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Making strides against melanoma: how can medical oncologists and interventional oncologists join forces to deliver smarter, patient-centered care? In this episode of BackTable, Dr. Tyler Sandow, hosts Dr. Sunandana Chandra, medical oncologist at Northwestern, and Dr. Riad Salem, interventional oncologist at Northwestern to discuss the evolving management of advanced melanoma. --- This podcast is supported by an educational grant from Replimune. --- SYNPOSIS The doctors open the episode with an overview of melanoma and recent advances in its treatment, highlighting key trials such as DREAMseq and CheckMate 067. The discussion explores the shift from medical oncologist as solo primary providers to a dynamic, multidisciplinary approach to advanced cancer care—emphasizing cutting-edge treatments like immunotherapy and intratumoral oncolytic viruses. Dr. Salem shares practical insights on the procedural techniques of administering intratumoral oncolytics like Replimune, emphasizing the importance of thorough documentation and patient-centered care. The doctors also provide an overview of the ongoing IGNYTE-3 Trial, a Phase 3 study assessing the safety and efficacy of the oncolytic immunotherapy RP1 in combination with nivolumab for the treatment of advanced melanoma. The episode underscores the transformative potential of innovative melanoma treatments and the crucial role of integrated, team-based approaches in improving cancer patient outcomes. --- TIMESTAMPS 00:00 - Introduction03:48 - The Evolution of Melanoma Treatment: From Chemotherapy to Immunotherapy14:05 - The Role of Oncolytic Viruses in Melanoma Treatment20:14 - Interventional Radiology's Role in Cancer Treatment27:00 - Collaborative Approach to Cancer Care32:53 - Hyper Documentation and Communication Efficiency44:47 - Future of Intratumoral Oncolytics48:10 - Multidisciplinary Approach in Advanced Cancer Management51:46 - Conclusion and Final Thoughts --- RESOURCES DREAMseq Trial: Atkins MB, Lee SJ, Chmielowski B, et al. Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186-197. doi:10.1200/JCO.22.01763 CheckMate 067 trial: Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med. 2025;392(1):11-22. doi:10.1056/NEJMoa2407417
Is minimally invasive ablation the future of metastatic cancer care? We now have the results of the COLLISION Trial, which investigates the non-inferiority of thermal ablation compared to surgical resection. How will these findings change treatment paradigms and practice patterns around metastatic colorectal cancer? In this week's episode of BackTable, interventional radiologist Dr. Chris Beck discusses the impact and implications of the COLLISION Trial with principal investigator Dr. Martijn Meijerink from Amsterdam UMC.---SYNPOSISThe doctors explore the COLLISION Trial's design, results, complication rates, and future directions. They also cover best practices for ablation techniques and the potential for interventional oncology to enter a “golden era.” Finally, Dr. Meijerink highlights the importance of standardizing intervention quality and being present in tumor boards to ensure optimal patient care.---TIMESTAMPS00:00 - Introduction 03:21 - Understanding Metastatic Colorectal Cancer and IR's Role05:18 - Introduction to the COLLISION Trial07:40 - Radiofrequency vs Microwave Ablation and Technological Advancements09:02 - Trial Design and Patient Eligibility16:20 - Ablation Techniques and Approaches22:05 - Trial Results and Analysis30:19 - Impact on Guidelines and Practice39:44 - Best Practices in Thermal Ablation43:27 - Future Directions in Interventional Oncology---RESOURCES“Surgery versus thermal ablation for small-size colorectal liver metastases (COLLISION): An international, multicenter, phase III randomized controlled trial.” (Meijerink, 2024)https://ascopubs.org/doi/10.1200/JCO.2024.42.17_suppl.LBA3501
Listen to ASCO's JCO Oncology Practice, Art of Oncology Practice article, "An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last” by Dr. David Johnson, who is a clinical oncologist at University of Texas Southwestern Medical School. The article is followed by an interview with Johnson and host Dr. Mikkael Sekeres. Through humor and irony, Johnson critiques how overspecialization and poor presentation practices have eroded what was once internal medicine's premier educational forum. Transcript Narrator: An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last, by David H. Johnson, MD, MACP, FASCO Over the past five decades, I have attended hundreds of medical conferences—some insightful and illuminating, others tedious and forgettable. Among these countless gatherings, Medical Grand Rounds (MGRs) has always held a special place. Originally conceived as a forum for discussing complex clinical cases, emerging research, and best practices in patient care, MGRs served as a unifying platform for clinicians across all specialties, along with medical students, residents, and other health care professionals. Expert speakers—whether esteemed faculty or distinguished guests—would discuss challenging cases, using them as a springboard to explore the latest advances in diagnosis and treatment. During my early years as a medical student, resident, and junior faculty member, Grand Rounds consistently attracted large, engaged audiences. However, as medicine became increasingly subspecialized, attendance began to wane. Lectures grew more technically intricate, often straying from broad clinical relevance. The patient-centered discussions that once brought together diverse medical professionals gradually gave way to hyperspecialized presentations. Subspecialists, once eager to share their insights with the wider medical community, increasingly withdrew to their own specialty-specific conferences, further fragmenting the exchange of knowledge across disciplines. As a former Chair of Internal Medicine and a veteran of numerous MGRs, I observed firsthand how these sessions shifted from dynamic educational exchanges to highly specialized, often impenetrable discussions. One of the most striking trends in recent years has been the decline in presentation quality at MGR—even among local and visiting world-renowned experts. While these speakers are often brilliant clinicians and investigators, they can also be remarkably poor lecturers, delivering some of the most uninspiring talks I have encountered. Their presentations are so consistently lackluster that one might suspect an underlying strategy at play—an unspoken method to ensure that they are never invited back. Having observed this pattern repeatedly, I am convinced that these speakers must be adhering to a set of unwritten rules to avoid future MGR presentations. To assist those unfamiliar with this apparent strategy, I have distilled the key principles that, when followed correctly, all but guarantee that a presenter will not be asked to give another MGR lecture—thus sparing them the burden of preparing one in the future. Drawing on my experience as an oncologist, I illustrate these principles using an oncology-based example although I suspect similar rules apply across other subspecialties. It will be up to my colleagues in cardiology, endocrinology, rheumatology, and beyond to identify and document their own versions—tasks for which I claim no expertise. What follows are the seven “Rules for Presenting a Bad Medical Oncology Medical Grand Rounds.” 1. Microscopic Mayhem: Always begin with an excruciatingly detailed breakdown of the tumor's histology and molecular markers, emphasizing how these have evolved over the years (eg, PAP v prostate-specific antigen)—except, of course, when they have not (eg, estrogen receptor, progesterone receptor, etc). These nuances, while of limited relevance to general internists or most subspecialists (aside from oncologists), are guaranteed to induce eye-glazing boredom and quiet despair among your audience. 2. TNM Torture: Next, cover every nuance of the newest staging system … this is always a real crowd pleaser. For illustrative purposes, show a TNM chart in the smallest possible font. It is particularly helpful if you provide a lengthy review of previous versions of the staging system and painstakingly cover each and every change in the system. Importantly, this activity will allow you to disavow the relevance of all previous literature studies to which you will subsequently refer during the course of your presentation … to wit—“these data are based on the OLD staging system and therefore may not pertain …” This phrase is pure gold—use it often if you can. NB: You will know you have “captured” your audience if you observe audience members “shifting in their seats” … it occurs almost every time … but if you have failed to “move” the audience … by all means, continue reading … there is more! 3. Mechanism of Action Meltdown: Discuss in detail every drug ever used to treat the cancer under discussion; this works best if you also give a detailed description of each drug's mechanism of action (MOA). General internists and subspecialists just LOVE hearing a detailed discussion of the drug's MOA … especially if it is not at all relevant to the objectives of your talk. At this point, if you observe a wave of slack-jawed faces slowly slumping toward their desktops, you will know you are on your way to successfully crushing your audience's collective spirit. Keep going—you are almost there. 4. Dosage Deadlock: One must discuss “dose response” … there is absolutely nothing like a dose response presentation to a group of internists to induce cries of anguish. A wonderful example of how one might weave this into a lecture to generalists or a mixed audience of subspecialists is to discuss details that ONLY an oncologist would care about—such as the need to dose escalate imatinib in GIST patients with exon 9 mutations as compared with those with exon 11 mutations. This is a definite winner! 5. Criteria Catatonia: Do not forget to discuss the newest computed tomography or positron emission tomography criteria for determining response … especially if you plan to discuss an obscure malignancy that even oncologists rarely encounter (eg, esthesioneuroblastoma). Should you plan to discuss a common disease you can ensure ennui only if you will spend extra time discussing RECIST criteria. Now if you do this well, some audience members may begin fashioning their breakfast burritos into projectiles—each one aimed squarely at YOU. Be brave … soldier on! 6. Kaplan-Meier Killer: Make sure to discuss the arcane details of multiple negative phase II and III trials pertaining to the cancer under discussion. It is best to show several inconsequential and hard-to-read Kaplan-Meier plots. To make sure that you do a bad job, divide this portion of your presentation into two sections … one focused on adjuvant treatment; the second part should consist of a long boring soliloquy on the management of metastatic disease. Provide detailed information of little interest even to the most ardent fan of the disease you are discussing. This alone will almost certainly ensure that you will never, ever be asked to give Medicine Grand Rounds again. 7. Lymph Node Lobotomy: For the coup de grâce, be sure to include an exhaustive discussion of the latest surgical techniques, down to the precise number of lymph nodes required for an “adequate dissection.” To be fair, such details can be invaluable in specialized settings like a tumor board, where they send subspecialists into rapturous delight. But in the context of MGR—where the audience spans multiple disciplines—it will almost certainly induce a stultifying torpor. If dullness were an art, this would be its masterpiece—capable of lulling even the most caffeinated minds into a stupor. If you have carefully followed the above set of rules, at this point, some members of the audience should be banging their heads against the nearest hard surface. If you then hear a loud THUD … and you're still standing … you will know you have succeeded in giving the world's worst Medical Grand Rounds! Final Thoughts I hope that these rules shed light on what makes for a truly dreadful oncology MGR presentation—which, by inverse reasoning, might just serve as a blueprint for an excellent one. At its best, an outstanding lecture defies expectations. One of the most memorable MGRs I have attended, for instance, was on prostaglandin function—not a subject typically associated with edge-of-your-seat suspense. Given by a biochemist and physician from another subspecialty, it could have easily devolved into a labyrinth of enzymatic pathways and chemical structures. Instead, the speaker took a different approach: rather than focusing on biochemical minutiae, he illustrated how prostaglandins influence nearly every major physiologic system—modulating inflammation, regulating cardiovascular function, protecting the gut, aiding reproduction, supporting renal function, and even influencing the nervous system—without a single slide depicting the prostaglandin structure. The result? A room full of clinicians—not biochemists—walked away with a far richer understanding of how prostaglandins affect their daily practice. What is even more remarkable is that the talk's clarity did not just inform—it sparked new collaborations that shaped years of NIH-funded research. Now that was an MGR masterpiece. At its core, effective scientific communication boils down to three deceptively simple principles: understanding your audience, focusing on relevance, and making complex information accessible.2 The best MGRs do not drown the audience in details, but rather illuminate why those details matter. A great lecture is not about showing how much you know, but about ensuring your audience leaves knowing something they didn't before. For those who prefer the structured wisdom of a written guide over the ramblings of a curmudgeon, an excellent review of these principles—complete with a handy checklist—is available.2 But fair warning: if you follow these principles, you may find yourself invited back to present another stellar MGRs. Perish the thought! Dr. Mikkael SekeresHello and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the oncology field. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. What a pleasure it is today to be joined by Dr. David Johnson, clinical oncologist at the University of Texas Southwestern Medical School. In this episode, we will be discussing his Art of Oncology Practice article, "An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last." Our guest's disclosures will be linked in the transcript. David, welcome to our podcast and thanks so much for joining us. Dr. David JohnsonGreat to be here, Mikkael. Thanks for inviting me. Dr. Mikkael SekeresI was wondering if we could start with just- give us a sense about you. Can you tell us about yourself? Where are you from? And walk us through your career. Dr. David JohnsonSure. I grew up in a small rural community in Northwest Georgia about 30 miles south of Chattanooga, Tennessee, in the Appalachian Mountains. I met my wife in kindergarten. Dr. Mikkael SekeresOh my. Dr. David JohnsonThere are laws in Georgia. We didn't get married till the third grade. But we dated in high school and got married after college. And so we've literally been with one another my entire life, our entire lives. Dr. Mikkael SekeresMy word. Dr. David JohnsonI went to medical school in Georgia. I did my training in multiple sites, including my oncology training at Vanderbilt, where I completed my training. I spent the next 30 years there, where I had a wonderful career. Got an opportunity to be a Division Chief and a Deputy Director of, and the founder of, a cancer center there. And in 2010, I was recruited to UT Southwestern as the Chairman of Medicine. Not a position I had particularly aspired to, but I was interested in taking on that challenge, and it proved to be quite a challenge for me. I had to relearn internal medicine, and really all the subspecialties of medicine really became quite challenging to me. So my career has spanned sort of the entire spectrum, I suppose, as a clinical investigator, as an administrator, and now as a near end-of-my-career guy who writes ridiculous articles about grand rounds. Dr. Mikkael SekeresNot ridiculous at all. It was terrific. What was that like, having to retool? And this is a theme you cover a little bit in your essay, also, from something that's super specialized. I mean, you have had this storied career with the focus on lung cancer, and then having to expand not only to all of hematology oncology, but all of medicine. Dr. David JohnsonIt was a challenge, but it was also incredibly fun. My first few days in the chair's office, I met with a number of individuals, but perhaps the most important individuals I met with were the incoming chief residents who were, and are, brilliant men and women. And we made a pact. I promised to teach them as much as I could about oncology if they would teach me as much as they could about internal medicine. And so I spent that first year literally trying to relearn medicine. And I had great teachers. Several of those chiefs are now on the faculty here or elsewhere. And that continued on for the next several years. Every group of chief residents imparted their wisdom to me, and I gave them what little bit I could provide back to them in the oncology world. It was a lot of fun. And I have to say, I don't necessarily recommend everybody go into administration. It's not necessarily the most fun thing in the world to do. But the opportunity to deal one-on-one closely with really brilliant men and women like the chief residents was probably the highlight of my time as Chair of Medicine. Dr. Mikkael SekeresThat sounds incredible. I can imagine, just reflecting over the two decades that I've been in hematology oncology and thinking about the changes in how we diagnose and care for people over that time period, I can only imagine what the changes had been in internal medicine since I was last immersed in that, which would be my residency. Dr. David JohnsonWell, I trained in the 70s in internal medicine, and what transpired in the 70s was kind of ‘monkey see, monkey do'. We didn't really have a lot of understanding of pathophysiology except at the most basic level. Things have changed enormously, as you well know, certainly in the field of oncology and hematology, but in all the other fields as well. And so I came in with what I thought was a pretty good foundation of knowledge, and I realized it was completely worthless, what I had learned as an intern and resident. And when I say I had to relearn medicine, I mean, I had to relearn medicine. It was like being an intern. Actually, it was like being a medical student all over again. Dr. Mikkael SekeresOh, wow. Dr. David JohnsonSo it's quite challenging. Dr. Mikkael SekeresWell, and it's just so interesting. You're so deliberate in your writing and thinking through something like grand rounds. It's not a surprise, David, that you were also deliberate in how you were going to approach relearning medicine. So I wonder if we could pivot to talking about grand rounds, because part of being a Chair of Medicine, of course, is having Department of Medicine grand rounds. And whether those are in a cancer center or a department of medicine, it's an honor to be invited to give a grand rounds talk. How do you think grand rounds have changed over the past few decades? Can you give an example of what grand rounds looked like in the 1990s compared to what they look like now? Dr. David JohnsonWell, I should all go back to the 70s and and talk about grand rounds in the 70s. And I referenced an article in my essay written by Dr. Ingelfinger, who many people remember Dr. Ingelfinger as the Ingelfinger Rule, which the New England Journal used to apply. You couldn't publish in the New England Journal if you had published or publicly presented your data prior to its presentation in the New England Journal. Anyway, Dr. Ingelfinger wrote an article which, as I say, I referenced in my essay, about the graying of grand rounds, when he talked about what grand rounds used to be like. It was a very almost sacred event where patients were presented, and then experts in the field would discuss the case and impart to the audience their wisdom and knowledge garnered over years of caring for patients with that particular problem, might- a disease like AML, or lung cancer, or adrenal insufficiency, and talk about it not just from a pathophysiologic standpoint, but from a clinician standpoint. How do these patients present? What do you do? How do you go about diagnosing and what can you do to take care of those kinds of patients? It was very patient-centric. And often times the patient, him or herself, was presented at the grand rounds. And then experts sitting in the front row would often query the speaker and put him or her under a lot of stress to answer very specific questions about the case or about the disease itself. Over time, that evolved, and some would say devolved, but evolved into more specialized and nuanced presentations, generally without a patient present, or maybe even not even referred to, but very specifically about the molecular biology of disease, which is marvelous and wonderful to talk about, but not necessarily in a grand round setting where you've got cardiologists sitting next to endocrinologists, seated next to nephrologists, seated next to primary care physicians and, you know, an MS1 and an MS2 and et cetera. So it was very evident to me that what I had witnessed in my early years in medicine had really become more and more subspecialized. As a result, grand rounds, which used to be packed and standing room only, became echo chambers. It was like a C-SPAN presentation, you know, where local representative got up and gave a talk and the chambers were completely empty. And so we had to go to do things like force people to attend grand rounds like a Soviet Union-style rally or something, you know. You have to pay them to go. But it was really that observation that got me to thinking about it. And by the way, I love oncology and I'm, I think there's so much exciting progress that's being made that I want the presentations to be exciting to everybody, not just to the oncologist or the hematologist, for example. And what I was witnessing was kind of a formula that, almost like a pancake formula, that everybody followed the same rules. You know, “This disease is the third most common cancer and it presents in this way and that way.” And it was very, very formulaic. It wasn't energizing and exciting as it had been when we were discussing individual patients. So, you know, it just is what it is. I mean, progress is progress and you can't stop it. And I'm not trying to make America great again, you know, by going back to the 70s, but I do think sometimes we overthink what medical grand rounds ought to be as compared to a presentation at ASH or ASCO where you're talking to subspecialists who understand the nuances and you don't have to explain the abbreviations, you know, that type of thing. Dr. Mikkael SekeresSo I wonder, you talk about the echo chamber of the grand rounds nowadays, right? It's not as well attended. It used to be a packed event, and it used to be almost a who's who of, of who's in the department. You'd see some very famous people who would attend every grand rounds and some up-and-comers, and it was a chance for the chief residents to shine as well. How do you think COVID and the use of Zoom has changed the personality and energy of grand rounds? Is it better because, frankly, more people attend—they just attend virtually. Last time I attended, I mean, I attend our Department of Medicine grand rounds weekly, and I'll often see 150, 200 people on the Zoom. Or is it worse because the interaction's limited? Dr. David JohnsonYeah, I don't want to be one of those old curmudgeons that says, you know, the way it used to be is always better. But there's no question that the convenience of Zoom or similar media, virtual events, is remarkable. I do like being able to sit in my office where I am right now and watch a conference across campus that I don't have to walk 30 minutes to get to. I like that, although I need the exercise. But at the same time, I think one of the most important aspects of coming together is lost with virtual meetings, and that's the casual conversation that takes place. I mentioned in my essay an example of the grand rounds that I attended given by someone in a different specialty who was both a physician and a PhD in biochemistry, and he was talking about prostaglandin metabolism. And talk about a yawner of a title; you almost have to prop your eyelids open with toothpicks. But it turned out to be one of the most fascinating, engaging conversations I've ever encountered. And moreover, it completely opened my eyes to an area of research that I had not been exposed to at all. And it became immediately obvious to me that it was relevant to the area of my interest, which was lung cancer. This individual happened to be just studying colon cancer. He's not an oncologist, but he was studying colon cancer. But it was really interesting what he was talking about. And he made it very relevant to every subspecialist and generalist in the audience because he talked about how prostaglandin has made a difference in various aspects of human physiology. The other grand rounds which always sticks in my mind was presented by a long standing program director at my former institution of Vanderbilt. He's passed away many years ago, but he gave a fascinating grand rounds where he presented the case of a homeless person. I can't remember the title of his grand rounds exactly, but I think it was “Care of the Homeless” or something like that. So again, not something that necessarily had people rushing to the audience. What he did is he presented this case as a mysterious case, you know, “what is it?” And he slowly built up the presentation of this individual who repeatedly came to the emergency department for various and sundry complaints. And to make a long story short, he presented a case that turned out to be lead poisoning. Everybody was on the edge of their seat trying to figure out what it was. And he was challenging members of the audience and senior members of the audience, including the Cair, and saying, “What do you think?” And it turned out that the patient became intoxicated not by eating paint chips or drinking lead infused liquids. He was burning car batteries to stay alive and inhaling lead fumes, which itself was fascinating, you know, so it was a fabulous grand rounds. And I mean, everybody learned something about the disease that they might otherwise have ignored, you know, if it'd been a title “Lead Poisoning”, I'm not sure a lot of people would have shown up. Dr. Mikkael Sekeres That story, David, reminds me of Tracy Kidder, who's a master of the nonfiction narrative, will choose a subject and kind of just go into great depth about it, and that subject could be a person. And he wrote a book called Rough Sleepers about Jim O'Connell - and Jim O'Connell was one of my attendings when I did my residency at Mass General - and about his life and what he learned about the homeless. And it's this same kind of engaging, “Wow, I never thought about that.” And it takes you in a different direction. And you know, in your essay, you make a really interesting comment. You reflect that subspecialists, once eager to share their insight with the wider medical community, increasingly withdraw to their own specialty specific conferences, further fragmenting the exchange of knowledge across disciplines. How do you think this affects their ability to gain new insights into their research when they hear from a broader audience and get questions that they usually don't face, as opposed to being sucked into the groupthink of other subspecialists who are similarly isolated? Dr. David Johnson That's one of the reasons I chose to illustrate that prostaglandin presentation, because again, that was not something that I specifically knew much about. And as I said, I went to the grand rounds more out of a sense of obligation than a sense of engagement. Moreover, our Chair at that institution forced us to go, so I was there, not by choice, but I'm so glad I was, because like you say, I got insight into an area that I had not really thought about and that cross pollination and fertilization is really a critical aspect. I think that you can gain at a broad conference like Medical Grand Rounds as opposed to a niche conference where you're talking about APL. You know, everybody's an APL expert, but they never thought about diabetes and how that might impact on their research. So it's not like there's an ‘aha' moment at every Grand Rounds, but I do think that those kinds of broad based audiences can sometimes bring a different perspective that even the speaker, him or herself had not thought of. Dr. Mikkael SekeresI think that's a great place to end and to thank David Johnson, who's a clinical oncologist at the University of Texas Southwestern Medical School and just penned the essay in JCO Art of Oncology Practice entitled "An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last." Until next time, thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all of ASCO's shows at asco.org/podcasts. David, once again, I want to thank you for joining me today. Dr. David JohnsonThank you very much for having me. 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. Show notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr David Johnson is a clinical oncologist at the University of Texas Southwestern Medical School.
In this episode, we discussed the management of systemic mastocytosis with Dr. Daniel DeAngelo from the Dana Farber Cancer Institute. Here are the key studies we discussed:Midostaurin https://www.nejm.org/doi/10.1056/NEJMoa1513098?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.govAvapritinibEXLPORER study: https://www.nature.com/articles/s41591-021-01538-9PATHFINDER study: https://www.nature.com/articles/s41591-021-01539-8Bezuclastinib: APEX trial: https://ashpublications.org/blood/article/144/Supplement%201/659/530240/Apex-Part-1-Updated-Assessment-of-BezuclastinibHSCT for Advanced SM: https://ascopubs.org/doi/10.1200/JCO.2014.55.2018
Host Dr. Davide Soldato and guest Dr. Harriet Kluger discuss the JCO article "Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Davide Soldato Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Harriet Kluger. Dr. Kluger is a professor of medicine at Yale School of Medicine, Director of the Yale SPORE in Skin Cancer, and an internationally recognized expert in immuno-oncology for melanoma and renal cell carcinoma. She leads early-phase and translational trials that pair novel immunotherapies with predictive biomarkers to personalized care. Today, Dr. Kluger and I will be discussing the article titled "Phase 2 Trial of Pembrolizumab in Combination with Bevacizumab for Untreated Melanoma Brain Metastases." In this study, Dr. Kluger and colleagues evaluated four cycles of pembrolizumab plus the anti-VEGF antibody bevacizumab followed by pembrolizumab maintenance in patients with asymptomatic non-hemorrhagic melanoma brain metastases that had not previously received PD-1 therapy. Thank you for speaking with us, Dr. Kluger. Dr. Harriet Kluger Thank you for inviting me. The pleasure is really all mine. Dr. Davide Soldato So to kick off our podcast, I just wanted to ask if you could outline a little bit the biological and clinical rationale that led you to test this type of combination for patients with untreated brain metastases from metastatic melanoma. Dr. Harriet Kluger Back in approximately 2012, patients who had untreated brain metastases were excluded from all clinical trials. So by untreated, I mean brain metastases that had not received local therapy such as surgery or radiation. The reason for it was primarily because there was this fear that big molecules wouldn't penetrate brain lesions because they can't pass the blood-brain barrier. Turns out that the blood-brain barrier within a tumor is somewhat leaky and drugs sometimes can get in there. When PD-1 inhibitors were first identified as the next blockbuster class of drugs, we decided to conduct a phase 2 clinical trial of pembrolizumab monotherapy in patients with untreated brain metastases. We actually did it also in lung cancer, and we could talk about that later on. Responses were seen. The responses in the brain and the body were similar. They were concordant in melanoma patients. Now, at approximately that time, also another study was done by the Australian group by Dr. Georgina Long, where they did a randomized trial where patients who didn't require immediate steroid therapy received either nivolumab alone or nivolumab with ipilimumab, and the combination arm was substantially superior. Subsequently, also, Bristol Myers Squibb also conducted a large phase 2 multicenter trial of ipilimumab and nivolumab in patients with untreated brain metastases. And there, once again, they saw that the responses in the brain were similar to the responses in the body. Now, somewhere along the line there, we completed our anti-PD-1 monotherapy trial. And when we looked at our data, we still didn't have the data on ipilimumab and nivolumab. And our question was, “Well, how can we do better?” Just as we're always trying to do better. We saw two really big problems. One was that patients had a lot of perilesional edema. And the other one was that we were struggling with radiation necrosis in lesions that were previously Gamma Knifed. The instance of radiation necrosis was in excess of 30%. So the rationale behind this study was that if we added bevacizumab, maybe we could treat those patients who had some edema, not requiring steroids, but potentially get them on study, get that PD-1 inhibitor going, and also prevent subsequent radiation necrosis. And that was the main rationale behind the study. We had also done some preclinical work in mouse models of melanoma brain metastases and in an in vitro blood-brain barrier model where we showed that bevacizumab, or anti-VEGF, really tightens up those leaky basement membranes and therefore would be very likely to decrease the edema. Dr. Davide Soldato Thank you very much for putting in context the combination. So this was a phase 2 trial, and you included patients who had at least one lesion, and you wanted lesions that were behind 5 and 20 millimeters. Patients could be included also if the brain metastasis was higher in dimension than 20 millimeters, but it had to be treated, and it was then excluded from the evaluation of the primary objective of the trial. So regarding, a little bit, these characteristics, do you think that this is very similar to what we see in clinical practice? And what does this mean in terms of applicability of these results in clinical practice? Dr. Harriet Kluger So that's an excellent question. The brain metastasis clinical research field has somewhat been struggling with this issue of inclusion/exclusion criteria. When we started this, we showed pretty clearly that 5 to 10 millimeter lesions, which are below the RECIST criteria for inclusion, are measurable if you use MRIs with slices that are 1 to 2 millimeters. Most institutions in the United States do use these high-resolution MRIs. I don't know how applicable that is on a worldwide scale, but we certainly lowered the threshold for inclusion so that patients who have a smattering of small brain metastases would be eligible. Now, patients with single large brain metastases, the reason that we excluded those from the trial was because we were afraid that if a patient didn't respond to the systemic therapy that we were going to give them, they could really then develop severe neurological symptoms. So, for patient safety, we used 20 millimeters as the upper level for inclusion. Some of the other trials that I mentioned earlier also excluded patients with very large lesions. Now, in practice, one certainly can do Gamma Knife therapy to the large lesions and leave the smaller ones untreated. So I think it actually is very applicable to clinical practice. Dr. Davide Soldato Thank you very much for that insight, because I think that sometimes criteria for clinical trials, they have to be very restrictive. But then we know that in clinical practice, the applicability of these results is probably broader. So, going a little bit further in the results of the study, I just wanted a little bit of comment from you regarding what you saw in terms of intracranial response rate and duration of response among patients who obtained a response from the combination treatment. Dr. Harriet Kluger So we were actually surprised. When we first designed this study, as I said earlier, we weren't trying to beat out ipilimumab and nivolumab. We were really just trying to exclude those patients who wouldn't have otherwise been eligible for ipilimumab and nivolumab because of edema or possibly even previous radiation necrosis. So it was designed to differentiate between a response rate of 34%, and I believe the lower bound was somewhere in the 20s, because that's what we'd seen in the previous pembrolizumab study. What we saw in the first 20 patients that we enrolled was actually a response rate that far exceeded that. And so we enrolled another cohort to verify that result because we were concerned about premature publishing of a result that we might have achieved just by chance. The two cohorts were very similar in terms of the response rates. And certainly this still needs to be verified in a second study with additional institutions. We did include the Moffitt Cancer Center, and the response rate with Moffitt Cancer Center was very similar to the Yale Cancer Center response rate. Now, your other question was about duration of response. So the other thing that we started asking ourselves was whether this high response rate was really because the administration of the anti-VEGF will decrease the gadolinium enhancement and therefore we might actually just be seeing prettier scans but not tumor shrinkage. And the way to differentiate those two is by looking at the duration of the response. Median progression-free survival was 2.2 years. That's pretty long. The upper bound on the 95% confidence interval was not reached. I can't tell you that the duration is as good as the duration would be when you give ipilimumab. Perhaps it is less good. This was a fairly sick population of patients, and it included some who might not have been able to receive ipilimumab and nivolumab. So it provides an alternative. I do believe that we need to do a randomized trial where we compare it to ipilimumab and nivolumab, which is the current standard of care in this patient population. We do need to interpret these results with caution. I also want to point out regarding the progression-free survival that we only gave four doses of anti-VEGF. So one would think that even though anti-VEGF has a long half-life of three or four weeks, two years later, you no longer have anti-VEGF effect, presumably. So it does something when it's administered fairly early on in the course of the treatment. Dr. Davide Soldato So, in terms of clinical applicability, do you see this combination of pembrolizumab and bevacizumab - and of course, as we mentioned, this was a phase 2 trial. The number of patients included was not very high, but still you saw some very promising results when compared with the combination of ipilimumab and nivolumab. So do you see this combination as something that should be given particularly to those patients who might not be able to receive ipilimumab and nivolumab? So, for example, patients who are very symptomatic from the start or require a high dose of steroids, or also to provide a quicker response in terms of patients who have neurological symptoms, or do you think that someday it could be potentially used for all patients? Dr. Harriet Kluger The third part of your question, whether it can be used someday for all patients: I think we need to be very careful when we interpret these results. The study was substantially smaller than the ipilimumab/nivolumab trial that was conducted by Bristol Myers Squibb. Also going to point out that was a different population of patients. Those were all frontline patients. Here we had a mix of patients who'd had previous anti-CTLA-4 and frontline patients. So I don't think that we can replace ipilimumab and nivolumab with these results. But certainly the steroid-sparing aspect of it is something that we really need to take into consideration. A lot of patients have lesions in locations where edema can be dangerous, and some of them have a hard time coming off the steroids. So this is certainly a good approach for those folks. Dr. Davide Soldato And coming back to something that you mentioned in the very introduction, when you said that there were two main problems, which was one, the problem of the edema, and the second one, the problem of the radionecrosis. In your trial, there was a fair percentage of patients who received some type of local treatment before the systemic one. So the combination of pembrolizumab and bevacizumab. And most of the patients received radiosurgery. So I just wanted a brief comment regarding the incidence of radionecrosis in the trial and whether that specific component of the combination with bevacizumab was reduced. And how do you think that this fares in terms of what we see in clinical practice in terms of radionecrosis? Dr. Harriet Kluger I'm not sure that we really reduced the incidence of radiation necrosis. We saw radiation necrosis here. We saw less of it than in the trial of pembrolizumab monotherapy, but these were also different patients, different time. We saw more than we thought that we were going to see. It was 27%, I believe, which is fairly high still. We only gave the four doses of bevacizumab. Maybe to really prevent radiation necrosis, you have to continue to give the bevacizumab. That, too, needs to be tested. The reason that we gave the four doses of bevacizumab was simply because of the cost of the bevacizumab at the time. Dr. Davide Soldato Thank you very much for that comment on radionecrosis. And I really think that potentially this is a strategy, so continuing the bevacizumab, that really makes a lot of sense, especially considering that the tolerability of the regimen was really very, very good, and you didn't see any significant or serious adverse events related to bevacizumab. So just wondering if you could comment a little bit on the toxicities, whether you had anything unexpected. Dr. Harriet Kluger There was one patient who had a microperforation of a diverticulum, which was probably related to the bevacizumab. It was conservatively managed, and the patient did fine and actually remains alive now, many years later. We had one patient who had dehiscence of a previous wound. So there is some. We did not see any substantial hypertension, proteinuria, but we only gave the four doses. So it is possible that if you give it for longer, we would see some side effects. But still, relative to ipilimumab, it's very, very well tolerated. Dr. Davide Soldato Yeah, exactly. I think that the safety profile is really different when we compare the combination of ipilimumab/nivolumab with the pembrolizumab/bevacizumab. And as you said, this was a very small trial and probably we need additional results. But still, these results, in terms of tolerability and safety, I think they are very interesting. So one additional question that I think warrants a little bit of comment on your part is actually related to the presence of patients with BRAF mutation and, in general, to what you think would be the best course of treatment for these patients who present with the upfront brain metastases. So this, it's actually not completely related to the study, but I think that since patients with BRAF mutation were included, I think that this warrants a little bit of discussion on your part. Dr. Harriet Kluger So we really believe that long-term disease control, particularly in brain metastases, doesn't happen when you give BRAF/MEK inhibitors. You sometimes get long-term control if you've got oligometastatic disease in extracranial sites and if they've previously been treated with a lot of immune checkpoint inhibitors, which wasn't the case over here. So a patient who presents early in the course of the disease, regardless of their BRAF status, I do believe that between our studies and all the studies that have been done on immunotherapy earlier in the course of disease, we should withhold BRAF/MEK inhibitors unless they have overwhelming disease and we need immediate disease control, and then we switch them very quickly to immunotherapy. Can I also say something about the toxicity question from the bevacizumab? I have one more comment to make. I think it's important. We were very careful not to include patients who had overt hemorrhage from brain metastases. So melanoma brain metastases relative to other tumor types tend to bleed, and that was an exclusion criteria. We didn't see any bleeding that was attributable to the bevacizumab, but we don't know for sure that, if this is widely used, that that might not be a problem that's observed. So I would advise folks to use extreme caution and perhaps not use it outside of the setting of a clinical trial in patients with overt hemorrhage in the melanoma brain metastases. Dr. Davide Soldato Thank you very much. I think that one aspect that is really interesting in the trial is actually related to the fact that you collected a series of biomarkers, both circulating ones, but also some that were collected actually from the tissue. So just wondering if you could explain a little bit which type of biomarkers you evaluated and whether you saw any significant results that could suggest higher or lower efficacy of the combination. Dr. Harriet Kluger Thank you for that. So yes, the biomarker studies are fairly exploratory, and I want to emphasize that we don't have anything that's remotely useful in clinical practice at this juncture. But we did see an association between vessel density in the tumors and improved response to this regimen. So possibly those lesions that are more vascular are more fed by or driven by VEGF, and that could be the reason that there was improved response. We also saw that when there was less of an increase in circulating angiopoietin-2 levels, patients were more likely to respond. Whether or not that pans out in larger cohorts of patients remains to be determined. Dr. Davide Soldato Still, do you envision validation of these biomarkers in a potentially additional trial that will evaluate, again, the combination? Because I think that the signals were quite interesting, and they really make sense from a biological point of view, considering the mechanism of action of bevacizumab. So I think that, yeah, you're right, they are exploratory. But still, I think that there is very strong biological rationale. So really I wanted to congratulate you on including that specific part and on reporting it. And so the question is, really, do you envision validation of these biomarkers in larger cohorts? Dr. Harriet Kluger I would hope to see that, just as I'd like to see validation of the clinical results as well. The circulating biomarkers are very easy to do. It's a simple ELISA test. And the vessel density on the tumor is essentially CD34 staining and units per area of tumor. Also very simple to do. So I'd love to see that happen. Dr. Davide Soldato Do you think that considering the quality of the MRI that we are using right now, it would be possible to completely bypass even the evaluation on the tissue? Like, are we going in a direction where we can, at a certain point, say the amount of vessels that we see in these metastases is higher versus lower just based on MRI results? Dr. Harriet Kluger You gave me an outstanding idea for a follow-up study. I don't know whether you can measure the intensity of gadolinium as a surrogate, but certainly something worth asking our neuroradiology colleagues. Excellent idea. Thank you. Dr. Davide Soldato You're welcome. So just moving a step further, we spoke a lot about the validation of these results and the combination. And just wanted your idea on what do you think it would be more interesting to do: if designing a clinical trial that really compares pembrolizumab/bevacizumab with ipilimumab and nivolumab or going directly for the triplet. So we know that there has been some type of exploration of triplet combination in metastatic melanoma. So just your clinical impression: What would you do as an investigator? Dr. Harriet Kluger So it's under some discussion, actually. It's very difficult to compare drugs from different companies in an investigator-initiated trial. Perhaps our European colleagues can do that trial for us. In the United States, it's much harder, but it can be done through the cooperative groups, and we are actually having some discussions about that. I don't have the answer for you. It would be lovely to have a trial that compared the three drugs to ipi/nivo and to pembrolizumab/bevacizumab. So a three-arm trial. But remember, these are frontline melanoma patients. There aren't that many of them anymore like there used to be. So accrual will be hard, and we have to be practical. Dr. Davide Soldato Yeah, you're right. And in the discussion of the manuscript, you actually mentioned some other trials that are ongoing, especially one that is investigating the combination of pembro and lenvatinib, another one that is investigating the combination of nivolumab and relatlimab. So just wondering, do you think that the molecule in terms of VEGF inhibition, so bevacizumab versus lenvatinib, can really make a difference or is going to be just a mechanism of action? Of course, we don't have the results from this trial but just wondering if you could give us a general comment or your opinion on the topic. Dr. Harriet Kluger So that's a really great question. The trial of pembrolizumab and lenvatinib was our answer to the fact that bevacizumab is not manufactured by the same company as pembrolizumab, and we're trying to give a practical answer to our next study that might enable us to take this approach further. But it does turn out from our preclinical studies that bevacizumab and VEGF receptor inhibition aren't actually the same thing in terms of the effects on the blood-brain barrier or the perilesional tumor microenvironment in the brain. And these studies were done in mice and in in vitro models. Very different effects. The lenvatinib has stronger effect on the tumors themselves, the tumor cells themselves, than the bevacizumab, which has no effect whatsoever. But the lenvatinib doesn't appear to tighten up that blood-brain barrier. Dr. Davide Soldato Thank you. I think that's very interesting, and I think it's going to be interesting to see also results of these trials to actually improve and give more options to our patients in terms of different mechanism of action, different side effects. Because in the end, one thing that we discussed is that some combination may be useful in some specific clinical situation while others cannot be applicable, like, for example, an all immunotherapy-based combination. Just one final comment, because I think that we focused a lot on the intracranial response and progression-free survival. You briefly mentioned this but just wanted to reinforce the concept. Did you see any differences in terms of intracranial versus extracranial response for those patients who also had extracranial disease with the combination of pembro and bevacizumab? Dr. Harriet Kluger So the responses were almost always concordant. There were a couple of cases that might have had a body response and not an intracranial response and vice-versa, but the vast majority had concordant response or progression. We do believe that it's a biological phenomenon. The type of tumor that tends to go to the brain is going to be the type of tumor that will respond to whatever the regimen is that we're giving. In the previous trial also, we saw concordance of responses in the body and the brain. Dr. Davide Soldato Thank you very much. Just to highlight that really the combination is worth pursuing considering that there was not so much discordant responses, and the results, even in a phase 2 trial, were very, very promising. So thank you again, Dr. Kluger, for joining us today and giving us a little bit of insight into this very interesting trial. Dr. Harriet Kluger Thank you for having me. Dr. Davide Soldato So we appreciate you sharing more on your JCO article titled "Phase 2 Trial of Pembrolizumab in Combination with Bevacizumab for Untreated Melanoma Brain Metastases," which gave us the opportunity to discuss current treatment landscape in metastatic melanoma and future direction in research for melanoma brain metastasis. If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts. 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.
