABCSG-16 trial, the Austrian Breast Cancer Study Group Trial 16, which randomized nearly 3,500 women following four to six years of adjuvant therapy with tamoxifen and AI or a sequence of tamoxifen and then an AI, to either two or five years of anastrozole as extended therapy. And finally, the study of letrozole extension, or the SOLE trial, randomized over 4,800 women with node-positive breast cancer who had completed five years of adjuvant endocrine therapy to receive either continuous letrozole for five years or five years of an intermittent schedule of letrozole given nine months on and three months off in years one to four and on continuously for a year or five.

So I know that's a lot to take in, but I do think it was important for our audience to understand the six trials that were included. These were all large studies, randomized, and patients had completed five years of adjuvant endocrine therapy. And then, were randomized either to placebo or different durations of an aromatase inhibitor or a placebo. For all of these studies, it's important to know that the primary outcome was disease-free survival. Overall survival and adverse events where secondary outcome.

Great. So given that research and those trials, what are the key recommendations for this guideline update?

Five key recommendations are included in this focused update to the previous guidelines. And they are for women with node-negative breast cancer, extended adjuvant aromatase inhibitor therapy can be offered for up to a total of five years of adjuvant therapy. Recommendations are based on considerations of recurrence risk using our usual established prognostic factors. However, since the recurrence risk is lower, the benefits are likely narrower in node-negative patients.

The guidelines panel recommends that women with low-risk, node-negative tumors should not routinely be offered extended adjuvant therapy. Now, that might sound vague. We did not make recommendations using genomic profiling results because we don't have sound data to support such views that we felt were strong enough to integrate genomic testing results. Our second recommendation is that women with node-positive breast cancer should be offered extended AI therapy for up to a total of 10 years of adjuvant endocrine therapy. And that means combined tamoxifen and aromatase endocrine therapy. That's the total that we meant to recommend.

Third recommendation is that women receiving extended adjuvant endocrine therapy should receive no more than 10 years of total treatment. The fourth recommendation is when given as prevention of secondary or contralateral breast cancer, the risk of second breast cancers based on prior therapy should inform the decision to pursue extended therapy. So what this means is specifically, a woman who has had a bilateral mastectomy will not reap the benefit of preventative therapy with endocrine therapy.

The fifth recommendation is that extended therapy carries ongoing risks and side effects, and these should be weighed against the potential absolute benefits of longer treatment in a shared decision-making process between the clinical team and the patient. Specifically, to date, none of the studies have shown improvement in overall survival with longer duration aromatase inhibitor therapy. As such, the recommendations, therefore, an extended adjuvant AI therapy are based on benefits that include prevention of distant recurrence and prevention of second breast cancers.

So why is this guideline so important and how will it change practice?

The importance of this guideline rests in the fact that it supports what many clinicians and patients are already doing in practice. The second is it recommends against durations of endocrine therapy longer than 10 years in the absence of data supporting such a practice. So it's our thought that doctors and patients and other care providers, nurse practitioners, physician assistants, primary care doctors, are already practicing what we're recommending, and it supports doing so. And the second is that for those providers and patients who aren't sure that 10 years is enough, this guideline suggests that 10 years is sufficient. We don't have any data supporting giving more than 10 years.

And the third recommendation is that this guideline really supports the need for shared decision-making, given the absence of data supporting an improvement in overall survival.

So finally, since you did mention shared decision-making, how does this guideline recommendation affect patients?

Well, the panel strongly believes that the tailored decision-making process is key in the decision to recommend extended adjuvant therapy. So tailoring on disease factors plays a role in the recommended duration of therapy. Obviously, since we stratified by high-risk and low-risk and what treatment's been received specifically. And if a woman's had bilateral mastectomy, she's not going to benefit from the risk reduction that's achieved with giving somebody extended therapy.

But in addition to disease factors, patient preferences and tolerance of therapy should inform clinician and patient decision-making. Again, since none of the studies have shown improvement in overall survival with longer duration of AI therapy, patients and their medical providers need to make decisions based on an awareness that the benefits include, specifically prevention of distant recurrence and prevention of second breast cancers. And the importance of those benefits is going to vary according to a patient and how she views her life going forward and how bad her side effects have been, how well she tolerates the therapy.

From my own personal point of view, as a breast oncologist, I believe two things. Number one, we should provide aggressive support for managing symptoms in patients who are most likely to benefit from extended therapy. That is, we should not stop therapy early if she is very likely to benefit if we haven't maximized control of her symptoms. There are many things we can do to improve symptoms and we shouldn't just stop therapy because she's not tolerating treatment if we haven't done the most that we can to improve her quality of life and her symptoms.

Conversely, my hope is that we are not doggedly persisting in recommending prolonged therapy in a patient who has a fear of recurrence but who has little to gain from extended therapy. In the latter case, high quality information support is more therapeutic than extended therapy with a medication that's proven, in randomized controlled trials and in her own personal experience, to decrease her quality of life with marginal, if any, medical benefit.

Thank you so much for the overview of this guideline today and thank you for your time.

Thank you.

And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

Dr. Daniel George is Professor of Medicine and Surgery, Director of GU Oncology for the Duke Cancer Institute, and Co-Chair of the DCI Center for Prostate and Urologic Cancers. Dr George's primary areas of interest are in drug development and optimizing care for patients with GU cancers, particularly prostate and kidney cancers. In this week's episode, Dr. George presents two contrasting cases with nephrectomy as a possible treatment path. Can you determine the best course of treatment for each patient?

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

TRANSCRIPT

Welcome to the ASCO University Weekly Podcast. My name is Dr. Daniel George. And I'm a professor of medicine and surgery at Duke University. I'm also the director of GU oncology at the Duke Cancer Institute and co-chair of the DCI Center for Prostate and Neurologic Cancers.

Today we'll discuss two similar cases of patients presenting with metastatic renal cell carcinoma in our multidisciplinary management options. Without any standard screening procedures, 20% to 30% of kidney cancer patients today present with metastatic disease. Historically, debulking nephrectomy has been our standard of care. And this has been based on old trials from the interferon era of treatments.

Since then, many drugs have been approved for the management of patients with metastatic renal cell carcinoma, many of which have improved the progression free survival and overall survival of patients with metastatic disease, which may have had an impact on the landscape and role for debulking nephrectomy.

Furthermore, metastatic kidney cancer patients can be risk stratified. There's a number of criteria used. But historically the most commonly used criteria has been the Memorial Sloan Kettering Cancer Center criteria. Which included five factors, including KPS score less than 70, a calcium score greater than 10, A serum hemoglobin of less than the lower limit of normal, and LDH greater than 1.5 times the upper limit of normal, or having their primary tumor in place, meaning no prior nephrectomy.

If patients had zero of these factors they were considered good risk with the best survival. Patients with one or two of these factors are considered intermediate risk. And patients with three or more of these factors historically have been very poor risk, with median survivals of six months or less.

The Carmena Study was a prospective, multi-center, randomized, non inferiority trial comparing upfront nephrectomy followed by sunitinib therapy, compared to upfront sunitinib therapy alone in patients with metastatic renal cell carcinoma amenable to cytoreductive nephrectomy.

We'll get to these results in a moment. But the study population included, importantly, patients with e cog performance status zero or one. And 40% plus of these patients were considered poor risk, with the average sum of metastatic tumor burden being greater than five centimeters.

So now, let's get to some modern cases. The first case we'll discuss is George. He's an 83-year-old man who presented with gross hematuria and a hemoglobin of 13.8 in the normal range. A CT scan revealed an eight centimeter right renal mass and multiple pulmonary mets, up to two centimeters in size.
His e cog performance status is zero. And his calcium was 8.4, and LDH was normal as well.

Our second case, for comparison, is Philip, a 76-year-old man who was found to have a 16 centimeter left renal mass incidentally on a spine MRI. This was confirmed by CT scan, along with some pulmonary nodules measuring up to 1.8 centimeters, as well as enlarged mediastinal lymph nodes up to two centimeters, and an eight millimeter liver lesion. His calcium score was 10.4. And his hemoglobin was 12.5, which was below the limit of normal. He had a normal LDH and an absolutely zero performance status.

So for these two cases, we have four choices. The first choice is for both cases a nephrectomy followed by systemic treatment, our historical approach. The second is systemic therapy first, with plus or minus a subsequent nephrectomy for both cases.

Our third choice would be to treat case number one with a nephrectomy, followed by systemic therapy, and case number two with systemic therapy first. And our fourth option would be systemic therapy first for case one and a nephrectomy first for case two.
Now, to me, when I look at these cases, the correct answer is three. Nephrectomy first for case one, and systemic therapy first for case two. Let me explain.

Even though these cases are fairly similar in age, gender, performance status, and had the presence of a large primary tumor, for case one this is an intermediate risk patient. This patient has lung only disease that's relatively low volume, a good performance status, and normal labs. In addition, he's symptomatic with gross hematuria. For these reasons, a debulking nephrectomy is really indicated. And because of his good performance status, he's very likely to recover well from the surgery, despite the fact that he's 83 years old.

Case two is subtly different. This is actually a poor risk patient. Even though his e cog performance status is zero, he has an elevated calcium, a decreased hemoglobin, and he's got his primary tumor still in place. That puts him into a poor risk category. And some of these patients never recover from surgery well enough to get systemic therapy.

He also has multi organ involvement, involving his lungs and nodes, and possibly even his liver. This is a patient that really mirrors the patient population of Carmena. Based upon this, I think systemic therapy first is a reasonable treatment option for this patient.
If we actually look at the results of Carmena, the study confirmed that sunitinib therapy alone, systemic therapy, was non inferior, and actually trended towards improved survival compared to cytoreductive nephrectomy followed by sunitinib.