In this episode, you'll hear about the latest developments in tailoring cancer treatments to individual patients using Precision Oncology. Two thought leaders, Simone Ndujiuba, a Clinical Oncology Pharmacist at Prime Therapeutics, and Karan Cushman, Head of Brand Experience and host of The Precision Medicine Podcast for Trapelo Health, discuss real-world research that is paving the way for Prime and our partners to help providers reduce turnaround times so patients can start treatment as soon as possible. Join your host Maryam Tabatabai as they dig into this evolving topic of precision oncology. www.primetherapeuitics.com ChaptersDefining precision medicine (08:50)Evaluating real-world operational process of biomarker testing (14:36)Turnaround times are crucial (17:40)A patients view into the importance of time (24:39)Technology and process aid in time and process (29:30)Helping bridge knowledge gaps for providers and payers (33:55) The focus is on Precision Oncology right now (37:00)Precision medicine in other disease categories (40:09)Future of precision oncology is bright (42:07) References Singh, B.P., et al. (2019). Molecular profiling (MP) for malignancies: Knowledge gaps and variable practice patterns among United States oncologists (Onc). American Society of Clinical Oncology. https://meetings. asco.org/abstracts-presentations/173392 Evangelist, M.C., et al. (2023). Contemporary biomarker testing rates in both early and advanced NSCLC: Results from the MYLUNG pragmatic study. Journal of Clinical Oncology, 41(Supplement 16). https://doi.org/10.1200/JCO.2023.41.16_suppl.9109. Ossowski, S., et al. (2022). Improving time to molecular testing results in patients with newly diagnosed, metastatic non-small cell lung cancer. Journal of Clinical Oncology, 18(11). https://doi.org/10.1200/OP.22.00260 Naithani N, Atal AT, Tilak TVSVGK, et al. Precision medicine: Uses and challenges. Med J Armed Forces India. 2021 Jul;77(3):258-265. doi: 10.1016/j.mjafi.2021.06.020. Jørgensen JT. Twenty Years with Personalized Medicine: Past, Present, and Future of Individualized Pharmacotherapy. Oncologist. 2019 Jul;24(7):e432-e440. doi: 10.1634/theoncologist.2019-0054. MedlinePlus. What is genetic testing? Retrieved on April 21, 2025 from https://medlineplus.gov/genetics/understanding/testing/genetictesting/. MedlinePlus. What is pharmacogenetic testing? Retrieved on April 21, 2025 from https://medlineplus.gov/lab-tests/pharmacogenetic-tests/#:~:text=Pharmacogenetics%20(also%20called%20pharmacogenomics)%20is,your%20height%20and%20eye%20color. Riely GJ, Wood DE, Aisner DL, et al. National Cancer Comprehensive Network (NCCN) clinical practice guidelines: non-small cell lung cancer, V3.2005. Retrieved April 21, 2025 from https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Benson AB, Venook AP, Adam M, et al. National Cancer Comprehensive Network (NCCN) clinical practice guidelines: colon cancer, V3.2025. Retrieved April 21, 2025 from https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Rosenberg PS, Miranda-Filho A. Cancer Incidence Trends in Successive Social Generations in the US. JAMA Netw Open. 2024 Jun 3;7(6):e2415731. doi: 10.1001/jamanetworkopen.2024.15731. PMID: 38857048; PMCID: PMC11165384. Smeltzer MP, Wynes MW, Lantuejoul S, et al. The International Association for the Study of Lung Cancer Global Survey on Molecular Testing in Lung Cancer. J Thorac Oncol. 2020 Sep;15(9):1434-1448. doi: 10.1016/j.jtho.2020.05.002.The views and opinions expressed by the guest featured on this podcast are their own and do not necessarily reflect the official policy or position of Prime Therapeutics LLC, its hosts, or its affiliates. The guest's appearance on this podcast does not imply an endorsement of their views, products, or services by Prime Therapeutics LLC. All content provided is for informational purposes only and should not be construed as professional advice.
There are now multiple phase 3 studies on combination transarterial chemoembolization (TACE) and immunotherapy showing a significant benefit over TACE alone. How do these findings change the hepatocellular carcinoma (HCC) treatment algorithm? In this multidisciplinary episode of the BackTable Podcast, Dr. Richard Finn (Medical Oncologist at UCLA) and Dr. Julius Chapiro (Interventional Radiologist at Yale University) join host Dr. Chris Beck to discuss immunotherapy, TACE, emerging trends in HCC treatment, and the future of the field.---This podcast is supported by an educational grant from Guerbet.---SYNPOSISThe doctors highlight the importance of high quality clinical data and the pivotal studies shaping current best practices. They explore the role of the different players on the multidisciplinary team and compare the oncologic and radiologic perspectives. Additionally, they discuss the synergy between TACE and immunotherapy, the criteria for selecting appropriate treatments, and the ongoing need for research and collaboration.---TIMESTAMPS00:00 - Introduction 03:35 - HCC from an Oncologic Perspective 05:33 - Radiological Perspective on Liver Cancer06:50 - Referral Patterns and Organizing a Multidisciplinary Approach18:01 - Explaining TACE and Variations in the Procedure27:27 - Choosing the Right Procedure for HCC36:13 - Making a Decision on Medical Treatment Candidacy 42:23 - Importance of Data Driven HCC Treatment, Practical Insights, and Studies to Know55:30 - Planning an Approach for a TACE Procedure01:02:26 - Final Thoughts and Future Prospects in Liver Cancer Treatment---RESOURCESBarcelona Staging System:https://www.ncbi.nlm.nih.gov/books/NBK569796/table/Ch3-t0001/TRACE Trial:https://pubs.rsna.org/doi/full/10.1148/radiol.211806PREMIERE Trial:https://www.gastrojournal.org/article/S0016-5085(16)34971-X/fulltextEMERALD-1 Trial:https://ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.LBA432LEAP O12 Study:https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02575-3/abstract
BRCA revision mutations may explain some of the limited benefit seen in long-term follow-up studies with PARP inhibitors. Bibliography: 1: BRCA reversion mutations predict resistance. https://doi.org/10.1158/2159-8290.CD-18-0715 2: SOLO3 Final OS Data. https://doi.org/10.1200/JCO.24.00933 3: Elucidating acquired PARP inhibitor resistance in advanced prostate cancer. https://doi.org/10.1016/j.ccell.2024.10.015
Listen to ASCO's Journal of Clinical Oncology Art of Oncology article, "Writing a Medical Memoir: Lessons From a Long, Steep Road” by David Marks, consultant at University Hospitals Bristol NHS Foundation Trust. The article is followed by an interview with Marks and host Dr. Mikkael Sekeres. Marks shares his challenging journey of writing a memoir describing his patients and career. Transcript Narrator: Writing a Medical Memoir: Lessons From a Long, Steep Road, by David Marks, PhD, MBBS, FRACP, FRCPath The purpose of this essay is to take hematologist/oncologist readers of the Journal on my challenging journey of trying to write a memoir describing my patients and career. This piece is not just for those who might wish to write a book, it also can be generalized to other creative writing such as short stories or other narrative pieces intended for publication. My experience is that many of my colleagues have considered doing this but do not know where to start and that many embarking on this journey lack the self-confidence most writers require. I also describe other issues that unexpectably arose, particularly my struggle to get the book to its intended target audience, and of writing about myself in such a personal way. In my book of semifiction, I tell the stories of my patients with leukemia, but also describe what it is like to be a physician looking after young patients with curable but life-threatening diseases. I recount my medical career and working in the United Kingdom's National Health Service (NHS), a very different health system to the one I experienced when I worked in Philadelphia during the early 1990s. Telling the stories of my patients with leukemia (and my story) was my main motivation but I also wanted to challenge my creative writing skills in a longer format. As a young person, I wrote essays and some poetry. As a hemato-oncologist, the major outputs of my writing have been over 300 scientific papers and a 230-page PhD thesis. The discipline required to write papers does help with writing a nonfiction book, and as with writing scientific papers, the first step is having a novel idea. I admired the work of Siddhartha Mukherjee (“The Emperor of all Maladies”) and Mikkael Sekeres (“When Blood Breaks Down”), but I wanted to write about my patients and their effect upon me from a more personal perspective. I obtained written consent from the patients I wrote about; nearly all of them were happy for me to use their first name; they trusted me to tell their stories. All of the patients' stories have a substantial basis in fact. I also wrote about colleagues and other people I encountered professionally, but those parts were semifiction. Names, places, times, and details of events were changed to preserve anonymity. For example, one subchapter titled “A tale of two managers” comprises events that relate to a number of interactions with NHS medical managers over 30 years. The managers I wrote about represent a combination of many people, but it would not have been possible to write this while still working at my hospital. I had wanted to write a book for years but like most transplanters never had the sustained free time to jot down more than a few ideas. In the second UK lockdown of 2020 when we were only allowed to go out to work and for an hour of exercise, we all had more time on our hands. A columnist in the Guardian said that people should have a “lockdown achievement”; this would be mine. This is how I went about it. I knew enough about writing to know that I could not just go and write a book. I considered a university writing degree, but they were all online: There was not the nourishment of meeting and interacting with fellow writers. I joined two virtual writing groups and got some private sessions with the group's leader. We had to write something every week, submitted on time, and open for discussion. In one writing group, there was a no negative criticism rule, which I found frustrating, as I knew my writing was not good enough and that I needed to improve. I had no shortage of ideas, stories to tell, and patients and anecdotes to write about. I have a pretty good memory for key conversations with patients but learned that I did not have to slavishly stick to what was said. I also wrote about myself: my emotions and the obstacles I encountered. To understand how I guided my patients' journeys, my readers would need to understand me and my background. I carried a notebook around and constantly wrote down ideas, interesting events, and phrases. Every chapter underwent several drafts and even then much was totally discarded. I was disciplined and tried to write something every day, realizing that if I did not make progress, I might give up. Most days the words flowed; refining and editing what I wrote was the difficult part. Very different to Graham Greene in Antibes. He would go to his local café, write 200-400 words, then stop work for the day and have his first glass of wine with lunch before an afternoon siesta. How would I tell the story? My story was chronological (in the main), but I felt no need for the patient stories to be strictly in time order. The stories had titles and I did not avoid spoilers. “Too late” is the story of a patient with acute promyelocytic leukemia who died before she could receive specialist medical attention. This had a devastating effect on the GP who saw her that morning. So, there were plenty of patient stories to tell, but I needed to learn the craft of writing. Visual description of scenes, plots, and giving hints of what is to come—I had to learn all these techniques. Everything I wrote was looked at at least once by my mentor and beta readers, but I also submitted my work for professional review by an experienced editor at Cornerstones. This person saw merit in my work but said that the stories about myself would only interest readers if I was “somebody like David Attenborough.” Other readers said the stories about me were the most interesting parts. So far, I have focused on the mechanics and logistics of writing, but there is more to it than that. My oncology colleague Sam Guglani, who has successfully published in the medical area, was very useful. I asked him how his second book was progressing. “Not very well.” “Why?” “It takes a lot of time and I'm not very confident.” Sam writes such lovely prose; Histories was positively reviewed yet even he still has self-doubt. Hematologists/oncologists, transplanters, and chimeric antigen receptor T cell physicians are often confident people. Most of the time we know what to do clinically, and when we give medical advice, we are secure in our knowledge. This is because we have undergone prolonged training in the areas we practice in and possess the scientific basis for our decisions. This is not the case when doctors take on creative writing. Few of us have training; it is out of our comfort zone. Nearly all new writers are insecure, in a constant state of worry that our outpourings are not “good enough,” that “nobody will like it.” Even high-quality memoirs may be hard to get published. I did not enter this thinking I would fail, and I have received feedback that I “can write.” But when you look at people who can really write, who have already been published, and earn a living from writing, you think that you will never be as good. Does this matter for a medical memoir? Yes, it does. I came to realize to improve it is important to surround yourself with people who read a lot and preferably with some who are well-regarded published writers. These people should offer unrestrained feedback, and you should take note. However, I learned you do not need to do everything they say—it is not like responding to the reviewers of scientific papers—your book should retain your individual stamp and cover what you think is important. I found there are risks in writing a memoir. Private matters become public knowledge to your family and friends. In a hospital you have lots of work relationships, not all of which are perfect. It can be a tense environment; you often have to keep quiet. Writing about them in a book, even if colleagues and events are disguised or anonymized, runs the risk of colleagues recognizing themselves and not being happy with how they are portrayed. Writing a book's first draft is hard; getting it to its final draft even harder but perhaps not harder than writing a major paper for JCO or Blood. (For me writing the discussion section of a paper was the most difficult task). However, finding an agent is perhaps the hardest of all. Every agent has their own laborious submission system. About a third of agents do not respond at all; they may not even read your book. Another third may send you a response (after up to 3 months) saying that the book is “not for me.” Three agents told me that their own experiences with cancer made it impossible for them to read the book while others said it was a worthwhile project but it was not their area of interest. That encouraged me. It required resilience to get Life Blood published. I did not have the skills to self-publish, but I found a publisher that would accept the book, provided I contributed to the costs of publishing. This was not easy either because my book did not have as much final editing as a conventional publisher provides. Getting the book to its target audience was another major challenge. A number of hematologic journals agreed to consider reviews of the book, and my colleagues were generous in offering to review it. However, I wanted my book to be read by people with cancer and their families: nearly all of us at some point in our lives. A digital marketing consultant helped me publicize the book on social media and construct a user-friendly Web site. I hope this reflection offers some encouragement for budding authors who are hematologists/oncologists. However, as all writers reading this will know, writing is a lonely pursuit; it is something you do on your own for long periods and you cannot be sure your work will ever see the light of day. One of the main ingredients is persistence; this is probably the main difference between people who finish books and those who do not. Of course there may be benefits to physicians from writing per se, even if it is never published, although most hematologists/oncologists I know are quite goal oriented. Was it all worthwhile? Yes, I think so. Writing about my career stirred up lots of memories and has been quite cathartic. Physicians often feel they have insufficient time to reflect on their practice. It made me reflect on my achievements and what I could have done better. Could I have worked harder for my patients (rarely) or thought of therapeutic interventions earlier (sometimes)? What about my professional relationships? In my efforts to do the best for my patients, was I sometimes too impatient (yes)? I hope the book inspires young people contemplating a career in hematology/oncology but also gives them a realistic idea of the commitment it requires; even relatively successful doctors encounter adversity. To all my hematologic/oncologic and transplant colleagues worldwide, if you think you have a book in you, find the time and the intellectual space, start writing but also get help. In telling the story of your patients you honor them; it is a very satisfying thing to do but there are risks. I have had lots of feedback from friends and colleagues, the great majority of it positive, but when my book was published, I prepared myself for more critical reviews. I learned a lot from writing Life Blood; at the end, I was a stronger, more secure writer and hematologist/oncologist, more confident that the story of my patients and career was worth telling and relevant to a wider audience. Dr. Mikkael Sekeres: Hello, and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the oncology field. I'm your host, Dr. Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. And what a pleasure it is today to be joined by Professor David Marks, a consultant at University Hospitals Bristol NHS Foundation Trust in the UK. In this episode, we will be discussing his Art of Oncology article, "Writing a Medical Memoir: Lessons from a Long, Steep Road." Our guest's disclosures will be linked in the transcript. David, welcome to our podcast, and thanks so much for joining us. Professor David Marks: Thank you very much for inviting me. It's a real honor. Dr. Mikkael Sekeres: David, I really enjoyed your piece. We've never had a "how to write a memoir" sort of piece in Art of Oncology, so it was a great opportunity. And, you know, I think 30 years ago, it was extraordinarily rare to have a doctor who also was a writer. It's become more common, and as we've grown, still among our elite core of doctor-writers, we've also birthed some folks who actually write in long form—actual books, like you did. Professor David Marks: I'd sort of become aware that I wasn't the only person doing this, that there were lots of people who liked creative writing, but they had difficulties sort of turning that into a product. This was the reason for sort of writing this. I'm hardly an expert; I've only written one book, but I sort of hope that my experiences might encourage others. Dr. Mikkael Sekeres: I think it's a terrific idea. And before we get started about the book, I, of course, know you because you and I run in some of the same academic circles, but I wonder if you could tell our listeners a little bit about yourself. Professor David Marks: So, I'm Australian. That's where I did my internal medical and hematology training in Melbourne. And then I did a PhD to do with acute lymphoblastic leukemia at the University of Melbourne. I then moved to London for three years to do some specialist training in bone marrow transplantation and some lab work, before spending three years in Philadelphia, where I did transplant, leukemia, and some more lab work. And then, mainly for family reasons, moved back to the UK to take up a post in Bristol. I have retired from patient-facing practice now, although I still give medical advice, and I'm doing some consulting for a CAR T-cell company based in LA. Dr. Mikkael Sekeres: Great. And can I ask you, what drew you to focus on treating people with leukemia and doing research in that area? Professor David Marks: I think leukemia is just such a compelling disease. From really the first patient I ever looked after, there was a person who is both life-threateningly ill, has had their life turned upside down. Yet, there is—increasingly now—there's an opportunity to cure them or, at the very least, prolong their life significantly. And also, its sort of proximity to scientific research—that was the attraction for me. Dr. Mikkael Sekeres: There is something compelling about cancer stories in general. I think we talk about the privilege of doing what we do, and I think part of that is being invited into people's lives at probably one of the most dramatic moments of those lives. We're, of course, unwelcome visitors; nobody wants a diagnosis of cancer and having to have that initial conversation with an oncologist. But I wonder if, as doctors and as writers, we feel compelled to share that story and really celebrate what our patients are going through. Professor David Marks: So, that absolutely is one of my main motivations. I thought- there aren't, to my mind, all that many books out there that sort of try and tell things from both the patient with leukemia's point of view and the doctors looking after them. And I thought that their stories should be told. It's such a dramatic and frightening time, but I think the struggles that people go through in dealing with this—I think this is something I sort of felt people should have the opportunity to learn about. Dr. Mikkael Sekeres: Yeah, we're really honoring our patients, aren't we? Professor David Marks: Absolutely. When you think of the patients you've looked after, their courage, their steadfastness in dealing with things, of just battling on when they're not well and they're scared of things like dying—you've just got to admire that. Dr. Mikkael Sekeres: Yeah, yeah. David, you have a tremendous number of academic publications and have been transformative in how we treat people who have acute lymphoblastic leukemia. How did you first get into writing narrative medicine? Professor David Marks: Although I have written quite a lot scientifically, although that is incredibly different to creative writing, some of the same sort of care that one needs with a scientific paper, you do need for creative writing. I always liked English at school, and, you know, even as a teenager, I wrote some, you know, some poetry; it frankly wasn't very good, but I had a go. I came to a point where I wanted to write about my patients and a bit about my career. I had trouble finding the time; I had trouble finding the sort of intellectual space. But then COVID and lockdown occurred, and, you know, all of us had a lot more time; you know, we weren't even allowed to leave the house apart from working. So, at that point, I started writing. Prior to that, though, I had sort of kept a notebook, a quite big notebook, about stories I wanted to tell and events in my career and life that I wanted to tell. So there was something of a starting point there to go from. But when I first started writing, I realized that I just didn't know enough about writing. I needed to learn the craft of writing, and so I also joined a couple of writing groups. Dr. Mikkael Sekeres: That's—I find that absolutely fascinating. I think there are a lot of people who want to write, and there are some who have the confidence to go ahead and start writing, right? Whether they know the craft or not. And there are others who pause and say, "Wait a second, I've done a lot of reading, I've done a lot of academic writing, but I'm not sure I know how to do this in a creative way." So, what was your first step? Professor David Marks: I had sort of notes on these stories I wanted to write, and I did just try and write the sort of two- to five-page story, but I then sort of realized that it was just—it just wasn't very good. And I needed to learn really all the basic things that writers need, like developing a plot, like giving hints of what's to come, using visual description. Those things are obviously completely different to scientific writing, and I—it was a bit like going back to school, really. Dr. Mikkael Sekeres: And how did you even find writing groups that were at the right level for someone who was starting on this journey? Professor David Marks: So, I got a recommendation of a sort of local group in Bristol and a very established sort of mentor who has actually mentored me, Alison Powell. But it is difficult because some people on the group had written and published a couple of books; they were way ahead of me. And some people were just really starting out. But there were enough people at my level to give me sort of useful criticism and feedback. But yes, finding the right writing group where there's a free interchange of ideas—that is difficult. And, of course, my—what I was writing about was pretty much different to what everybody else was writing about. Dr. Mikkael Sekeres: So, you joined a writing group that wasn't specific to people in healthcare? Professor David Marks: There was something at my hospital; it was a quite informal group that I joined, and that had a whole number of healthcare professionals, but that didn't keep going. So, I joined a group that was really a mixture of people writing memoirs and also some people writing fiction. And I actually found a lot of the things that people writing fiction write, I needed to learn. A lot of those skills still apply to a sort of non-fictional or semi-fiction book. Dr. Mikkael Sekeres: You write in your Art of Oncology piece—I think a very insightful portion of it—where you're identifying people who can give you feedback about your writing, and you're looking for honest feedback. Because there are a lot of people where you might show them a piece and they say, "Gee, this is David Marks, I better say something nice. I mean, it's David Marks after all.” Right? So, you don't want that sort of obsequiousness when you're handing over a piece of writing because you need truth to be told if it's compelling or if it's not compelling. How did you identify the people who could give you that honest feedback, but also people you trust? Because there are also people who might read a piece and might be jealous and say, "Gee, David's already going on this journey, and I wish I had done this years ago," and they might not give you the right kind of feedback. Professor David Marks: Yeah, I mean, one of the writing groups I joined, there was a sort of "no criticism, no negative criticism" rule, and I did not find that to be useful because I knew my writing, frankly, wasn't good enough. So, funnily enough, my wife—she's very lucky—she has this reading group that she's had for 25 years, and these are—they're all women of her age, and they are just big, big readers. And those were my principal beta readers. And I sort of know them, and they knew that I wanted direction about, you know, what was working and what was not working. And so they were fairly honest. If they liked something, they said it. And if there was a chapter they just didn't think worked, they told me. And I was really very grateful for that. The other thing I did at a sort of critical moment in the book, when I just thought I was not on track, is I sent it to a professional editor at Cornerstones. And that person I'd never met, so they had no—you know, they didn't need to sort of please me. And that review was very helpful. I didn't agree with all of it, but it was incredibly useful. Dr. Mikkael Sekeres: That's fascinating. So, I've submitted pieces in venues where people can post comments, and I always force myself to read the comments. And sometimes that hurts a little bit when you get some comments back and think, "Oh my word, I didn't mean that." Sometimes those comments illuminate things that you never intended for people to take away from the piece. And sometimes you get comments where people really like one aspect, and you didn't even know that would resonate with them. So, any comments you can think of that you got back where you thought, "Oh my word, I never intended that," or the opposite, where the comments were actually quite complimentary and you didn't anticipate it? Professor David Marks: I was reviewed by an independent reviewer for The Lancet Haematology. And you've read my book, so you sort of know that looking after people with leukemia, you do encounter quite a lot of people who die. And she sort of, almost as a criticism, said, "Professor David Marks seems to have encountered an extraordinary number of people who've died." And I thought—almost as a sort of criticism—and I thought, "I'm sort of sorry, but that's the area we occupy, unfortunately." There's lots of success, but there is, you know, sometimes we don't succeed. So I found that—I found that hard to read. But when you open yourself up as a writer, when you talk about your personal things, you've got to develop a bit of a thick skin. And I really haven't ego about my writing. I sort of still feel it's very much in its formative stages, so I'm quite open to criticism. Dr. Mikkael Sekeres: And were there comments that you got that were—you were pleasantly surprised that people liked one aspect of the book, and you didn't know it would really hit with them that way? Professor David Marks: I think they particularly liked the patient stories. There's one thing in the book about a young woman who has this amazing experience of being rescued by CAR T-cell therapy. This young lady's still alive. And that very much sort of captured the imagination of the readers. They really identified her and wanted to sort of know about her and, you know, was she still okay and so on. Dr. Mikkael Sekeres: I remember there was a piece I wrote, and included a patient, and it was an entree to write about a medical topic, and my editor got back to me and said, "What happened to the patient?" Right? People get invested in this. We've done this our entire careers for, for decades for some people who've been in the field for that long, and you forget that it's still a diagnosis, a disease that most people don't encounter in their lives, and they get invested in the patients we describe and are rooting for them and hope that they do okay. Professor David Marks: Yeah, I found people got very involved with the patients, and I've had actually several sort of inquiries; they want to know if the patients are still okay. And I think that I can definitely understand that from a sort of human level. Dr. Mikkael Sekeres: So, you wrote a memoir. How long did it take you? Professor David Marks: I suppose from the time I really started writing properly, I'd say about two and a half years. So, quite a long time. Dr. Mikkael Sekeres: Two and a half years. That can be daunting to some people. What advice would you give them if they're thinking about going down this path? Professor David Marks: I think it's a very rewarding thing to do. It is hard work, as you and I know, and it's sort of extra work. The only way to find out if you can do it is to try to do it. And try and find some time to do it, but get help. You know, seek the company of other people who are more experienced writers and sort of find a mentor. Somehow, you've got to, I guess, believe in yourself, really, and trust yourself that what you're writing about is worthwhile. And yeah, I don't know that I have specific advice for people about that aspect of things. Dr. Mikkael Sekeres: Well, I think that's a great place actually to end: to tell people to believe in themselves and trust in themselves. And I want to encourage everyone listening to this podcast to please check out Professor David Marks' book, Lifeblood: Tales of Leukemia Patients and Their Doctor. It's a terrific read. David, thank you so much for joining us today. Professor David Marks: Thanks very much, Mikkael. It's been a pleasure. Dr. Mikkael Sekeres: It's been delightful from my perspective. Until next time, thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all of ASCO's shows at asco.org/podcasts. Until next time, thank you, everyone. 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. Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review. ADD URLhttps://ascopubs.org/journal/jco/cancer-stories-podcast Guest Bio: Professor David Marks is a consultant at University Hospitals Bristol NHS Foundation Trust in the UK. Additional Reading: Life Blood: Stories of Leukaemia Patients and Their Doctor, by David Marks
The International Psycho-Oncology Society (IPOS) deemed April 9th, 2025, the first-ever World Psycho-Oncology Day (WPOD). This day was meant to spread awareness of the importance of prioritizing psychosocial care for patients with all types of cancer as well as to honor Jimmie C. Holland, MD. Prior to WPOD, CancerNetwork® spoke with Cristiane Decat Bergerot, PhD, BS, MS, a psychologist and the head of supportive care at Grupo Oncoclinicas in Brazil, and a member of IPOS, about the importance of psychosocial care and the impact it has on patients with cancer. As stated by Bergerot and listed on the official IPOS website, the primary goals of WPOD are as follows: raise awareness, honor Jimmie Holland, engage stakeholders, promote action, and support fundraising efforts.1 These goals are geared towards paying homage to the history of psycho-oncology and pushing for a more advanced future. “We aim to empower patients, caregivers, and healthcare professionals, fostering a future where psychosocial support is an integral part of oncology worldwide,” Bergerot said. Psycho-oncology has become more prevalent as a cancer care field since Jimmie C. Holland, MD, worked to help found it in the 1970s. Holland, a “pioneer” of psycho-oncology, was the first ever Chief of Psychiatry Services—a department that was the first of its kind anywhere in the world—at Memorial Sloan Kettering Cancer Center, and a founding member of IPOS. Bergerot stated that, in her work, she sees that patients who receive psychological support exhibit improved pain management and quality of life. Trials now focus more on end points such as quality of life and patient-reported outcomes, and guidelines have emerged to create standards of care. The National Comprehensive Cancer Network and the American Society of Clinical Oncology each offer guidelines that detail how to manage patient distress as they progress through cancer therapy.2,3 Distress screenings and earlier recommendations for palliative care have also become more standard in treatment. As for the future, Bergerot highlighted that psychosocial care needs to be more integrated into care as a necessary, rather than optional, component. New developments around the world, however, have created a landscape where telehealth and new research demonstrate the potential to help psycho-oncology grow rapidly. References 1. World Psycho-Oncology Day (WPOD). IPOS. Accessed April 2, 2025. https://tinyurl.com/43c9rr2c 2. Distress during cancer care. NCCN. 2024. Accessed April 2, 2025. https://tinyurl.com/ycxxvnmt 3. Andersen BL, Lacchetti C, Ashing K, et al. Management of anxiety and depression in adult survivors of cancer: ASCO guideline update. J Clin Oncol. 2023;41(18):3426-3453. doi:10.1200/JCO.23.00293
Dr. Ko Un “Clara” Park and Dr. Mylin Torres present the latest evidence-based changes to the SLNB in early-stage breast cancer guideline. They discuss the practice-changing trials that led to the updated recommendations and topics such as when SLNB can be omitted, when ALND is indicated, radiation and systemic treatment decisions after SLNB omission, and the role of SLNB in special circumstances. We discuss the importance of shared decision-making and other ongoing and future de-escalation trials that will expand knowledge in this space. Read the full guideline update, “Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: ASCO Guideline Update” at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-00099 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Ko Un "Clara" Park from Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Dr. Mylin Torres from Glenn Family Breast Center at Winship Cancer Institute of Emory University, co-chairs on “Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: ASCO Guideline Update.” Thank you for being here today, Dr. Park and Dr. Torres. Dr. Mylin Torres: Thank you, it's a pleasure to be here. Brittany Harvey: And before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Torres and Dr. Park, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. To start us off, Dr. Torres, what is the scope and purpose of this guideline update on the use of sentinel lymph node biopsy in early-stage breast cancer? Dr. Mylin Torres: The update includes recommendations incorporating findings from trials released since our last published guideline in 2017. It includes data from nine randomized trials comparing sentinel lymph node biopsy alone versus sentinel lymph node biopsy with a completion axillary lymph node dissection. And notably, and probably the primary reason for motivating this update, are two trials comparing sentinel lymph node biopsy with no axillary surgery, all of which were published from 2016 to 2024. We believe these latter two trials are practice changing and are important for our community to know about so that it can be implemented and essentially represent a change in treatment paradigms. Brittany Harvey: It's great to hear about these practice changing trials and how that will impact these recommendation updates. So Dr. Park, I'd like to start by reviewing the key recommendations across all of these six overarching clinical questions that the guideline addressed. So first, are there patients where sentinel lymph node biopsy can be omitted? Dr. Ko Un "Clara" Park: Yes. The key change in the current management of early-stage breast cancer is the inclusion of omission of sentinel lymph node biopsy in patients with small, less than 2 cm breast cancer and a negative finding on preoperative axillary ultrasound. The patients who are eligible for omission of sentinel lymph node biopsy according to the SOUND and INSEMA trial are patients with invasive ductal carcinoma that is size smaller than 2 cm, Nottingham grades 1 and 2, hormone receptor-positive, HER2-negative in patients intending to receive adjuvant endocrine therapy, and no suspicious lymph nodes on axillary ultrasound or if they have only one suspicious lymph node, then the biopsy of that lymph node is benign and concordant according to the axillary ultrasound findings. The patients who are eligible for sentinel lymph node biopsy omission according to the SOUND and INSEMA trials were patients who are undergoing lumpectomy followed by whole breast radiation, especially in patients who are younger than 65 years of age. For patients who are 65 years or older, they also qualify for omission of sentinel lymph node biopsy in addition to consideration for radiation therapy omission according to the PRIME II and CALGB 9343 clinical trials. And so in those patients, a more shared decision-making approach with the radiation oncologist is encouraged. Brittany Harvey: Understood. I appreciate you outlining that criteria for when sentinel lymph node biopsy can be omitted and when shared decision making is appropriate as well. So then, Dr. Torres, in those patients where sentinel lymph node biopsy is omitted, how are radiation and systemic treatment decisions impacted? Dr. Mylin Torres: Thank you for that question. I think there will be a lot of consternation brought up as far as sentinel lymph node biopsy and the value it could provide in terms of knowing whether that lymph node is involved or not. But as stated, sentinel lymph node biopsy actually can be safely omitted in patients with low risk disease and therefore the reason we state this is that in both SOUND and INSEMA trial, 85% of patients who had a preoperative axillary ultrasound that did not show any signs of a suspicious lymph node also had no lymph nodes involved at the time of sentinel node biopsy. So 85% of the time the preoperative ultrasound is correct. So given the number of patients where preoperative ultrasound predicts for no sentinel node involvement, we have stated within the guideline that radiation and systemic treatment decisions should not be altered in the select patients with low risk disease where sentinel lymph node biopsy can be omitted. Those are the patients who are postmenopausal and age 50 or older who have negative findings on preoperative ultrasound with grade 1 or 2 disease, small tumors less than or equal to 2 cm, hormone receptor-positive, HER2-negative breast cancer who undergo breast conserving therapy. Now, it's important to note in both the INSEMA and SOUND trials, the vast majority of patients received whole breast radiation. In fact, within the INSEMA trial, partial breast irradiation was not allowed. The SOUND trial did allow partial breast irradiation, but in that study, 80% of patients still received whole breast treatment. Therefore, the preponderance of data does support whole breast irradiation when you go strictly by the way the SOUND and INSEMA trials were conducted. Notably, however, most of the patients in these studies had node-negative disease and had low risk features to their primary tumors and would have been eligible for partial breast irradiation by the ASTRO Guidelines for partial breast treatment. So, given the fact that 85% of patients will have node-negative disease after a preoperative ultrasound, essentially what we're saying is that partial breast irradiation may be offered in these patients where omission of sentinel node biopsy is felt to be safe, which is in these low risk patients. Additionally, regional nodal irradiation is something that is not indicated in the vast majority of patients where omission of sentinel lymph node biopsy is prescribed and recommended, and that is because very few of these patients will actually end up having pathologic N2 disease, which is four or more positive lymph nodes. If you look at the numbers from both the INSEMA and the SOUND trial, the number of patients with pathologic N2 disease who did have their axilla surgically staged, it was less than 1% in both trials. So, in these patients, regional nodal irradiation, there would be no clear indication for that more aggressive and more extensive radiation treatment. The same principles apply to systemic therapy. As the vast majority of these patients are going to have node-negative disease with a low risk primary tumor, we know that postmenopausal women, even if they're found to have one to three positive lymph nodes, a lot of the systemic cytotoxic chemotherapy decisions are driven by genomic assay score which is taken from the primary tumor. And therefore nodal information in patients who have N1 disease may not be gained in patients where omission of sentinel lymph node biopsy is indicated in these low risk patients. 