The results suggest that for poor risk or for high volume metastatic patients, that systemic therapy first should be the standard of care.
But, importantly, not included in a Carmena study were patients that had low volume metastatic disease and intermediate risk features, or good prognosis. These patients not included in the Carmena study might still benefit first from a debulking or cytoreductive nephrectomy.

So thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the role of cytoreductive nephrectomy, including additional patient cases and opportunities for self-evaluation, visit the Comprehensive eLearning Center at university.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.

Dr. Yosef Landman is a graduate of the Sackler School of Medicine, Tel Aviv University. He is currently a medical oncology resident at Davidoff Cancer Center, Rabin Medical Center in Petach Tiqva, Israel. In today's episode, he discusses the recent approval of larotrectinib for tumor-agnostic treatment of advanced solid tumors containing NTRK gene fusion. Dr. Landman, a co-author on the journal paper Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion (Clinical Breast Cancer, June 2018), provides background on the recent approval as well as a case-based example of larotrectinib treatment.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

Dr. Ian Flinn, Medical Oncologist specializing in hematologic malignancies at Tennessee Oncology, discusses the recent FDA approval of duvelisib for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

TRANSCRIPT

(Intro Music Playing)
As a background to today's discussion, the PI3K are a family of lipid kinases that sit at the crossroads of numerous signaling events that drive many malignancies, including certain lymphomas, and chronic lymphocytic leukemia. There are four isoforms of the PI3K-- alpha, beta, delta, and gamma. Isoform specific inhibitors are attractive because they may lead to efficacy without the toxicity of pan inhibitors.

Idelalisib, which is a delta isoform inhibitor, was the first PI3K inhibitor be approved for lymphoma in CLL. The delta isoform is a particular interest in B cell malignancies because its expression is normally restricted to cells of a hematopoietic origin. In data from gene knockout models, show that it has a key role in B cell signaling, development, and survival.
Selective targeting of the delta isoform should not alter insulin signaling, which is mediated by the ubiquitously expressed alpha isoform. However, narrow targeting could lead to mechanisms of resistance to upregulation of other isoforms. This has been demonstrated in mantle cell lymphoma where the alpha isoform is expressed in relapse patients.

Duvelisib is a dual inhibitor of both the delta and gamma isoforms of the PI3K. Inhibiting the gamma isoform may be important because of its inhibitory effect, not only in the malignant cell, but also in the micro-environment, which provides important survival signals to malignant cells. Both idelalisib and copanlisib, an inhibitor of the delta and alpha isoforms, are currently FDA approved for third line follicular cell lymphoma. And idelalisib is approved in combination with rituximab in relapse CLL.

On September 24, 2018, the Food and Drug Administration granted approval for duvelisib for patients with relapsed refractory chronic lyphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma after at least two prior therapies. The approval of duvelisib in CLL was based on the DUO trial, a large international randomized phase III trial comparing duvelisib, at 25 milligrams orally, twice daily, to ofatumumab, given according to the package label. The results of the duo trial have been published in Blood.
In a subset analysis of 196 patients receiving at least two prior therapies, the median progression pre-survival was 16.4 months in the duvelisib arm, and 9.1 months in the ofatumumab arm, with a hazard ratio of 0.40. The overall response rate of 78% with duvelisib was twice the 39% seen with ofatumumab.

The follicular lymphoma indication is based on the Dynamo trial, a single arm multi-center trial of duvelisib, which enrolled 83 patients with follicular lymphoma who are refractory to rituximab and to either chemotherapy or radioimmunotherapy. The overall response rate, determined by an independent response committee, was 42%. Of the 35 responding patients, 15, or 43%, maintained responses for at least six months. And 6, or 17%, maintained responses for at least 12 months. The most common adverse reactions with an instance of greater than or equal to 20% were diarrhea, or colitis, neutropenium, rash, fatigue, pyrexia, cough, nausea, upper respiratory tract infection, pneumonia, muscle skeletal pain, and anemia.

Over the last decade, we've seen substantial advances in the treatment of low grade lymphoma and CLL, especially in the front-line setting. Unfortunately for patients with relapse and refractory disease, new agents are needed. The approval of duvelisib is an important addition to our armamentarium for these patients. And we'll have an immediate impact.

However, to have its greatest effect, strategies will need to be devised to move this drug earlier in the natural history of these diseases. Such approaches might include alternative dosing and scheduling, as well as combination regiments. Duvelisib is a novel PI3K inhibitor and is differentiated from other PI3K inhibitors, because it targets both the delta and gamma isoforms. Consequently, it is being studied in a broader array of diseases, including T cell malignancies, where promising activity has been seen.

(Outro Music Playing)
Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on drug approvals visit the comprehensive e-learning center at university.asco.org.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

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. Is my name Shannon McKernin and today, I'm interviewing Dr. Elena Stoffel from the University of Michigan, lead author of "Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion." Thank you for being here today, Dr. Stoffel.

I'm delighted to join you.

So first, can you tell us what a professional clinical opinion is and why this topic is so important to ASCO?

Well, a provisional clinical opinion is a statement that ASCO puts out when we are seeing trends that are relevant to the care of our patients but that may not necessarily have the level of evidence needed to include in a true clinical guideline. This particular provisional clinical opinion that deals with the management of patients with pancreatic cancer and their families is based on some new data that has been published regarding the prevalence of inherited factors influencing pancreatic cancer risk.

So what are the key statements of this Provisional Clinical Opinion or also known as a PCO?

This particular provisional clinical opinion, which is about just the inherited susceptibility to pancreatic cancer, was prompted by several recent publications, which found that the prevalence of genetic predisposition among patients with pancreatic cancer was much higher than we had originally anticipated. And this is relevant because in talking about pancreatic cancer as one of the deadliest cancers in both in the United States and worldwide, we are very interested in finding ways to reduce the morbidity from this cancer to patients and their families. And this particular provisional clinical opinion addresses the role that genetic risk assessment should have in the care of pancreatic cancer patients and also the role for clinical genetic testing, as well as the risks and benefits of pancreatic cancer screening for at risk family members.

What considerations are there for having these conversations with patients and their families?

Well, many times when we see families affected with cancer, one of the questions they have is what is the likelihood that this will happen to other individuals in our family and what can we do to prevent cancers in other family members. And I think what's important here is that review of the data from multi-gene panel genetic testing in unselected individuals diagnosed with pancreatic cancer identified pathogenic germline variants in 1 out of every 10 individuals. And this is really important because when you think about it, if 1 out of every 10 patients with pancreatic cancer develop their cancer in the setting of a genetic predisposition syndrome, this has tremendous implications for management both for them as well as for their family members.

One of the most common inherited cancer syndromes identified in families affected with pancreatic cancer is hereditary breast ovarian cancer associated with mutations of BRCA1 and BRCA2. As you know, there are definite screening recommendations we make for individuals who carry these genetic alterations. And certainly if a family member is diagnosed with a genetic alteration, then that has an impact for cancer screening and management.

Furthermore, there are emerging data about the utility of pancreatic cancer screening in high risk individuals. And while there's still some controversy about how to screen individuals at risk for pancreatic cancer, certainly there are some emerging data suggesting that this may have a role for early detection.

And finally, the panel included a discussion section on the limitations of the research and future directions. So what are the key points of this section?

I think that what we're learning is with genetic testing, and particularly with multi-gene panel testing, we are we often find unexpected results. Certainly variants of uncertain significance are not uncommon when multi-gene panel tests are used. And being able to interpret the clinical significance of some of these genetic test results can pose some challenges, especially for clinicians who don't have specific expertise in genetics. Certainly being able to deal with the volumes of patients who need genetic testing who are also battling pancreatic cancer, we want to make sure that we have the resources to be able to offer genetic testing to everyone who needs it.

And finally, in talking about screening for pancreas cancer, while there are some studies that have demonstrated that screening with MRIs and/or endoscopic ultrasounds has led to early detection and down staging of cancers in some cases, larger studies are needed to be able to refine more specifically who and how to screen individuals at risk for pancreas cancer.

Great. Thank you so much for taking your time today to discuss this PCO with us, Dr. Stoffel.

Thank you very much for having me.

And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. If you've enjoyed what you heard today, please rate and review the podcast and refer the show to a colleague.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

TRANSCRIPT

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

Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Scott Morgan from the Ottawa Hospital and University of Ottawa, lead author on "Hypofractionated Radiation Therapy for Localized Prostate Cancer: an ASTRO, ASCO, and AUA Evidence-Based Guideline." Thank you so much for being here today, Dr. Morgan.

It's my pleasure, Shannon. I'm happy to take part in the podcast and hopefully share the highlights of the guideline with your listeners.

So first, can you give us a general overview of what this guideline covers?

Yeah. So the guideline covers really hypofractionated external beam radiation therapy, which is a treatment for localized prostate cancer, and for the non-radiation oncology folks in your audience, I think it's important to begin by placing the guideline sort of in its context and going over some of the terminology that we use as radiation oncologists. So external beam radiotherapy, it's a standard treatment-- standard local treatment option for men with localized prostate cancer. It gives outcomes which are really equivalent to those of radical prostatectomy or brachytherapy, which are the other two standard local treatment options.

And traditionally, it's given in small daily fractions over several weeks and the usual daily fraction size is 1.8 to 2 Gray per day. And this is called conventional fractionation. And that really translates into a course of about seven and a half to nine weeks of treatment. And so that total dose which is delivered in those daily treatments, five days a week, is about 76 to 80 Gray. And that's what we call conventional or standard fractionation.

And there's a theoretical framework in radiation medicine and there's some evidence to accompany that that suggests that prostate cancer is quite sensitive to radiation fraction size. And just to give a brief primer, for any tissue, cancerous or non-cancerous, there's a sensitivity to fraction size and it's characterized by something called the alpha-beta ratio. And for prostate cancer, that's felt to be low compared to most other cancers, the alpha-beta ratio, and indeed, it's thought to be lower than the adjacent dose-limiting normal structure, which is the rectum.

And so an implication of that is that hypofractionation, and by that we mean daily fraction size of more than 2 Gray, might improve the therapeutic ratio of radiation therapy in localized prostate cancer. Now the guideline-- and I think it's important to emphasize this-- it draws a distinction between what we call moderate hypofractionation and ultra-hypofractionation. Clearly, fraction size is a continuous variable, so any subdivision that we might make is necessarily a bit arbitrary, but it turns out that at least in clinical practice, there's been really two distinct approaches to hypofractionation that have arisen.

And one of these is moderate hypofractionation and that's an approach where the fraction size is modestly higher than 2 Gray per fraction, and in the guideline, it's been defined as a fraction size between 2.4 and 3.4 Gray, whereas ultra-hypofractionation, this is defined in the guideline as a fraction size greater than 5 Gray. And it's also been referred to in the literature as extreme hypofractionation or Stereotactic Body Radiation Therapy, SBRT, or SABR, Stereotactic Ablative Radiation Therapy.

But in any case, we are talking here about, with ultra-hypofractionation, with radical courses of treatment that are often delivered over as few as five fractions, often on an alternate day approach over two or two and a half weeks. And so the guideline really was largely motivated by the publication of a number of randomized trials, including four large-scale trials in the past two years that have compared conventionally fractioned radiation therapy and moderately hypofractionated radiation therapy. So that is really what stimulated the guideline, which was the evidence concerning moderately hypofractionated radiation therapy.

But at the same time, there has been an increasing use in routine clinical practice that's been observed of ultra-hypofractionated radiotherapy, so the decision was made to make recommendations on it as well. So ASTRO, American Society for Radiation Oncology, in collaboration with ASCO and the AUA, convened a panel of radiation oncologists, medical physicists, urologists, radiation oncology resident, patient representative, and a systematic review of the literature was conducted and their recommendations have been made on the basis of this systematic review. So the aim was to provide recommendations on use of both moderate hypofractionation and ultra-hypofractionation, in particular with reference to oncologic outcomes, toxicity, and quality of life. So we didn't directly consider health economic endpoints, though clearly the very nature of hypofractionation is such that there are potential advantages in terms of cost and convenience for patients.

And what are the key recommendations of this guideline?

We separated the key recommendations into three main groups and the first set of recommendations pertains to moderate hypofractionation, and these are generally based on the highest-quality evidence. So they could be viewed as the strongest recommendations in the guideline. And the second set of recommendations concern ultra-hypofractionation. They're somewhat less strong given they're based on somewhat weaker evidence. And then the third set of recommendations relate to some of the technical aspects of the planning and delivery of hypofractionated radiation therapy.

So, dealing with the moderate hypofractionation recommendations first, arguably the most important recommendation of the guideline is that the panel has recommended that in patients with localized prostate cancer who are candidates for external beam radiation therapy, moderate hypofractionation should be offered. And this is graded as a strong recommendation. It's based on high-quality evidence and it applies to patients across all risk groups.

So it applies to patients with low-risk prostate cancer who require active treatment or who have declined active surveillance and it also applies to patients with intermediate-risk or high-risk localized prostate cancer. And why really does it apply to all these groups? It's essentially because these groups are well-represented in the trials of moderate hypofractionation. And the trials have shown that moderate hypofractionation really gives similar outcomes in terms of efficacy to conventional fractionation.

Now one caveat I guess that I should say is that the trials generally only looked at radiation therapy to the prostate rather than radiation therapy to the prostate as well as the pelvic lymph nodes. So the panel's recommendations regarding moderate hypofractionation don't apply to the scenario where the clinician has decided to include the pelvic lymph nodes in the radiation therapy volume. The panel also made recommendations with respect to toxicity and quality of life, and specifically, they did recommend that men should be counseled about a small increased risk of acute gastrointestinal toxicity, typically rectal toxicity, with moderately hypofractionated radiation therapy. And they should also be counseled that moderately hypofractionated radiation therapy has a similar risk of late GI toxicity and also has a similar risk of both acute and late GU toxicity compared to conventional fractionation. The only difference was seen in acute GI toxicity.

And I think it's probably worth dwelling on this a little bit more. Probably the most granular data on acute GI toxicity comes from the CHHiP trial. This was a trial from the UK. It was far and away the largest randomized trial of moderate hypofractionation versus conventional fractionation.

And they followed the amplitude of GI toxicity very carefully over the short and long term and what they did found was that in the early weeks, there was greater peak acute GI toxicity with moderate hypofractionation, but this difference had really disappeared by about 18 weeks after the start of radiotherapy. So within a few months, there was no difference, and afterwards, there was no consistent difference in long-term GU or GI toxicity across these trials. Now I guess I should mention that, at the current time, that the median follow-up of most of these trials is between five and six years, so arguably, the last word hasn't been written.

The panel also offered conditional recommendations on particular moderate hypofractionation regimens. There were multiple different regimens that were evaluated but most were not compared head-to-head. And the panel preferred two particular regimens-- 60 Gray and 20 fractions over four weeks or 70 Gray and 28 fractions over five and a half weeks, as these were the two regimens that were evaluated in the largest populations. And of these two, likely the strongest evidence supports 60 Gray and 20 fractions, given it was used in two different trials and it was used across all risk groups and with or without concomitant hormonal therapy. So those were the recommendations regarding moderate hypofractionation.

So moving to ultra-hypofractionation, again, this is talking about fraction size of at least 5 Gray, typically a course of as few as five fractions over perhaps two or two and a half weeks. I think it's important to say that, at the time we were preparing this guideline, there were no published efficacy or toxicity data from randomized trials comparing ultra-hypofractionation and conventional fractionation. So the strengths of the recommendations made by the panel is correspondingly lower than was the case for moderate hypofractionation.

But having said that, there are several prospective non-randomized studies that have been published and have documented safe delivery of ultra-hypofractionation for appropriately-selected patients and pretty good biochemical control and low toxicities have been observed in these studies. But again, relatively few have follow-up beyond five years.

So what the panel recommended was that in men with low-risk prostate cancer-- and the bulk of the data to date for ultra-hypofractionation has been in this group-- panel conditionally recommended that in those who decline active surveillance and choose active treatment with radiation therapy, that ultra-hypofractionation may be offered as an alternative to conventional fractionation. Again, this is a conditional recommendation.

In men with intermediate-risk prostate cancer, the panel has conditionally recommended that ultra-hypofractionation may be offered as an alternative to conventional fractionation but it's strongly recommended in this group that these patients be treated as a part of a clinical trial-- and there are several clinical trials ongoing-- or as part of the multi-institutional registry. And then finally, in patients with high-risk localized prostate cancer, there was really insufficient comparative evidence for the panel to suggest offering this outside of a clinical trial or outside of a registry.

Regarding particular regimens, that the panel again made a conditional recommendation that a schedule of 35 Gray to 36.25 Gray and five fractions delivered to the planning target volume could be offered and that it recommended against consecutive daily treatments for this schedule. So I think it's again important to note that compared to moderate hypofractionation, the ultra-hypofractionation literature is really substantially less mature and it is evolving rapidly. And therefore, a short-term update of this guideline to address new data pertaining specifically to ultra-hypofractionation is likely going to be necessary.

And then I mentioned there was a third set of recommendations and these pertain to the technical aspects of planning and delivering radiation therapy. And these probably are not of core interest to your audience, but briefly, the guideline recommends that in the planning of hypofractionated radiotherapy, that normal tissue constraints and target volumes derive from published reference standards the use and that image guidance and intensity modulation at one form or another are recommended in delivering hypofractionated radiotherapy.

Great. Thank you for the overview of those guideline recommendations. So why is this guideline so important and how will it change practice?

Yeah. I guess the first point to make is that the guideline potentially can inform the care of a very large number of patients. Across North America, about 200,000 patients a year are diagnosed with prostate cancer and its far and away that the most prevalent non-dermatologic cancer in men and it's the third-leading cause of cancer death in men, at least in North America. So the vast majority of those 200,000 men are diagnosed with localized disease at the time of presentation and therefore they're potentially treatable with radiation therapy and therefore the guideline is relevant to these patients.

Prior to the publication of the trials that motivated this guideline, the overwhelming majority of these men who chose external beam radiotherapy as their primary treatment have been treated with conventionally fractionated therapy. In other words, seven and a half to nine weeks of treatment. And already, since the publication of these trials-- the trials of moderate hypofractionation-- we're talking really about moderate hypofractionation because I think that is where the guideline will have its impact, at least in the short term. In the jurisdiction where I practice in Canada, practice has already substantially changed in light of these trials, and I think a large majority of patients with localized prostate cancer choosing external beam radiation therapy are now typically being treated with a moderately hypofractionated approach, typically a four-week schedule. So it will be interesting to see if a similar change is occurring or will occur over time in the United States, particularly informed or potentially informed in part by this guideline.

And then finally, with respect to ultra-hypofractionation, I think again I have to note that this is a very dynamic space in terms of evidence and there are a number of large-scale trials looking at ultra-hypofractionation and comparing it to either conventional fractionation or moderate hypofractionation that are in progress or near to reporting. And so again, an update of the guideline in the short-term as data emerges from these studies will likely be important and it may ultimately influence practice as well on a large scale.

And finally, how will these guideline recommendations affect patients?

So I think in the short term, that the recommendation that has the potential to impact patients in the greatest way is the recommendation regarding moderate hypofractionation. And the guideline really recommends that this is a management approach that substantially reduces the treatment burden without compromising treatment efficacy and without increasing the risk of long-term side effects. So in my view, the move to moderately hypofractionated radiation therapy is a win for patients with localized prostate cancer who choose radiation therapy as their primary treatment modality.