14% of patients have 1 to 3 positive lymph nodes in the SOUND trial and that number is about 15% in the INSEMA trial. Really only the clinically actionable information to be gained is if a patient has four or more lymph nodes or N2 disease in this low risk patient population. So, essentially when that occurs it's less than 1% of the time in these patients with very favorable primary tumors. And therefore we thought it was acceptable to stand by a recommendation of not altering systemic therapy or radiation recommendations based on omission of sentinel nodes because the likelihood of having four more lymph nodes is so low. Dr. Ko Un "Clara" Park: I think one thing to add is the use of CDK4/6 inhibitors to that and when we look at the NATALEE criteria for ribociclib in particular, where node-negative patients were included, the bulk majority of the patients who were actually represented in the NATALEE study were stage III disease. And for stage I disease to upstage into anatomic stage III, that patient would need to have pathologic N2 disease. And as Dr. Torres stated, the rate of having pathologic N2 disease in both SOUND and INSEMA studies were less than 1%. And therefore it would be highly unlikely that these patients would be eligible just based on tumor size and characteristics for ribociclib. So we think that it is still safe to omit sentinel lymph node biopsy and they would not miss out, if you will, on the opportunity for CDK4/6 inhibitors. Brittany Harvey: Absolutely. I appreciate you describing those recommendations and then also the nuances of the evidence that's underpinning those recommendations, I think that's important for listeners. So Dr. Park, the next clinical question addresses patients with clinically node negative early stage breast cancer who have 1 or 2 sentinel lymph node metastases and who will receive breast conserving surgery with whole breast radiation therapy. For these patients, is axillary lymph node dissection needed? Dr. Ko Un "Clara" Park: No. And this is confirmed based on the ACOSOG Z0011 study that demonstrated in patients with 1 to 3 positive sentinel lymph node biopsy when the study compared completion axillary lymph node dissection to no completion axillary lymph node dissection, there was no difference. And actually, the 10-year overall survival as reported out in 2017 and at a median follow up of 9.3 years, the overall survival again for patients treated with sentinel lymph node biopsy alone versus those who were treated with axillary lymph node dissection was no different. It was 86.3% in sentinel lymph node biopsy versus 83.6% and the p-value was non-inferior at 0.02. And so we believe that it is safe for the select patients who are early stage with 1 to 2 positive lymph nodes on sentinel lymph node biopsy, undergoing whole breast radiation therapy to omit completion of axillary lymph node dissection. Brittany Harvey: Great, I appreciate you detailing what's recommended there as well. So then, to continue our discussion of axillary lymph node dissection, Dr. Torres, for patients with nodal metastases who will undergo mastectomy, is axillary lymph node dissection indicated? Dr. Mylin Torres: It's actually not and this is confirmed by two trials, the AMAROS study as well as the SENOMAC trial. And in both studies, they compared a full lymph node dissection versus sentinel lymph node biopsy alone in patients who are found to have 1 to 2 positive lymph nodes and confirmed that there was no difference in axillary recurrence rates, overall survival or disease-free survival. What was shown is that with more aggressive surgery completion axillary lymph node dissection, there were higher rates of morbidity including lymphedema, shoulder pain and paresthesias and arm numbness, decreased functioning of the arm and so there was only downside to doing a full lymph node dissection. Importantly, in both trials, if a full lymph node dissection was not done in the arm that where sentinel lymph node biopsy was done alone, all patients were prescribed post mastectomy radiation and regional nodal treatment and therefore both studies currently support the use of post mastectomy radiation and regional nodal treatment when a full lymph node dissection is not performed in these patients who are found to have N1 disease after a sentinel node biopsy. Brittany Harvey: Thank you. And then Dr. Park, for patients with early-stage breast cancer who do not have nodal metastases, can completion axillary lymph node dissection be omitted? Dr. Ko Un "Clara" Park: Yes, and this is an unchanged recommendation from the earlier ASCO Guidelines from 2017 as well as the 2021 joint guideline with Ontario Health, wherein patients with clinically node-negative early stage breast cancer, the staging of the axilla can be performed through sentinel lymph nodal biopsy and not completion axillary lymph node dissection. Brittany Harvey: Understood. So then, to wrap us up on the clinical questions here, Dr. Park, what is recommended regarding sentinel lymph node biopsy in special circumstances in populations? Dr. Ko Un "Clara" Park: One key highlight of the special populations is the use of sentinel lymph node biopsy for evaluation of the axilla in clinically node negative multicentric tumors. While there are no randomized clinical trials evaluating specifically the role of sentinel lymph nodal biopsy in multicentric tumors, in the guideline, we highlight this as one of the safe options for staging of the axilla and also for pregnant patients, these special circumstances, it is safe to perform sentinel lymph node biopsy in pregnant patients with the use of technetium - blue dye should be avoided in this population. In particular, I want to highlight where sentinel lymph node biopsy should not be used for staging of the axilla and that is in the population with inflammatory breast cancer. There are currently no studies demonstrating that sentinel lymph node biopsy is oncologically safe or accurate in patients with inflammatory breast cancer. And so, unfortunately, in this population, even after neoadjuvant systemic therapy, if they have a great response, the current guideline recommends mastectomy with axillary lymph node dissection. Brittany Harvey: Absolutely. I appreciate your viewing both where sentinel lymph node can be offered in these special circumstances in populations and where it really should not be used. So then, Dr. Torres, you talked at the beginning about how there's been these new practice changing trials that really impacted these recommendations. So in your view, what is the importance of this guideline update and how does it impact both clinicians and patients? Dr. Mylin Torres: Thank you for that question. This update and these trials that inform the update represent a significant shift in the treatment paradigm and standard of care for breast cancer patients with early-stage breast cancer. When you think about it, it seems almost counterintuitive that physicians and patients would not want to know if a lymph node is involved with cancer or not through sentinel lymph node biopsy procedure. But what these studies show is that preoperative axillary ultrasound, 85% of the time when it's negative, will correctly predict whether a sentinel lymph node is involved with cancer or not and will also be negative. So if you have imaging that's negative, your surgery is likely going to be negative. Some people might ask, what's the harm in doing a sentinel lymph node biopsy? It's important to recognize that upwards of 10% of patients, even after sentinel lymph node biopsy will develop lymphedema, chronic arm pain, shoulder immobility and arm immobility. And these can have a profound impact on quality of life. And if there is not a significant benefit to assessing lymph nodes, particularly in someone who has a preoperative axillary ultrasound that's negative, then why put a patient at risk for these morbidities that can impact them lifelong? Ideally, the adoption of omission of sentinel lymph node biopsy will lead to more multidisciplinary discussion and collaboration in the preoperative setting especially with our diagnostic physicians, radiology to assure that these patients are getting an axillary ultrasound and determine how omission of sentinel lymph node biopsy may impact the downstream treatments after surgery, particularly radiation and systemic therapy decisions, and will be adopted in real world patients, and how clinically we can develop a workflow where together we can make the best decisions for our patients in collaboration with them through shared decision making. Brittany Harvey: Absolutely. It's great to have these evidence-based updates for clinicians and patients to review and refer back to. So then finally, Dr. Park, looking to the future, what are the outstanding questions and ongoing trials regarding sentinel lymph node biopsy in early-stage breast cancer? Dr. Ko Un "Clara" Park: I think to toggle on Dr. Torres's comment about shared decision making, the emphasis on that I think will become even more evident in the future as we incorporate different types of de-escalation clinical studies. In particular, because as you saw in the SOUND and INSEMA studies, when we de-escalate one modality of the multimodality therapy, i.e., surgery, the other modalities such as radiation therapy and systemic therapy were “controlled” where we were not de-escalating multiple different modalities. However, as the audience may be familiar with, there are other types of de-escalation studies in particular radiation therapy, partial breast irradiation or omission of radiation therapy, and in those studies, the surgery is now controlled where oftentimes the patients are undergoing surgical axillary staging. And conversely when we're looking at endocrine therapy versus radiation therapy clinical trials, in those studies also the majority of the patients are undergoing surgical axillary staging. And so now as those studies demonstrate the oncologic safety of omission of a particular therapy, we will be in a position of more balancing of the data of trying to select which patients are the safe patients for omission of certain types of modality, and how do we balance whether it's surgery, radiation therapy, systemic therapy, endocrine therapy. And that's where as Dr. Torres stated, the shared decision making will become critically important. I'm a surgeon and so as a surgeon, I get to see the patients oftentimes first, especially when they have early-stage breast cancer. And so I could I guess be “selfish” and just do whatever I think is correct. But whatever the surgeon does, the decision does have consequences in the downstream decision making. And so the field really needs to, as Dr. Torres stated earlier, rethink the workflow of how early-stage breast cancer patients are brought forth and managed as a multidisciplinary team. I also think in future studies the expansion of the data to larger tumors, T3, in particular,reater than 5 cm and also how do we incorporate omission in that population will become more evident as we learn more about the oncologic safety of omitting sentinel lymph node biopsy. Dr. Mylin Torres: In addition, there are other outstanding ongoing clinical trials that are accruing patients right now. They include the BOOG 2013-08 study, SOAPET, NAUTILUS and the VENUS trials, all looking at patients with clinical T1, T2N0 disease and whether omission of sentinel lymph node biopsy is safe with various endpoints including regional recurrence, invasive disease-free survival and distant disease-free survival. I expect in addition to these studies there will be more studies ongoing even looking at the omission of sentinel lymph node biopsy in the post-neoadjuvant chemotherapy setting. And as our imaging improves in the future, there will be more studies improving other imaging modalities, probably in addition to axillary ultrasound in an attempt to accurately characterize whether lymph nodes within axilla contain cancer or not, and in that context whether omission of sentinel lymph node biopsy even in patients with larger tumors post-neoadjuvant chemotherapy may be done safely and could eventually become another shift in our treatment paradigm. Brittany Harvey: Yes. The shared decision making is key as we think about these updates to improve quality of life and we'll await data from these ongoing trials to inform future updates to this guideline. So I want to thank you both so much for your extensive work to update this guideline and thank you for your time today. Dr. Park and Dr. Torres. Dr. Mylin Torres: Thank you. Dr. Ko Un "Clara" Park: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Listen to ASCO's Journal of Clinical Oncology Art of Oncology article, "Tamales” by Megan Dupuis, an Assistant Professor of Hematology and Oncology at Vanderbilt University Medical Center. The article is followed by an interview with Dupuis and host Dr. Mikkael Sekeres. Dupuis reflects on how patients invite their doctors into their culture and their world- and how this solidified her choice to be an oncologist. TRANSCRIPT Narrator: Tamales, by Megan Dupuis, MD, PhDI do not know if you know this, but tamales are an important—nay, critical—part of the Mexican Christmas tradition. Before I moved to Texas, I certainly did not know that. I did not know that the simple tamal, made of masa flour and fillings and steamed in a corn husk, is as essential to the holiday season as music and lights. Whole think pieces have been written in The Atlantic about it, for God's sake. But, I did not know that. A total gringa, I had grown up in upstate NY. We had the middle-class American version of Christmas traditions—music, snow, Santa, and a Honey Baked Ham that mom ordered 2 weeks before the holiday. I had never tried a homemade tamal until I moved to Texas. We had relocated because I was starting a fellowship in hematology/oncology. A central part of our training was the privilege of working at the county hospital cancer clinic. Because we were the safety-net hospital, our patients with cancer were often under- or uninsured, frequently had financial difficulty, and were almost always immigrants, documented or otherwise. In a typical clinic day, over 90% of my patients spoke Spanish; one or two spoke Vietnamese; and typically, none spoke English. From meeting my very first patient in clinic, I knew this was where I needed to be. Have you ever been unsure of a decision until you have been allowed to marinate in it? That is how I felt about cancer care; I had not been sure that my path was right until I started in the county oncology clinic. I loved absorbing the details of my patients' lives and the cultures that centered them: that Cuban Spanish is not Mexican Spanish and is not Puerto Rican Spanish; that many of my patients lived in multigenerational homes, with abuelos and tios and nietos all mixed together; and that most of them continued to work full-time jobs while battling cancer. They had hobbies they pursued with passion and lived and died by their children's accomplishments. I learned these details in the spaces between diagnosis and treatment, in the steady pattern woven in between the staccato visits for chemotherapy, scans, pain control, progression, and hospice. In one of those in-betweens, my patient Cristina told me about tamales. She had faced metastatic breast cancer for many years. She was an impeccable dresser, with matching velour tracksuits or nice slacks with kitten heels or a dress that nipped in at the waist and flared past her knees. Absolutely bald from treatment, she would make her hairlessness look like high fashion rather than alopecia foisted upon her. Her makeup was always painstakingly done and made her look 10 years younger than her youthful middle age. At one visit in August, she came to clinic in her pajamas and my heart sank. This was a familiar pattern to me by now; I had taken care of her for 2 years, and pajamas were my canary in the coal mine of progressing cancer. So on that sunny day, I asked Cristina what her goals would be for the coming months. The cancer had circumvented many of her chemotherapy options, and I only had a few left. “Doctora D, I know my time is limited…” she started in Spanish, with my interpreter by my side translating, “but I would really like to make it to Christmas. My family is coming from Mexico.” “Oh that's lovely. Do you have any special Christmas plans?” I ventured, wanting to understand what her holidays look like. “Plans? Doctora D, of course we are making tamales!” She laughed, as though we were both in on a joke. “Tamales? At Christmas?” I asked, signaling her to go on. “Yes yes yes, every year we make hundreds and hundreds of tamales, and we sell them! And we use the money to buy gifts for the kids, and we eat them ourselves too. It is tradicio´ n, Doctora D.” She underlined tradicio´ n with her voice, emphasizing the criticality of this piece of information. “Okay,” I said, pausing to think—December was only four months away. “I will start a different chemotherapy, and we will try to get you to Christmas to make your tamales.” Cristina nodded, and the plan was made. Later that evening, I asked one of my cofellows, a Houston native, about tamales. He shared that these treats are an enormous part of the Houston Christmas tradition, and if I had any sense, I would only purchase them from an abuela out of the trunk of a car. This was the only way to get the best homemade ones. “The ones from restaurants,” he informed me, “are crap.” So summer bled into fall, and fall became what passes for winter in Texas. On 1 day in the middle of December, Cristina came into clinic, dressed in a colorful sweater, flowing white pants, black boots, and topped off with Barbie-pink lipstick. “Cristina!” I exclaimed, a bit confused. “You don't have an appointment with me today, do you?” She grinned at me and held up a plastic grocery bag with a knot in the handles, displaying it like a prize. “Tamales, Doctora D. I brought you some tamales so you can join our Christmas tradition.” I felt the sting of tears, overwhelmed with gratitude at 11:30 in a busy county clinic. I thanked her profusely for my gift. When I brought them home that night, my husband and I savored them slowly, enjoying them like you would any exquisite dish off a tasting menu. Sometimes, people think that oncologists are ghouls. They only see the Cristinas when they are in their pajamas and wonder why would any doctor ever give her more treatment? My answer is because I also got to see her thriving joyfully in track suits and lipstick, because I got to spend countless in-betweens with her, and because I helped get her to the Christmas tradiciones I only knew about because of her. And in return, she gave of herself so easily, sharing her life, her passion, her struggles, and her fears with me. Caring for Cristina helped me marinate in the decision to become an oncologist and know that it was the right one. And if you are wondering—yes. Now tamales are a Christmas tradicio´n in the Dupuis household, too. Mikkael Sekeres: Hello, and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the oncology field. I'm your host, Mikkael Sekeres. I'm a professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. What a pleasure it is today to be joined by Dr. Megan Dupuis from Vanderbilt University Medical Center. She is Assistant Professor of Hematology and Oncology and Associate Program Director for the Fellowship program. In this episode, we will be discussing her Art of Oncology article, "Tamales." Our guest's disclosures will be linked in the transcript. Both she and I have talked beforehand and agreed to refer to each other by first names. Megan, welcome to our podcast, and thank you for joining us. Megan Dupuis: Oh, thanks so much for having me, Mikkael. I'm excited to be here. Mikkael Sekeres: I absolutely loved your piece, "Tamales," as did our reviewers. It really did resonate with all of us and was beautifully and artfully written. I'm wondering if we could just start—tell us about yourself. Where are you from, and where did you do your training? Megan Dupuis: Sure. I'm originally from upstate New York. I grew up outside of Albany and then moved for college to Buffalo, New York. So I consider Buffalo home. Big Buffalo Bills fan. And I spent undergrad, medical school, and my PhD in tumor immunology at the University of Buffalo. My husband agreed to stick with me in Buffalo for all twelve years if we moved out of the cold weather after we were done. And so that played some factor in my choice of residency program. I was lucky enough to go to Duke for residency—internal medicine residency—and then went to MD Anderson for fellowship training. And then after Anderson, I moved up to Nashville, Tennessee, where I've been at Vanderbilt for almost four years now. Mikkael Sekeres: That's fantastic. Well, I have to say, your Bills have outperformed my Pittsburgh Steelers the past few years, but I think I think we have a chance this coming year. Megan Dupuis: Yeah. Yep. Yep. I saw they were thinking about signing Aaron Rodgers, so we'll see how that goes. Mikkael Sekeres: Yeah, not going to talk about that in this episode. So, I'm curious about your story as a writer. How long have you been writing narrative pieces? Megan Dupuis: I have always been a writer—noodled around with writing and poetry, even in college. But it was when I started doing my medicine training at Duke that I started to more intentionally start writing about my experiences, about patients, things that I saw, things that weighed either heavily on me or made a difference. So when I was at Duke, there was a narrative medicine writing workshop—it was a weekend workshop—that I felt like changed the trajectory of what my interest is in writing. And I wrote a piece at that time that was then sort of critiqued by colleagues and friends and kicked off my writing experience. And I've been writing ever since then. We formed a narrative medicine program at Duke out of this weekend workshop experience. And I carried that through to MD Anderson when I was a fellow. And then when I joined at Vanderbilt, I asked around and said, "Hey, is there a narrative medicine program at Vanderbilt?" And somebody pointed me in the direction of a colleague, Chase Webber, who's in internal medicine, and they said, "Hey, he's been thinking about putting together a medical humanities program but needs a co-conspirator, if you will." And so it was perfect timing, and he and I got together and started a Medical Humanities Certificate Program at Vanderbilt about four years ago. And so- Mikkael Sekeres: Oh, wow. Megan Dupuis: Yeah. So I've been doing this work professionally, but also personally. You know, one of the things that I have been doing for a long time is anytime there's an experience that I have that I think, “Gosh, I should write about this later,” I either dictate it into my phone, “write about this later,” or I write a little message to myself, “Make sure that you remember this experience and document it later.” And I keep a little notebook in my pocket specifically to do that. Mikkael Sekeres: Well, it's really a fabulous, updated use of technology compared to when William Carlos Williams used to scribble lines of poetry on his prescription pad and put it in his rolltop desk. Megan Dupuis: Although I will admit, you know, I don't think I'm much different. I still do prefer often the little leather notebook in the pocket to dictating. It'll often be when I'm in the car driving home from a clinic day or whatever, and I'll go, “Oh, I have to write about this, and I can't forget.” And I'll make myself a little digital reminder if I have to. But I still do keep the leather notebook as well for the more traditional type of writing experience. Mikkael Sekeres: I'm curious about what triggers you to dictate something or to scribble something down. Megan Dupuis: I think anything that gives me an emotional response, you know, anything that really says, “That was a little bit outside the normal clinical encounter for me.” Something that strikes me as moving, meaningful—and it doesn't have to be sad. I think a lot of novice writers about medical writing think you have to write only the tragic or the sad stories. But as often as not, it'll be something incredibly funny or poignant that a patient said in clinic that will make me go, “Ah, I have to make sure I remember that for later.” I think even surprise, you know? I think all of us can be surprised in a clinical encounter. Something a patient says or something a spouse will reflect on will make me sit back and say, “Hmm, that's not what I expected them to say. I should dive into why I'm surprised by that.” Mikkael Sekeres: It's a great notion as a starting point: an emotional connection, a moment of surprise. And that it doesn't have to be sad, right? It can be- sometimes our patients are incredibly inspirational and have great insights. It's one of the marvelous things about the career we've chosen is that we get to learn from people from such a variety of backgrounds. Megan Dupuis: That's it. It's a privilege every day to be invited into people's most personal experiences, and not just the medical experience. You know, I say to my patients, “I think this cancer diagnosis is in some ways the least interesting thing about you. It's not something you pick. It's not a hobby you cultivate. It's not your family life. It's a thing that's happened to you.” And so I really like to dive into: Who are these people? What makes them tick? What's important to them? My infusion nurses will say, "Oh, Dr. D, we love logging in and reading your social histories," because, yeah, I'll get the tobacco and alcohol history, or what have you. But I have a little dot phrase that I use for every new patient. It takes maybe the first five or six minutes of a visit, not long. But it's: Who are you? What's your preferred name? Who are your people? How far do you live from the clinic? What did you used to do for work if you're retired? If you're not retired, what do you do now? What are the names of your pets? What do you like to do in your spare time? What are you most proud of? So those are things that I ask at every new patient encounter. And I think it lays the foundation to understand who's this three-dimensional human being across from me, right? What were they like before this diagnosis changed the trajectory of where they were going? To me, that's the most important thing. Mikkael Sekeres: You've so wonderfully separated: The patient is not the diagnosis; it's a person. And the diagnosis is some component of that person. And it's the reason we're seeing each other, but it doesn't define that person. Megan Dupuis: That's right. We're crossing streams at a very tough point in their life. But there was so much that came before that. And in the piece that I wrote, you know, what is the language? What is the food? What is the family? What are all of those things, and how do they come together to make you the person that you are, for what's important to you in your life? And I think as oncologists, we're often trying to unravel in some way what is important. I could spend all day talking to you about PFS and OS for a specific drug combination, but is that really getting to meeting the goals of the patient and where they're at? I think it's easy to sort of say, “Well, this is the medicine that's going to get you the most overall survival.” But does it acknowledge the fact that you are a musician who can't have neuropathy in your fingers if you still want to play? Right? So those things become incredibly important when we're deciding not just treatment planning, but also what is the time toxicity? You know, do you have the time and ability to come back and forth to clinic for weekly chemotherapy or what have you? So those things, to me, become incredibly important when I'm talking to a person sitting across from me. Mikkael Sekeres: Do your patients ever get surprised that you're asking such broad questions about their life instead of narrowing down to the focus of their cancer? Megan Dupuis: Sometimes. I will say, sometimes patients are almost so anxious, of course, with this new diagnosis, they want to get into it. You know, they don't want to sit there and tell me the name of the horses on their farm, right? They want to know, “What's the plan, doc?” So I acknowledge that, and I say to them in the beginning, “Hey, if you give me five minutes of your time to tell me who you are as a person, I promise this will come back around later when we start talking about the options for treatments for you.” Most of the time, though, I think they're just happy to be asked who they are as a person. They're happy that I care. And I think all of us in oncology care—I think that's... you don't go into a field like this because you're not interested in the human experience, right? But they're happy that it's demonstrable that there is a... I'm literally saying, “What is the name of your dog? What is the name of your child who lives down the street? Who are your kids that live far away? You know, do you talk to them?” They want to share those things, and they want to be acknowledged. I think these diagnoses can be dehumanizing. And so to rehumanize somebody does not take as much time as we may think it does. Mikkael Sekeres: I 100% agree with you. And there can be a selfish aspect to it also. I think we're naturally curious people and want to know how other people have lived their lives and can live those lives vicariously through them. So I'm the sort of person who likes to do projects around the house. And I think, to the dismay of many a professional person, I consider myself an amateur electrician, plumber, and carpenter. Some of the projects are actually up to code, not all. But you get to learn how other people have lived their lives and how they made things. And that could be making something concrete, like an addition to their house, or it can be making a life. Megan Dupuis: Yeah, I love that you say that it is selfish, and we acknowledge that. You know, sometimes I think that we went into internal medicine and ultimately oncology... and I don't mean this in a trite way: I want the gossip about your life. I want the details. I want to dig into your hobbies, your relationships, what makes you angry, what makes you excited. I think they're the fun things to learn about folks. Again, in some ways, I think the cancer diagnosis is almost such a trite or banal part of who a human is. It's not to say that it's not going to shape their life in a very profound way, but it's not something they picked. It's something that happened to them. And so I'm much more excited to say, “Hey, what are your weekend hobbies? Are you an amateur electrician?” And that dovetails deeply into what kind of treatment might help you to do those things for longer. So I think it is a little bit selfish that it gives me a lot of satisfaction to get to know who people are. Mikkael Sekeres: So part of what we're talking about, indirectly, is the sense of otherness. And an undercurrent theme in your essay is otherness. You were an 'other' as a fellow in training and working in Texas when you grew up in upstate New York. And our patients are also 'others.' They're thrust into this often complicated bedlam of cancer care. Can you talk about how you felt as an 'other' and how that's affected your approach to your patients? Megan Dupuis: I think in the cancer experience, we are 'other,' definitionally, from the start, for exactly the reasons that you said. I'm coming to it as your physician; you're coming to it as my patient. This is a new encounter and a new experience for both of us. I think the added layer of being this person from upstate New York who didn't... I mean, I minored in Spanish in college, but that's not the same thing as growing up in a culture that speaks Spanish, that comes from a Spanish-speaking country—the food, the culture. It's all incredibly different. And so the way that I approached it there was to say, “I am genuinely curious. I want to know what it's like to be different than the culture that I was raised in.” And I'm excited to know about that thing. And I think we can tell—I think, as humans—when somebody is genuinely curious about who you are and what's important to you, versus when they're kind of just checking the boxes to try to build a relationship that's necessary. I think my patients could tell that even though I'm not necessarily speaking their language, I want to know. I ask these questions because I want to know. I think if you go to it from a place of curiosity, if you are approaching another person with a genuine sense of curiosity... You know, Faith Fitzgerald wrote her most remarkable piece on curiosity many, many years ago. But even the quote-unquote “boring” patient, as she put it, can have an incredible story to tell if you're curious enough to ask. And so I think that no matter how different I might be culturally from the patient sitting across from me, if I approach it with a genuine sense of curiosity, and they can sense that, that. that's going to build the bond that we need truly to walk together on this cancer journey. I think it's curiosity, and I think it's also sharing of yourself. I think that nobody is going to open up to you if they feel that you are closed to sharing a bit of yourself. Patients want to know who their doctor is, too. So when I said I asked those five or six minutes' worth of questions at the beginning of a new patient encounter, I share that info with them. I tell them where I live, how long it takes for me to get to clinic, who my people are, the name of my dog, what I like to do in my spare time, what I'm proud of. So I share that with them too, so it doesn't feel like a one-way grilling. It feels like an introduction, a meeting, the start of a... I don't want to say friendship necessarily, but a start of a friendliness, of a shared communal experience. Mikkael Sekeres: Well, it's a start of a relationship. And you can define 'relationship' with a broad swath of definitions, right? Megan Dupuis: That's right. Mikkael Sekeres: It can be a relationship that is a friendship. It can be a relationship that's a professional relationship. And just like we know some personal things about some of our colleagues, the same is true of our patients. I was wondering if I could pick up on... I love that notion of curiosity that you brought out because that's something I've thought a lot about, and I've thought about whether it could be at least one way to combat burnout. So could you put that in context of burnout? Do you think maintaining that curiosity throughout a career is one potential solution to burnout? And do you think that being open with yourself also helps combat burnout, which is counterintuitive to what we've always been taught? Megan Dupuis: Wow. I think that this is such an important question, and it's almost like you read my justification for a Medical Humanities Certificate Program. One of the foundational arguments for why I thought the GME should support the creation of this program at Vanderbilt was because we hypothesized that it would improve burnout. And one of the arms of that is because it engenders a sense of genuine curiosity. When you're thinking about the arms of burnout: it's loss of meaning in your work; it's depersonalization of patients, right, when they're treated as objects or numbers or a ticket in the system that you have to shuffle through; when it's disconnection from the work that you do. I absolutely think that curiosity is an antidote to burnout. I don't think it's the whole solution, perhaps, because I think that burnout also includes systemic injury and structures of our medical healthcare system that no individual can fix in a vacuum. But I do think when we're thinking about what are the changes that we as individual physicians can make, I do think that being open and curious about your patient is one of the best salves that we have against some of these wounds. You know, I've never left a room where a patient has shared a personal story and felt worse about it, right? I've always felt better for the experience. And so I do think curiosity is an incredibly important piece of it. It's hard, I will acknowledge. It's hard for the speed that we move through the system, the pace that we move through the system. And I'm thinking often about my trainees—my residents, my fellows—who are seeing a lot, they're doing a lot, they are trying to learn and drink from the fire hose of the pace of medical development, checking so many boxes. And so to remain curious, I think at times can feel like a luxury. I think it's a luxury I have boomeranged back into as an attending. You know, certainly as a resident and a fellow, I felt like, “Gosh, why does this attending want to sit and chitchat about this person's music career? I'm just trying to make sure their pain is controlled. I'm trying to make sure they get admitted safely. I'm trying to make sure that they're getting the right treatment.” And I think it's something that I've tried to teach my trainees: “No, we have the time. I promise we have the time to ask this person what their childhood was like,” if that's something that is important to the narrative of their story. So it sometimes feels like a luxury. But I also think it's such a critical part of avoiding or mitigating the burnout that I know all of us face. Mikkael Sekeres: I think you touched on a lot of really important points. Burnout is so much more complicated than just one inciting factor and one solution. It's systemic. And I love also how you positioned curiosity as a bit of a luxury. We have to have the mental space to also be curious and engaged enough in our work that we can take interest in other people. I wanted to touch on one more question. You write in your essay that a patient in pajamas is a canary in the coal mine for deteriorating health. And I completely, completely agree with that. I can vividly recall a number of patients where I saw them in my clinic, and I would look down, and they had food spilled on their sweatshirt, or they were wearing mismatched socks, or their shoes weren't tied. And you thought to yourself, “Gee, this person is not thriving at home.” Do you think telemedicine has affected our ability to recognize that in our patients? Megan Dupuis: Yes, I do think so. I can remember vividly being a fellow when COVID first began in 2020, and I was training in an environment where most of my patients spoke Spanish or Vietnamese. And so we were doing not just telemedicine; we were doing telephone call clearance for chemotherapy because a lot of the patients didn't have either access to the technology or a phone that had video capability. A lot of them had flip phones. And trying to clear somebody for chemotherapy over the phone, I'll tell you, Mikkael, was the number one way to lead to a recipe of moral injury and burnout. As a person who felt this deep responsibility to do something safe... I think even now with telemedicine, there are a lot of things that you can hide from the waist down, right? If you can get it together enough to maybe just put a shirt on, I won't know that you're sitting there in pajama bottoms. I won't know that you're struggling to stand or that you're using an assistive device to move when you used to be able to come into clinic without one, or that your family member is helping you negotiate stepping over the curb in clinic. These are real litmus tests that you and I, all of us, use when we're deciding whether somebody is safe to receive a treatment. And I think telemedicine does mask some of that. Now, on the other hand, does telemedicine provide an access point for patients that otherwise it would be a challenge to drive into clinic for routine visits and care? It does, and I think it's been an incredible boon for patients who live far away from the clinic. But I think we have to use it judiciously. And there are patients where I will say, “If you are not well enough to get yourself to clinic, I worry that you are not well enough to safely receive treatment.” And when I'm thinking about the rules of chemo, it's three: It has to be effective, right? Cancer decides that. It has to be something the patient wants. They decide. But then the safety piece—that's my choice. That's my responsibility. And I can't always decide safety on a telemedicine call. Mikkael Sekeres: I completely agree. I've said to my patients before, “It's hard for me to assess you when I'm only seeing 40% of you.” So we will often negotiate them having to withstand the traffic in Miami to come in so I can feel safe in administering the chemotherapy that I think they need. Megan Dupuis: That's exactly right. Mikkael Sekeres: Megan Dupuis, it has been an absolute delight getting to chat with you. It has been just terrific getting to know you and talk about your fabulous essay, "Tamales." So thank you so much for joining me. Megan Dupuis: Thank you for having me. It was a wonderful time to chat with you as well. Mikkael Sekeres: Until next time, thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all of ASCO's shows at asco.org/podcasts. Thank you again. 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. Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr Megan Dupuis is an Assistant Professor of Hematology and Oncology at Vanderbilt University Medical Center.