And so moderate hypofractionation really represents about a halving of the overall treatment time in some patients. And those who live, for example, in rural or remote areas and who need to travel considerable distance to have their treatment, a halving of treatment time is significant. But I think even more generally, halving of treatment time is significant for patients regardless of where they live. And clearly there are also benefits potentially in terms of cost and also benefits in terms of for the health care system but those really weren't specifically studied in the guideline.

Great. Thank you so much for your time today, Dr. Morgan, and thank you for your work on this important guideline.

My pleasure, Shannon, and thank you for having me.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

Dr. Axel Hauschild, professor of dermatology and head of the dermato-oncology department at the University Hospital of Kiel in Germany, discusses the recent FDA approval of cemiplimab, a PD-1 antibody treatment for patients with metastatic or locally advanced cutaneous squamous cell carcinomas.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

TRANSCRIPT

[MUSIC PLAYING]
Welcome to the Recent Approvals episode of the ASCO University Weekly Podcast. My name is Axel Hauschild. I'm a professor of dermatology and head of dermato-oncology at the University Hospital of Kiel in Germany.
Today, we will discuss the approval of cemiplimab, a new PD-1 antibody for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinomas. As a background to today's discussion, immune checkpoint inhibitors are active therapies in patients with other cutaneous malignancies, like melanomas and mucosal carcinomas already.
So far, chemotherapy was given as a routine for patients with advanced or metastatic cutaneous malignancies, and occasionally, cetuximab, an EGFR inhibitor. However, in almost all of these patients, the responses were short-lasting. The analysis of the tumor mutational burden indicated a high sensitivity of more or less all UV-induced cutaneous malignancy for immune checkpoint inhibitors. Therefore, theoretically, cutaneous squamous cell carcinomas are ideal tumors for the treatment with PD-1 or PD-ligand 1 antibodies.
On September 28 of 2018, cemiplimab was approved by the FDA for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinomas who are not candidate for curative surgery or curative radiation. These data led to the approval of a flat dose of 350 milligrams cemiplimab infused over 30 minutes every three weeks.
The approval of cemiplimab was based on a high number of clinically meaningful and durable objective responses observed in patients with two different clinical trials. The results have already been published in 2018, in June, in the New England Journal of Medicine.
Both clinical trials were non-randomized, multicenter studies in patients for whom surgery or irradiation was not recommended. Among 108 patients with advanced cutaneous squamous cell carcinomas, including 75 metastatic patients, the overall response rate was 47%, with 4% complete and 44% partial responses. There were no significant differences in the response rate between patients with metastatic and those with locally advanced disease.
The median response duration was not reached. And 61% of the responses were durable for six months or longer. Response rates and durability results were consistent across the advanced squamous cell carcinoma subtypes. For patients with locally advanced cutaneous squamous cell carcinomas, the radiographic response rate correlated with clinically relevant shrinkage of visible and often disfiguring tumors demonstrated in the photographic data obtained in these clinical trials.
Safety data were evaluable from 434 patients who received cemiplimab in both clinical trials. Serious adverse events were typically immune-mediated, such as colitis or pulmonitis. And in some patients, infusion reactions were observed. The most common adverse events were fatigue, rash, and diarrhea. The treatment discontinuation rate was 12%.
The approval of cemiplimab marks a significant advancement in the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinomas. Cemiplimab is considered as a new standard of care in these patients, since not only an impressive response rate of almost 50%, but also durable responses were observed.
As mentioned before, previously, chemotherapies and cetuximab have been used for these patients with limited efficacy, particularly because most responses were only short-lasting. Important to mention is that the approval is not going along with a biomarker test, such as the measurement of PD-ligand 1 expression. Therefore, cemiplimab can be used for all comers with metastatic or locally advanced cutaneous squamous cell carcinomas.
So far, there are no data available when cemiplimab has been combined with other agents or irradiation. Also, data from the adjuvant of PD-1 antibodies in high-risk cutaneous squamous cell carcinoma patients are outstanding. However, clinical trials on cemiplimab and other PD-1 antibodies are already planned.
In conclusion, cemiplimab adds significantly to the success story of PD-1 and PD-ligand 1 antibodies in cutaneous malignancies. The approval of cemiplimab for cutaneous squamous cell carcinomas leads to changes in the current guidelines for this tumor.
Thank you very much for listening to this week's episode of the ASCO University Weekly Podcast. For more information on immune therapy and the treatment of cutaneous squamous cell carcinomas, visit the comprehensive eLearning Center at university.asco.org.
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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.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a moment to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

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. My name is Shannon McKernin and today I'm interviewing Dr. Valerie de Haas from Princess Máxima Center for Pediatric Oncology in the Netherlands, lead author on "Initial Diagnostic Workup of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the CAP and ASH Guideline."

Thank you for being here today, Dr. de Haas.

Thank you.

So first, can you give us a general overview of what this guideline covers?

Well, yes. The laboratory evaluation of patients who are suspected of having acute leukemia is very complex, and it has evolved significantly with the incorporation of advanced laboratory techniques. The traditional backbone of initial workup of AL, of acute leukemia, is composed of ctyomorphology, cytochemistry, immunophenotyping, and molecular cytogenetics.

These techniques are the backbone of the initial diagnostic workup of acute leukemia. This is leading to risk stratification and fine tuning of the therapy by molecular signatures. The advanced molecular diagnostics, such as next-generation sequencing, has become more important in the diagnosis and in the risk stratification of acute leukemia.

This guideline is meant for both pediatric and adult patients, and it was initially published in 2017. This year, we reviewed this guideline, and we have taken into account two important developments.

First, since 2017, we've seen that there are major advances in molecular techniques and also that we can identify and validate new molecular markers. And those two events have contribute to a better risk stratification. And the second development is the effect that the WHO classification was revised in 2017 which also has led to new risk recoveries and refined subclassifications.

So what are the key recommendations of this guideline?

Well, in total, we have reviewed 27 guideline statements by the ASCO endorsement expert panelists. And discussion points are used to summarize issues that were identified from the updated literature. The ASCO expert panel determined that the recommendations from the guideline as published in 2016 are clear, thorough, and they are based upon the most relevant scientific evidences.

We fully endorse the CAP-ASH guideline on initial diagnostic workup of acute leukemia. And we decided to include some discussion points according to clinical practice and according to the updated literature. In fact, we identified four categories of key recommendations. The first one is the initial diagnostics focusing on basic diagnostics and determination of risk parameters.

This concerns, in total, about 11 guideline recommendations, and they give an overview of the initial workup varying from the collection of the clinical history of the patient to initial basic diagnostics by cytomorphology, flow cytometry and molecular cytogenetic analysis of peripheral blood, bone marrow, and cerebrospinal fluids.

Secondly, the second category were molecular markers and MRD detection, and they were addressed by 10 of the recommendations. And these recommendations give a structural overview of the molecular and cytogenetic workup for acute lymphoblastic leukemia versus acute myeloid leukemia identifying different prognostic markers.

Also, the detection of MRD is taken into account in this recommendation. There is a major difference between children and adults, and this part is given most attention in the discussion part as the developments have been major during the past few years.

The third one is the context of referral to another institution with expertise in the management of acute leukemia. This is addressed by four recommendations, emphasizing the point that referral to an institution with specific expertise is of major importance for the central workup of acute leukemia.

And finally, the final reporting and report keeping is reflected in three recommendations, mainly supporting conclusions from 2017 which were describing the fact that the complete report with basic diagnostics in one central report should be available within 48 to 72 hours. And this should be followed by complete, final, comprehensive report in one or two weeks.

So can you tell us about those discussion points that were made and why the panel decided to include these?

The discussion points include mostly issues regarding diagnostics that involve flow cytometry and molecular techniques as addressed in part one and two of the guidelines. We think that the cytomorphologic assessment is essential for initial diagnosis of acute leukemia.

Multicolor flow cytometry using 8 to 10 colors has led to a better distinction between myeloids, lymphoid, and mixed lineage blast origin. Even when the number of cells are limited, for instance in CNS involvement, fine needle aspirate of extramedullary leukemic infiltration, or skin biopsy for leukemic cutis.

Also, it was suggested to better assess the central nervous system involved in leukemia. The expert panel recommends the immunophenotyping studies as an additional detection technique next to the cytomorphological examination of cytospins and particularly for those with a low level involvement of acute leukemia that cannot be well addressed by a morphologic examination only.

The TDT immunohistochemistry staining of cytospins has alternatively been used for detection of CNS disease in AML and evaluation of CSF by multicolor flow cytometry has been recently adopted in some centers. Flow cytometry, using at least six, but we now use in some laboratories, even 8 to 10 colors has led to a much more specific in tentative diagnosis. And this has improved the detection of CNS involvement.

The use of molecular tools, for instance, polymerase change reaction, PCR, NGS for low-level CSF involvement is still under study, and therefore, we did not recommend this in our discussion.

Regarding the molecular markers and MRD detection, the discussion here was mainly based upon the results of translational research supported by better molecular detection techniques. And those molecular diagnoses have been developing in the past few years with the inclusion of many more molecular markers. And they included one of the key diagnostic criteria in the revised WHO classification, which was revised in 2017. And we made substantial changes that have been made in the ASH-CAP guidelines concerning molecular diagnostics.

Those newly identified targets by advanced molecular techniques give possibilities for better risk stratification. Some examples of better molecular characterization of acute lymphoblastic leukemia are, for instance, additional testing for MLL translocations. Furthermore, we can look in patients with T-ALL for NOTCH1, and FBXW7 mutations.

The Ikaros family zinc finger gene, the IKZF1 gene is frequently deleted in adults as well in children with B-ALL. And it was shown to have an independent prognostic significance and was also associated with poor clinical outcome.

In the current text of the current risk that the protocols IKZF1 should be regularly included in the screening panels for all ALL patients.

If we look for examples for better characterization of AML, acute myeloid leukemia, we have found an increasing number of additional cytogenetic aberrations, like for instance FLT3 ITD which is associated with poor outcome.