Host Dr. Davide Soldato and guests Dr. Jessica Burris discuss the article "Longitudinal Results from the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment in American College of Surgeons Accredited Cancer Programs" and how persistent smoking following cancer diagnosis causes adverse outcomes while smoking cessation can improve survival. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Davide SoldatoHello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy. Today we are joined by JCO author Dr. Jessica Burris. Dr. Burris is an Associate professor of Psychology at the University of Kentucky and co leader of the Cancer Prevention and Control Research Program at the Markey Cancer Center. Her research focuses on smoking cessation among cancer survivors, health disparities, and behavioral interventions to promote health equity. She also leads the BIRDS Lab, which explores the intersection of smoking, social determinants of health, and cancer survivorship. Today I will be discussing with Dr. Burris on the article titled Longitudinal Results from the Nationwide Just Ask Initiative to Promote Routine Smoking Assessment in American College of Surgeons Accredited Cancer Program. So, thank you for Speaking with us, Dr. Burris. Dr. Jessica BurrisThank you for inviting me. Dr. Davide SoldatoSo today we'll be discussing an important study on the implementation of smoking assessment in cancer care and specifically through the Just Ask Initiative. So, we know that tobacco use is a critical factor in cancer treatment outcomes in general, and yet integrating systematic smoking assessment into oncology care has faced various challenges. So, Dr. Burris, to start off our interview, I would like to ask you to briefly introduce the Just Ask Initiative for those of our readers and listeners who may not be familiar with it. So, a little bit about the primary goals and why do you think that routine smoking assessment is such an important aspect of cancer care and why the Just Ask Initiative focuses on this specific issue? Dr. Jessica BurrisSure. So, as you mentioned before, smoking is a really critical factor in terms of cancer care and cancer outcomes. It impacts a lot of things, from complications after surgery up into cancer mortality, but it also impacts patient's quality of life. Their pain may be more severe, they're more tired, their distress levels are higher. So, there's just a lot of different reasons why we need to understand and address smoking in the context of cancer care. But like you said too, there's a lot of barriers as well. But in order to effectively treat nicotine dependence and tobacco use, we really need to know who is currently smoking. And so that was really the driver for Just Ask, wanting to make sure that we are asking every person with cancer at their diagnosis and as they go through treatment, what their smoking history is, if they are currently smoking, which we usually consider to be any smoking or other tobacco use in the past 30 days, so that once we can identify that person, then we know who we need to help. Dr. Davide SoldatoThank you very much. That was very clear. And in terms of methodology, Just Ask was really a quality improvement type of initiative that involved the programs that were contacted and approached to participate in this type of initiative. And the methodology is pretty standard for this type of implementation science, which is the Plan Do Study Act methodology. So just a little bit of background on this type of methodology and why do you think it might be so successful when implementing these types of changes at the structural level and when we are implementing these types of programs. Dr. Jessica BurrisRight. So, the American College of Surgeons requires all the accredited cancer programs, both Commission on Cancer and the NAPBC or the ones that focus on breast cancer, to do at least one quality improvement project annually. And most of the programs do use the evidence-based Plan Do Study Act approach. I think it's a great one. It has a lot of evidence behind it, but it also is very practical or pragmatic. So, you're using data from your local healthcare system or clinic or program to inform what it is that you do. And then you're constantly pulling data out to see how well you're addressing the clinical practice change that you're hoping to achieve. And so, data is going in and coming out and you're using that to inform exactly what it is that you're doing over time. So, it's an iterative approach to practice change and again, one that has proven successful time and time again. And so that's the program that these programs and Just Ask used in order to increase the frequency by which they ask patients about smoking. Dr. Davide SoldatoSo as you were saying, the main objective of the initiative was really to understand if we are asking patients diagnosed with cancer and survivors if they are smoking. And how can we better report this information inside of the medical chart of the patient. So, what was the primary endpoint or the objective that you had for this type of intervention? And can you give us a little bit of results? So, what did you find the implementation of this quality improvement? How did it change the percentages of patients that were asked about smoking habits? And a little bit, what is your opinion on the results that you obtain in the study? Dr. Jessica BurrisSure. So, the goal was simple and that was to have an ask rate that was at least 90%. The way that we defined an ask rate is among all newly diagnosed cancer patients, how many were asked about their smoking history and their current status at that initial visit? And so, we wanted all of the participating programs who opted in to Just Ask in 2022 to achieve that 90% ask rate by the end of this one-year quality improvement project. And again, using the Plan Do Study Act approach, it was a very pragmatic study in some ways. So, what we did was we provided an intervention change package that we made available online. And programs could access that whenever they needed to and pull-down educational resources, patient facing materials, practical tools for changing the EHR or pulling data out of the EHR, any of those number of things. And then we also hosted webinars over the course of the year. And those webinars were great because half the time they were in response to questions that programs were asking as they went through the Just Ask QI project. And the other half of time we were really just reminding programs of the rationale and the reason for making sure that they're asking. And then of course, letting them know that they don't have to stop there, they should be advising patients to quit and assisting them with cessation. Even though that wasn't the goal of Just Ask, the goal again of Just Ask was getting that 90% rate. And so, we had over 750 programs who opted in to Just Ask and did this QI study with us, and it was successful. So, we met the goal, or rather the programs met the goal of that 90% ask rate. And that was maintained over time. And that was just fantastic. So again, we know that the end goal is really to assist patients with quitting, but we can't do that unless we know who to help. And so, you have to ask first. And again, they were able to do that. Dr. Davide SoldatoSo thank you very much. The quality improvement program was absolutely successful. And to go a little bit in the numbers, by the end of the one-year implementation of the program, you report a 98% rate of asking patients who first approached the centers or over time if they were or not smokers. So, you said before that you targeted a 90% ask rate in terms of smoking habits. But when looking at the data, I noticed that you already had in the baseline survey where you asked the programs about what were the practice before the implementation of the Just Ask initiative, already something that was quite close to the 90%. And yet, despite starting from such a good point, which was basically your endpoint, you still observed a major change over the years of the implementation. So, I wanted to just underline a little bit what is the value of this type of programs. And still starting from such a very high standard still, we managed to further improve. And as you were saying, this is pivotal and I think it's fundamental to really understand and see who are the patients that we need to refer and then to help in the smoking cessation. So, I just wanted a little bit of a comment on these very important results, despite already starting from a very good background from the centers. Dr. Jessica BurrisYeah, I'm glad that you brought up the baseline. So, I think one thing that's important about this study is that we looked at our ask rate or the asking as a clinical practice in two different ways. So, the 98% that you referred to that we found at the final survey is based on a response to a question on the frequency of asking. So, it's a Likert type question. And essentially what we did was we combined programs that reported usually asking or almost always asking into one, and that's where we arrived at the 98%. And at baseline it was 92%. What's interesting though is that we also asked them to report the specific number of patients who were seen in their cancer program during the prior six months and the number of patients who were asked about smoking in the prior six months. And with that we could get a proportion. And in every case, the self-report Likert question had a higher outcome than the raw data based on the data that was pulled from the EHR. And so, we saw this increase significantly over time, both in the self-report Likert question, but also in the EHR based data. And so, it was a win in two ways. What I think is really interesting though is that at baseline, even though 92% of programs said that they regularly ask about their patient smoking status, 16% of programs could not provide data that would allow calculation of an ask rate. So, they were reporting that they were able to do so but then could not actually do so. So, I think what that means essentially is that there's a disconnect between what programs are doing regularly or they believe that they're doing regularly and what their data actually shows. And it could be an issue with the quality of the data that's going into the EHR, or it could be an issue with pulling the data out of the EHR. And so one of the things that we saw that I think is a second indicator of success of Just Ask is that the quality of the data that programs were inputting into the EHR related to their patients smoking history and smoking status did improve over time, which meant that by the end it really was the case that the vast majority of programs were asking. And not only that, but they were also documenting it in a way to where it could inform patient care. Does that make sense? Dr. Davide SoldatoAbsolutely. And I think that that explanation really is truly important because I think that it also connects a little bit to how the initiative was able also to change things at the structural level, to be sure that there was the best possible way of asking, but also of having that information readily available inside of the EHR. This also connects a little bit to my next question, which was a little bit about organizational structure and also implementation barriers, which you report also as a self-reported information by the specific programs. So, there was a little bit of implementation barriers that was reported by the programs and this was not a specific endpoint of the Just Ask initiative, but you kind of mentioned it a little bit. The difficulties in pulling data from the EHR in understanding whether the information was collected and how it was collected. This might be one of the implementation barrier when we are looking at initiatives like Just Ask. So, I just wanted a little bit of your opinion if you think that these implementational barriers are more on the organizational side or on the provider side. And how can we use these quality improvement programs to really tackle this type of barriers to improve overall the reach and the importance of our action regarding smoking cessation. Dr. Jessica BurrisThe devils in the details, right? So I think it's a “both and” situation and not either or I think for providers, for individual providers, oncologists, nurses, supportive care providers, the issue of feeling like they're not fully trained in tobacco use assessment and treatment, and also feeling because of a lack of training that they don't feel confident or competent or even comfortable having conversations with their patients about their smoking history or being in the position to where they can really help someone who wants to quit in choosing the best path and way forward to do that that really matters. And so organizational readiness, these programs that participated were pretty high even at baseline in terms of the organizational readiness. They understood that it's a problem and they wanted to do something about it. And they were really eager and chomping at the bit to do so. But that has to trickle down to individual providers. And so, I think one of the implementation strategies that was used was staff training and provider education. And a lot of the participating programs chose that strategy. And I think as staff and providers are trained in how to ask and how to do so in a way that is nonjudgmental and that doesn't lean into things like stigma or blame or making patients feel guilty that perhaps their behavior led to their cancer, but really just understanding tobacco history and understanding nicotine dependence and the best strategies that we have to address those things that helped and that made a difference but it also is things at the system level, like having good EHR data, being able to pull those data out at a regular interval every three months or every four months, or even every six months to make sure that you're tracking smoking and also quitting over time. Both of those things need to happen. And I think those were things that we saw change as a result of Just Ask participation. Dr. Davide SoldatoRelating to this, provider readiness also to counsel patients on how to stop smoking or what is the best strategy. Despite, as you said in the very beginning, this was not the objective of Just Ask because you just wanted to improve the rate of smoking assessment and the quality of reporting of smoking assessment. You still observed higher rates of patients and survivors that were actually referred to some kind of intervention for smoking cessation. So, I was just wondering, why do you think that even though that was not required, you still observe this type of improvement? Like, is it just inherent to the fact that we are improving and we are placing more interest and more attention on the fact that patients should quit smoking, or do you think that it relates to something else completely? Dr. Jessica BurrisI think there's probably multiple things going on. One is once you're fully aware of the fact of the impact of smoking after a cancer diagnosis, you're going to be compelled to do something, I think. And so just the simple fact of knowing now that the patient sitting in front of you has smoked in the past week or two, they may be under a lot of stress because they're coping with cancer and they're coping with the side effects of their treatment. They may even have increased their smoking since their cancer diagnosis. And now you have this information. I think people who are providing cancer care, they want to improve the health and the life of the person sitting in front of them. And if they understand that smoking is a detriment or a hurdle to their doing so, then they're also more inclined to try and help that person quit smoking. And so, I think the asking and the documenting likely led to an increase in assistance and referrals to tobacco treatment specialists or to a state quit line, which was also common, simply because that's part of providing quality care. I think also there's been a greater emphasis nationally, in part led by the National Cancer Institute and a cancer moonshot initiative that it led, they're really focused on getting more treatment to more patients with smoking and increasing the reach and the effectiveness of the treatments that we provide. And so, I think there has been a shift in oncology care broadly to put more attention on smoking and smoking cessation as part of standard cancer care. And so, I think this kind of shift in the field also informed things as well as, again, thinking about the patient and the individual who's in the room and wanting to do something about the problem that you've just identified. Dr. Davide SoldatoAnd one thing that I believe is truly exceptional about the Just Ask initiative is really also the diversity of the type of programs that you involved. Like, you went from community centers to more academic centers. And really, I did not have the impression reading the manuscript that there was any difference in the way this type of quality improvement initiative can really benefit all these programs and all these centers. So, I was just wanting to have your opinion or comment on how do you think this type of initiative could be transferable across the country and across different settings and different types of cancer care? Dr. Jessica BurrisYeah, I'm really glad that you brought that up, because I think most of the clinical trials that are done in this area are done at academic medical centers, which are admittedly kind of resource rich places to receive cancer care. And so, what works in academic medical center may not work in a small rural practice in the middle of Kansas, for example, or in Mississippi. And it may not work in other community-based practices, even if they're larger and set in an urban setting. And so, one of the things that frankly I loved about Just Ask is that it was very heterogeneous in terms of the sites and the participating groups. And so not only was it national and by far the largest initiative in this area, again with over 750 different programs, but the programs were diverse. So, we had large community-based programs, integrated networks, smaller community programs. And then the academic centers were actually the smallest. Only like 10 or 12 out of the 750 plus were academic. And so, it was very different than what is the norm in this research area and in this area generally in terms of clinical practice. And we were able to show that the type of program that participated had no bearing on their success. And so, when we think about initiatives that work and interventions that work, we also really have to think about what is scalable and what could be disseminated across different practices. And this is one of those things that can. It worked and it worked across different swaths of group, which was great. Dr. Davide SoldatoAbsolutely. And just one last comment about the intervention, and it's also a point that you raised in the manuscript. This initiative, like many others also at the national levels that have been reported previously, they rarely had really the participation or the perspective of the patients embodied inside of them. So, I was wondering, how do you see the field moving forward. Like you envision something that would implement sort of a co-creation with patients or cancer survivors in order to really create something that is more appealing and takes more into consideration what is the patient perspectives when we are approaching something like smoking cessation, which as you were mentioning before, it can have a lot of stigma or already some negative feelings by the patients and feelings of guilt regarding the fact that they smoked and that might have caused that cancer. So just a little bit of your opinion as to how you see the implementation science in smoking cessation moving forward while integrating also the patient perspectives. Dr. Jessica BurrisYeah, that's a great question. So, this is something that I've thought about a lot in my lab and at Market Cancer center, which I'll use as an example. But oftentimes what we see is that even when tobacco treatment is offered as part of standard cancer care, even when we try to remove barriers like the financial cost of treatment at Markey, we embed it within our psych oncology program. And so, all of those services are offered for free. The rate at which patients say, yes, they want to engage in treatment is much, much lower than what we would want. And so that means two things. One, we need to offer help repeatedly to patients and understand that their willingness to quit and their willingness to accept treatment likely would change over time. And so, we need to keep coming back to people. It's not a one and done situation. But then also we need to understand what the barriers are from a patient's perspective. So why are they saying no? That they're either not ready or that they don't want treatment. They want to, quote, unquote, go it alone. And oftentimes what we hear is that patients want to be able to do this by themselves. They want to feel like, I quit smoking and I did it all by myself. And this is this huge thing that I've overcome. Not too different from the perspective that a lot of patients have about fighting cancer. They want to fight this addiction, this dependence that they've had oftentimes for multiple decades. And so, I think one thing that might be beneficial is to think about having peer led tobacco treatment. So have a patient who was able to quit successfully and have them provide counseling alongside a trained provider so that patients see someone like them who's went through it in the context of cancer care and who was able to overcome and to fight and win against tobacco, essentially. I think the other thing is trying to make sure that when we're asking about smoking and when we're offering treatment that we are not accidentally harming patients by bringing up feelings of stigma or guilt or shame. And I think one way to make sure we don't do that is to really lean on clinicians who are trained in addressing social determinants of health and other supportive care. So, our social workers, I think would be great. They're oftentimes embedded within oncology care. They are surely able to be trained as tobacco treatment specialists. They're already working with patients; they're addressing other barriers to care. They're sensitive in how they ask questions oftentimes. And so, they're really an ideal partner for this work. And we have found in a lot of settings that social workers are great in terms of being tobacco treatment specialists, including what we saw in Just Ask. Dr. Davide SoldatoThank you very much. That was really very, very interesting. And so, last question, moving forward, we improved the rate of asking patients. We are able to document this addiction more clearly in the EHR. So how do you see the field moving forward? In the manuscript, you speak a little bit about the Beyond Ask initiative. So just a little bit of a background about what is this initiative, what you are planning to do, and what do you think would be the best way to really act on this information that we are starting to collect in a better way and more frequently. Dr. Jessica BurrisYeah. So Beyond Ask really took everything that we did in Just Ask and amplified it. So instead of focusing on asking, we really said to make a difference and to improve cancer outcomes, ultimately patients need to be able to quit smoking. It's not enough that we know who is smoking, but that we help that individual or those groups of people quit. And so Beyond Ask had the goal to increase cessation assistance. So, either prescribing medication to help with smoking cessation, referring to a quit line, or another evidence-based program, or personally providing cessation counseling on site at that cancer program and to try and improve again within assistance. It was another one-year study, but we increased the frequency of surveys. I think we ended up with five total surveys. So, we were capturing two to three months at a time instead of a six-month period. And the data that we were capturing was very similar to what we did in Just Ask. And I can say we're still doing the data analysis, but it was another major success. So, with Beyond Ask, we had about 350 participating programs, many of whom not all, but many did participate in Just Ask. So, I think Just Ask kind of energized people around addressing the issue of smoking in their patient population. And again, they were really chomping at the bit to do more. And so, we offered Beyond Ask just after Just Ask. So Just Ask was 2022. Beyond ask was 2023. It ended in the spring of 2024. And again, another success. Dr. Davide SoldatoThank you very much. So, we are eager to see the results of this study. So that leads us to the end of this interview. So, thank you again, Dr. Burris for joining us today and speaking about your work. Dr. Jessica BurrisThank you. Dr. Davide SoldatoSo we appreciate you sharing more on the JCO article titled Longitudinal Results from the Nationwide Just Ask Initiative to Promote Routine Smoking Assessment in American College of Surgeons Accredited Cancer Program. If you enjoy our show, please leave us a rating and a review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcast. 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.
In a Nutshell: The Plant-Based Health Professionals UK Podcast
April is bowel cancer awareness month. With this in mind we talk to Dr Alan Desmond, consultant gastroenterologist, about how to reduce our risk of developing bowel cancer, one of the commonest cancers in the Western world, and how diet and lifestyle can improve prognosis for people already living with this condition. Alan is a practising clinician, author of 'The Plant-Based Diet Revolution', a well known speaker and now a successful podcaster with his new podcast - ‘Eat This with Dr Alan Desmond', as well as being an Ambassador for Plant-Based Health Professionals UK. For many years Alan has been advocating for a high fibre whole food plant-based diet, for gut health and to reduce the risk of many chronic conditions. To connect with Alan: https://www.alandesmond.com/ https://www.instagram.com/dr.alandesmond/ Details and tickets for the Nutrition and Lifestyle Medicine Conference: https://nlmc.org.uk/ Details for joining Plant-Based Health Professionals UK: https://plantbasedhealthprofessionals.com/membership Factsheets from Plant-Based Health Professionals : https://plantbasedhealthprofessionals.com/wp-content/uploads/2019/07/Bowel-Cancer-Prevention.pdf https://plantbasedhealthprofessionals.com/wp-content/uploads/2019/07/Colon-Cancer.pdf https://plantbasedhealthprofessionals.com/wp-content/uploads/2023/12/Colonoscopy-on-a-vegan-diet-231208.pdf Studies discussed: https://www.who.int/news-room/questions-and-answers/item/cancer-carcinogenicity-of-the-consumption-of-red-meat-and-processed-meat https://www.bmj.com/content/378/bmj-2021-068921 https://eatforum.org/eat-lancet-commission/the-planetary-health-diet-and-you/ https://www.ceu.ox.ac.uk/research/epic-oxford-1 https://adventisthealthstudy.org/studies/AHS-2/findings-lifestyle-diet-disease https://www.bluezones.com/ https://www.wcrf.org/preventing-cancer/cancer-prevention/our-cancer-prevention-recommendations/ https://ascopubs.org/doi/full/10.1200/JCO.21.01784 https://www.nature.com/articles/s41467-024-55219-5
Reacting to the new JCO registration requirements in Los Angeles as presented by Dennis Block, Esquire of The Law Firm of Dennis Block and Associates.Webinar link: https://www.youtube.com/watch?v=y8uX45ghPQkhttps://theandressegovia.start.page/Try my preferred streaming software Streamyard!https://streamyard.com/pal/d/4974941498245120
In this JCO Article Insights episode, Lauren Shih summaries "Longitudinal Results From the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment in American College of Surgeons–Accredited Cancer Programs" by Jessica L. Burris, et al published November 19, 2024. Come back for the next episode where JCO After Hours host, Dr. Davide Soldato interviews the author of the JCO article discussed, Dr. Jessica Burris. TRANSCRIPT Lauren Shih: Hello and welcome to JCO Article Insights. I'm your host Lauren Shih, and today we will be discussing the article, “Longitudinal Results From the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment in American College of Surgeons–Accredited Cancer Programs” by Dr. Jessica Burris and colleagues published in the March issue of JCO. This study reports the finding of the Just ASK Initiative, an effort aimed at improving universal smoking assessment in cancer programs nationwide. We know that smoking after a cancer diagnosis is associated with numerous negative outcomes including worse survival, increased treatment related complications, poorer quality of life and higher healthcare costs. Patients who smoke are also at increased risk for cancer recurrence and second primary malignancies. Despite these risks, data show that a significant number of patients with newly diagnosed cancer still smoke and around 15% of cancer survivors continue smoking. Recognizing this discrepancy, national oncology organizations strongly recommend routine smoking assessment and cessation support as part of standard cancer care. However, despite these guidelines, smoking assessment and cessation assistance remain inconsistent across oncology practices. Surveys show that most National Cancer Institute designated cancer centers have insufficient resources to effectively support smoking cessation efforts. To address this gap, several large scale initiatives have been launched, including efforts by the National Cancer Institute, the Canadian Partnership Against Cancer, and the American College of Surgeons. The largest of these initiatives, through the American College of Surgeons, is the subject of our report today. In 2022, the American College of Surgeons introduced the Just ASK Quality Improvement Program with the goal of increasing routine smoking assessment. As member institutions, accredited programs are required to complete at least one quality improvement program annually. And in 2022, 40% of programs chose to participate in Just ASK. The primary goal of this quality improvement program was to ask at least 90% of newly diagnosed cancer patients about their smoking status. Offering smoking cessation support was encouraged, but not a mandatory component or primary endpoint for the initiative. To implement Just ASK, participating programs used a well-established Plan-Do-Study-Act methodology which is a structured, iterative approach for improving healthcare processes. Programs used local quality improvement teams and resources for implementation and had access to online training, educational webinars, and technical resources to help integrate smoking assessment into routine care. Programs completed three surveys: a baseline survey reflecting smoking assessment practices in the year before Just ASK; a midpoint survey after six months of participation; and a final survey after one year in the program. The surveys assess program characteristics, barriers to smoking assessment, readiness to change, and the frequency of smoking related clinical practices such as asking about smoking, documenting smoking status, and advising smoking cessation. Programs reported on implementation strategies they adopted to improve smoking assessment. Finally, programs reported the number of newly diagnosed cancer patients they saw, how many were asked about their smoking status and how many were identified as current smokers during each reporting period. Results from 762 participating cancer center programs were analyzed. The programs represented a diverse mix of practice sites with over 50% identified as community based. Retention in the program was high, with nearly 90% of programs completing the final survey. Most programs reported moderate organizational readiness at baseline along with an average of 4.6 implementation barriers to conducting routine smoking assessment. Barriers included factors such as lack of time, competing clinical priorities, and lack of designated tobacco treatment specialists. At baseline, the ask rate was 87.8% and this increased to 91.9% at the final survey, meeting the previously identified goal for the initiative. Throughout the initiative, programs reported increases over time in assessing smoking status, in advising patients who smoked and quit, and in documenting these assessments and recommendations in the medical record. Importantly, the smoking rate among patients asked ranged from 18.5% to 19.8% across the three surveys, demonstrating a high rate of current smoking among newly diagnosed cancer patients. The most common implementation strategies adopted by programs to promote change included gaining leadership support, improving documentation on the electronic health record, and training staff and providers. There were no major differences in implementation strategies based on program type. Organizational readiness was positively associated with better smoking assessment practices, and implementation barriers had a negative impact, although not always statistically significant. The number of implementation strategies used by programs showed a positive, significant association with smoking assessment practices at the final survey. Exploratory analyses did not suggest that program type or patient volume had a consistent relationship with the outcomes. Although the primary goal of Just ASK was smoking assessment and not cessation assistance or intervention, programs did report on cessation related practices. For example, programs reported providing education or self-help materials increased from 26% to 48%, referrals to tobacco treatment specialists increased from 25% to 35%, and referrals to quit lines increased from 27% to 45%. Prescribing or recommending FDA approved cessation medications increased from 17% to 21%. In conclusion, Just ASK is the largest nationwide initiative to standardize and improve smoking assessment in cancer care. It successfully improves smoking assessment across a diverse range of cancer practices, ensuring that hundreds of thousands of newly diagnosed cancer patients were asked about their smoking status. As nearly 20% of the cohort reported smoking, this represents a critical first step in helping patients access smoking cessation resources. Participating programs demonstrated small but sustained practice changes in smoking assessment, meeting the a priori determined goal of a 90% ask rate. However, as a quality improvement initiative, Just ASK was not designed as a clinical trial, so conclusions regarding the efficacy of the program as an intervention are limited. Selection bias may have also played a role in the findings as program participation was voluntary. Additionally, the initiative lasted just one year and while the initial improvements were steady during that time, the long term impacts of Just ASK on smoking assessment remain uncertain. Looking ahead, the American College of Surgeons recently completed the Beyond ASK initiative. This initiative is designed to go a step further and focuses on improving smoking cessation assistance and we await the results. The Just ASK initiative demonstrates the routine smoking assessment is feasible to complete as routine cancer care. This assessment is essential as identifying patients that smoke is the first and critical step towards offering smoking cessation support, which in turn can improve health outcomes and reduce cancer treatment costs. While Just ASK was a success in increasing assessment, the challenge now is ensuring that smoking cessation support is readily available for all patients who need it. Thank you for listening to JCO Article Insights. Please give us a rating or review and subscribe so you never miss a JCO episode. You can find all ASCO shows at asco.org/podcasts. 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.
Lidia Schapira, MD, is a Professor of Medicine at Stanford Comprehensive Cancer Institute and Director of Stanford's Cancer Survivorship program. A nationally renowned expert in breast cancer, Dr. Schapira has pioneered workshops and helped develop innovative educational programs to improve the communication skills of cancer clinicians by building experienced and compassionate teams. She has been a champion of promoting patient activation and self-management at all phases of the cancer journey. She is the former Editor-in-Chief of cancer.net, and consultant editor for the Journal of Clinical Oncology. She also hosts JCO's Cancer Stories: The Art of Oncology podcast which features stories, dialogue, and personal reflections that explore the experience of living with cancer or caring for people with cancer. “We need to redefine what we mean by failure and success. Failure is not that the patient dies. Failure is that the patient dies abandoned, alone, or in pain. One can still die of an incurable illness, but that doesn't necessarily mean that we as the treating physicians have failed. If we can figure out how to treat an illness and support a person in a family, this is the best combination.” In this episode of The Medicine Mentors, Dr. Lidia Schapira offers an innovative perspective on success, teaches us how to find strength in the bleakest moments, and mentors us on how to outgrow conventional definitions of failure. Pearls of Wisdom: 1. The most important thing to look for within is what it is that tickles us, inspires us. Then trying to preserve at least some of our time to work on that to keep us engaged. 2. The Art of Oncology is finding the human side of the patients we care for. 3. I do this meditative hand-washing before I enter a room so I can be fully present and let them know I'm interested in them, not just the disease. 4. Have an open mind and be very curious, pursue answers in places that aren't obvious. 5. I've learned over the years to sit with emotion and not be eager to fix or stop it. Support people by letting them express their emotions.
Listen to ASCO's Journal of Clinical Oncology Art of Oncology poem, "The First Hero” by Christopher Kim, who is a research assistant at Institute for Stem Cell Biology and Regenerative Medicine at Stanford University. The poem is followed by an interview with Kim and host Dr. Mikkael Sekeres. Kim reflects on his post-surgery sonnet. TRANSCRIPT Narrator: The First Hero, by Christopher Kim, BS When he is like this—eyes closed, face still— he is unfamiliar. He wears a face younger than usual; fragile limbs washed in fluorescent light, eyes blurred with a diagnosis or ripe hyacinths or the last words we shared. Be good, son. Be bright. When he is still, anesthetized into memory, so too are the aphids in the garden. Lines of buzzing bodies descended from flight but clustered in quiet surrender. Fathers of sons who are trying to heal, who are failing, who retreat into the silence of sterile rooms. A heartbeat stutters and everything sings. Like the birds we watch outside the ICU window: how they peck at unyielding concrete and fill themselves with sharpness, their bodies frenzied, their bodies temporary. Mikkael Sekeres: Hello and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the oncology field. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. Today, I am so thrilled to be joined by Christopher Kim. He's a research assistant at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University. In this episode, we will be discussing his Art of Oncology poem, “The First Hero.” At the time of this recording, our guest has no disclosures. Both he and I have agreed to address each other by first names during the podcast. Chris, welcome to our podcast and thank you for joining us. Christopher Kim: Of course. Thank you so much for having me. It's just such an honor to be here. Mikkael Sekeres: We absolutely loved your poem. It was incredible and addressed a topic I think a lot of us face at some point in our lives and that's when we see a family member who's sick. Before we get into that, I was wondering if you can tell us a little bit about yourself. Where are you from and how did you get to this point? Christopher Kim: Absolutely, yeah. As you mentioned before, I'm working as a research assistant at the Stanford Medical School and I pretty much only recently graduated from college so I feel like I'm still in this like ‘in between' stage. I'm a Bay Area native. I went to Stanford for undergrad, just kind of stayed on with the lab that I worked with while I was an undergrad. I would like to go on to medical school in the future. I'm learning a lot working as a research assistant, getting some hands-on experience with basic biology research. And another thing about myself is I'm an avid musician, play violin, play guitar. I like to sing. And of course, I really enjoy writing as well. Mikkael Sekeres: That's a great background. Well, we definitely need more doctors who are writers, musicians and singers. So you fit that bill. And then the fact that you do some lab based research is just amazing. You sound like a polymath. Christopher Kim: Oh, I don't know about that. I try my best. Mikkael Sekeres: Can you tell us a little bit about your own story as a writer? How long have you been writing poetry? When did you get started? And how did you get started? Christopher Kim: Yeah, absolutely. So, I've always written sort of on my own, so I don't think I ever had the courage to share my writing with others because, you know, it's kind of a vulnerable thing to share your inner thoughts with someone. So I have been kind of writing on my own since maybe late middle school and early high school. That's when I started putting my thoughts onto paper. But I only recently started to submit my poetry to, you know, these journals because, you know, after a while I was thinking, I think they're worth sharing with others because maybe some people may be going through similar situations where they can feel a little bit encouraged by the words that I write in terms of, you know, feeling the emotions that they feel. Mikkael Sekeres: Well, lucky for us, you made that decision. So when you were an undergrad, did you take any writing courses? Because it's interesting, you've been in the area of writing since you were in middle school, high school. That must have continued through college. And sometimes formal courses help us refine those skills. But then there are also plenty of examples of people who just did it on their own. Christopher Kim: Absolutely. The main writing course I took, funnily enough, they weren't really creative writing courses. They were more rhetoric based or kind of just like the regular English writing classes at college undergraduates take. However, I did have a group of friends who I would share my writing with. I think that was like the most important part of my sort of evolution as a writer. Because before I would just kind of write on my own and maybe kind of hide it away, you know, in my little locked box, I guess. But then having this opportunity to meet other people my age, my peers, who, you know, I finally gained enough kind of courage to– I say courage, but I really mean, like I finally gained enough comfort to share it with them. And, you know, gaining their feedback and seeing their response was really the most important part of, I think, my writing in college. So not necessarily like formal classes, but more like the people I met and how they responded to my writing, which is- I'm really thankful for them. Mikkael Sekeres: You know, it's so interesting because there is this temptation to be like Emily Dickinson and write your poems and squirrel them away in your desk and never show them to anyone. And then, you know, the body of your work is discovered posthumously, which I think is kind of sad. I mean, you know, great that we have Emily Dickenson poetry, but it would have been nice that, you know, she had known how appreciated she was during her lifetime. Christopher Kim: Oh, absolutely. Mikkael Sekeres: And I think the hardest first step is that word that you use, courage. The courage to identify people outside of ourselves, to share our poetry with, or our narrative pieces. So how did you find those people? Christopher Kim: It's often the case that, you know, you make your closest friends when you kind of struggle together. So I think a lot of these friends I met were through taking courses together that were difficult and that sort of combined, I don't want to say misery, that's maybe too strong a word, combined struggle against one common goal. I think that's when we started becoming close. And then it was like outside of a writing context. But I think, I don't know, it's like part luck and part finding these people in these classes and then having conversations with them late at night and then eventually going towards sharing your arts, whatever. Some of them are musicians. They share their music. Some of us share our writing. Mikkael Sekeres: Yeah. No, I hear you. There's that shared experience of being in difficult situations. I think a lot of us who've gone through undergrad and med school and then became doctors and started our training, we have incredibly close friends. We met in our residencies and fellowship because those were major stressor points in our lives and major transitional phases also when we felt that we grew. The other aspect that I've heard in identifying people to be first readers of your poetry or prose is to identify people you trust. People who are friends will give you a good read, will be appropriately critical, and will also be encouraging. You need those people to feed back to you truth about the quality of your writing and provide substantive criticism that helps you grow as a writer. Christopher Kim: Definitely agree. You know, you've found your true friends when they're not afraid to criticize you because they're so close to you and they really want you to be better. So, yeah, I definitely agree with that. Mikkael Sekeres: Yeah. And those who will take it seriously where, I think plenty of times in my own life where I've given a piece of writing to somebody, hoping for good feedback, and then you feel like you have to hound them to finally get that feedback. And obviously they're not invested in it, as opposed to a trusted body of readers where they are going to take it seriously, they're going to read it closely, and then they're going to get back to you without you feeling as if you're imposing on them. Christopher Kim: Absolutely. Yeah. It's very valuable once you've found that group of people or friends, and you know, I still contact them regularly today. So, yeah, as you mentioned, you know, I think it's definitely like maybe a lifelong process or lifelong friendship where you can always go back to them for sort of that support. And you also are able to provide that support for your friends, too. Mikkael Sekeres: Yeah. I'm curious about your writing process. What triggers you to start a poem? And, you know, how do you face that dreaded blank page? Christopher Kim: Bay Area traffic can be very long and the commute can be pretty rough. Mikkael Sekeres: Not at all like that in Miami, by the way. In Miami, we just breeze through traffic. Yeah, not at all. Christopher Kim: I would love to visit someday to compare. But yeah, Bay Area traffic can be pretty rough. As much as I love podcasts and music, there comes a point where I kind of run out of things to listen to after a while. So I really found myself driving along, but then letting my thoughts wander. And funnily enough, that's when my creative inspirations hit. Maybe it's because there's something about driving that's like the perfect amount of not thinking. You know, it's like an automatic process and that let's your– obviously I'm paying attention to the road - but you kind of let your mind wander through creative thoughts, and that's on place of creative inspiration. I've had close family members who have struggled with cancer specifically, and other serious health issues, and I've had experiences being a caretaker for them, like ‘The First Hero'. Being in that position really inspires you to write, I think, for me. Mikkael Sekeres: So I wonder if I could follow up on that and if you're only comfortable doing so. Can you tell us what prompted you to write “The First Hero”? Christopher Kim: So it's kind of a combination of experiences. My grandfather struggled with cancer for a long time, and eventually he passed away from cancer. Mikkael Sekeres: I'm sorry. Christopher Kim: I appreciate that. Thank you. And he had cancer when I was a young child, which luckily went into remission for a couple years. But then later on, you know, as I started college, that's when it came back, and that's when he passed. And I think seeing his struggles with cancer, that was one big part of inspiration for this poem. But also another thing was my father also went through some health issues where he had to go through surgery and a long period of recovery, and he still kind of struggles with some issues today. And seeing people that you love that much in a position where it's really hard, especially when they're father figures in your life. They're your grandfather and your father. And, you know, when you're a kid, you know, your dad is like, they're a superhero. Your dad is the hero who can do anything, who can achieve any answer, any question you have, who can build anything you want, can buy you things, you know, all that stuff. But now seeing them in this reverse state of being vulnerable and not being able to do too much, it really affected me. And those two experiences were my main inspiration for this poem. Mikkael Sekeres: That was really beautifully said, Chris. I'm a parent of three, and I think that it comes with a lot of responsibility to remember that just carrying the title of mom or dad implies so much to one of your own children that you have to remember the import of everything that you do for them, for your kids, and everything that you say. And it carries just that much added significance because of the role we play as parents. It's so interesting to hear it enunciated by you in that way as well. And I think part of what makes good parents, there are a thousand things that go into the formula of a good parent, and we only know for sure if we made it, if, depending on the amount of therapy our kids have to go through when they're older, right? I think part of that, though, is remembering the great responsibility that comes with just simply the title of being a parent. Christopher Kim: Absolutely. Mikkael Sekeres: You started to talk a little bit about this. I'm curious about how the dynamic between parents and children changes when a parent is sick. Christopher Kim: Yeah, it's kind of a reversal of roles in a way, because your parents, when you're born, you're the most vulnerable. They're responsible for sort of ushering you into this world, keeping you alive. Seeing your parents grow older and seeing them aging is a tough experience. And my mom often tells me whenever she would see her parents, after a while, in her mind, she still sees her parents as when they were their younger selves, when she was younger. But then suddenly it would hit her that they're, like, much older and that also makes you feel a little bit more aware of how you are aging and how much older you are. But at the end of the day, they're always going to be your parents. Mikkael Sekeres: They really are. Our parents age and we age with them, and we evolve in how we view parents, and we all go through this, and I don't think it ever ends until your parents pass. I'm sure you're familiar with this. There's a saying that you never really become an adult until your parents pass. Christopher Kim: You mentioned that you're more aware of what parenthood is as you get older. I mean, obviously I don't have any kids myself, but I'm sure my parents always USED say to me, you know, “You'll understand when you have kids.” Mikkael Sekeres: You sort of do. You sort of do. Christopher Kim: I sort of do. Right, exactly. Mikkael Sekeres: My dad always said to me that parenting is unskilled labor. So you sort of get it when you're a parent, you're still really figuring it out. Christopher Kim: Absolutely. Yeah. And the older I get, it's like I realize. I think I've gained more appreciation for the sacrifices my parents have made for me, and I've definitely taken their parenthood lessons to heart for whenever, if I choose to have kids later on. Mikkael Sekeres: So that's great. I'm sure they'd be thrilled to hear that, Chris. I wanted to end with one last question for you. Are there poets who've been a particular influence on you or favorite poets you want to name? Christopher Kim: One name that kind of comes to mind is there's a poet named Ocean Vuong. Their work blends together personal history and like, family history with beautiful lyricism. They always feel like musical in a way. Their words kind of often linger on with you long after. Mikkael Sekeres: That's great. Well, listen, Chris Kim, I'd like to thank you so much for joining us on today's podcast and for your absolutely beautiful poem, “The First Hero.” Christopher Kim: Thank you so much for having me. I'm super thrilled to be on. This is my first podcast ever, so it was such a great experience. I felt so welcomed. So thank you for, you know, hearing my thoughts or listening to my thoughts. I appreciate it. Mikkael Sekeres: Well, you're good at them. Keep them up. Until next time. Thank you for listening to JCO's Cancer Stories: The art of Oncology. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all of the ASCO shows at asco.org/podcasts. Until next time. Thanks so much for joining us. 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. Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Christopher Kim is a research assistant at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University.
Dr. Irene Su and Dr. Alison Loren present the latest evidence-based recommendations on fertility preservation for people with cancer. They discuss established, emerging, and investigational methods of fertility preservation for adults and children, and the role of clinicians including discussing the risk of infertility with all patients. Dr. Su and Dr. Loren also touch on other important aspects of fertility preservation, including the logistics of referral to reproductive specialists, navigating health insurance, and costs. They also discuss ongoing research and future areas to explore, including risk stratification, implementing screening, referral, and navigation processes in lower resource settings, fertility measurements, and health care policy impacts. Read the full guideline update, “Fertility Preservation in People with Cancer: ASCO Guideline Update” at www.asco.org/survivorship-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02782 In this guideline, the terms "male" and "female" were defined based on biological sex, specifically focusing on reproductive anatomy at birth. "Male" refers to individuals born with testes, while "female" refers to those born with ovaries. The guideline, and this podcast episode, we will refer to individuals as "males" or "females" based on this definition. Brittany Harvey Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Irene Su from the University of California, San Diego, and Dr. Alison Loren from the University of Pennsylvania, co-chairs on “Fertility Preservation in People With Cancer: ASCO Guideline Update.” Thank you for being here today, Dr. Su and Dr. Loren. Dr. Irene Su: Thanks for having us. Dr. Alison Loren: Thanks for having us. Brittany Harvey: Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Su and Dr. Loren, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content here, Dr. Loren, this is an update of a previous ASCO guideline. So what prompted this update to the 2018 guideline on fertility preservation? And what is the scope of this particular update? Dr. Alison Loren: Yeah, thanks, Brittany. So, yeah, a couple of things, actually. I would say the biggest motivation was the recognition that the field was really moving forward in several different directions. And we felt that the previous guidelines really hadn't adequately covered the need for ongoing reproductive health care in survivorship, including the fact that fertility preservation methods can be engaged in even after treatment is finished. And then also recognizing that there is increasing data supporting various novel forms of fertility preservation in both male and female patients. And we wanted to be able to educate the community about the wide array of options that are available to people with cancer, because it really has changed quite a bit even in the last six years. And then lastly, as I'm sure this audience, and you definitely know, ASCO tries to update the guidelines periodically to make sure that they're current. So it sort of is due anyhow, but I would say motivated largely by those changes in the field. Brittany Harvey: Great. I appreciate that background information. So then I'd like to dive a little bit more into those updates that you discussed. So, Dr. Su, I'd like to review the key recommendations across the main topics of this guideline. So starting with what are the recommendations regarding discussing the risk of infertility with patients undergoing cancer treatment? Dr. Irene Su: Thanks, Brittany. So for every child, adolescent, and adult of reproductive age who's been diagnosed with cancer, the recommendation remains that healthcare clinicians should discuss this possibility of infertility as early as possible before treatment starts, because that allows us, as reproductive endocrinologists and fertility specialists, to preserve the full range of options for fertility preservation for these young people. Where it's possible, I think risk stratification should be a part of the clinical infertility risk counseling and then the decision making. And then for patients and families who have an expressed interest in fertility preservation, and for those who are uncertain, the recommendation is to refer these individuals to reproductive specialists. And it turns out this is because fertility preservation treatments are medically effective for improving post-treatment fertility and counseling can ultimately reduce stress and improve quality of life, even for those who don't undergo fertility preservation. And as Dr. Loren said, a change in the guideline is specifically about continuing these discussions post-treatment yearly or when cancer treatments change because that changes their infertility risk or when pregnancy is being considered. Brittany Harvey: Absolutely. Discussing that risk of infertility at the beginning, before any treatment is initiated, and when treatment changes, is key. So then talking about the options for patients, Dr. Loren, what are the recommended fertility preservation options for males? Dr. Alison Loren: There has been a little bit of an evolution in options for male patients. The standard of care option which is always recommended is cryopreservation of sperm, or otherwise known as sperm banking. And this is something that should be offered ideally prior to initiating cancer directed therapy. The guideline does reflect the fact that we're starting to understand in a little bit more depth the impact of cancer-directed treatments on the health and quantity of sperm. And so trying to understand when, if ever, it's appropriate to collect sperm after initiation of treatment, but before completion of treatment remains an area of active research. But the current understanding of the data and the evidence is that sperm banking should be offered prior to initiating cancer-directed therapy. And all healthcare clinicians should feel empowered to discuss this option with all pubertal and post-pubertal male patients prior to receiving their treatment. We do offer a little bit more information about the ideal circumstances around sperm banking, including a minimum of three ejaculates of sufficient quality, if possible, but that any collections are better than no collections. We also talk about the fact that there is a relatively new procedure known as testicular sperm extraction, which can be offered to pubertal and post-pubertal males who can't produce a semen sample before cancer treatment begins. There remains no evidence for hormonal protection of testicular function - that has been a long-standing statement of fact and that remains the case. And then we also begin to address some of the potential risk of genetic damage in sperm that are collected soon after initiation of cancer-directed therapy. We are starting to understand that there is a degradation in the number and DNA integrity of sperm that can occur even after a single treatment. And so, really highlighting the fact that collecting samples, again, to Dr. Su's point, as early as possible and as many as possible to try to optimize biological parenthood after treatment. Brittany Harvey: Yes. Thank you for reviewing those options and what is both recommended and not recommended in this scenario. So then, following those recommendations, Dr. Su, what are the recommended fertility preservation options for female patients? Dr. Irene Su: There are a number of established and effective methods for fertility preservation for people with ovaries, and this includes freezing embryos, freezing oocytes, freezing ovarian tissue. For some patients, it may be appropriate to do ovarian transposition, which is to surgically move ovaries out of the field of radiation in a conservative gynecologic surgery, for example, preserving ovaries or preserving the uterus in people with gynecologic cancers. We do recommend that the choice between embryo and oocyte cryopreservation should be guided by patient preference and clinical considerations, their individual circumstances, including future flexibility, the success rates of embryo versus egg freezing that we detail more in the guideline, and legal considerations. And what is new in this guideline, as Dr. Loren alluded to earlier, is consideration of post-treatment fertility preservation for oocyte and embryo freezing. And this is going to be because, for some females, there's going to be a shortened but residual window of ovarian function that may not match when they are in their life ready to complete their families. And so for those individuals, there may be an indication to consider post-treatment fertility preservation. We clarify that gonadotropin releasing hormone agonists, GNRH agonists, while they shouldn't be used in the place of established fertility preservation methods, e.g., oocyte and embryo freezing, they can definitely be offered as an adjunct to females with breast cancer. Beyond breast cancer, we don't really understand the benefits and risks of GNRH agonists and feel that clinical trials in this area are highly encouraged. And also, that for patients who have oncologic emergencies that require urgent chemotherapy, these agonists can be offered because they can provide additional benefits like menstrual suppression. What's emerging is in vitro maturation of oocytes. It's feasible in specialized labs. It may take a little bit shorter time to retrieve these oocytes. There are cases of live births following IVM, in vitro maturation, that have been reported. But these processes remain inefficient compared to standard controlled ovarian stimulation. And therefore, it's really being treated as an emerging method. Finally, uterine transposition. It's experimental, but it's a novel technique for us. It's really moving the uterus out of the field of radiation surgically. We recommend that this is done under research protocols. So taken together, there are improvements in fertility preservation technology, and consideration of which of any of these methods really depends on tailoring to what is that patient's risk, what is the time that they have, what is feasible for them, and what is the effectiveness comparatively among these methods for them. Brittany Harvey: I appreciate you reviewing those recommendations and considerations of patient preferences, the clarification on GNRH agonists, and then those emerging and experimental methods as well. So then the next category of recommendations, Dr. Loren, what are the recommended fertility preservation options for children? Dr. Alison Loren: Thanks, Brittany. This remains a very challenging area. Certainly for older children and adolescents who have begun to initiate puberty changes, we support proceeding with previously outlined standard methods of either sperm or oocyte collection and cryopreservation. For younger children who are felt to be at substantial risk for harm to fertility, the really only options available to them are gonadal tissue cryopreservation, so ovarian tissue or testicular tissue cryopreservation. As Dr. Su mentioned, the ovarian tissue cryopreservation methods are quite effective and well established. There's less data in children, but we know that in adults and older adolescents that this is an effective method. Testicular cryopreservation remains experimental, and we suggest that if it is performed, that strong consideration should be given to doing this as an investigational research protocol. However, because these are the only options available to children, we understand there may be reasons why there might need to be some flexibility around this in the proper setting of informed consent and ascent when appropriate for children. Brittany Harvey: Absolutely. And so we've discussed a lot of recommendations on fertility preservation options. So, Dr. Loren, what is recommended regarding the role of clinicians in advising people about these fertility preservation options? Dr. Alison Loren: Yeah, this is a really important question, Brittany, and I think that we really hope to empower the entire oncology clinical team to bring these issues to the forefront for patients. We know from qualitative studies that oncology providers sometimes feel uncomfortable bringing these issues up because they feel inexpert in dealing with them or because it's so overwhelming. Obviously, these are usually younger patients who are not expecting a cancer diagnosis, and there can be quite a lot of distress, understandably, around the diagnosis itself and the treatment plan, and it can be sometimes overwhelming to also bring up fertility as a potential risk of therapy. We are seeing that as patients are becoming more familiar and comfortable kind of speaking up, I think, social media and lots of sort of online communities have raised this issue, that we're seeing that young people with cancer do spontaneously bring this up in their visits, which we really appreciate and encourage. But I think sometimes clinicians feel it's sometimes described as a dual crisis of both the cancer diagnosis and a risk to future fertility and it can be a really challenging conversation to initiate. I feel, and we hope that the guidelines convey, that the whole point is just to bring it up. We do not expect an oncology clinician of any kind, including social workers, nurses, to be able to outline all of the very complex options that are articulated in this guideline. And in fact, the reason that the co-chairs include myself, a hematologist oncologist, and Dr. Su, who's a reproductive specialist, is because we understand that the complex reproductive options for our patients with cancer require expert conversations. So we do not expect the oncology team to go into all the guideline options with their patients. We really just want to empower everyone on the team to bring up the issue so that we can then get them the care that they need from our colleagues in reproductive endocrinology so that they can be fully apprised of all of their options with enough time before initiation of treatment to be able to embark on whichever therapies they feel are most suited to their family planning wishes. Brittany Harvey: Absolutely. And then jumping off of that, as a reproductive endocrinologist, Dr. Su, what do you think clinicians should know as they implement these updated recommendations? Dr. Irene Su: I wholly echo what Dr. Loren has said about- this is a team effort and it's been really fun to work as a team of various specialties on this guideline, so we hope that the guideline really reflects all of the partnerships that have occurred. I think that what clinicians should know is it may be well worth spending some time in identifying a pathway for our patients. So that starts off with the oncology team. How are we going to screen? How are we going to screen with fidelity? And then from the time of screening, really anybody who has an interest or potentially is unsure about their future fertility needs, who are the reproductive specialists, male and female, that you are in the community with to refer to? What is that referral process going to be like? Is it emails? Is it a phone? Is it a best practice advisory in your electronic health record system? From our standpoint as fertility specialists, we need to spend some time implementing in this system a way to receive these referrals urgently and also be able to support insurance navigation. Because actually, what is really exciting in this field is for the purpose of equitable access, there is increasing insurance coverage, whether it is because employers feel that this is the right thing to do to offer, or 17 states and the District of Columbia also have state mandates requiring fertility preservation coverage by many insurances, as well as, for example, federal employees and active military members. So more than ever, there is a decreased cost barrier for patients and still early days, so navigating health insurance is a little bit challenging. And that is the role, in part, of navigators and fertility clinic teams to help support these patients to do that. Dr. Alison Loren: Forming these relationships and reinforcing them so early and often is really key. Because although these patients come up with some infrequency, when they occur, they're really emergencies and we want to make sure that there's a well-established path for these patients to get from their oncology clinicians to the reproductive specialists. And as Dr. Su said, whatever works best for your system - there's a lot of different ways that people have tackled these challenging referrals - but it is really important to have an expedited path and for the receiving reproductive specialist office to understand that these are urgent patients that need to be expedited and that the oncology clinician's responsibility is to make sure that that's communicated appropriately. Brittany Harvey: Definitely. Thinking in advance about those logistics of referral and navigating health insurance and cost is key to making sure that patients receive the care that they want and that they'd like to discuss with clinicians. So then, Dr. Loren, you touched on this a little bit earlier in talking about the dual crisis, but how does this guideline impact people diagnosed with cancer? Dr. Alison Loren: Well, what we're hoping is that this is sort of a refresher. I think that many or hopefully most or all oncology clinicians are aware that this is a potential concern. And so part of our hope is that, as this guideline rolls out, it'll sort of bring to the top of people's memories and action items that this is an important part of oncology care is the reproductive health care of our patients. And it's a critical component of survivorship care as well. We want to remind people that the field continues to advance and progress. In oncology, we're very aware of oncologic progress, but we may not be so aware of reproductive healthcare progress. And so letting people know, “Hey, there's all these new cool things we can do for people that open up options, even in situations where we might have thought there were no options before.” It's a reminder to refer, because we're not going to be able to keep up with all the advances in the field. But Dr. Su and her colleagues will be able to know what might be an option for patients. I want to highlight that communication piece again because our reproductive colleagues need to know what treatments are going to be given, what the urgency is, what the risks are. And so part of our responsibility as part of the team is to make sure that it's clear to both our patients and our reproductive specialist colleagues what the risks are. And Dr. Su mentioned this earlier, but one really important open question is risk stratification. We know that not all cancer treatments are created equal. There are some treatments, such as high dose alkylating agents, such as cyclophosphamide or busulfan, or high doses of radiation directly to the gonadal tissue, that are extremely high risk for causing permanent gonadal harm very immediately after exposure. And there are other therapies, particularly emerging or novel therapies, that we really just have no idea what the reproductive impact will be. And in particular, as patients are living longer, which is wonderful for our patients, how do we integrate reproductive care and family building into the management of perhaps a younger person who's on some chronic maintenance therapies, some of which we know can harm either the developing fetus or reproductive health, and some of which we really don't know at all. And so there's a very large open question around emerging therapies and how to counsel our patients. And so we hope that this guideline will also raise to the forefront the importance of addressing these questions moving forward and helping our patients to understand that we don't necessarily have all the answers either, which we hope will enrich the discussion and really have it be a good example of shared decision making between the clinical teams and the patient, so that ultimately the patients are able to make decisions that make the most sense for them and reduce the potential for decision regret in the future. Dr. Su, I know you have spent a lot of time thinking about this. Dr. Irene Su: Yeah. I really echo this notion that not all cancer treatments are going to be toxic to future reproductive function. And as clinicians, I and colleagues know that patients want to know as much when there is no effect on their fertility, because that feels reassuring in that that prevents them from having to go through the many hoops that sometimes it can be to undergo fertility preservation, as it is to know high risk, as it is to know we don't know. This is key and central, and we need more data. So, for example, we often chat about, wouldn't it be great if from the time of preclinical drug development all the way to clinical trials, that reproductive health in terms of ovarian function, testicular function, fertility potential, is measured regularly so that we are not having to look back 30, 40, 50 years later to understand what happened. And so this is one of our key research questions that we hope the field takes note of going forward. Dr. Alison Loren: This is an important point. We focus greatly, as we should, on potential harms to fertility, making sure that there's access to all the reproductive options for young people with cancer. But to Dr. Su's point, not all therapies are created equal, and there are some therapies that are somewhat lower risk or even much lower risk, including, I'm a blood cancer specialist and so certainly in the patients that I take care of, the treatments related to AML, ALL, and some lymphomas are actually fairly low risk, which is why the post-treatment fertility preservation options are so important. And particularly for patients who potentially present acutely ill with acute leukemia do not have the time or the ability to engage in fertility preservation because of their medical circumstances, it's important to have that conversation. I want to emphasize to oncology clinicians that even if you know medically that this patient is unable to undergo fertility preservation techniques at the time of diagnosis of their cancer, that it's still appropriate to talk about it and to say, “We're going to keep talking about this, this is something that we're going to raise again once you're through this initial therapy. I'm not forgetting about this. It may not be something we can engage in now, but it's a future conversation that's important in your ongoing care.” And then to think about pursuing options when possible, particularly for patients who may require a bone marrow transplant in their future, either due to higher risk disease at presentation or in the event of a relapse, we know that generally bone marrow transplants, because of the high intensity conditioning that they require for most patients who are young, that permanent gonadal insufficiency will be a fixture. And so there can be a window of time in between initial therapy and transplant where a referral might be appropriate. So my public service announcement is that it's never the wrong time to refer to a reproductive specialist. And sometimes people make assumptions about chemotherapy that, “Oh, they've already been treated, so there's nothing we can do,” and I want to make sure that people know that that's not true and that it's always appropriate to explore options. Dr. Irene Su: I think we talk a lot about how important screening and referral is and I can imagine that it's hard to actually know how to implement that. One of our other research questions to look out for is that we see a lot of tertiary care centers that have put together big teams, big resources, and that's not always feasible to scale out to all kinds of settings. And so what's emerging is: What are the key processes that have to happen and how can we adapt this screening, referral, financial navigation process from larger centers to smaller centers to less resource settings. So I guess my public service announcement is there's research in this area, there's focus in this area, so keep an eye out because there will be hopefully better tools to be able to fit in different types of settings. And more research is actually needed to be able to trial these different screening, referral, navigation processes in lower resource settings as well. Brittany Harvey: Absolutely. It's important to think about the research questions on how to improve both the delivery of fertility preservation options and the discussion of it, and it's important to recognize, as you mentioned, the different fertility risks of different cancer directed treatment options and the importance to have the conversations around this. So then just to expand on this notion a little bit, Dr. Su, we've touched on the research needed here in terms of discussing fertility options with patients and referring and then also in some of the experimental and emerging treatment options. So, what are the other outstanding research questions regarding fertility preservation for people with cancer? Dr. Irene Su: A couple others I'd like to add and then have Dr. Loren chime in in case I missed anything in all of our discussions, there's so many wants. So head to head comparisons of which method is best for which patient and what the long term outcomes are: How many kiddos? Do we complete family building? That is still missing. Being able to invest in novel methods from - there's fertoprotective agents that are being tested, potentially spermatogonial stem cell transplant. These are closer to clinical trials to really early research on ovarian, testicular, uterine biology. This is needed in order to inform downstream interventions. One of the questions that is unanswered is: After treatment starts, when is it safe to retrieve oocytes? And so this is a question because, for example, for our leukemia patients who are in the middle of treatment, when is it safe to retrieve eggs? And we don't know. And then post-treatment, for people who have a reduced window, when do you optimally have the most number of eggs or embryos that you can cryopreserve? That's unknown. But I think the question around once treatment has started, is recent exposure of anti-cancer treatments somehow mutagenic or somehow toxic to the oocytes with regard to long term offspring health? That is unanswered. I'm going to scope out a little bit and maybe policy nerd this a little bit. It's been very exciting to see advocacy, advocacy from our patients, from our clinicians on trying to improve health care policy. Like how can we use mandates to improve this delivery? But we actually don't know because actually the mandates from states that require health insurance coverage for fertility preservation, they vary. And so actually what are the key ingredients and policies that will ultimately get the most patients to the care they need? That is in question and would be really interesting. And so what is a part of this guideline which is not often seen in clinical guidelines, is a call for what we think are best practices for health insurance plans to help patients be able to access. And so this means that we recommend being specific and comprehensive in the coverage of these established fertility preservation services that have been recommended. And this means, for example, an egg freezing covering the whole process from consultation to office visits, to ultrasounds and laboratories, to medicines, to the retrieval, and then to long term storage. Because particularly for the youngest of our patients, these gametes could be frozen for a number of years and may not always be so affordable without health insurance coverage. We think that fertility preservation benefits really should be at parity, that you should not be having more cost sharing on the patient compared to other medical services that are covered. This is an inequity and where possible we should eliminate prior authorization because that timing is so short between diagnosis and needing to start anti-cancer treatment. And so prior authorization having to go through multiple layers of health insurance is really a key barrier because we all know that health insurance literacy is limited for all of us. And so whatever we can do to support our patient for the intent of these benefits would be recommended. Dr. Alison Loren: That was so well said, Dr. Su. I'll take the oncology perspective and say that from our side, really being able to understand the risks of infertility and understanding better measurements of fertility capacity, understanding where our patients are - every patient is different. These conversations are very different for a 37-year-old than they are for a 17-year-old. And so what we haven't really talked about is the fact that certainly at least female patients, as they age, their reproductive potential declines naturally. And so their infertility trajectory may be accelerated, they may have a shorter timeline or have less reserve than younger patients. And so being able to tailor our risk discussions not just based on the specific treatments, but on the reproductive age of the patient sitting in front of us and really being able to tailor those to very personalized risks would be really helpful. Because, as Dr. Su mentioned, and I think, as many people know, undergoing fertility preservation techniques can be really arduous. Even if they're covered and paid for, and all of those logistics are easy, which they seldom are, the physical drain of having to do injections, go for labs, all of the parts of those therapies can be really difficult for patients. And so being able to really understand who needs to have these interventions and who could pass, and understanding what the risks are, as I mentioned earlier, for these novel and emerging therapies would be really helpful. Another really important aspect of future research questions is we would like to encourage all clinicians, both reproductive specialists and oncology clinicians, and also our young people with cancer, to participate in clinical studies pertaining to fertility measurements and preservation. We also exhort our industry colleagues to consider including important reproductive endpoints, including biomarkers of ovarian and testicular reserve, if possible, in clinical trials. It will enhance our ability to provide counseling and support for these therapies in the future to be able to understand what the true impact of infertility, family building and health of offspring to be able to include these data in prospective databases and trials. Brittany Harvey: Definitely. And I want to thank you both for raising those really important points. So we'll look forward to this ongoing research and optimizing policies for covering fertility preservation benefits for all patients with cancer. I want to thank you both so much for your work to update this critical guideline and talk about these important needs of people with cancer. And thank you for your time today, Dr. Su and Dr. Loren. Dr. Alison Loren: Thanks so much for having us. Dr. Irene Su: You're welcome. This was really fun. Dr. Alison Loren: It was fun. And I just will add that the team at ASCO is amazing and really made this a pleasure. Dr. Irene Su: I couldn't agree more. And from the point of being a fertility specialist, being invited to be a part of this with ASCO and with all of our colleagues, it's been really amazing. And so thanks for allowing us to contribute. Brittany Harvey: Definitely. And a big thanks to the entire panel as well. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Dr. Ebony Hoskins and Dr. Andreas Obermair discuss the surgical management of gynecologic cancers, including the role of minimally invasive surgery, approaches in fertility preservation, and the nuances of surgical debulking. TRANSCRIPT Dr. Ebony Hoskins: Hello and welcome to the ASCO Daily News Podcast, I'm Dr. Ebony Hoskins. I'm a gynecologic oncologist at MedStar Washington Hospital Center in Washington, DC, and your guest host of the ASCO Daily News Podcast. Today we'll be discussing the surgical management of gynecologic cancer, including the role of minimally invasive surgery (MIS), approaches in fertility preservation, and the nuances of surgical debulking, timing, and its impact on outcomes. I am delighted to welcome Dr. Andreas Obermair for today's discussion. Dr. Obermair is an internationally renowned gynecologic oncologist, a professor of gynecologic oncology at the University of Queensland, and the head of the Queensland Center for Gynecologic Cancer Research. Our full disclosures are available in the transcript of this episode. Dr. Obermair, it's great speaking with you today. Dr. Andreas Obermair: Thank you so much for inviting me to this podcast. Dr. Ebony Hoskins: I am very excited. I looked at your paper and I thought, gosh, is everything surgical? This is everything that I deal with daily in terms of cancer in counseling patients. What prompted this review regarding GYN cancer management? Dr. Andreas Obermair: Yes, our article was published in the ASCO Educational Book; it is volume 44 in 2024. And this article covers some key aspects of targeted precision surgical management principles in endometrial cancer, cervical cancer, and ovarian cancer. While surgery is considered the cornerstone of gynecologic cancer treatment, sometimes research doesn't necessarily reflect that. And so I think ASCO asked us to; so it was not just me, there was a team of colleagues from different parts of the United States and Australia to reflect on surgical aspects of gynecologic cancer care and I feel super passionate about that because I do believe that surgery has a lot to offer. Surgical interventions need to be defined and overall, I see the research that I'm doing as part of my daily job to go towards precision surgery. And I think that is, well, that is something that I'm increasingly passionate for. Dr. Ebony Hoskins: Well, I think we should get into it. One thing that comes to mind is the innovation of minimally invasive surgery in endometrial cancer. I always reflect on when I started my fellowship, I guess it's been about 15 years ago, all of our endometrial cancer patients had a midline vertical incision, increased risk of abscess, infections and a long hospital stay. Do you mind commenting on how you see management of endometrial cancer today? Dr. Andreas Obermair: Thank you very much for giving the historical perspective because the generation of gynecologic oncologists today, they may not even know what we dealt with, what problems we had to solve. So like you, when I was a fellow in gynecologic oncology, we did midline or lower crosswise incisions, the length of stay was, five days, seven days, but we had patients in hospital because of complications for 28 days. We took them back to the operating theaters because those are patients with a BMI of 40 plus, 45, 50 and so forth. So we really needed to solve problems. And then I was exposed to a mentor who taught minimal invasive surgery. And in Australia he was one of the first ones who embarked on that. And I can remember, I was mesmerized by this operation, like not only how logical this procedure was, but also we did rounds afterwards. And I saw these women after surgery and I saw them sitting upright, lipstick on, having had a full meal at the end of the day. And I thought, wow, this is the most rewarding experience that I have to round these patients after surgery. And so I was thinking, how could I help to establish this operation as standard? Like a standard that other people would accept this is better. And so I thought we needed to do a trial on this. And then it took a long time. It took a long time to get the support for the [LACE - Laparoscopic Approach to Cancer of the Endometrium] trial. And in this context, I just also wanted to remind us all that there were concerns about minimal invasive surgery in endometrial cancer at the time. So for example, one of the concerns was when I submitted my grant funding applications, people said, “Well, even if we fund you, wouldn't be able to do this trial because there are actually no surgeons who actually do minimally invasive surgery.” And at the time, for example, in Australia, there were maybe five people, a handful of people who were able to do this operation, right? This was about 20 years ago. The other concern people had was they were saying, could minimally invasive surgery for endometrial cancer, could that cause port side metastasis because there were case reports. So there were a lot of things that we didn't know anyway. We did this trial and I'm super happy we did this trial. We started in 2005, and it took five years to enroll. At the same time, GOG LAP2 was ramping up and the LACE trial and GOG LAP2 then got published and provided the foundations for minimally invasive surgery in endometrial cancer. I'm super happy that we have randomized data about that because now when we go back and now when people have concerns about this, should we do minimally invasive surgery in P53 mutant tumors, I'm saying, well, we actually have data on that. We could go back, we could actually do more research on that if we wanted to, but our treatment recommendations are standing on solid feet. Dr. Ebony Hoskins: Well, my patients are thankful. I see patients all the time and they have high risk and morbidly obese, lots of medical issues and actually I send them home most the same day. And I think, you know, I'm very appreciative of that research, because we obviously practice evidence-based and it's certainly a game changer. Let's go along the lines of MIS and cervical cancer. And this is going back to the LACC [Laparoscopic Approach to Cervical Cancer] trial. I remember, again, one of these early adopters of use of robotic surgery and laparoscopic surgery for radical hysterectomy and thought it was so cool. You know, we can see all the anatomy well and then have the data to show that we actually had a decreased survival. And I even see that most recent updated data just showing it still continued. Can you talk a little bit about why you think there is a difference? I know there's ongoing trials, but still interested in kind of why do you think there's a survival difference? Dr. Andreas Obermair: So Ebony, I hope you don't mind me going back a step. So the LACC study was developed from the LACE trial. So we thought we wanted to reproduce the LACE data/LAP2 data. We wanted to reproduce that in cervix cancer. And people were saying, why do you do that? Like, why would that be different in any way? We recognize that minimally invasive radical hysterectomy is not a standard. We're not going to enroll patients in a randomized trial where we open and do a laparotomy on half the patients. So I think the lesson that really needs to be learned here is that any surgical intervention that we do, we should put on good evidence footing because otherwise we're really running the risk of jeopardizing patients' outcomes. So, that was number one and LACC started two years after LACE started. So LACC started in 2007, and I just wanted to acknowledge the LACC principal investigator, Dr. Pedro Ramirez, who at the time worked at MD Anderson. And we incidentally realized that we had a common interest. The findings came totally unexpected and came as an utter shock to both of us. We did not expect this. We expected to see very similar disease-free and overall survival data as we saw in the endometrial cancer cohort. Now LACC was not designed to check why there was a difference in disease-free survival. So this is very important to understand. We did not expect it. Like, so there was no point checking why that is the case. My personal idea, and I think it is fair enough if we share personal ideas, and this is not even a hypothesis I want to say, this is just a personal idea is that in endometrial cancer, we're dealing with a tumor where most of the time the cancer is surrounded by a myometrial shell. And most of the time the cancer would not get into outside contact with the peritoneal cavity. Whereas in cervix cancer, this is very different because in cervix cancer, we need to manipulate the cervix and the tumor is right at the outside there. So I personally don't use a uterine manipulator. I believe in the United States, uterine manipulators are used all the time. My experience is not in this area, so I can't comment on that. But I would think that the manipulation of the cervix and the contact of the cervix to the free peritoneal cavity could be one of the reasons. But again, this is simply a personal opinion. Dr. Ebony Hoskins: Well, I appreciate it. Dr. Andreas Obermair: Ebony at the end of the day, right, medicine is empirical science, and empirical science means that we just make observations, we make observations, we measure them, and we pass them on. And we made an observation. And, and while we're saying that, and yes, you're absolutely right, the final [LACC] reports were published in JCO recently. And I'm very grateful to the JCO editorial team that they accepted the paper, and they communicated the results because this is obviously very important. At the same time, I would like to say that there are now three or four RCTs that challenge the LACC data. These RCTs are ongoing, and a lot of people will be looking forward to having these results available. Dr. Ebony Hoskins: Very good. In early-stage cervical cancer, the SHAPE trial looked at simple versus radical hysterectomy in low-risk cervical cancer patients. And as well all know, simple hysterectomy was not inferior to radical hysterectomy with respect to the pelvic recurrence rate and any complications related to surgery such as urinary incontinence and retention. My question for you is have you changed your practice in early-stage cervical cancer, say a patient with stage 1B1 adenocarcinoma with a positive margin on conization, would you still offer this patient a radical hysterectomy or would you consider a simple hysterectomy? Dr. Andreas Obermair: I think this is a very important topic, right? Because I think the challenge of SHAPE is to understand the inclusion criteria. That's the main challenge. And most people simplify it to 2 cm, which is one of the inclusion criteria but there are two others and that includes the depth of invasion. Dr. Marie Plante has been very clear. Marie Plante is the first author of the SHAPE trial that's been published in the New England Journal of Medicine only recently and Marie has been very clear upfront that we need to consider all three inclusion criteria and only then the inclusion criteria of SHAPE apply. So at the end of the day, I think what the SHAPE trial is telling us that small tumors that would strictly fulfill the criteria of a 1B or 1B1 cancer of the cervix can be considered for a standard type 1 or PIVA type 1 or whatever classification we're trying to use will be eligible. And that makes a lot of sense. I personally not only look at the size, I also look at the location of the tumor. I would be very keen that I avoid going through tumor tissue because for example, if you have a tumor that is, you know, located very much in one corner of the cervix and then you do a standard hysterectomy and then you have a positive tumor margin that would be obviously, most people would agree it would be an unwanted outcome. So I'd be very keen checking the location, the size of the tumor, the depths of invasion and maybe then if the tumor for example is on one side of the cervix you can do a standard approach on the contralateral side but maybe do a little bit more of a margin, a parametrial margin on the other side. Or if a tumor is maybe on the posterior cervical lip, then you don't need to worry so much about the anterior cervical margin, maybe take the rectum down and maybe try to get a little bit of a vaginal margin and the margin on the uterus saccals. Just really to make sure that you do have margins because typically if we get it right, survival outcomes of clinical stage 1 early cervix cancer 1B1 1B 2 are actually really good. It is a very important thing that we get the treatment right. In my practice, I use a software to record my treatment outcomes and my margins. And I would encourage all colleagues to be cognizant and to be responsible and accountable to introduce accountable clinical practice, to check on the margins and check on the number on the percentage of patients who require postoperative radiation treatment or chemo radiation. Dr. Ebony Hoskins: Very good. I have so many questions for you. I don't know the statistics in Australia, but here, there's increased rising of endometrial cancer and certainly we're seeing it in younger women. And fertility always comes up in terms of kind of what to do. And I look at the guidelines and, see if I can help some of the women if they have early-stage endometrial cancer. Your thoughts on what your practice is on use of someone who may meet criteria, if you will. The criteria I use is grade 1 endometrioid adenocarcinoma. No myometria invasion. I try to get MRI'd and make sure that there's no disease outside the endometrium. And then if they make criteria, I typically would do an IUD. Can you tell me what your practice is and where you've had success? Dr. Andreas Obermair: So, we initiated the feMMe clinical trial that was published in 2021 and it was presented in a Plenary at one of the SGO meetings. I think it was in 2021, and we've shown complete pathological response rates after levonorgestrel intrauterine device treatment. And so in brief, we enrolled patients with endometrial hyperplasia with atypia, but also patients with grade 1 endometrial adenocarcinoma. Patients with endometrial hyperplasia with atypia had, in our series, had an 85 % chance of developing a complete pathological response. And that was defined as the complete absence of any atypia or cancer. So endometrial hyperplasia with atypia responded in about 85%. In endometrial cancer, it was about half, it was about 45, 50%. In my clinical practice, like as you, I see patients, you know, five days a week. So I'm looking after many patients who are now five years down from conservative treatment of endometrial cancer. There are a lot of young women who want to get pregnant, and we had babies, and we celebrate the babies obviously because as gynecologist obstetricians it couldn't get better than that, right, if our cancer patients have babies afterwards. But we're also treating women who are really unfit for surgery and who are frail and where a laparoscopic hysterectomy would be unsafe. So this phase is concluded, and I think that was very successful. At least we're looking to validate our data. So we're having collaborations, we're having collaborations in the United States and outside the United States to validate these data. And the next phase is obviously to identify predictive factors, to identify predictors of response. Because as you can imagine, there is no point treating patients with a levonorgestrel intrauterine joint device where we know in advance that she's not going to respond. So this is a very, very fascinating story and we got our first set of data already, but now we just really need to validate this data. And then once the validation is done, my unit is keen to do a prospective validation trial. And that also needs to involve international collaborators. Dr. Ebony Hoskins: Very good. Moving on to ovarian cancer, we see patients with ovarian cancer with, say, at least stage 3C or higher who started neoadjuvant chemotherapy. Now, some of these patients are hearing different things from their medical oncologist versus their gynecologic oncologist regarding the number of cycles of neoadjuvant chemotherapy after getting diagnosed with ovarian cancer. I know that this can be confusing for our patients coming from a medical oncologist versus a gynecologic oncologist. What do you say to a patient who is asking about the ideal number of chemotherapy cycles prior to surgery? Dr. Andreas Obermair: So this is obviously a very, very important topic to talk about. We won't be able to provide a simple off the shelf answer for that, but I think data are emerging. The ASCO guidelines should also be worthwhile considering because there are actually new ASCO Guidelines [on neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer] that just came out a few weeks ago and they would suggest that we should be aiming for R0 in surgery. If we can maybe take that as the pivot point and then go back and say, okay, so what do need to do to get the patient to zero? I'm not an ovarian cancer researcher; I'm obviously a practicing gynecologic oncologist. I think about things a lot and things like that. In my practice, I would want a patient to develop a response after neoadjuvant chemotherapy. So, if a patient doesn't have a response after two or three cycles, then I don't see the point for me to offer her an operation. In my circle with the medical oncologists that I work with, I have a very, very good understanding. So, they send the patient to me, I take them to the theater. I take a good chunk of tissue from the peritoneum. We have a histopathologic diagnosis, we have a genomic diagnosis, they go home the same day. So obviously there is no hospital stay involved with that. They can start the chemotherapy after a few days. There is no hold up because the chances of surgical complication in a setting like this is very, very low. So I use laparoscopy to determine whether the patient responds or not. And for many of my patients, it seems to work. It's obviously a bit of an effort and it takes operating time. But I think I'm increasing my chances to make the right decision. So, coming back to your question about whether we should give three or six cycles, I think the current recommendations are three cycles pending the patient's response to neoadjuvant chemotherapy because my aim is to get a patient to R0 or at least minimal residual disease. Surgery is really, in this case, I think surgery is the adjunct to systemic treatment. Dr. Ebony Hoskins: Definitely. I think you make a great point, and I think the guideline just came out, like you mentioned, regarding neoadjuvant. And I think the biggest thing that we need to come across is the involvement of a gynecologic oncologist in patients with ovarian cancer. And we know that that survival increases with that involvement. And I think the involvement is the surgery, right? So, maybe we've gotten away from the primary tumor debulking and now using more neoadjuvant, but surgery is still needed. And so, I definitely want to have a take home that GYN oncology is involved in the care of these patients upfront. Dr. Andreas Obermair: I totally support that. This is a very important statement. So when I'm saying surgery is the adjunct to medical treatment, I don't mean that surgery is not important. Surgery is very important. And the timing is important. And that means that the surgeons and the med oncs need to be pulling on the same string. The med oncs just want to get the cytotoxic into the patients, but that's not the point, right? We want to get the cytotoxic into the patients at the right time because if we are working under this precision surgery, precision treatment mantra, it's not only important what we do, but also doing it at the right time. And ideally, I I would like to give surgery after three cycles of neoadjuvant chemotherapy, if that makes sense. But sometimes for me as a surgeon, I talk to my med onc colleagues and I say, “Look, she doesn't have a good enough response to her treatment and I want her to receive six cycles and then we re-evaluate or change medical treatment,” because that's an alternative that we can swap out drugs and treat upfront with a different drug and then sometimes they do respond. Dr. Ebony Hoskins: I have maybe one more topic. In the area I'm in, in the Washington D.C. area, we see lots of endometrial cancer and they're not grade 1, right? They're high-risk endometrial cancer and advanced. So a number of patients with stage 3 disease, some just kind of based off staging and then some who come in with disease based off of the CT scan, sometimes omental caking, ascites. And the real question is we have extrapolated the use of neoadjuvant chemotherapy to endometrial cancer. It's similar, but not the same. So my question is in an advanced endometrial cancer, do you think there's still a role, when I say advanced, I mean, maybe stage 4, a role for surgery? Dr. Andreas Obermair: Most definitely. But the question is when do you want to give this surgery? Similar to ovarian cancer, in my experience, I want to get to R0. What am I trying to achieve here? So, I reckon we should do a trial on this. And I reckon we have, as you say, the number of patients in this setting is increasing, we could do a trial. I think if we collaborate, we would have enough patients to do a proper trial. Obviously, we would start maybe with a feasibility trial and things like that. But I reckon a trial would be needed in this setting because I find that the incidence that you described, that other people would come across, they're becoming more and more common. I totally agree with you, and we have very little data on that. Dr. Ebony Hoskins: Very little and we're doing what we can. Dr. Obermair, thank you for sharing your fantastic insights with us today on the ASCO Daily News Podcast and for all the work you do to advance care for patients with gynecologic cancer. Dr. Andreas Obermair: Thank you, Dr. Hoskins, for hosting this and it's been an absolute pleasure speaking with you today. Dr. Ebony Hoskins: Definitely a pleasure and thank you to our listeners for your time today. Again, Dr. Obermair's article is titled, “Controversies in the Surgical Management of Gynecologic Cancer: Balancing the Decision to Operate or Hesitate,” and was published in the 2024 ASCO Educational Book. And you'll find a link to the article in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. 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. Find out more about today's speakers: Dr. Ebony Hoskins @drebonyhoskins Dr. Andreas Obermair @andreasobermair Follow ASCO on social media: @ASCO on Twitter ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Ebony Hoskins: No relationships to disclose. Dr. Andreas Obermair: Leadership: SurgicalPerformance Pty Ltd. Stock and Ownership Interests: SurgicalPerformance Pty Ltd. Honoraria: Baxter Healthcare Consulting or Advisory Role: Stryker/Novadaq Patents, Royalties, and Other Intellectual Property: Shares in SurgicalPerformance Pty Ltd. Travel, Accommodation, Expenses: Stryker
Listen to ASCO's Journal of Clinical Oncology Art of Oncology article, "I Hope So Too” by Dr. Richard Leiter from Dana-Farber Cancer Institute. The article is followed by an interview with Leiter and host Dr. Mikkael Sekeres. Leiter shares that even in the most difficult moments, clinicians can find space to hope with patients and their families. TRANSCRIPT Narrator: I Hope So Too, by Richard E. Leiter, MD, MA “You're always the negative one,” Carlos' mother said through our hospital's Spanish interpreter. “You want him to die.” Carlos was 21 years old. A few years earlier he had been diagnosed with AML and had undergone an allogeneic bone marrow transplant. He was cured. But now, he lay in our hospital's bone marrow transplant (BMT) unit, his body attacked by the very treatment that had given him a new life. He had disseminated graft-versus-host disease (GVHD) in his liver, his lungs, his gut, and, most markedly, his skin. The BMT team had consulted us to help with Carlos' pain. GVHD skin lesions covered his body. They were raw and weeping. Although the consult was ostensibly for pain, the subtext could not have been clearer. Carlos was dying, and the primary team needed help navigating the situation. As his liver and kidney function declined, the need to address goals of care with Carlos' mother felt like it was growing more urgent by the hour. Difficult cases, like a young person dying, transform an inpatient unit. Rather than the usual hum of nurses, patient care associates, pharmacy technicians, and unit managers going about their daily work, the floor becomes enveloped in tension. Daily rhythms jump a half step ahead of the beat; conversations among close colleagues fall out of tune. “Thank goodness you're here,” nurse after nurse told my attending and me, the weight of Carlos' case hanging from their shoulders and tugging at the already puffy skin below their eyes. I was a newly minted palliative care fellow, just over a month into my training. I was developing quickly, but as can happen with too many of us, my confidence sat a few steps beyond my skills. I thought I had a firm grasp of palliative care communication skills and was eager to use them. I asked for feedback from my attendings and genuinely worked to incorporate it into my practice. At the same time, I silently bristled when they took charge of a conversation in a patient's room. Over the ensuing week, my attending and I leaned in. We spent hours at Carlos' bedside. If I squinted, I could have convinced myself that Carlos' pain was better. Every day, however, felt worse. We were not making any progress with Carlos' mother, who mostly sat silently in a corner of his room. Aside from occasionally moaning, Carlos did not speak. We learned little, if anything, about him as a person, what he enjoyed, what he feared. We treated him, and we barely knew him. Each morning, I would dutifully update my attending about the overnight events. “Creatinine is up. Bili is up.” She would shake her head in sadness. “Doesn't she get that he's dying?” one of the nurses asked us. “I feel like I'm torturing him. He's jaundiced and going into renal failure. I'm worried we're going to need to send him to the ICU. But even that won't help him. Doesn't she understand?” We convened a family meeting. It was a gorgeous August afternoon, but the old BMT unit had no windows. We sat in a cramped, dark gray family meeting room. Huddled beside Carlos' mother was everyone on the care team including the BMT attending, nurse, social worker, chaplain, and Spanish interpreter. We explained that his kidneys and liver were failing and that we worried time was short. Carlos' mother had heard it all before, from his clinicians on rounds every day, from the nursing staff tenderly caring for him at his bedside, and from us. “He's going to get better,” she told us. “I don't understand why this is happening to him. He's going to recover. He was cured of his leukemia. I have hope that his kidneys and liver are going to get better.” “I hope they get better,” I told her. I should have stopped there. Instead, in my eagerness to show my attending, and myself, I could navigate the conversation on my own, I mistakenly kept going. “But none of us think they will.” It was after this comment that she looked me right in the eyes and told me I wanted Carlos to die. I knew, even then, that she was right. In that moment, I did want Carlos to die. I could not sit with all the suffering—his, his mother's, and his care team's. I needed her to adopt our narrative—that we had done all we could to help Carlos live, and now, we would do all we could to help him die comfortably. I needed his mother to tell me she understood, to accept what was going on. I failed to recognize what now seems so clear. Of course, his mother understood what was happening. She saw it. But how could we have asked her to accept what is fundamentally unacceptable? To comprehend the incomprehensible? At its best, serious illness communication not only empathetically shares news, be it good or bad, but also allows patients and families adequate time to adjust to it. For some, this adjustment happens quickly, and in a single conversation, they can digest difficult news and move to planning the next steps in care for themselves or their loved ones. For most, they need more time to process, and we are able to advance the discussion over the course of multiple visits. My attending led the conversations from then on. She worked with the BMT attending, and they compassionately kept Carlos out of the intensive care unit. He died a few days later, late in the evening. I never saw his mother again. I could not have prevented Carlos' death. None of us could have. None of us could have spared his mother from the grief that will stay with her for the rest of her life. Over those days, though, I could have made things just a little bit less difficult for her. I could have protected her from the overcommunication that plagues our inpatient units when patients and families make decisions different from those we would make for ourselves and our loved ones. I could have acted as her guide rather than as her cross-examiner. I could have hoped that Carlos stopped suffering and, genuinely, hoped he got better although I knew it was next to impossible. Because hope is a generous collaborator, it can coexist with rising creatinines, failing livers, and fears about intubation. Even in our most difficult moments as clinicians, we can find space to hope with our patients, if we look for it. Now—years later, when I talk to a terrified, grieving family member, I recall Carlos' mother's eyes piercing mine. When they tell me they hope their loved one gets better, I know how to respond. “I hope so too.” And I do. Dr. Mikkael Sekeres: Hello and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the oncology field. I'm your host, Mikkael Sekeres. I'm professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center at University of Miami. Today I am thrilled to be joined by Dr. Ricky Leiter from the Dana-Farber Cancer Institute. In this episode, we will be discussing his Art of Oncology article, “I Hope So, Too.” Our guest's disclosures will be linked in the transcript. Ricky, welcome to our podcast and thank you so much for joining us. Dr. Ricky Leiter: Thanks so much for having me. I'm really excited to be here. Dr. Mikkael Sekeres: Ricky, I absolutely adored your essay. It really explored, I think, a combination of the vulnerability we have when we're trying to take care of a patient who's dying and the interesting badlands we're placed in when we're also a trainee and aren't quite sure of our own skills and how to approach difficult situations. But before we dive into the meat of this, can you tell us a little bit about yourself? Where are you from and where did you do your training? Dr. Ricky Leiter: Sure, yeah. Thanks so much. So I grew up in Toronto, Canada, and then moved down to the States for college. I was actually a history major, so I never thought I was going to go into medicine. And long story short, here I am. I did a Post-Bac, did a year of research, and ended up at Northwestern Feinberg School of Medicine for med school, where I did a joint degree in medical humanities and bioethics. And that really shaped my path towards palliative care because I found this field where I said, “You know, wow, I can use these skills I'm learning in my Master's at the bedside with patients thinking about life and death and serious illness and what does that all mean in the broader context of society.” So, moved from Chicago to New York for residency, where I did residency and chief residency in internal medicine at New York Presbyterian Cornell, and then came up to the Harvard Interprofessional Palliative Care Program, where I did a clinical fellowship, then a research fellowship with Dana-Farber, and have been on faculty here since. Dr. Mikkael Sekeres: Fantastic. Any thoughts about moving back to Canada? Dr. Ricky Leiter: We talk about it every now and then. I'm really happy here. My family's really happy here. We love life in Boston, so we're certainly here for the time being. Definitely. Dr. Mikkael Sekeres: And the weather's so similar. Dr. Ricky Leiter: Yeah, I'm used to the cold. Dr. Mikkael Sekeres: I apparently did not move to Miami. I'm curious, this may be an unfair question, as you have a really broad background in humanities and ethics. Are there one or two books that you read where you think, “Gee, I'm still applying these principles,” or, “This really still resonates with me in my day to day care of patients who have cancer diagnosis”? Dr. Ricky Leiter: Oh, wow, that is a great question. There are probably too many to list. I think one is When Breath Becomes Air by Paul Kalanithi, which I didn't read in my training, I read afterwards. And I think he's such a beautiful writer. The story is so poignant, and I just think Paul Kalanithi's insights into what it means to be living with a serious illness and then ultimately dying from cancer as a young man, as someone in medicine, has really left an imprint on me. Also, Arthur Kleinman. The Illness Narratives, I think, is such a big one, too. And similarly, Arthur Frank's work. I mean, just thinking about narrative and patient stories and how that impacts our clinical care, and also us as clinicians. Dr. Mikkael Sekeres: And I suspect us as writers also. Dr. Ricky Leiter: Absolutely. Dr. Mikkael Sekeres: We imprint on the books that were influential to us. Dr. Ricky Leiter: Certainly. Dr. Mikkael Sekeres: So how about your story as a writer? How long have you been writing narrative pieces? Is this something you came to later in your career, or did you catch the bug early as an undergrad or even younger? Dr. Ricky Leiter: So I caught it early, and then it went dormant for a little while and came back. As a history major, as someone who is humanities minded, I loved writing my papers in college. Like, I was one of those nerds who got, like, really, really excited about the history term paper I was writing. You know, it was difficult, but I was doing it, particularly at the last minute. But I really loved the writing process. Going through my medical training, I didn't have as much time as I wanted, and so writing was sort of on the back burner. And then actually in my research fellowship, we had a writing seminar, our department, and one of the sessions was on writing Op-eds and perspective pieces. And we had a free write session and I wrote something sort of related to my research at the time I was thinking about, and Joanne Wolfe, who was helping to lead the session, pediatric palliative care physician, she said, “You know, this is really great. Like, where are you going to publish this?” And I said, “Joanne, what do you mean? I just wrote this in this session as an exercise.” She said, “No, you should publish this.” And I did. And then the bug came right back and I thought, “Wow, this is something that I really enjoy and I can actually make a difference with it. You know, getting a message out, allowing people to think a little bit differently or more deeply about clinical cases, both in the lay press and in medical publications.: So I've essentially been doing it since and it's become a larger and larger part of my career. Dr. Mikkael Sekeres: That's absolutely wonderful, Ricky. Where is it that you publish then, outside of Art of Oncology? Dr. Ricky Leiter: So I've had a couple of pieces in the New York Times, which was really exciting. Some in STAT News on their opinion section called First Opinion, and had a few pieces in the New England Journal as well, and in the Palliative Care Literature, the Journal of Palliative Medicine. Dr. Mikkael Sekeres: Outstanding. And about palliative care issues and end of life issues, I assume? Dr. Ricky Leiter: Sort of all of the above. Palliative care, serious illness, being in medical training, I wrote a fair bit about what it was like to be on the front lines of the pandemic. Dr. Mikkael Sekeres: Yeah, that was a traumatic period of time, I think, for a lot of us. Dr. Ricky Leiter: Absolutely. Dr. Mikkael Sekeres: I'm curious about your writing process. What triggers a story and how do you face the dreaded blank page? Dr. Ricky Leiter: So it's hard to pin down exactly what triggers a story for me. I think sometimes I'm in a room and for whatever reason, there's a moment in the room and I say, “You know what? There's a story here. There's something about what's going on right now that I want to write.” And oftentimes I don't know what it is until I start writing. Maybe it's a moment or a scene and I start writing like, “What am I trying to say here? What's the message? And sometimes there isn't a deeper message. The story itself is so poignant or beautiful that I want to tell that story. Other times it's using that story. And the way I think about my writing is using small moments to ask bigger questions in medicine. So, like, what does it mean to have a good death? You know, one piece I wrote was I was thinking about that as I struggled to give someone what I hoped would be a good death, that I was thinking more broadly, what does this mean as we're thinking about the concept of a good death? Another piece I wrote was about a patient I cared for doing kidney palliative care. And she was such a character. We adored her so much and she was challenging and she would admit that. This was someone I wanted to write about. And I talked to her about it and she was honored to have her story told. Unfortunately, it came out shortly after her death. But she was such a vibrant personality. I said, “There's something here that I want to write about.” In terms of the blank page, I think it's overcoming that fear of writing and procrastination and all of that. I think I have a specific writing playlist that I put on that helps me, that I've listened to so many times. You know, no words, but I know the music and it really helps me get in the zone. And then I start writing. And I think it's one of those things where sometimes I'm like, “Oh, I really don't like how this is sounding, but I'm going to push through anyways.” as Anne Lamott's blank first draft, just to get something out there and then I can play with it and work with it. Dr. Mikkael Sekeres: Great. I love the association you have with music and getting those creative juices flowing and picking ‘le mot juste' in getting things down on a page. It's also fascinating how we sometimes forget the true privilege that we have as healthcare providers in the people we meet, the cross section of humanity and the personalities who can trigger these wonderful stories. Dr. Ricky Leiter: Absolutely. Absolutely. It's such a privilege and I think it often will go in unexpected directions and can really impact, for me certainly, my practice of medicine and how I approach the next patients or even patients years down the road. You remember those patients and those stories. Dr. Mikkael Sekeres: Right. You write with such obvious love and respect for your patients. You also write about that tenuous phase of our careers when we're not yet attendings but have finished residency and have demonstrated a modicum of competence. You know, I used to say that fellowship is really the worst of all worlds, right? As an attending, you have responsibility, but you don't have to do as much of the grunt work. As a resident, you do the grunt work, but you don't really have the responsibility. And in fellowship, you've got it all. You've got to do the grunt work, and you have the responsibility. Can you tie those two concepts together, though? How does our relationship to our patients change over the course of our careers? Dr. Ricky Leiter: Early on, if you think about the imprinting of patients as you go down the road, so many of the patients who have imprinted on me were the ones earlier in my career, before I was more formed as a clinician because of experiences like the one I wrote about in “I Hope so Too,” where the skills are forming, and sometimes where it's smooth sailing, and sometimes we're muddling through. And those cases where we feel like we're muddling through or things don't go as we hope, those are the ones that really leave an impact. And I think it's those little moments that sort of nudge your career and your skill set in different ways. I think the patients now, they still leave a mark on me, but I think it's in different ways. And I think oftentimes it's less about my skills. Although my skills are still very much developing, even, you know, almost a decade out, they impact me differently than they once did. I feel more confident in what I'm doing, and it's more about my relationship to this situation rather than the situation's impact on my skills. Dr. Mikkael Sekeres: Got it. Got it. It's interesting. I once wrote a piece with Tim Gilligan, who also spent some time at Dana Farber and is a communications expert, about how there's this kind of dualism in how we're trained. We're trained with communications courses and how to talk to patients, and it almost does the opposite. It kind of raises the flag that, “Wait a second, maybe I've been talking to people the wrong way.” And as you get more mature in your career, I almost feel as if you revert back to the way you were before medical school, when you just talked to people like they were people and didn't have a special voice for patients. Dr. Ricky Leiter: Yeah, I think that's right. And I think in palliative care, we spend so much time thinking about the communication. And this was the most challenging piece about fellowship because then- and our fellowship directors told this to us, and now we teach it to our fellows. You know that you come in, the people who choose to go into palliative care, have a love of communication, have some degree of skill coming in, and then what happens is we break those skills down and teach them a new skill set. So it gets clunkier before it gets better. And the time I was writing about in this piece was August of my fellowship year, exactly when that process was happening, where I'm trying to incorporate the new skills, I had my old way of doing things, and it's just not always aligning. And I think you're right that as the skills become embedded, as you go on throughout your career, where it feels much more natural, and then you do really connect with people as people still using the skills and the techniques that we've learned in our communication courses, but they become part of who you are as a clinician. Dr. Mikkael Sekeres: Nicely put. Your story is particularly poignant because the patient you described was dying from the very treatment that cured his leukemia. It's this, I'm going to use the term badlands again. It's this terrible badlands we sometimes find ourselves where, yes, the treatment has been successful, but at the cost of a human life. Do you think that as healthcare providers, we react differently when a patient is sick, from side effects to our recommendations, as opposed to sick from their disease? Dr. Ricky Leiter: I think we probably do. It's hard because I think every patient in every case pulls at us in different directions. And this case was Carlos, who I called him, it was such a challenging situation for so many reasons. He was young. He really couldn't communicate with us. We were talking to his mom. Like, there were so many layers to this. But I think you're right. that underlying this, there's a sense of “We did everything we could beautifully, to cure him of his disease, and now he's dying of that, and what does that mean for us as clinicians, physicians. That becomes really hard and hard to sit with and hold as we're going back every day. And I say that as the palliative care consultant. So I can only imagine for the oncology team caring for him, who had taken him through this, what that felt like. Dr. Mikkael Sekeres: Well, you describe, again, beautifully in the piece, how the nursing staff would approach you and were so relieved that you were there. And it was, you know, you got the sense- I mean, obviously, it's tragic because it's a young person who died, but you almost got the sense there was this guilt among the providers, right? Not only is it a young person dying, but dying from graft versus host disease, not from leukemia. Dr. Ricky Leiter: Absolutely. There was guilt because of what he was dying of, because of how he was dying that he was so uncomfortable and it took us so long to get his pain under control and we really couldn't get him that balance of pain control and alertness that we always strive for was pretty much impossible from the beginning. And so it was layer upon layer of distress and guilt and sadness and grief that we could just feel every day as we stepped onto the floor. Dr. Mikkael Sekeres: Yeah. I don't know if you've ever read- there's a biography of Henry Kaplan, who was considered the father of radiation therapy, where there was this incredible moment during his career when he presented at the AACR Annual Meeting the first cures for cancers, right? No one believed it. It was amazing, actually curing cancer. And then a couple years later, people started dribbling into his clinic with cancers because of the radiation therapy he gave, and he actually went into a clinical depression as a result of it. So it can affect providers at such a deep level. And I think there's this undiscussed guilt that permeates the staff when that happens. Dr. Ricky Leiter: Absolutely, absolutely. It's right there under the surface. And we rarely give ourselves the space to talk about it, right? To really sit down and say, how are we approaching this situation? How do we feel about it? And to sit with each other and acknowledge that this is horrible. It's a horrible situation. And we feel guilty and we feel sad and we feel grief about this. Dr. Mikkael Sekeres: It's been just terrific getting to know you and to read your piece, Ricky Leiternd, a we really appreciate your writing. Keep doing what you do. Dr. Ricky Leiter: Oh, thank you so much. It's a privilege to get the piece out there and particularly in JCO and to be here with you. So I really appreciate it. Dr. Mikkael Sekeres: Until next time, thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all of ASCO's shows at asco.org/podcasts. 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. Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr. Ricky Leiter is from the Dana-Farber Cancer Institute.