Another example is appropriate mutational analysis for kids, which can be detected both in adult patient as pediatric patients with a confirmed core binding factor acute myeloid leukemia. So this is myeloid leukemia with a translocation A21, RUNX1, or inversion 16.

This recommendation is very strong in adults, whereas in children, this prognostic fact impact remains unclear. So there have been proven several publications which refer to a similar prognosis for children and others who refer to a poor prognosis in comparison to known mutated genes. So we suggest to test for this mutation in adults, especially, but also in children to learn from it.

Finally, emerging evidence supports molecular studies as principle test for monitoring minimal residual disease of acute leukemia. And there are several key molecular markers that are included in the initial workup, which will be carried on for monitoring MRD, for instance, PML- RAR-alpha, RUNX1-RUNXT1, CBFB-MYH11, and NPM1, CEBP-alpha and others.

Beside those aforementioned markers, it's very important to screen for other molecular markers that have predictive or prognostic value in the individual. And it is possible to use them for MRD. We have found a recent consensus from the European Leukemia Net MRD Working Group, who was proposing that for detection of molecular MRD, and they refer the RT PCR platform to NGS and digital PCR platforms.

Although all those molecular techniques have been developed very quickly and it is very tempting to use them for initial diagnostics, currently, not all laboratories will have all those techniques available. So the expert panel strongly advises understanding to make distinction between diagnostic that are needed in the first phase to start treatment and subsequently, treatment stratification, in contrast to the usual dose findings in a broader research.

For instance, available karyotyping, FISH, PCR techniques, if possible, NGS can be used in the initial start of treatment, whereas techniques like whole exome sequencing, whole genome sequencing, RNA sequencing, and epigenomic studies are meant for a broader research.

And finally, how will these guideline recommendations affect patients?

Well, in the end, the patients will receive better and especially, more personalized treatment. If we have results available within two weeks from diagnosis, it will be possible to better identify which basis will better benefit from more intensified and more personalized treatment, whereas others may need less intensive treatment with less toxicity.

If you use traditional techniques to do this supported by molecular techniques like karyotyping, FISH, and PCR techniques, and in the end, following MRD to see which patients are responding to treatment, MRD detection will help to identify these patients and stratify them finally to the best treatment.

Great. Thank you for your work on this important guideline, and thank you for your time today, Dr. de Haas.

OK. Thanks a lot.

And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

In this episode of ASCO Educational podcasts, we'll explore how we interpret and integrate recently reported clinical research into practice. Part One involved a 72-year old man with high-risk, localized prostate cancer progressing to hormone-sensitive metastatic disease. Today's scenario focuses on de novo metastatic prostate cancer.

Our guests are Dr. Kriti Mittal (UMass Chan Medical School) and Dr. Jorge Garcia (Case Western Reserve University School of Medicine). Together they present the patient scenario (1:13), going beyond the one-size-fits-all approach (4:54), and thinking about the patient as a whole (13:39).

Speaker Disclosures
Dr. Kriti Mittal: 
Honoraria – IntrinsiQ; Targeted Oncology; Medpage; Aptitude Health; Cardinal Health 
Consulting or Advisory Role – Bayer; Aveo; Dendreon; Myovant; Fletcher; Curio Science; AVEO; Janssen; Dedham Group 
Research Funding - Pfizer

Dr. Jorge Garcia: 
Honoraria - MJH Associates: Aptitude Health; Janssen
Consulting or Advisor – Eisai; Targeted Oncology
Research Funding – Merck; Pfizer; Orion Pharma GmbH; Janssen Oncology;  Genentech/Roche; Lilly 
Other Relationship - FDA

Resources 
ASCO Article: Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019

ASCO Course: How Do I Integrate Metastasis-directed Therapy in Patients with Oligometastatic Prostate Cancer? (Free to Full and Allied ASCO Members)

If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org.

TRANSCRIPT

Disclosures for this podcast are listed on the podcast page. 

Dr. Kriti Mittal: Hello and welcome to this episode of the ASCO Education Podcast. Today, we'll explore how we interpret and integrate recently reported clinical research into practice. In a previous episode, we explored the clinical scenario of localized prostate cancer progressing to metastatic hormone-sensitive disease. Today, our focus will be on de novo metastatic prostate cancer. My name is Kriti Mittal and I am the Medical Director of GU Oncology at the University of Massachusetts. I am delighted to co-host today's discussion with my colleague, Dr. Jorge Garcia. 

Dr. Garcia is a Professor of Medicine and Urology at Case Western Reserve University School of Medicine. He is also the George and Edith Richmond Distinguished Scientist Chair and the current Chair of the Solid Tumor Oncology Division at University Hospitals Seidman Cancer Center. 

Here are the details of the patient case we will be exploring: The patient also notes intermittent difficulty in emptying his bladder with poor stream for the last six months. A CT scan of the abdomen and pelvis demonstrates enlarged prostate gland with bladder distension, pathologically enlarged internal and external iliac lymph nodes, and multiple osteolytic lesions in the lumbar sacral, spine, and pelvic bones. A CT chest also reveals supraclavicular lymphadenopathy and sclerotic foci in three ribs. So this patient meets the criteria for high-volume disease and also has axial and appendicular lesions. 

The patient was admitted for further evaluation. A bone scan confirmed uptake in multiple areas identified on the CT, and a PSA was found to be greater than 1500. Biopsy of a pelvic lymph node confirmed the diagnosis of prostate cancer. This patient is somewhat different from the first case we presented in terms of timing of presentation; this patient presents with de novo metastatic high-volume disease, in contrast to the first patient who then became metastatic after undergoing treatment for high-risk localized disease. 

Would you consider these two cases different for the purposes of dosing docetaxel therapy when you offer upfront triplet therapy combinations? 

Dr. Jorge Garcia: That's a great question. I actually do not. The natural history of someone with localized disease receiving local definitive therapy progressing over time is different than someone walking in with de novo metastatic disease. But now, with the challenges that we have seen with prostate cancer screening, maybe even COVID, to be honest with you, in North America, with the late care and access to testing, we do see quite a bit of patients actually walking in the office with de novo metastatic disease. So, to me, what defines the need for this patient to get chemotherapy is the volume of his disease, the symptoms of his disease – to be honest with you – and the fact that, number one, he is clinically impaired. He has symptomatic disease, and he does have a fair amount of disease, even though he may not have visceral metastasis. Then his diseases give him significant pain. 

Oral agents are very good for pain control. I'm not disputing the fact that that is something that actually these agents can do. But I also believe I'm senior enough and old enough to remember that chemotherapy, when it works, can actually really alleviate pain quite drastically. So for me, I think that the way that I would probably counsel this patient is to say, "Listen, we can give you ADT plus an oral agent, but I really believe your symptomatic progression really talks about the importance of rapid control of your disease." And based upon the charted data from the United States, and equally important, PEACE-1, which is the French version of ADT, followed by abiraterone, if you will, and certainly ARASENS is the standard of care for me for a patient like this will be triple therapy with ADT and docetaxel. 

What I think is important for us to remember is that, in ARASENS, it was triple therapy together. I am worried sometimes about the fatigue that patients can have during the first six cycles of docetaxel. So oftentimes, I tell them if they're super fit, I may just do triple therapy up front, but if they I think they're going to struggle, what I tell them is, "Hey, we're going to put you on ADT chemotherapy. Right after you're about to complete chemo, we'll actually add on the darolutamide." So I do it in a sequence, and I think that's part of the data; we just still don't know if it should be given three at front or ADT chemo, followed by immediately, followed by an ARI. So I love to hear if that's how you practice or you perhaps have a different thought process.

Dr. Kriti Mittal: So I usually start the process of prior authorization for darolutamide the day I meet them for the first time. I think getting access to giving docetaxel at the infusion center is usually much faster than the few weeks it takes for the prior authorization team to get copay assistance for darolutamide. So, in general, most of my patients start that darolutamide either with cycle two or, depending on their frailty, I do tend to start a few cycles in like you suggested. I've had a few patients that I've used the layered-in approach, completing six cycles of chemotherapy first and then layering in with darolutamide. 

I think conceptually the role of intensifying treatment with an androgen receptor inhibitor is not just to get a response. We know ADT will get us a PSA response. I think the role of an androgen receptor inhibitor is to prevent the development of resistance. So, delaying the development of resistance will be pertinent to whether we started with cycle one, cycle six, or after. So, we really have to make decisions looking at the patient in front of us, looking at their ECOG performance status, their comorbidities, and frailty, and we cannot use a one-size-fits-all approach. 

Dr. Jorge Garcia: Yeah, I like that and I concur with that. Thank you for that discussion. I think that you may recall some of our discussions in different venues. When I counsel patients, I tell the patients that really the goal of their care is on the concept of the three Ps, P as in Peter. The first P is we want to prolong your life. That's the hallmark of this regimen, the hallmark of the data that we have. That's the goal, the primary goal of these three indications is survival improvement. So we want to prolong your life so you don't die anytime soon from prostate cancer. 

The second P, as in Peter, is to prevent, and the question is preventing what? We want to prevent your cancer from growing, from growing clinically, from growing radiographically, and from growing serologically, which is PSA and blood work. Now, you and I know and the audience probably realize that the natural history of prostate cancer is such that traditionally your PSA will rise first. There is a lead time bias between the rise and the scan changes and another gap in time between scans and symptoms. So it's often not the case when we see symptomatic disease preceding scans or PSAs, but sometimes in this case, it's at the same time. So that is the number one. And as you indicated, it's prevention of resistance as well, which obviously we can delay rPFS, which is a composite endpoint of radiographic progression, symptomatic progression, and death of any cause. 

But the third P is I called it the P and M, which is protecting and maintaining, and that is we want to protect your quality of life while we treat you. And we want to maintain your quality of life while we treat you. So to me, it's critically important that in addition of aiming for an efficacy endpoint, we don't lose sight of the importance of quality of life and the protection of that patient in front of us. Because, undoubtedly, where you get chemo or where you get an oral agent, anything that we offer our patients has the potential of causing harm. And I think it is a balance between that benefit and side effect profile that is so critically important for us to elucidate and review with the patient. 

And as you know, with the charted data, Dr. Alicia Morgans now at Dana-Farber, published a very elegant paper in JCO looking at the impact of docetaxel-based chemotherapy as part of the charted data in the North American trial and into quality of life. And we clearly define that your quality of life may go down a bit in the first few months of therapy, predictably because you're getting chemotherapy. But at the end of the six months, nine months, and certainly at the end of a year mark, the quality of life data for those who receive ADT and chemotherapy was far better than those who actually got ADT alone. 

Now, if you look at the quality of data for RSNs, a similar pattern will appear that although chemotherapy is tied to misconceptions of significant toxicity, in our hands, in good hands, and I think our community of oncology in North America are pretty familiar with the side effects and how to manage and minimize side effects on chemotherapy, I think it still requires a balance and a thoughtful discussion to make sure that we're not moving forward chasing a PSA reduction at the expense of the quality of life of the patient. So I think orchestrating that together with the patient as a team is critically important as well. 

Dr. Kriti Mittal: Thank you, Dr. Garcia. Moving on to the next concept we'd like to discuss in today's podcast the role of PARP inhibitors. Case Two was treated with androgen deprivation docetaxel and darolutamide. Consistent with current guidelines, the patient was also referred to germline testing and was found to be BRCA 2-positive. The patient's disease remained stable for 24 months, at which time he demonstrated disease progression, radiographically and clinically, and his disease was termed castration-resistant. There has been a lot published in the last few years regarding the role of PARP inhibitors in metastatic castration-resistant prostate cancer, or mCRPC. 

The PROfound trial led to the approval of olaparib in patients with deleterious mutations in HRR genes for those who had been treated previously with AR-directed therapy. The TRITON2 trial led to the approval of rucaparib in the same month for mCRPC patients with BRCA mutation for those patients who had previously been treated with AR inhibitors and taxine-based chemotherapy. More recently, we saw data from the TRITON3 trial exploring the role of rucaparib versus physicians' choice of docetaxel versus AR-inhibitor therapy in the mCRPC space for patients harboring BRCA 1, BRCA 2, or ATM mutation. Based on these data, it would be very tempting to offer a PARP inhibitor to the patient in case two. While regulatory authorities are still reviewing those data for approval, how would you consider treating this newly castrate-resistant patient in the frontline setting? Would you consider a PARP inhibitor in the frontline treatment of mCRPC in this patient with a BRCA 2 mutation?

Dr. Jorge Garcia: So that's a loaded question, to be honest with you. We have compelling data, but controversial data, as you know as well. So I think that since we have a genomic profile on this patient and we know he had high volume disease, then the first thought to me is not a genetic or a genomic question or a sequence. It's actually a clinical question, to be honest with you. And that is: How are you progressing? Because I think that if you're progressing serologically, you and I may think of that patient differently. If you're progressing radiographically with alone plus minus PSA production but no symptoms, you may also tilt your scale into this life-prolonging agents in a different way. Whereas if you have true symptomatic disease, knowing what you know, prior therapy, CrPC with a BRCA 2 alteration, then you may actually go for something different.  

So if it's a rising PSA, if it is radiographic, but the patient is stable clinically, is not basically compromised by symptomatic disease, I do feel that a PARP inhibitor as a single agent would be a very reasonable choice. In this case, you can use, obviously, rucaparib. You can use olaparib. I don't have a vested interest in either/or. I think either/or is fine. The subtleties and side effects, as you know, the olaparib data was probably the data that you and I probably are more accustomed to, used to the most just by virtue of how the agents got registered in the United States. But either/or, I think a PARP inhibitor would be a reasonable approach.  

I think the question perhaps, and I pitch that back to you, is what are you looking for with a PARP inhibitor? Because, as you know, all DNA repair deficiencies are not biologically the same. They do not respond the same way to PARP inhibitors. And even BRCA 2, where we think it's monoallelic or biallelic, may have subtleties in how those patients respond to PARP therapy. But the answer is yes, obviously, you have a biomarker, the patient has it, you can use it. I think the question is, how are you going to follow the patient? And what is going to be the endpoint that you're going to pay attention to in this case to find that the patient has a benefit or not granted, that could be PSA driven, but I think that perhaps I'm pushing you to think beyond PSA. 

Dr. Kriti Mittal: I agree, Dr. Garcia. I think we need to think about the patient as a whole. PSA-based changes in treatment are not generally part of our practice. I think evaluating the patient for symptoms and also thinking about the sites of progression, sites of disease they've had in the past, preventing development of cord compression, because some of these patients progress very rapidly and present with cord compression at the time of progression. Those are the things we are trying to predict and prevent. I think in a patient with BRCA 2 mutation, in this situation, I would feel compelled to offer rucaparib, given that even in the intention-to-treat analysis, the hazard ratio was 0.6 in terms of median progression-free survival. I think what was quite impressive was the subset analysis comparing rucaparib versus docetaxel. And that was something surprising. And I think we'll have to wait for long-term outcomes. But certainly, for a BRACA 2-mutated patient, this could be a reasonable consideration provided the drug is available and approved. 

Dr. Jorge Garcia: As you know, the three most common DNA repair deficiencies that we see are BRCA1, BRCA2, and ATM. BRCA2 is probably the one that we see the most. But we also recognize that with the limited data we have for ATMs, that patients with an ATM abnormality do not tend to benefit the most. And then yet we have also another series of DNA repair deficiencies, deficiencies, PALB2, CHEK2, CDK12 and so forth. And yet we have some exquisite responses to some of those patients.  

So I can tell you that I have a patient of mine who had an ATM mutation, a germline ATM mutation, and I predicted that initially that the likelihood of benefit to a PARP inhibitor would be low. He was placed on a PARP inhibitor and surprise, surprise, he was on a PARP inhibitor for almost a couple of years. What I want to convey to the audience is that if you have the appropriate biomarker, you certainly should consider a PARP inhibitor in this scenario.  

I think the bigger question is also understanding that not every DNA repair would benefit the same way. So being very thoughtful and very structured as to how you're going to manage the patient, it cannot be PSA only, the patient has to be followed radiographically and clinically because I would argue that if this patient had just a serologic progression, I would put the patient on a PARP inhibitor and the PSA kinetics change north, but slowly, what is the urgency of you switching the patient to something else?  

And also the misconception that if you look at PROfound, that olaparib for that matter has to always be given after docetaxel. That's not the case. The makeup of PROfound is different than this patient, obviously, because this patient got triple therapy upfront, whereas most patients on the PROfound were CRPC who receive chemotherapy in the CRPC space. But yet undoubtedly, I think that your case illustrates the importance of next-generation sequencing and the importance of understanding the access to two oral PARP inhibitors that are super solid. 

I think that perhaps the bigger question is going to be should you do a PARP inhibitor alone or should we use a combination of a PARP inhibitor plus an oral agent, such as in this case, maybe abiraterone acetate plus olaparib. Or maybe even thinking of TALAPRO, maybe enza plus a PARP inhibitor. So I don't know where you sit on those thoughts, Doctor-.

Dr. Kriti Mittal: I change toxicity considerations, temper my enthusiasm for offering PARP inhibitors in combination with AR inhibitors or abiraterone at this time. I think I would certainly consider monotherapy with rucaparib for a patient in this situation. I am not entirely convinced that putting a patient through dual treatment in the mCRPC setting in the frontline, I don't think we are there yet.

Dr. Jorge Garcia: There are two very important trials that are looking at the combination of an adrenal biosynthesis inhibitor plus olaparib in this context, and one is PROpel and the other one is MAGNITUDE. And both trials have very different results in many ways because they look at patients with a biomarker, meaning DNA repair, and patients without the biomarker. And I think the bigger question is, should this patient who was an abiraterone– Let's say this patient hypothetically was on a PEACE-1-like style. So the patient got ADT or triple therapy but was an abiraterone or an adrenal biosynthesis inhibitor instead of chemotherapy. And the patient was progressing slowly on abiraterone, you knew that the patient had a DNA repair deficiency. How comfortable with the PROpel and MAGNITUDE data would you and I feel to add on or layer, if you allow me to express it like that, a PARP inhibitor into this regime?

Dr. Kriti Mittal: My personal interpretation of the currently available data is that at this point, combination therapy is not something I would use in my clinical practice. I think there are two camps in the GU oncology community of how people interpret the PROpel, MAGNITUDE, TRITON, and TALAPRO data in full. I think each of these trials had very different patient populations. I think in a biomarker unselected population, I would certainly not advocate for combination therapy. But even in the biomarker-selected population, I think how the biomarkers were tested and how the populations were defined may not always match what we are doing in clinical practice. And so I would, at this time, advocate for monotherapy over combination therapy.

Dr. Jorge Garcia: I'm sure the audience will have probably read or heard about PROpel and MAGNITUDE and the data in patients without a biomarker positivity disease. So I'd love to hear your thoughts as to if you had no biomarker. By that I mean if you had a patient with CRPC, with metastatic CRPC without a DNA repair deficiency, would you consider using an adrenal biosynthesis inhibitor and a PARP inhibitor together based upon the potential synergistic of additive benefits and some of the data to suggest that you can delay rPFS when you combine therapy, but in the absence of biomarker positivity.

Dr. Kriti Mittal: In the absence of biomarker positivity, I think the preclinical data are stronger than the clinical results we are seeing in trials. So while I think we should continue researching further into this because there certainly is preclinical rationale, looking at the clinical outcomes from these several trials, I would not offer PARP inhibitor to an unselected patient.