Dr. Shannon Westin and her guest, Dr. Breelyn Wilky, discuss the JCO article, "“Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas." TRANSCRIPT Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on research that has been published in the Journal of Clinical Oncology. I am your host, Gynecologic Oncologist and Social Media Consultant Editor of the JCO, Shannon Westin. I serve here from the University of Texas MD Anderson Cancer Center. And I am so excited to welcome Dr. Breelyn Wilky. She's an Associate Professor and the Director of Sarcoma Medical Oncology in the Department of Medicine Division of Medical Oncology, and the Cheryl Bennett & McNeilly family endowed chair in Sarcoma Research, the Deputy Associate Director of Clinical research at the University of Colorado Cancer Center. Welcome. Dr. Breelyn Wilky: Thank you so much. I'm delighted to be here. Shannon Westin: And with all those titles, I'm super impressed that she was able to complete the manuscript that we're going to discuss today, which is “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas.” And this was published in the JCO on January 27, 2025. And please note, our participants do not have any conflicts of interest. So this is exciting. Let's first level set. Can you review with us just the current state of sarcoma incidents, survival outcomes, that kind of thing so we all know where we're starting? Dr. Breelyn Wilky: Yes. So, you know, sarcomas are really, I like to call them the black box cancer type. And the big thing is that there's really more than a hundred different kinds of sarcomas, which collectively altogether make up only 1% of adult cancers. And so we talk about these as being bone and soft tissue tumors, but really, the heterogeneity is just incredible. You're talking maybe 10,000 to 12,000 new cases of soft tissue sarcoma per year, which is pretty rare in the grand scheme of things. And the trouble with these is that while you can cure sarcomas if you find them early and they're localized, when they metastasize and spread and are not resectable, we're looking at median overall survivals of really only 12 to 18 months, even, you know, with our best therapies that we have. So, really there's just a dire need for new treatments for this really tough group of diseases. Shannon Westin: Yeah, I agree. I'm a gynecologic oncologist, and we have our little subset of sarcomas that I know there's a little bit out of every one. So I'm really excited to pull this manuscript as one of our podcasts offerings because I think we're all seeing these patients in the clinic and certainly our listeners that have sarcoma or have family members with sarcoma, this is so good to have a real focus on a rare group of tumors that have been a little bit lumped together. Now, with that being said, I know this is such a heterogeneous population, but can you briefly overview a little bit around the standard of care for treatment of recurrent sarcomas? Dr. Breelyn Wilky: We have actually been using the same drugs really since about the 1970s, and up until very recently, nothing had really challenged doxorubicin, the old ‘red devil', like we used to call it. And this has been the mainstay of treatment for metastatic sarcomas and really used across the board. In the GYN literature, for uterine leiomyosarcoma, we did see some promising activity with the combination of doxorubicin and trabectedin coming out of the French group. But, except for that study, no combination therapy or new drug has been proven better in terms of overall survival compared to doxorubicin monotherapy, really over 40, 50 years. So it's definitely a tough situation. Now, we do have other drugs that we use, so most patients will wind up getting doxorubicin-based therapy. There's a couple of other regimens that we'll reach to, like gemcitabine docetaxel. And once you get into the specific subtypes, we have some approvals in liposarcomas and leiomyosarcomas for some other drugs. But really the median progression for survival for most of these regimens is somewhere four to six months. And response rates typically are somewhere like 10%, 15% for most of these. So it's really just a very tough field and a tough group of patients to try to make an impact for. Shannon Westin: So let's talk a little bit more kind of getting focused on what you've studied here. What's been the role of immunotherapy thus far in the treatment of sarcomas maybe prior to this particular study? Dr. Breelyn Wilky: Clearly, we all know that immune therapy has just changed cancer care forever over the last few years for so many different types of cancers and diseases like melanoma and renal cell and lung cancer have just been transformed by checkpoint inhibitors specifically directed against PD-1 or CTLA-4 or both. And so, of course, you know, sarcoma docs we're super excited to try to see if these might potentially have activity in our tumors as well. I never had seen myself in my career getting into immunotherapy until I was able to run an investigator-initiated study during my role in Miami, where we combined pembrolizumab, so PD-1 inhibitor, with axitinib which was a pan-VEGF inhibitor. And lo and behold, like I had patients that I was seeing responses when other treatments, all those chemotherapies I was just talking about had failed. And one of my first patients I treated was about a 60-year-old lady with something called cutaneous angiosarcoma. So this is a blood vessel sarcoma all over her face. And we had treated her with 10 different therapies, all the chemotherapy regimens, targeted therapies, clinical trials, and nothing was working. But I put her on a phase 1 trial with a baby dose of CTLA-4 and this woman had a complete response. And so for me, once I saw it work in even just those couple of patients, like that was nothing that we'd ever seen with our chemotherapy regimens. And so that sort of shifted my career towards really focusing on this, and this is about the time where some of the studies started to come out for sarcomas. And the take home with sarcoma is about 20% of sarcomas have this sort of immune hot physiology. So what that basically means is if you look at gene expression of immune related gene signatures, or you look for infiltrating T-cells, sort of the SWAT team of our immune system, like you can find those in the tumors. And it's sort of evidence that the immune system had some clue for that 20% of patients that this was a foreign tumor and that it should be attacking it and maybe just needed a little help. But globally, about 80% of sarcomas are these immune cold tumors, which means the immune system has no clue that these things are even a threat. And there's almost no immune activation, very, very few antigens. In other cancer types, high neoantigens or tumor antigens help the immune system work better. And so that basically goes with what we've seen with trials of PD-1 or CTLA-4 blockade. About 20% of sarcomas, with some exceptions, can respond. But really 80% across the board, you're stuck, you just can't get them to be recognized. And so that's where I think this data is so interesting is there's some signals of activity in these immune cold tumors which, at least historically with the trials we've done so far, we really haven't seen that with sort of the traditional checkpoints. Shannon Westin: So I think now this is a great time to maybe talk about the study design in general, the eligibility and just give us kind of a run through of that. Dr. Breelyn Wilky: So this trial was a phase 1 trial of a drug called botensilimab, which is a next generation CTLA-4 directed immune modulator. So what makes botensilimab different is that the CTLA-4 end is very similar to other CTLA-4 inhibitors that are out there, but it's been engineered on the back end of the molecule that binds to Fc gamma receptors to basically bind tighter with higher affinity. And what this translates to in laboratory models and increasingly now in patients is it does a better job of priming, of educating our T cells, our, again, these highly intelligent antigen specific cells, but also natural killer cells. It does a better job of sort of educating those. It helps to activate macrophages and other supporting actors in the immune response. And so the idea here is that there's evidence that botensilimab may do a better job at creating new responses in immune cold tumors. The study combined either botensilimab as monotherapy or in combination with a PD-1 inhibitor called balstilimab. And this was all comers, really a variety of tumor types. And to date I think we're close to about 500 patients with a variety of solid tumors that have been accrued to this study, this C-800-01 phase 1 trial. This paper reports on the sarcoma patients that were enrolled as part of this study. And so, again, given what I've told you about sarcomas being really immune cold, we were just so excited to have the opportunity to enroll on a next generation immune therapy for these tumors that really we were running into roadblocks trying to use immunotherapy previously. Shannon Westin: It's a very compelling idea and I'm so excited for you to tell people what you found. I think first things first, it was an early phase trial. So why don't we talk a little bit about the safety of the regimen. Was there anything that you didn't expect? Dr. Breelyn Wilky: Right. So similar to other checkpoint inhibitors, you know, the idea is that these drugs can cause immune mediated toxicities, right? So essentially you're revving up the immune system and it can sometimes get a bit confused and start attacking our normal cells, our normal organs, leading to essentially any number of toxicities of basically head to toe, something can get inflamed and you can develop a toxicity from that. So the key take homes with this particular drug with, botensilimab with balstilimab, we saw colitis was sort of the primary immune mediated toxicity and it was about a third of patients, give or take. It happens and it can be aggressive and needs to be managed aggressively. And you know, one of the things that we learned very quickly taking part in this study is how important it is that as soon as patients start to get diarrhea, immunosuppression gets on board. So steroids, early use of TNF alpha blockade, so infliximab for example, if we jumped on it quickly and we recognized it and we got the patients treated, it would resolve fairly quickly and even some patients could remain on treatment. So I think that was sort of the first take home is “Okay if you get colitis, you treat it fast, you treat it early and you can still have patients not only recover, which essentially everybody recovered from this colitis and then being able to continue on treatment and still have their anti-tumor responses.” So that's the first point. The second thing that was really interesting is part of the engineering of botensilimab on the back end of the molecule, it's been designed to decrease complement binding and it's thought that that triggers some of these other toxicities that we've seen with prior CTLA-4 inhibitors like pneumonitis or hypophysitis. We actually don't see that with botensilimab. So there's sort of this selective toxicity that may reflect the design of the molecule. But overall the treatment was, we didn't see any new safety signals that were outside of what we would expect in class. And colitis was sort of the dominant thing that we had to be ready for and ready to manage. Shannon Westin: We've been doing it for a while now, so we kind of know what to do and we can act quickly and really try to mitigate and avoid some of the major toxicities. So that's great that that was what was reflected in what you found. And then of course I think: What about the efficacy?” Right. This is what we care about as practitioners, as patients. Does it work and are there any subtypes that seem to benefit the most from this combination? Dr. Breelyn Wilky: Right. So for the sarcoma patients, we treated 64 patients and 52 of those patients were evaluable for efficacy. So a decent size group of patients in sarcomas, where, you know, typically our trials are pretty small, they're very rare, but we had 52 evaluable with at least one post baseline scan. So that was our criteria. And basically we saw across all of the patients, and keep in mind, these are heavily pre-treated patients, as you mentioned, so a median of 3 prior lines of therapy, so most of these patients had had chemotherapies and then about 20% had also had prior immunotherapy as well. So PD-1 treatments or so on. The overall response rate by RECIST was 19.2% for all of the evaluable patients. And then with iRECIST, which is sort of that immune adapted response criteria that allows for early pseudo progression, we actually had another patient who did have that. And so that response rate was 21.2%. Overall, we were really excited to see this in a heavily pre-treated group of patients. But what was really exciting to me was when we looked at the subset of patients that had angiosarcoma, that blood vessel tumor I was talking about earlier with my other patient. So angios come in two flavors. One is this sort of cutaneous type, or meaning involving the skin that has a UV signature, a UV damage signature, very similar to melanoma. So these tumors tend to have a high mutation burden. And oftentimes there is a track record that we've seen responses with immunotherapy in cutaneous angiosarcomas. But the other group that we deal with is called visceral angiosarcomas. And so these are totally different biologically. These are often driven by mutations in MYC or KDR amplification, and they arise in organs, so primary breast angiosarcoma, not associated with radiation, or they can arise in the liver or the spleen or an extremity. So these are very, very different tumors, and the visceral ones almost never historically have responded to checkpoint inhibitors. So we had 18 patients with angio split - 9 with cutaneous, 9 with visceral. And we were just blown away because the response rate for that group was 27.8%. And if you looked at the responses between the hot ones and the cold ones, it was almost equal and a little bit better in the visceral. So we had a 33% response rate in visceral angiosarcoma, which is crazy, historically speaking, and about 20% again in the cutaneous angios. So for a disease where visceral angio gets treated with chemotherapy, might respond initially, but then rapidly progresses - like these people go through multiple lines of therapy - to have a third of patients responding, and then some of those responses were durable. Our median duration of response for the study was 21.7 months, which is just nuts for sarcomas where we just don't see those sorts of long term benefits with the drugs that we have. So I think those are kind of the two main things. There were other subtypes that had clinical benefit and responses as well in d-diff liposarcoma, soft tissue leiomyosarcoma, which are again thought to be fairly cold immune subtypes. So just really exciting to kind of see responses we hadn't expected in a very challenging group of tumors. Shannon Westin: We see all these patients and we have patients that respond so well to immunotherapy with other histotypes. And so it's so exciting to see an option for these really hard to treat tumors that our patients struggle with. So this is so, so very exciting. I wanted to make mention, you know, I was really impressed with the amount of translational work you were able to do in this early phase study. So do you want to review just maybe a few of the key findings that you guys discovered? Dr. Breelyn Wilky: It's always great. I'm a translational researcher at heart and we do a lot of immune correlative work. And I think the reason I got so excited about this field to begin with was trying to learn why it works for some patients and why it doesn't work for other patients. So I'm a huge believer in learning from every patient that we can. So it's such a testament to the company, Agenus, who sponsored this trial to invest their time and resources into correlative studies at this phase. It's huge. So we learned a couple of things. IL-6 or interleukin 6 is a cytokine that basically has, in other tumor types, been associated with worse outcomes. And what we were interested in this group is we saw the same thing. And again, sarcomas have very, very little correlative biology that's done. We're really in infancy and understanding the microenvironment and how that milieu balances out in our tumors. So we were really excited to see again that lower peripheral interleukin 6 associated with improved overall survival. So again, kind of sorting out a group of patients that might be immunologically favorable when it comes to this type of therapy. The other thing that's important to know about sarcoma is so the other tumor types are lucky and have PD-L1 expression and the tumor is a biomarker, but we never have PD-L1 expression. We can find it in sarcomas and it can be loosely correlated with a chance of benefit with immunotherapy. But I've had patients respond that were PD-L1 negative, and I've had patients that were loaded with PD-L1 that didn't seem to make a difference. And that's not just in this study. So we saw in this trial a trend towards improved overall survival with PD-L1 expression that wasn't significant, but there was like this trend. And it's really interesting because, again, this is largely a CTLA-4 directed therapy. And so what we wondered is if PD-L1 expression is an index of sort of this underlying potential immunogenicity. And actually PD-1 works very late in the whole immune process. That's really at the very end where you've got the T cell that's facing the tumor cell and it's just activating that T cell that's already grown up and already educated and ready to go. Whereas CTLA-4 is really educating in early immune responses and expanding the T cells that have potential to kill. So I'm interested to look into this in more depth in the future to see if this is actually the biomarker for CTLA-4 directed therapy that we've been looking for, because we really don't have a great sense about that. And then the last piece just to note is that in this trial, like most others, very, very few sarcomas had high mutational burden. Everybody was very low, which reflects the population. And it's just really more encouragement than an immune cold tumor with very crappy neoantigens can still respond to immunotherapy if we get them the right agents. Shannon Westin: Yeah, I mean, I'm taking notes because we have such a struggle with this across the gynecologic tumors. I'm like, “Okay, maybe this is finally it.” So hopefully your work will go on to really inspire us across a number of solid tumors that have been traditionally cold. So, so very exciting. And I would just say for my last question, obviously, congratulations on this successful study. What do you think are the next steps for this combination in sarcomas? Dr. Breelyn Wilky: So, again, just to your point, this trial enrolled a bunch of different subtypes, and sarcomas are not the only immune cold tumor that this combo has looked really promising for, microsatellite stable colorectal cancer, ovarian cancer that was platinum refractory, non-small cell lungs. So I think the future is really bright for immune cold tumors kind of across the board. So, yes, lots of hope for not just sarcomas but in terms of our patients, I just have to be so grateful to Agenus for their interest in a rare disease. Sometimes it's hard to get that interest for a very challenging group of patients that are all heterogeneous, they are not all the same and our big clinical trials are a few hundred patients. It's just a very different environment. But they have been so supportive and involved in making sure that sarcomas are represented in their priorities. So there are ongoing discussions about what the optimal way to explore this further in sarcomas is going to be and I cannot wait to have the official plans in place. But my hope is this will not be the last that we see of these drugs for our patients. Shannon Westin: Well, I support that and my vote is on your side. So, thank you so much again, Dr. Wilky. This time just flew by. This was such a great discussion and I mean, I think it's, again, a testament to your exciting data. And thank you to all of our listeners. This has been JCO After Hours' discussion of “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas,” published in the JCO on January 27, 2025. So be sure to check out the full manuscript. And we hope that you enjoyed this podcast. And if you want to hear more about research published in the JCO, check this out on our ASCO JCO website or wherever you get your podcasts. Have an awesome day. 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. Wilky Disclosures Consulting or Advisory Role: SpringWorks Therapeutics, Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, AADi, InhibRx Research Funding: Exelixis Travel, Accommodations, Expenses: Agenus
Dr. John Sweetenham and Dr. James Foran discuss the evolving treatment landscape in acute myeloid leukemia, including new targeted therapies, advances in immunotherapy, and the current role for allogeneic transplantation. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. There has been steady progress in the therapies for acute myeloid leukemia (AML) in recent years, largely based on an increasing understanding of the molecular mechanisms which underlie the disease. On today's episode, we'll be discussing the evolving treatment landscape in AML. We'll explore risk group stratification, new targeted therapies, advances in immunotherapy for AML, and also a little about the current role for allogenic transplantation in this disease. I'm delighted to welcome Dr. James Foran to this discussion. Dr. Foran is a professor of medicine and chair of the Myeloid Malignancies and Blood and Marrow Transplant Disease Group at the Mayo Clinic Comprehensive Cancer Center. He's based in Jacksonville, Florida. Our full disclosures are available in the transcript of this episode. James, it's great to have you join us on the podcast today, and thanks so much for being here. Dr. James Foran: I'm delighted and thank you for the invitation. Thank you very much. Dr. John Sweetenham: Sure, James, let's get right into it. So, our understanding of the molecular mechanisms underlying AML has resulted not only in new methods for risk stratification in this disease, which have added refinement to cytogenetics, but also has resulted in the development of many new targeted agents. Understanding that this is a complex area of investigation, and our time is somewhat limited, can you give us a high-level update on the current state of the art in terms of how risk factors are being used for treatment selection now? Dr. James Foran: Absolutely. I think in the past, you know, we had things broken down pretty simply into make a diagnosis based on morphology, do cytogenetics, break patients into the groups of those who were more likely to benefit from therapy – so-called favorable risk – those where the intensive therapies were less likely to work – so-called poor adverse risk, and then this large intermediate group that really had variable outcomes, some better, some worse. And for a long time, the progress was in just identifying new subtle cytogenetic risk groups. And then, late 1990s, we began to understand that FLT3 mutations or NRAS mutations may be more adverse than others that came along. In the first part of this millennium, in the, you know, 2000-2010 range, a lot of work was being done to understand better or worse risk factors with single genes. The ability to do multiplex PCR, and then more recently NGS platforms, have allowed us to really look at many genes and identify many mutations in patients. At the beginning that was used just to sort of refine – who did a little better, who did a little worse with intensive therapy – helped us decide who may benefit more from an allogeneic transplanter for whom that would not be necessary. But the good news is that really, we're now starting to target those mutations. One of the first molecularly targeted treatments in leukemia was FLT3 mutations, where we knew they were adverse. Then along came targeted treatments. I was involved in some of those early studies looking at sunitinib, sorafenib, more recently midostaurin, now quizartinib, FDA approved, and gilteritinib in the relapse refractory setting. So we're moving into a state where we're not just refining prognosis, we're identifying targets. You know, it's been slow progress, but definite incremental progress in terms of outcomes by looking for FLT3 mutations, then looking for IDH mutations, and more recently, mutations involving NPM1 or rearrangement of what we used to call the MLL gene, now the lysine methyltransferase 2A or KMT2A rearrangement, where we now have targets. And it's not just for refinement of prognosis, but now we're identifying therapeutic targets for patients and ways to even look for measurable residual disease which is impacting our care. Dr. John Sweetenham: That's great, James. And I'm going to expand on that theme just a little bit and perhaps ask you to elaborate a little bit more on how the introduction of these new therapies have specifically impacted frontline therapy. And a couple of ancillary questions maybe to go along with that: First of all, is ‘7+3' a standard therapy for anybody in 2025? And maybe secondly, you know, could you comment also maybe briefly on older patients with AML and how you think maybe the treatment landscape is changing for them compared with, say, 5 or 10 years ago? Dr. James Foran: I'll start with the therapy and then work my way back. So we've had ‘7+3' cytarabine daunorubicin or cytarabine anthracycline since 1976, and we're still using it as the backbone of our intensive therapy. There is still an important role for it, particularly in younger or fitter patients, and particularly for those with intermediate or favorable risk genetic groups or cytogenetic risk groups just because we achieve high rates of remission. Our 30-day induction mortality rates are lower now than they were 10 and 20 years ago. Our supportive care is better. And we still have a busy inpatient hospital service here at Mayo Florida and my colleagues in Rochester and Arizona as well giving intensive therapy. So that remains the backbone of curative therapy for younger adults. We are trying to be a little more discriminating about who we administer that to. We are trying to add targeted agents. We know from, now, two different randomized trials that the addition of a FLT3 inhibitor, either midostaurin or more recently quizartinib, has a survival advantage in patients with a FLT3 mutation, or for quizartinib, a FLT3/ITD mutation. And so yes, ‘7+3' remains important. Off protocol for somebody who just comes in with acute leukemia in a 40-year-old or 30-year-old or even early 60s and fit, we would still be considering ‘7+3' therapy and then waiting for an expedited gene mutation panel and an expedited cytogenetics panel to come back to help us discriminate is that a patient for whom we should be giving a FLT3 inhibitor? I think there's a little more nuance about when we do a day 14 bone marrow, do they really matter as much anymore? I still do them. Some of my colleagues find them less important. But we're still giving intensive therapy. We're still giving high-dose ARA-C consolidation for younger patients who achieve complete remission. In older adults, it's a different story. You know, it was only in the early part of the 2000s – 2004, 2007 range – where we really got buy-in from randomized studies that low-dose therapy was better than no therapy. There was a lot of nihilism before then about therapy for older adults, especially over age 75. We know that low-dose ARA-C is better than nothing. It looked like azacitidine was better than ARA-C or at least equivalent or slightly better. But with the advent of venetoclax it was a game changer. I ran a national randomized study of intensive therapy in AML. It was the last national randomized study of intensive therapy in older patients right before venetoclax got approved. And we were very excited about our results, and we thought we had some really interesting clinical results. And suddenly that's a little bit obsolete in patients over 70 and particularly over age 75 because of the high remission rates with azacytidine venetoclax or hypomethylating agents, so-called HMAs and venetoclax and the survival advantage. Now, it's not a home run for everybody. We quote 60% to 70% remission rates, but it's a little different based on your cytogenetics and your mutation profile. You have to continue on therapy so it's continuous treatment. It's not with curative intent, although there are some people with long-term remission in it. And the median survival went from 10 months to 15 months. So home run? No, but definitely improved remissions, meaningful for patients off transfusions and better survival. So right now it's hard to find an older adult who you wouldn't give azacitidine and venetoclax or something similar, decitabine, for instance, and venetoclax, unless somebody really was moribund or had very poor performance status or some reason not to. And so ‘7+3' is still relevant in younger adults. We're trying to get better results with ‘7+3' by adding targeted agents and azacitine and venetoclax in older adults. I think the area of controversy, I guess there are two of them, is what to do in that overlap age between 60 and 75. Should people in that age still get intensive therapy, which we've used for years – the VIALE-A trial of aza-venetoclax was age 75 plus – or with cardiac comorbidities? And I think if you're 68 or 72, many of us are starting to bias towards aza-venetoclax as generally being better tolerated, generally being more outpatient, generally being slow and steady way to get a remission. And it doesn't stop you from going to transplant for somebody who might still be a candidate. The other area of controversy is somebody under 60 who has adverse cytogenetics where we don't do very well with ‘7+3,' we still give it and we might do just as well with decitabine venetoclax. A lot of us feel that there's equipoise in the 60 to 75 group where we really can ask a question of a randomized study. Retrospective studies might suggest that intensive therapy is a little better, but there are now a couple of randomized studies happening saying, “Can we replace ‘7+3' in that intermediate age with aza-venetoclax?” And for younger adults similarly, we're looking to see how we apply that technology. Those are the areas where we're really trying to investigate what's optimal for patients and that's going to require randomized trials. Dr. John Sweetenham: Oh, that's great, thank you. And I'll just extend that question a little bit more, particularly with respect to the new targeted therapies. How much are they impacting the treatment of these patients in the relapse and refractory setting now? Dr. James Foran: Oh, they're definitely impacting it. When I trained and probably when you trained, AML was still a medical emergency. But that was the thing that you admitted to the hospital immediately, you started therapy immediately. The rule was always that's the one thing that brings the fellow and the consultant in at night to see that new patient on a Friday or Saturday. Now, we'll still admit a patient for monitoring, but we try not to start therapy for the first three or five or seven days if they're stable, until we get those genetics and those genomics back, because it helps us discriminate what therapy to pursue. And certainly, with FLT3 mutations, especially FLT3/ITD mutations, we're adding FLT3 inhibitors and we're seeing a survival advantage. Now, on the surface, that survival advantage is in the range of 7% or 10%. But if you then pursue an allogeneic transplant in first remission, you're taking disease where we used to see 30%, 40% long-term survival, maybe less, and you're pushing that to 60%, 70% in some studies. And so we're now taking a disease that– I don't want to get off topic and talk about Ph+ ALL. But that's a disease where we're actually a little excited. We have a target now, and it used to be something really adverse and now we can do a lot for it and a lot about it. The other mutations, it's a little more subtle. Now, who knew until 2010 that a mutation in a sugar metabolism gene, in isocitrate dehydrogenase, or IDH was going to be so important, or even that it existed. We know that IDH1 and IDH2 mutations are still a minority of AML, certainly less than 10% to 15%, maybe overall. But we're able to target those with specific IDH1 and IDH2 inhibitors. We get single-agent responses. There are now two approved IDH1 inhibitors on the market. We don't yet have the randomized data that adding those to intensive therapy is better, but we're getting a very strong hint that it might be better in older adults who have an IDH mutation, maybe adding those is helpful and maybe adding those to low-intensity therapy is helpful. Those studies are ongoing, and we're also trying with low-intensity treatments to add these agents and get higher remission rates, deeper remissions, longer remissions. I think a lot of work has to be done to delineate the safety of that and the long-term efficacy. But we're getting hints it's better, so I think it is impacting. The other area it's impacting is when you pick up adverse mutations and those have crept into our classification systems like an ASXL1 mutation or RUNX1 mutation for instance, or some of the secondary AML mutations like BCOR and others, where that's helping us discriminate intermediate-risk patients who we think aren't going to do as well and really helping us select a group who's more likely to get benefit from allogeneic transplant or for whom at least our cure rates without allo transplant are low. And so I think it's impacting a lot. Dr. John Sweetenham: Great. And I'm going to pick up now, if I may, on a couple of things that you've just mentioned and continue the theme of the relapsed and refractory setting. We've started to see some reports which have looked at the role of immune strategies for patients with AML, in particular CAR T or NK cells. Can you comment a little on this and let us know whether you think either these two strategies or other immune strategies are likely to have a significant role in AML in the future? Dr. James Foran: They are, but I think we're still a step behind finding the right target or the right way to do it. If you think of allogeneic transplantation as the definitive immune therapy, and we know for adverse AML we can improve survival rates and cure rates with an allotransplant, then we know inherently that immune therapy matters. And so how do we do what they've done in large cell lymphoma or in CD19 targeting for B cell malignancies? How do we bring that to acute myeloid leukemia? There have been a number of efforts. There have been at least 50 trials looking at different targets. CD33, CD123, CD7, others, CLL-1. So, there have been a number of different trials looking at how to bind a CAR T or a CAR T construct that can be active. And we have hints of efficacy. There was kind of a provocative paper in the New England Journal of Medicine a year ago in April of last year from a Chinese group that looked at a CD7-based CAR T and it was 10 patients, but they used CD7 positive acute leukemia, AML or ALL and had a CD7-targeted CAR T and they actually incorporated that with a haploidentical transplant and they had really high remission rates. People tolerated it quite well. It was provocative. It hasn't yet been reproduced on a larger scale, but the strong hints that the strategy is going to work. Now, CD33 is a little tricky to have a CAR T when CD33 is expressed on normal hematopoietic cells. CD123 likewise. That's been something where there's, I think, still promise, but we've struggled to find the trials that make that work. Right now, there's a lot of interest in leveraging NK cells and looking, for a couple of reasons, but NK cells are attractive and NK cell markers might be attractive targets. NK cells might have similar degrees of immune efficacy. It's speculative, but they are likely to have less cytokine release syndrome and less neurotoxicity than you see with CAR T. And so it's kind of attractive to leverage that. We have had some ongoing trials looking at it with bispecifics and there certainly are trials looking at it with CAR NK-based strategies. One of the antigens that people looked at is the NK group 2D. NK group 2D or NKG2D is overexpressed in AML and its ligands overexpressed. And so that's a particular potential target. So, John, it's happening and we're looking for the hints of efficacy that could then drive a pivotal trial to get something approved. One of the other areas is not restricting yourself just to a single antigen. For instance, there is a compound that's looking at a multi-tumor-associated antigen-specific T-cell therapy, looking at multiple antigens in AML that could be overexpressed. And there were some hints of activity and efficacy and actually a new trial looking at a so-called multi-tumor associated antigen-specific T cell therapy. So without getting into specific conflicts of interest or trials, I do think that's an exciting area and an evolving area, but still an investigational area. I'll stop there and say that we're excited about it. A lot of work's going there, but I'm not quite sure which direction the field's going to pivot to there. I think that's going to take us some time to sort out. Dr. John Sweetenham: Yeah, absolutely. But as you say, exciting area and I guess continue to watch this space for now. So you've mentioned allogeneic stem cell transplants two or three times during this discussion. Recognizing that we don't have an imatinib for AML, which has kind of pushed transplant a long way further back in the treatment algorithm, can you comment a little on, you know, whether you think the role of stem cell transplantation is changing in AML or whether it remains pretty much as it was maybe 10 years ago? Dr. James Foran: By the way, I love that you use imatinib as an introduction because that was 6 TKIs ago, and it tells you the evolution in CML and you know, now we're looking at myristoyl pocket as a target, and so on. That's a great way to sort of show you the evolution of the field. Allogeneic transplant, it remains a core treatment for AML, and I think we're getting much smarter and much better about learning how to use it. And I'm just going to introduce the topic of measurable residual disease to tell you about that. So I am a little bit of a believer. Part of my job is I support our allogeneic transplant program, although my focus is acute myeloid leukemia, and I've trained in transplant and done it for years and did a transplant fellowship and all that. I'm much more interested in finding people who don't need a transplant than people who do. So I'm sort of looking for where can we move away from it. But it still has a core role. I'll sidestep and tell you there was an MDS trial that looked at intermediate or high-risk MDS and the role of allogeneic transplant that shows that you about double your survival. It was a BMT CTN trial published several years ago that showed you about double your three-year survival if you can find a donor within three months and get to a transplant within six months. And so it just tells you the value of allotransplant and myeloid malignancy in general. In AML we continue to use it for adverse risk disease – TP53 is its own category, I can talk about that separately – but adverse risk AML otherwise, or for patients who don't achieve a really good remission. And I still teach our fellows that an allotransplant decreases your risk of relapse by about 50%. That's still true, but you have to have a group of patients who are at high enough risk of relapse to merit the non-relapse mortality and the chronic graft versus host disease that comes with it. Now, our outcomes with transplant are better because we're better at preventing graft versus host disease with the newer strategies such as post-transplant cyclophosphamide. There are now new FDA-approved drugs for acute and chronic graft versus host disease, ruxolitinib, belumosudil, axatilimab now. So we have better ways of treating it, but we still want to be discriminating about who should get it. And it's not just a single-minded one-size-fits-all. We learned from the MORPHO study that was published in the JCO last year that if you have FLIT3-positive AML, FLIT3/IDT-positive AML, where we would have said from retrospective studies that your post-transplant survival is 60% give or take, as opposed to 15% or 20% without it, that we can discriminate who should or shouldn't get a transplant. Now that trial was a little bit nuanced because it did not meet its primary endpoint, but it had an embedded randomization based upon MRD status and they used a very sensitive test of measurable residual disease. They used a commercial assay by Invivoscribe that could look at the presence of a FLT3/ITD in the level of 10 to the minus 5th or 10 to the minus 6th. And if you were MRD-negative and you went through a transplant, you didn't seem to get an advantage versus not. That was of maintenance with gilteritinib, I'll just sort of put that on there. But it's telling us more about who should get a transplant and who shouldn't and who should get maintenance after transplant and who shouldn't. A really compelling study a year ago from I don't know what to call the British group now, we used to call them the MRC and then the NCRI. I'm not quite sure what to call their studies at the moment. But Dr. Jad Othman did a retrospective study a year ago that looked at patients who had NPM1 mutation, the most common mutation AML, and looked to see if you were MRD positive or MRD negative, what the impact of a transplant was. And if you're MRD negative there was not an advantage of a transplant, whereas if you're MRD positive there was. And when they stratified that by having a FLT3 mutation that cracked. If you had a FLT3 mutation at diagnosis but your NPM1 was negative in remission, it was hard to show an advantage of a transplant. So I think we're getting much more discriminating about who should or should not get a transplant by MRD testing for NPM1 and that includes the patients who have a concomitant FLT3 mutation. And we're really trying to learn more and more. Do we really need to be doing transplants in those who are MRD-negative? If you have adverse risk genetics and you're MRD-negative, I'll really need good data to tell me not to do a transplant, but I suspect bit by bit, we'll get that data. And we're looking to see if that's really the case there, too. So measurable residual disease testing is helping us discriminate, but there is still a core role of allogeneic transplant. And to reassure you, compared to, I think your allotransplant days were some time ago if I'm right. Dr. John Sweetenham: Yes. Dr. James Foran: Yeah. Well, compared to when you were doing transplants, they're better now and better for patients now. And we get people through graft versus host disease better, and we prevent it better. Dr. John Sweetenham: That's a great answer, James. Thanks for that. It really does help to put it in context, and I think it also leads us on very nicely into what's going to be my final question for you today and perhaps the trickiest, in a way. I think that everything you've told us today really emphasizes the fact that the complexity of AML treatment has increased, primarily because of an improved understanding of the molecular landscape of the disease. And it's a complicated area now. So do you have any thoughts on what type of clinical environment patients with AML should be evaluated and treated in in 2025? Dr. James Foran: Yeah, I want to give you a kind of a cautious answer to that because, you know, I'm a leukemia doctor. I work at a leukemia center and it's what we focus on. And we really pride ourselves on our outcomes and our diagnostics and our clinical trials and so on. I am very aware that the very best oncologists in America work in private practice and work in community practice or in networks, not necessarily at an academic site. And I also know they have a much harder job than I have. They have to know lung cancer, which is molecularly as complicated now as leukemia, and they have to know about breast cancer and things that I don't even know how to spell anymore. So it's not a question of competence or knowledge. It's a question of infrastructure. I'll also put a little caveat saying that I have been taught by Rich Stone at Dana-Farber, where I did a fellowship a long time ago, and believe Rich is right, that I see different patients than the community oncologists see with AML, they're seeing different people. But with that caveat, I think the first thing is you really want to make sure you've got access to excellence, specialized hematopathology, that you can get expedited cytogenetics and NGS testing results back. There was a new drug, approved just a few months ago, actually, for relapsed AML with a KMT2A rearrangement, revumenib. We didn't talk about the menin inhibitors. I'll mention them in just a second. That's a huge area of expansion and growth for us. But they're not found on NGS platforms. And normal cytogenetics might miss a KMT2A-rearrangement. And we're actually going back to FISH panels, believe it or not, on AML, to try to identify who has a KMT2A-rearrangement. And so you really want to make sure you can access the diagnostic platforms for that. I think the National Referral Labs do an excellent job. Not always a really fast job, but an excellent job. At my institution, I get NGS results back within three days or four days. We just have an expedited platform. Not everybody has that. So that's the key, is you have to be able to make the diagnosis, trust the pathologist, get expedited results. And then it's the question of trying to access the targeted medications because a lot of them are not carried in hospital on formulary or take time to go through an insurance approval process. So that's its own little headache, getting venetoclax, getting gilteritinib, getting an IDH1 inhibitor in first line, if that's what you're going for. And so I think that requires some infrastructure. We have case managers and nurses who really expedite that and help us with it, but that's a lot of work. The other piece of the puzzle is that we're still with AML in the first month and maybe even the second month. We make everybody worse before we make them better. And you have to have really good blood bank support. I can give an outpatient platelet transfusion or red cell transfusion seven days a week. We're just built for that. That's harder to do if you're in a community hospital and you have to be collaborating with a local blood bank. And that's not always dead easy for somebody in practice. So with those caveats, I do find that my colleagues in community practice do a really good job making the diagnosis, starting people on therapy, asking for help. I think the real thing is to be able to have a regional leukemia center that you can collaborate with, connect with, text, call to make sure that you're finding the right patients who need the next level of diagnostics, clinical trial, transplant consults, to really get the best results. There was some data at ASH a couple of years ago that looked at – the American Society of Hematology and ASCOs had similar reports – that looked at how do we do in academic centers versus community practice for keeping people on therapy. And on average, people were more likely to get six cycles of therapy instead of three cycles of therapy with azacitidine venetoclax at an academic center. Now, maybe it's different patients and maybe they had different cytogenetics and so on, but I think you have to be patient, I think you have to collaborate. But you can treat those patients in the community as long as you've got the infrastructure in place. And we've learned with virtual medicine, with Zoom and other platforms that we can deliver virtual care more effectively with the pandemic and beyond. So I think we're trying to offer virtual consults or virtual support for patients so they can stay in their home, stay in their community, stay with their oncologists, but still get access to excellent diagnostics and supportive care and transplant consults, and so on. I hope that's a reasonable answer to that question. It's a bit of a nuanced answer, which is, I think there's an important role of a leukemia center, and I think there's a really fundamental role of keeping somebody in the community they live in, and how we collaborate is the key to that. And we've spent a lot of time and effort working with the oncologists in our community to try to accomplish that. John, I want to say two other things. I didn't mention in the molecular platforms that NPM1 mutations, we can now target those on clinical trials with menin inhibitors. We know that NPM1 signals through the Hoxa9/Meis1 pathway. We know that similar pathways are important in KMT2A rearrangements. We know that there are some other rare leukemias like those with NUP98 rearrangement. We can target those with menin inhibitors. The first menin inhibitor, revuminib, was approved by the FDA for KMT2A. We have others going to the FDA later this year for NPM1. There are now pivotal trials and advanced expanded phase 1/2 studies that are showing 30% response rates. And we're looking to see can we add those into the first-line therapy. So, we're finding more targets. I'll say one last thing about molecular medicine. I know I'm a little off topic here, but I always told patients that getting AML was kind of like being struck by lightning. It's not something you did. Now, obviously, there are risk factors for AML, smoking or obesity or certain farm environments, or radioactive exposures and so on. But bit by bit, we're starting to learn about who's predisposed to AML genetically. We've identified really just in the last five or eight years that DDX41 mutations can be germline half the time. And you always think germline mutations are going to cause AML in a younger patient, but the median age is 60 to 70 just like other AMLs. They actually might do pretty well once they get AML. We've reported that in several papers. And so we're trying to understand who that has a RUNX1 mutation needs germline testing, who with a DDX41 needs germline testing. And we're trying to actually come up with a cleaner pathway for germline testing in patients to really understand predisposition, to help with donor selection, to help with family counseling. So I think those are other areas where a leukemia center can contribute for somebody in who's community practice to understand genomic or genetic complexity in these patients. And we're starting to develop the databases that support that. Dr. John Sweetenham: Yeah, great. Thanks, James. I loved your answer about the clinical environment too. And I know from a patient-centric perspective that I know that patients would certainly appreciate the fact that we're in a situation now where the folks taking care of them will make every effort to keep them close to home if they possibly can. I want to thank you, James, for an incredible review of a very complex subject and I think you did a great job. I think we all will have learned a lot. And thanks again for being willing to share your insights with us today on the ASCO Daily News Podcast. Dr. James Foran: John, it's my pleasure. And as you know, I'll do anything for a latte, so no problem at all. Dr. John Sweetenham: Okay. I owe you one, so thank you for that. And thank you to our listeners for your time today. You'll find links to the studies we've discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. 