Dr. Jorge Garcia: Great.

Dr. Kriti Mittal: Moving on to second-line treatment for castration-resistant prostate cancer. I think talking of access issues and talking about the current treatment paradigms in the United States, there is still not widespread availability of lutetium. The listeners would love to hear your thoughts, Dr. Garcia, on practical management tips, safety issues, and the multidisciplinary nature of the management of lutetium therapy. 

Dr. Kriti Mittal: So I think the challenges with lutetium are multiple. Number one is the correct identification of the patient, the ideal patient for lutetium. Secondly is who manages the patient and as you indicated, the importance of a team approach in that. Thirdly is how do we follow that patient during therapy? So it's beyond the technical aspects of who infuses the patient. Fourthly is what are the true goals of lutetium for that patient population and the side effects that those patients may embark on that some people may not be fully aware of and creates complexity. And lastly, perhaps, is how the movement, how we develop lutetium in CRPC and how we're going to move lutetium or have started to move lutetium and alike, meaning radiopharmaceuticals, radioligand-based therapies outside lutetium opinion and others as you know, earlier into the natural history of prostate cancer, maybe even in the locally advanced disease in combination with radiation or for patients with N1 positive disease. So it's a lot of movement in that space. I think that this is just the beginning of radiopharmaceutical entering diagnostics.

But let me just address this succinctly, if I may. Number one, you do need a PET PSMA in order for you to select the patient because we're talking about a potential biomarker. But this is what I call an imaging biomarker. If you see it, you treat it.  So the standard of care right now for lutetium is very simple: you need to have men with metastatic castration-resistant prostate cancer. Two, you need to have failed a prior oral agent, in this case, a novel hormonal agent, independent of which agent you have seen, independent of the timing when you have seen an oral agent at the front, the middle, the end. And lastly, you have to have progress through chemotherapy. Yet again, it depends on when you see chemo. 

So if you have someone who has high volume metastatic disease from the beginning, de novo disease, and you got ADT, daro, and docetaxel, and the patient progresses, that patient can go on. If that patient has a positive PSMA PET, that patient can go on to get lutetium. Similarly, if you have someone who got ADT alone in the adjuvant space for radiation therapy, progress, got an oral agent, progress, got a PARP or not, or got docetaxel, that patient could also be a candidate for lutetium. It's dependent on how you run the patient through therapy. 

Secondly is who gives lutetium? So I do believe, and I may be biased, I certainly believe in the importance of a team approach with radiation oncology and nuclear medicine. But the reality of it is, I believe these patients are so advanced in their stage of their disease, then the idea of quarterback, in my personal opinion, resides in medical oncology. And I think the bigger question is going to be if nuclear medicine at your given institution is going to be delivering lutetium, or is it going to be radiation oncology? And I think, as you know, in places in America, it's RadOnC, in other places is NucMed, in our institution right now it is NucMed. Having said that, I do predict that for those places where nuclear medicine is heavily involved in delivering lutetium or partnering with MedOnc to deliver lutetium, radiation oncology in the future will have a bigger role as well because we are moving lutetium earlier in settings where radiation oncology is commonly used, such as high-risk prostate cancer patients, or even in the salvage setting, or even in patients with metastatic disease, where we want to combine radiation and lutetium, which are part of clinical trials as we think through for the future. But either/or, I think the quarterback should be really MedOnc in this case. 

Thirdly is how do we do it? So clearly, at least in my practice, and I think it's probably standard across the United States, MedOnc will see the patient, determine viability and feasibility of therapy, determine who's the ideal candidate, discusses the pros and the cons, and then works along with RadOnc or NucMed to start the process. As you know, it is once every six weeks. So here in my practice, we will see the patient every time before treatment. Sometimes we see them the day off, sometimes we see them a few days before. Patients will get blood work. Specifically, we're interested in seeing everything CMPs, but certainly blood counts, red cell counts, platelets, and white cell counts, just to make sure that patients do not start with impaired bone marrow that can increase the risk for myelosuppression and therefore significant challenges with side effects, hematologic side effects, specifically. And we do that.  

Sometimes we see them, sometimes our nurse practitioners would do so. And then the patient will basically follow through and complete up to six cycles of treatments. Six times six, that's actually 36 weeks or so. That's a long time on therapy for those who can get six cycles. I think the question becomes how do you follow those patients? And if we pay attention to the VISION data, as you know, those patients were actually followed serially quite closely on trial every eight weeks for the first 24 weeks, and then they stretch the scans out. But the scans that we're using in the trial are conventional imaging. 

And I think the bigger question that you and I will have is if we get a PET PSMA to use to make that decision to get on lutetium PSMA, should I go back and use a CT or so to stage the patient? I think we're moving more toward PET follow-up, but we also don't know fully the impact of lutetium PSMA on PSMA metabolically during treatment. I think that we all recognize anecdotally and at least with some of the emerging data and we have the SUV may change, that PSA reductions also appear to be important as to define who is likely to benefit or not. But those are questions that remain to be seen, to be honest with you. We follow the patients serologically, clinically, and radiographically. And at least in my group, we tend to do PSMA PETs in between therapy to ascertain the impact of therapy in radiographic and also metabolic changes.

And lastly is how we manage side effects. So I think that I'm pretty OCD about these patients because I have seen in my practice patients having outstanding responses to therapy but unfortunately become transfusion dependent, either transiently or permanently, just by virtue of side effects. And I think the importance of understanding the most common side effects of lutetium, in this case fatigue, myelosuppression, xerostomia, are really, really important. And that is the importance of having a multi-team effort approach so everybody is fully aware of the baseline characteristics of that patient or how the patient is enduring therapy and how the therapy is impacting the quality of life and impacting bone marrow production for those patients. 

I think I remind the audience that the vast majority of our patients do have bone metastases. In fact, in the VISION trial it was around what, over 85, 90% of patients are so with bone metastases. So their marrow has already been impacted not only by disease but equally importantly by the prior chemotherapy that they may have seen. And some of the patients that we have in the first bubble effect is they have seen probably docetaxel, some may even have seen dual therapy with cabazitaxel as a second-line chemotherapy. So I think the understanding as to how you manage the side effects is critically important for our patients as well. 

Dr. Kriti Mittal: Those are very relevant, practical life issues. Thank you Dr. Garcia for a terrific discussion on the application of recent advances in prostate cancer to clinical practice. [28:54] The ASCO Education podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncologists' well-being and professional development. If you have an idea for a topic or a guest you'd like to see on the ASCO Education Podcast, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, please visit education.asco.org.

Dr. Jorge Garcia: Thank you, Kriti. It's great to see you and thanks again to ASCO for the amazing opportunity to be here with you guys today. I hope the audience can see the benefit of understanding how the many changes we have seen have impacted our patients in a positive way. So thank you again for the opportunity.

Dr. Kriti Mittal: Thank you, Dr. Garcia, and thank you so much to the ASCO team for inviting me. This was a great experience. 

Thank you Dr. Garcia for sharing your perspective on incorporating recent research advances into the management of patients with de novo metastatic prostate cancer.

The ASCO Education Podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncologists' well-being and professional development. If you have an idea for a topic or a guest you'd like to see on the ASCO Education Podcast, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, please visit education.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, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this week's episode, Dr. Danielle Shafer, Medical Director of the Clinical Trials Office at Massey Cancer Center at Virginia Commonwealth University, explores the recent FDA approval of ivosidenib for the treatment of relapsed or refractory acute myeloid leukemia. Dr. Shafer's primary clinical focus is leukemia & lymphoma in adult patients. Her research focus is limited to the same population, with a particular interest in relapsed/refractory AML.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

TRANSCRIPT

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Welcome to the Recent Approvals episode of the ASCO University Weekly Podcast. My name is Danielle Shafer, and I'm an assistant professor at the Massey Cancer Center at Virginia Commonwealth University. My area of specialty is leukemia and lymphoma. Today, we will discuss the approval of ivosidenib in patients with relapsed and refractory AML with a susceptible IDH1 mutation.
As a background to today's discussion, somatic mutations of IDH have been identified in multiple tumor types, including AML and MDS. As a result of the mutation, there is impaired hematopoietic differentiation, as well as epigenetic alteration. IDH mutations occur in approximately 20% of adults with AML, and 5% of adults with MDS. IDH1 mutations occur in approximately 6% to 9% of adult AML patients. Enasidenib was approved by the FDA in 2017 for adult patients with relapsed and refractory AML with an IDH2 mutation.

On July 20, of 2018, ivosidenib was approved by the FDA for the treatment of adult patients with relapsed and refractory AML with a susceptible IDH1 mutation, as detected by an FDA approved test. The approval of ivosidenib in the relapse to refractory setting was based on the results of a phase I dose escalation and dose expansion study published in the New England Journal of Medicine.
The primary objectives of the study were to assess the safety, maximum tolerated dose, and recommended phase II dose. Of the 258 patients receiving study drug, 179 patients had relapsed and refractory disease. The median age was 67, with a range of 18 to 87 years. Patients had a median of two prior therapies, 24% had relapsed after transplant, and 59% were refractory to induction or re-induction.

59% had favorable cytogenetics. The most common co-occurring mutation was NPM1 in 26% of patients. A maximum tolerated dose was not defined, and ivosidenib 500 milligrams was selected for dose expansion. The most common adverse reactions were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, Q/T prolongation, rash, pyrexia, cough, and constipation.
In the overall population, 30 day all-cause mortality was 7%. The majority of deaths were related to disease progression or complications of underlying AML. No treatment-related adverse events leading to death were seen in patients with a starting dose of 500 milligrams.

IDH differentiation syndrome is of special interest, as early identification is necessary. It is similar to what has been described with ATRA and arsenic trioxide. In this study, IDH differentiation syndrome was reported in 19 patients, and was of grade 3 or higher in nine patients. Leukocytosis grade 2 or 3 accompanied differentiation syndrome in 7 of the 19 patients.

Median time to onset was 29 days, with a range of 5 to 59 days. Treatment included glucocorticoids, diuretics, and hydroxyurea, if leukocytosis was present. With intervention, 17 of the 19 patients had resolution. The two remaining patients had differentiation syndrome at data cutoff. In the relapsed refractory population, the rate of complete remission or complete remission with partial hematologic recovery was 30.4%.
The median duration of complete remission, or complete remission with partial hematologic recovery, was 8.2 months. The median time to response was 2.7 months. With a median follow-up of 14.8 months, the median overall survival was 8.8 months. ivosidenib is the first IDH1 inhibitor to enter the clinic for relapsed refractory AML, and clearly represents a step forward for this population. The drug is, overall, well-tolerated.
Differentiation syndrome represents a unique toxicity, as early recognition is critical. Practicing physicians may encounter difficulties differentiating disease progression from differentiation syndrome in some patients. Given the success of the drug in the relapsed refractory setting, it is now being combined with other therapies and moving earlier in the treatment course. Based on the encouraging results of a phase I study, ivosidenib is currently being combined with intensive chemotherapy in a phase III study, for newly-diagnosed AML patients with IDH1 mutations.

Although the drug is termed a success, the majority of patients are still dying of their disease. While some patients were bridged to transplant in the New England study, the benefit is not yet entirely clear. Additional questions emerge regarding co-mutations and IDH1 mutation clearance. Not surprisingly, in this study, there was some preliminary data to suggest that patients with IDH1 clearance had longer durations of remission and survival. We anticipate better understanding as more patients are treated with the drug.
Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the treatment of AML, visit the comprehensive e-learning center at university.asco.org.

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Dr. Shaheenah Dawood is the Head of Medical Oncology and the Head of the Breast Cancer Program at Dubai Hospital in the United Arab Emirates. Dr. Dawood completed her M.B.B.Ch at Dubai Medical College in 1998 and a Master of Public Health degree at the Harvard School of Public Health, Boston, USA in 2008. Her postgraduate medical training programs include a Fellowship at McGill University in Canada in 2006, and the Susan Komen Breast Cancer Fellowship at the University of Texas M.D. Anderson Cancer Center in 2007. Dr. Dawood is a member of various professional organizations, including the American Society of Clinical Oncology (ASCO), the American Association of Cancer Research (AACR), the Canadian Association of Medical Oncologists, the Emirates Medical Association, and the Inflammatory Breast Cancer Research Group. She is also the co-director of the Middle East Research Network.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

TRANSCRIPT

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Welcome to the self-evaluation episode of the ASCO University Weekly Podcast. My name is Shaheena Dawood, and I am a consulting medical oncologist and lead of the Oncology Research program at the Comprehensive Cancer Center at the Mediclinic City Hospital in Dubai, United Arab Emirates. Today, we feature a self-evaluation question looking at the predictive and prognostic role of pathological complete response attained in the treatment of breast cancer.

Let us begin by reading the question stem. Here, we have a 55-year-old woman who presents with a 4 centimeter right breast mass and palpable right axillary lymph nodes. A needle biopsy of the breast mass and a lymph node are both positive for infiltrating ductal carcinoma negative for hormone receptors and negative for HER2/neu expression. The patient is interested in breast-conserving therapy, and she is referred to you for consideration of neoadjuvant chemotherapy. Which of the following do you tell her? Your choices are, A-- patients having a complete response to neoadjuvant chemotherapy have lower local and regional recurrence rates, B-- mastectomy will be required regardless of clinical response to chemotherapy, C-- chemotherapy will be administered before and after surgery, or D-- randomized trials have shown that radiotherapy is not necessary following surgery and chemotherapy if she has a complete response.

At this point, please feel free to pause the recording before we discuss the correct answer.

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The correct answer to this question is A. Pathological complete response in the breast and lymph nodes is associated with lower local and regional recurrence rates. A combined analysis of the NSABP B18 and B27, two large trials that evaluated the role of neoadjuvant chemotherapy, revealed that the rate of local regional recurrence decreased amongst patients who initially presented with positive lymph nodes prior to neoadjuvant chemotherapy, and who become pathologically node negative after neoadjuvant chemotherapy, especially if they also achieved a pathological complete response in the breast.

Briefly, the other choices presented in this question do not represent the most appropriate answer for the following reasons. The decision regarding type of surgery in the form of mastectomy versus breast-conserving surgery is dependent on multiple factors. One of the early established benefits of neoadjuvant therapy is that it increases the probability of breast-conserving surgery, making more women candidates for lumpectomy and breast radiotherapy, who otherwise would have been treated with mastectomy.
Studies have shown that chemotherapy before surgery in the neoadjuvant setting versus chemotherapy after surgery in the adjuvant setting is associated with similar outcomes. And finally, attaining a pathological complete response currently does not preclude the need for adjuvant radiation therapy, the decision of which would be made on clinical stage of disease at presentation. The NSABP51 RTOG phase III trial is ongoing to evaluate the role of regional radiotherapy in women presenting with clinical N1 axillary node disease before neoadjuvant chemotherapy, and who become pathologically node negative at the time of surgery.

Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the treatment of breast cancer, including opportunities for self-evaluation and board review, please visit the comprehensive e-learning center at university.asco.org.
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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.

This week's host, Dr. Thomas Karasic, is an assistant professor at University of Pennsylvania specializing in the treatment of gastrointestinal malignancies. In this episode, Dr. Karasic discusses the recent FDA approval of lenvantinib for patients with unresectable hepatocellular carcinoma.

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TRANSCRIPT

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Welcome to the Recent Approvals episode of the ASCO University Weekly Podcast. My name is Thomas Karasic, I'm an assistant professor at the University of Pennsylvania, specializing in the treatment of gastrointestinal malignancies. Today, we will discuss the approval of lenvatinib for the treatment of patients with un-resectable hepatocellular carcinoma. As background to our discussion today, the only FDA approved therapy prior to 2017 for hepatocellular carcinoma was sorafenib. This is based on results of the SHARP trial published in the New England Journal in 2008, which demonstrated an overall survival benefit of 10.7 months in the sorafenib arm, versus 7.9 months in the placebo arm.
In the 10 years after the approval of sorafenib, a number of phase III trials attempted to establish additional drugs or combination regiments in both the first line and the second line setting for advanced hepatocellular carcinoma. But all trials failed to meet their primary endpoint, and no other treatments were approved.
However, in 2017, two new drugs were approved for the second line treatment of hepatocellular carcinoma-- regorafenib, a drug similar to sorafenib, as well as the PD-1 inhibitor, nivolumab. Lenvatinib is an anti-angiogenic tyrosine kinase inhibitor that targets VEGF-1 3, FGFR 1 through 4, PDGFRA, KIT, and RET. On August 16, 2018, lenvatinib was FDA approved for the first line treatment of un-resectable hepatocellular carcinoma. Two different doses were approved-- 12 milligrams for patients with actual body weight greater than or equal to 60 kilograms, and 8 milligrams for patients with actual body weight less than 60 kilograms.
The approval of lenvatinib in the first line setting was based on the results of a non-inferiority study comparing lenvatinib to sorafenib for unresectable hepatocellular carcinoma. The primary endpoint of the study was overall survival.
A total of 1,492 patients were recruited, and 954 patients were randomized one-to-one between lenvatinib or sorafenib. Lenvatinib was given at a dose of 12 milligrams daily for patients of at least 60 kilograms actual body weight, or 8 milligrams for those below 60 kilograms-- while sorafenib was given at the FDA approved dose of 400 milligrams twice daily.

This trial met its primary endpoint of non-inferiority for overall survival. Overall survival was 13.6 months in the lenvatinib arm, and 12.3 months in the sorafenib arm. While it met its endpoint for non-inferiority, it did not establish superiority in terms of overall survival. The hazard ratio for overall survival was 0.92.
Lenvatinib did demonstrate a statistically significant increase in time to progression-- 8.9 months in the lenvatinib arm, versus 3.7 months in the sorafenib arm. It also showed a statistically significant improvement in overall response rate.

Using the study endpoint of modified RECIST criteria, the objective response rate with lenvatinib was 41% versus 12% with sorafenib. Using more standard RECIST 1.1 criteria, the overall response rate of lenvatinib was 19%, versus 7% with sorafenib.

Adverse events were common in both arms of the study, with 57% of those treated with lenvatinib experiencing grade 3 or greater toxicity, compared to 49% of those treated with sorafenib. Toxicities that were more common with lenvatinib included hypertension, proteinuria, hypothyroidism, weight loss, anorexia, nausea, and vomiting-- while sorafenib more commonly had hand/foot syndrome and alopecia. Toxicities, such as fatigue and diarrhea, were similar between the two arms.

The approval of lenvatinib marks the first positive front line study comparing an agent to sorafenib in the first line treatment for HCC. Lenvatinib demonstrated improvements in overall response rate, as well as progression-free survival, and a modest trend towards improved overall survival, although this was not statistically significant.

The toxicities of sorafenib and lenvatinib were largely comparable, although some toxicities-- such as hand/foot syndrome are more common with sorafenib-- whereas hypertension and proteinuria are more common with lenvatinib.

These study results established lenvatinib as a reasonable firstline option for the treatment of HCC, and choice of sorafenib versus lenvatinib can be made based on toxicity profile, as well as the symptoms of the patient that may dictate the need for an agent with a higher response. Pending results from the CheckMate 459 study, as well as other ongoing immunotherapy front line studies, may well change the sequence of immunotherapy and anti-angiogenic therapy for HCC. But for now, lenvatinib is a reasonable front line option.

Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on lenvatinib and the treatment of hepatocellular carcinoma, visit the comprehensive e-learning center at university.asco.org.

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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.