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. Find out more about today's speakers: Dr. John Sweetenham Dr. James Foran Follow ASCO on social media: @ASCO on Twitter ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. John Sweetenham: No relationships to disclose Dr. James Foran: Stock and Other Ownership Interests: Aurinia Pharmaceuticals Consulting or Advisory Role: Peerview, CTI BioPharma Corp, Remix Therapeutics, Cardinal Health, Medscape, Syndax, Autolus Therapeutics Research Funding (Inst.): Chordia Therapeutics, Abbvie, Actinium Pharmaceuticals, Kura Oncology, Sellas Life Sciences, Novartis, Roivant, Celgene/Bristol-Myers Squibb, Astellas Pharma, SERVIER Travel, Accommodations, Expenses: Peerview
Is there a way to treat liver metastasis secondary to uveal melanoma without introducing systemic, treatment-related toxicity? Dr. Altan Ahmed (interventional radiologist at Moffitt Cancer Center) and Dr. Sid Padia (interventional radiologist at UCLA) join guest-host Dr. Kavi Krishnasamy to discuss HEPZATO, a novel device-based treatment for liver metastases from uveal melanoma. --- This podcast is supported by: RADPAD® Radiation Protection https://www.radpad.com/ --- SYNPOSIS Dr. Ahmed and Dr. Padia begin by exploring the design and setup of the HEPZATO clinical trials, while also speaking on patient selection criteria. The doctors then talk through the technical aspects of the intervention. After covering workflow and considerations related to procedure timing and coordination, the doctors go on to discuss drug dosing and optimizing treatment cycles. The episode concludes with current gaps in literature, current and future research aims, and potential future applications of the HEPZATO modality in treating other malignancies such as colorectal cancer. --- TIMESTAMPS 00:00 - Introduction 05:40 - Patient Selection Criteria 09:49 - Workflow 19:17 - Procedure Timing and Coordination 29:39 - Challenges and Considerations in Drug Dosing 32:39 - Optimizing Treatment Cycles and Patient Response 37:56 - Managing Post-Treatment and Adverse Effects 43:43 - Future Research and Gaps in Current Interventions 50:45 - Exploring New Applications for PHP Therapy 55:02 - Conclusion --- RESOURCES Hepzato: https://hepzatokit.com/ FOCUS Trial - Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study: https://pubmed.ncbi.nlm.nih.gov/38704501/ FOCUS phase 3 trial results: Percutaneous hepatic perfusion (PHP) with melphalan for patients with ocular melanoma liver metastases (PHP-OCM-301/301A): https://ascopubs.org/doi/pdf/10.1200/JCO.2022.40.16_suppl.9510 Combining Melphalan Percutaneous Hepatic Perfusion with Ipilimumab Plus Nivolumab in Advanced Uveal Melanoma: First Safety and Efficacy Data from the Phase Ib Part of the Chopin Trial: https://pubmed.ncbi.nlm.nih.gov/36624292/ Troponin Elevation in Patients Undergoing Percutaneous Hepatic Perfusion for Metastatic Uveal Melanoma: https://pmc.ncbi.nlm.nih.gov/articles/PMC11010739/ Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study: https://pmc.ncbi.nlm.nih.gov/articles/PMC7801354/ Southampton group - Quality of life after melphalan percutaneous hepatic perfusion for patients with metastatic uveal melanoma: https://pmc.ncbi.nlm.nih.gov/articles/PMC10906212/ Leiden group - Quality of Life Analysis of Patients Treated with Percutaneous Hepatic Perfusion for Uveal Melanoma Liver Metastases: https://pubmed.ncbi.nlm.nih.gov/38587534/
Dr. Jyoti Patel is back on the podcast to discuss the updates to the living guideline on therapy for stage IV NSCLC with driver alterations. She shares updated recommendations in the first- and second-line settings for patients with stage IV NSCLC and classical EGFR mutations, and the impact of these updates for clinicians and patients. We also look to the future to discuss ongoing developments in the field. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02785 Brittany Harvey: Welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Patel. Dr. Jyoti Patel: Thanks so much. Happy to be here. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline and in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this update, Dr. Patel, this clinical practice guideline for systemic therapy for patients with stage IV non small cell lung cancer with driver alterations is living, meaning that it's continuously reviewed and updated. So what data prompted this latest change to the recommendations? Dr. Jyoti Patel: Thanks so much. So it's really been an exciting time in the treatment of EGFR lung cancer, particularly this past year has required us to rethink approaches to front- and second-line therapy. In this particular update, we examined what patients in the front-line setting may be offered by their clinicians. And so we're talking about the population of classical EGFR mutations, so exon 19 and exon 21 L858R substitution. And so certainly for this population, osimertinib has a high level of evidence and should be offered to all patients at the time of diagnosis when they present with advanced disease. Our last update included a recommendation that patients could also get platinum doublet chemotherapy with osimertinib or osimertinib alone. This current recommendation also introduces another alternative therapy and that's the combination of amivantamab plus lazertinib. And so now, clinicians are faced with three really good options for their patients with EGFR exon19 deletion or L858R. Brittany Harvey: It's great to hear that there's this advance in the space, particularly for patients with these classical EGFR mutations that you mentioned. So what should clinicians know as they implement these new first-line recommendations? Dr. Jyoti Patel: I think it's become more complex than ever. Certainly, we know again that patients should get osimertinib in the frontline setting. But we've been kind of stuck at progression-free survival that's between a year and a half and two years. And so we've really been looking at opportunities to intensify therapy. So one could certainly be with chemotherapy or switching over to amivantamab, the bispecific antibody that targets EGFR and MET plus lazertinib, an oral TKI that's very similar in structure to osimertinib. And when you're talking to a patient, it's really a conversation about balancing efficacy with toxicity. Unfortunately, as we know, there aren't that many free lunches. And so if we think about what a patient is hoping for in their therapy and how we can further personalize treatment options, really is important to look at some of the analyses for this study. So in the study of amivantamab plus lazertinib, we know that there were increased toxicities with a combination of both therapies. In fact, up to 75% of patients had over grade 3 toxicities, versus about 43% of patients with osimertinib monotherapy. And we know if we look back at FLAURA2, almost two thirds of patients with osimertinib and chemotherapy had grade 3 toxicities, compared to 27% of patients with osimertinib alone. So we certainly see an increase in toxicities. Then we have to ask ourselves, are those paper toxicities or ones that really impact patients? And we know that amivantamab, for example, causes significant cutaneous toxicities. With both of these therapies, whether it's chemotherapy or adding amivantamab, there's the burden of infusional visits and increased time in the doctor's office. Certainly with chemotherapy, there can be an increased incidence of myelosuppression. And so when we're thinking about advising our patients, certainly we need to talk about the toxicities. But one thing that we've been able to do is to look at the patients that were included in this trial. And what we really find is that in higher risk cohorts, particularly those that we know historically have done less well with standard osimertinib, so patients, for example, with CNS metastasis, for those patients with co-mutations, it may be that that additive benefit is significant. And so one example I think would be from the MARIPOSA study, again, the study of amivantamab and lazertinib versus chemotherapy. What we can say is that patients who had co-mutations, so patients with EGFR mutations as well as TP53, lazertinib and amivantamab led to a hazard ratio of 0.65 compared to osimertinib alone. So that was 18.2 months versus 12.9 months. And so this may be really important to patients. And we also see conversely that patients with wild type TP53, so those patients who didn't have the mutation, probably had equivalent survival regardless of therapy. So certainly, we need to prospectively study some of these high-risk cohorts. We've only seen progression-free survival in these studies. And so at this juncture, we can advise our patients about toxicity, the improvements in certain categories of progression-free survival, but we really still don't know how this pans out in overall survival. In many of these studies, all patients do not necessarily cross over to the study arm and so they may have lost the benefit of subsequent therapy. Brittany Harvey: Absolutely. It's very important to talk about that balance of benefits and risks and particularly those toxicities that you discussed. So I appreciate reviewing that recommendation and the considerations for clinicians for first-line therapy. This update also included a second-line treatment update. What is that update for patients with EGFR alterations? Dr. Jyoti Patel: So this is where it gets super tricky because we have a frontline option with amivantamab and now we've had an update in the second line option. So what we said is that for patients who have progressed on an EGFR TKI, and in the United States, certainly that's predominantly osimertinib, or those in other parts of the world that may have gotten an earlier generation TKI, but do not have evidence of T790M or other targetable mutations, we can offer patients chemotherapy with or without amivantamab. And so certainly we have seen that this again leads to improved survival. There have also been a number of studies looking at incorporation of PD-L1 and anti-VEGF therapies. And what we can say, I think pretty clearly is that multiple phase 3 trials have really shown no benefit of the addition of PD-1 to platinum chemotherapy. But there are some emerging bispecific antibodies that may target PD-1 as well as VEGF, or combinations of antibodies that target both of those pathways that may improve outcome. At this juncture, I think we feel that the evidence surrounding chemotherapy plus amivantamab is strongest, but there is certainly work in this space that will be of interest. Now, what happens if your patient received amivantamab and lazertinib in the frontline setting and then has progression? And so we're trying to understand resistance mechanisms and opportunities for treatment. What the panel decided to recommend, based on the available evidence, was that certainly those patients should get platinum-based chemotherapy, but there may also be a role for antivascular endothelial growth factor targeting therapy such as bevacizumab in patients in whom it would be safe. Brittany Harvey: Great. I appreciate you detailing those recommendations when it gets complicated in the second-line setting. So what should clinicians know as they implement these second-line recommendations too? Dr. Jyoti Patel: So certainly the frontline setting matters significantly. So if a patient gets osimertinib in the frontline setting, we generally suggest that patients undergo repeat testing to see if they have another targetable mutation. If they don't, then I think preferred therapy would be chemotherapy with or without amivantamab. And amivantamab leads to a significant improvement in progression-free survival and response rate at the cost of increased risk of toxicity. For patients who get FLAURA2 in the frontline setting, chemotherapy plus osimertinib, it's a little bit of an unclear space. Those patients most likely would get docetaxel with or without ramucirumab. But there are other agents that we hope to have available to our patients in the near future. For patients who receive amivantamab and osimertinib, we recommend that those patients get chemotherapy probably with anti-VEGF as demonstrated by multiple trials that have shown the improved progression-free survival with introduction of an anti-VEGF agent. And we've seen evidence of amivantamab in the third line setting, so it is likely that this question about sequencing really takes center stage in our next set of trials. When you're talking to a patient, I think again, it's absolutely important to discuss: What are their goals? How symptomatic or how fast is their progression? Are there ways in which patients may benefit from spot treatment oligoprogression such as radiation? When is the right time for introduction of amivantamab and when do we think patients need chemotherapy? Is it up front or predominantly in the second-line setting? Brittany Harvey: Definitely. And then you've just touched on the goals of treatment for individual patients. So in your view, what does this update mean for patients with stage IV non-small cell lung cancer and an EGFR alteration? Dr. Jyoti Patel: For patients, this is a time in which shared decision making really needs to take center stage. So our best patients are those patients that are best informed not only about their disease but also have a good understanding about what is important to them and their families in terms of care. And so bringing that shared understanding to the table again helps us think about this particular cancer as more of a journey rather than just a one off treatment. Therapy will hopefully be prolonged, and so it's absolutely important that we address toxicities, make therapies more tolerable, again, with the shared goal of living long and living well. Brittany Harvey: Absolutely. Those are key points to making sure that patients are living both longer and have a good quality of life during that time as well. So then, before you mentioned the possibility of future sequencing trials and other ongoing developments. What additional studies or future directions is the panel examining for future updates to this living guideline? Dr. Jyoti Patel: So certainly we're thinking about trials that look at, for example, cfDNA clearance. So are there patients that do well and can we detect that early on without having to intensify therapy on day 1 so it may be that we add chemotherapy a little bit later. I think really exciting are some of the new bispecific. The HARMONi-A trial was a trial in China of a novel bispecific, ivonescimab. And this drug targets both PD-1 and VEGF and it was combined with chemotherapy. And this trial found almost a doubling of progression-free survival with this drug in combination chemotherapy in an EGFR patient population. That study is being planned and being run in the United States to see if we have similar outcomes with a more diverse population. So certainly that's exciting. There are a number of antibody drug conjugates that are being studied in the post-chemotherapy setting as well. And I think we'll likely soon see a better understanding of what co-mutations and burden of disease really mean when we're thinking about assigning treatment. So which patients, again, need intensification of therapy and which patients may do really well on just an oral agent that they're taking at home with more tolerable toxicity than dual treatment. Brittany Harvey: Yes, we'll look forward to continued developments in these fields and seeing some of those studies come to fruition. So with that, I want to thank you for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Patel. Dr. Jyoti Patel: Thanks so much, Brittany. It's really an exciting time for lung cancer and we hope that these updates really help physicians decide the best treatments for their patients. Again, it's a rapidly evolving landscape which is fantastic, but it does become more cumbersome to stay ahead of the literature. Brittany Harvey: Definitely. And so we appreciate your time and the panel's time spent reviewing this literature and providing this much needed information to clinicians everywhere. So finally, thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Dr. Lyudmila Bazhenova joins us again to share the newest changes to the living guideline on therapy for stage IV NSCLC without driver alterations. She discusses new evidence reviewed by the panel and changes to second-line recommendations for patients with good performance status and HER2 overexpression, and what these updates mean in practice. We discuss ongoing evidence generation as we await further updates to these living guidelines. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02786 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on “Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It's my pleasure to be here as always. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline panel, including Dr. Bazhenova, who has joined us here today, are available online with the publication of the guide in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, first, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations has frequent updates to the recommendations. What prompted this latest update? Dr. Lyudmila Bazhenova: Living ASCO guidelines are created to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. As a committee, we review published literature on a specific topic at the regular intervals and determine if it alters any recommendations. This time, upon our literature review, we felt that there are new data that requires an update in the guidelines and therefore the guidelines were updated. Brittany Harvey: Great. Thank you for that updated information. So then it looks like the panel updated recommendations for second line and subsequent treatment options for patients with good performance status and HER2 overexpression. What is that updated recommendation from the panel? Dr. Lyudmila Bazhenova: Yes, this is correct. We now added an extra recommendation for patients with stage IV non-small cell lung cancer who have overexpression of the protein called HER2. HER2 overexpression with 2+/3+ level via immunohistochemistry is seen in approximately 8% to 20% of patients with lung cancer. And the data behind our recommendation comes from the DESTINY-Lung01 trial where patients with HER2 overexpression were treated with trastuzumab deruxtecan. And we saw that if patients with stage IV non-small cell lung cancer had a HER2 IHC score of 3+, overall response rate was seen at 53% and median duration of response was 6.9 months and, therefore, that in our opinion qualified for updated recommendation. We are still waiting for additional results that will be released later on another clinical trial where we see preliminary data presented at the World Conference of Lung Cancer in 2024. They looked at 36 patients also with HER2 overexpression and saw the overall response rate of almost 45%. It is important to highlight in this smaller study that a majority of the patients in the study were actually having EGFR mutation and the response rate in those patients who had an EGFR mutation was higher than the response rate in patients without EGFR mutations who just had a HER2 overexpression. So for now this is updated in the guidelines, but we will wait for additional data or formal publication of a World Lung Conference presentation and see if those recommendations need to be changed. Brittany Harvey: Understood, and I appreciate you providing the context of some of those ongoing developments as well. So then what should clinicians know as they implement this updated recommendation? Dr. Lyudmila Bazhenova: Number one, we should all start from remembering to test for HER2 via immunohistochemistry. There is a slight difference in what considers HER2 positive in lung versus breast. In lung, we use what's called the gastric scoring and the difference is the circumferential versus non circumferential staining of the membrane. And number two, immunohistochemistry is not always included in next generation sequencing panels. So when you order your next generation sequencing, I think it's important to know if your company that you're using is testing for HER2 via immunohistochemistry. And if it's not, make sure that you find a company that does or work with your local pathology department to make sure that this testing is offered. It is also important to know the difference between HER2 overexpression and HER2 exon 20 insertion mutation even though the treatment for those two abnormalities is the same, which is trastuzumab deruxtecan. But the benefit that you can cite your patients and the rigor of the literature supporting the usage of trastuzumab deruxtecan in mutation versus overexpression is different. Brittany Harvey: Yes. And as you mentioned, it's essential that, in the first place, patients are actually receiving the testing so that we know if they're eligible for these treatment options. So what additionally does this change mean for patients with stage IV non-small cell lung cancer and HER2 overexpression? Dr. Lyudmila Bazhenova: So for patients, it adds another treatment modality which is now FDA approved. So if there are patients listening to me, make sure that your physician has tested your tumor for HER2 overexpression. So I think proactive asking of your physician would be very appropriate in this situation. Brittany Harvey: Absolutely. And then earlier you mentioned an ongoing trial that the panel was looking to for the future. But what other additional trials did the panel review during this guideline update and what is the panel examining for future updates to this living guideline? Dr. Lyudmila Bazhenova: So at this point we reviewed three additional studies. The results of those studies did not make it into a change in guidelines. So we reviewed the HARMONi-2 trial. HARMONi-2 trial so far does not have an official publication and, as per our strategy on how we come up with ASCO guidelines, we need to wait for an official publication. So this is one thing we're going to be expecting in the future. Once this is published, we will review it and decide if we need to make an additional change in recommendations. For those of you who are not aware, HARMONi-2 trial used bispecific monoclonal antibody against VEGF and PD-1 and was a phase III randomized trial comparing their investigational product which is called ivonescimab over pembrolizumab for patients with PD-L1 more than 50. And again, we are waiting for the final publication to make our recommendation. The second trial we reviewed was a LUNAR trial and the LUNAR trial looked at addition of tumor treating fields to chemotherapy or immunotherapy in patients whose cancer progressed with platinum doublet. The key point about this study is that immunotherapy was not required to be administered in a first line setting which is a current standard of care in the United States. And even though the study met their primary endpoint of overall survival, there were more benefits in patients who were immunotherapy naive in the second line. And we felt that given the potential lifestyle implication of wearing a device for 18 hours per day, and the lack of evidence in immunotherapy-pretreated population, and the absence of data in the first-line setting where we currently using immunotherapy in the United States, we felt that there is insufficient data to definitely recommend addition of tumor treating fields to systemic chemotherapy for most patients. And we are waiting for additional trials that are ongoing in this setting to formalize or change our recommendations. And we also reviewed- the final study that we reviewed was TROPION-Lung01. TROPION-Lung01 study was a phase III study in post platinum doublet setting which compared efficacy of Dato-DXd and docetaxel and trials showed improvement in progression free survival but not in overall survival. And progression free survival benefit was more pronounced in non-squamous carcinoma histology subgroup and we felt that the results do appear promising, but the strength of evidence which was based on unplanned subgroup analysis was not sufficient enough to make a change in treatment recommendation at this time. Brittany Harvey: I appreciate your transparency on why some of that data did not prompt a change to recommendations at this time. And additionally, we'll look forward to those future published results and potential incorporation of new data into future versions of this living guideline. So, I want to thank you so much for your work to rapidly and continuously update this guideline and for your time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It is my pleasure. Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
In a conversation with CancerNetwork®, Marwan G. Fakih, MD, spoke about the FDA approval of sotorasib (Lumakras) plus panitumumab (Vectibix), and how it may affect the treatment paradigm for patients with KRAS G12C-mutant metastatic colorectal cancer (CRC). Fakih is a professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of GI Medical Oncology, and co-director of the Gastrointestinal Cancer Program at City of Hope Comprehensive Cancer Center in Duarte, California. According to Fakih, the approval of this combination regimen is a “welcome step” for those with metastatic CRC harboring KRAS G12C mutations. Based on supporting data from the phase 3 CodeBreaK 300 trial (NCT05198934), sotorasib/panitumumab may prolong progression-free survival (PFS) and reduce disease burden in patients while offering improvements in other outcomes vs prior standards of care (SOC) like trifluridine/tipiracil (Lonsurf) and regorafenib (Stivarga). Topline data at the time of the approval showed a median PFS of 5.6 months (95% CI, 4.2-6.3) with sotorasib at 960 mg plus panitumumab vs 2.0 months (95% CI, 1.9-3.9) in the SOC arm, in which patients were assigned to receive trifluridine/tipiracil or regorafenib (HR, 0.48; 95% CI, 0.30-0.78; P = .005). Additionally, the overall response rate was 26% (95% CI, 15%-40%) vs 0% (95% CI, 0%-7%) in each respective arm. Looking ahead, Fakih highlighted the potential next steps for research associated with the sotorasib combination as well as other novel therapeutic strategies in the gastrointestinal cancer space. For example, he described the phase 3 CodeBreaK 301 study (NCT06252649), which will evaluate sotorasib/panitumumab as frontline therapy when administered in combination with folinic acid, fluorouracil, and irinotecan (FOLFIRI) vs FOLFIRI plus bevacizumab (Avastin) in metastatic KRAS G12C-mutant CRC. Other novel agents under development in the space include RAS inhibitors and immunotherapy regimens combining CTLA-4 inhibitors with anti–PD-L1 agents. References 1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. News release. FDA. January 16, 2025. Accessed February 12, 2025. https://shorturl.at/1WviB 2. Kim TW, Price T, Grasselli J, et al. A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with KRAS G12C–mutated metastatic colorectal cancer (CodeBreaK 301). J Clin Oncol. 2025;43(suppl 4):TPS326. doi:10.1200/JCO.2025.43.4_suppl.TPS326
Host Dr. Shannon Westin and guests Dr. Bill Aronson discuss the article "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial" and how Omega-6 are predominant in the American diet while the study significantly lowered the intake of Omega- 6 fats. TRANSCRIPT Dr. Shannon Westin: Hello everyone and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, GYN Oncologist by trade and one of the grateful Social Media Editors of the JCO. And I am very excited to welcome a special guest today, Dr. William Aronson. He is professor of Urology in the UCLA Department of Urology, the Chief of Urology at Olive View UCLA Medical Center, and Chief of Urologic Oncology at the Veterans Administration West Los Angeles. Welcome, Dr. Aronson. Dr. William Aronson: Thank you, Shannon, and delighted to be here. Dr. Shannon Westin: We are so excited to have you discussing your manuscript, “High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial,” which was published in the Journal of Clinical Oncology on December 13, 2024. So let's get right to it. First of all, you know we have a very mixed audience, so can you just level set for us and speak about the population you studied in this important trial - that low risk, favorable, intermediate risk prostate cancer. How common is that? How is it defined? That would really help. Dr. William Aronson: I would say about 50% of the patients that we diagnose with prostate cancer either have low risk disease or what we call favorable intermediate risk disease. So when the pathologists look at the cancer under the microscope, they assign what's called a Gleason grade. Grade 3 is the slower growing type of prostate cancer, grade 5 is the fastest growing type, and grade 4 is somewhere in between. So a low risk group would be only the grade 3, the slower growing type. And the favorable intermediate risk group would actually be the grade 3+4, which means they mostly see the low risk type in there, but they also see the slightly faster growing type, grade 4. So this is what we typically see. We see these patients on a very regular basis when they're newly diagnosed with prostate cancer. Dr. Shannon Westin: Okay, got it. And then can you walk us through just what the management options are typically for this patient population? Dr. William Aronson: So typically for what we call the low risk group, the patients with a low PSA and only that grade 3 type, slower growing type of prostate cancer, the standard recommendations are active surveillance. So typically, we'll periodically monitor these patients with PSA blood testing and periodically do prostate biopsies depending upon the patient's other medical problems. Dr. Shannon Westin: So I think it would also be really helpful just to understand what your typical management options are for this patient population. Dr. William Aronson: So for patients with low risk prostate cancer, they only have the Gleason Grade 3+3 with a low PSA. The standard practice is observation. And so these men will periodically see them and measure their PSA values. And periodically, they'll undergo prostate biopsy to make sure they're not getting progression of their disease. For men with favorable intermediate risk prostate cancer, that's a little different. In some practices, the patient and the urologist will decide to do active surveillance. In other scenarios, these patients will definitely elect treatment, either with radical prostatectomy or radiation therapy or other treatments that are available. Dr. Shannon Westin: So your manuscript notes that there was a high level of interest in dietary supplements and approaches among patients with prostate cancer that do elect for active surveillance. Prior to the results of CAPFISH-3, did we have any data to support those types of recommendations? Dr. William Aronson: We actually don't have any long term prospective randomized trials that support that recommendation. There have been a number of very interesting epidemiologic studies, for example, suggesting maybe a plant-based diet might be helpful. Or a number of other studies suggesting maybe more tomato-based products like tomato sauces or tomato paste may be helpful. But no prospective longer term randomized trials that were positive. Dr. Shannon Westin: Okay, that makes sense. So what led you all to explore the high omega-3, low omega-6 fatty acid diet in this trial? Dr. William Aronson: After our initial omega-6 studies, we subsequently did some studies where we raised the omega-3 from fish oil and lowered the 6, looking at a more favorable ratio of the omega-3 to omega-6. And once again, we found that in our animal models, there was a significant delay in progression of prostate cancer. That then led us to perform a clinical trial. It was a short term trial in men prior to undergoing radical prostatectomy. And in these men, they were randomly assigned to one of two groups, either a western high fat diet or a low fat diet with fish oil. And we found after just four to six weeks, a significant change in the Ki67 level in their radical prostatectomy tissue. And Ki67 is actually a strong indicator of prostate cancer progression, spread, or even death from prostate cancer. Dr. Shannon Westin: Well, and I think that leads us really nicely into the design of the current study. So why don't you walk us through how CAPFISH-3 was designed. And you've already spoken a little bit about your primary endpoint. Dr. William Aronson: Based on the results of what we saw in the lab and what we saw in our short term clinical trial, we decided to perform a one year trial, a longer term trial in men on active surveillance. And these men were randomly assigned to either a diet with slight reduction in dietary fat, specifically reduction in the omega-6 intake as well as increase in foods with omega-3 and fish oil capsules. The other group, we asked the men to just not take fish oil capsules, but they could eat whatever else they wanted during the course of the study. Men in the diet where we lowered the omega-6 and raised the omega-3, they were seen by a dietitian once a month to really ensure that they were compliant with that intervention, which they were. The other intriguing part of our study, which I think is super important, is the precision that was used when these men underwent prostate biopsy. So, at baseline and at one year, when these men underwent prostate biopsy, they had the same site within the prostate biopsied. That's important because it's not so easy to find the same site within the prostate because of heterogeneity throughout the prostate. And so we were able to obtain that high level of precision as they were in an active surveillance program at UCLA with Dr. Leonard Marks. Dr. Shannon Westin: So we spoke a little bit about what's important about the Ki67 index as your primary endpoint. Can you talk a little bit about what the study found with your intervention? Dr. William Aronson: So we found that the Ki67 index increased by 24% in the control group and decreased by 15% in the low omega-6, high omega-3 group with fish oil capsules. So that ended up resulting in a statistically significant change between the groups favoring the low omega-6, high omega-3 group. Dr. Shannon Westin: And then what were the secondary endpoints that CAPFISH-3 explored? Anything of note that you want to review for the listeners? Dr. William Aronson: So a number of positive secondary endpoints from the trial. Firstly, we saw that the triglyceride levels were lower, which is what can typically be seen with omega-3 intake. We also saw reduced levels of a cytokine, a circulating factor in the bloodstream called ‘macrophage colony stimulating factor'. And that's particularly interesting because there's a certain type of macrophage which is well known to be involved in prostate cancer progression in men with more advanced prostate cancer, and we've been able to inhibit that in our animal models and in our tissue culture studies. And it was especially interesting to see that we did have an effect on this particular cytokine in this prospective randomized trial. We did not see changes in a number of other measures, including Gleason grade or PSA. These are measures that we use in clinical practice. To see an effect on those would have required a longer term and larger study to be performed. Dr. Shannon Westin: That makes sense. I think it's always great to try to get as much of these types of translational data as we can. But sometimes you just have to do what is reasonable and you get what you get. It looks to me like this regimen was fairly well tolerated. Did you obtain any patient reported outcomes or feedback on the trial? Dr. William Aronson: So, there were four patients in the fish oil group that did have some side effects, and we withdrew them from the study. They did have some effects on their upset stomach, and a number of men also had some diarrhea as well. And so for those four patients, we did withdraw them from the study. Dr. Shannon Westin: And then I guess the last question I have is really, what's next for this intervention? Are we ready to move this to the clinic or what do you see as next steps? Dr. William Aronson: Well, this next step that we're working on right now is to better understand exactly what happened in these patients. So we have blood, we have tissue, we're doing genetic studies on these patients. So that's really the first step, in our mind, to better understand what happened before moving to the next step. I'm particularly intrigued about trying this intervention in men with more advanced prostate cancer, specifically because of what we see, this particular diet and how it's affecting the patient's immune system and how that may favorably affect their course of their prostate cancer. Dr. Shannon Westin: Well, great. Well, thank you so much for taking the time to chat with us about such an important clinical trial, and I really appreciate all the work you're doing and hope to get to see you soon. Dr. William Aronson: Well, thanks for having me, Shannon. It's really an exciting finding and I think it's something that clinicians and patients are going to be super interested in. Dr. Shannon Westin: We love straightforward interventions that actually make a difference, so you guys are to be congratulated for that. And I just want to thank all of you for listening. Thanks again, and I hope you enjoyed this episode of JCO After Hours. Be sure to check out our other podcast offerings wherever you get your podcasts. Have an awesome day. 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. Aronson Disclosures: Stock and Other Ownership Interests Johnson and Johnson Speakers' Bureau Company name: Janssen Oncology, Bayer, Blue Earth Diagnostics, AstraZeneca, Pfizer/Astellas Research Funding: Lantheus Medical Imaging UCLA Health Article Video
Bispecific antibodies (BsAbs) have the potential to transform cancer treatment and are being actively integrated into community oncology practices. To support oncology practices as they introduce BsAbs into their treatment protocols, the Association of Cancer Care Centers (ACCC) has developed a comprehensive blueprint for this process. This resource highlights key strategies, best practices, and considerations for successful implementation. It gives guidance on capacity building, care coordination, and adverse event management, reflecting ACCC's commitment to providing education and expanding access to this innovative treatment for patients with cancer. In this episode, CANCER BUZZ speaks with Donald Moore, PharmD, clinical oncology pharmacy manager at Atrium Health Levine Cancer, about the role of bispecific antibodies in oncology care and unique challenges associated with interdisciplinary collaboration. Dr Moore also discusses how the new Blueprint is designed to empower cancer practices to optimize the rollout of these innovative therapies. “I think that the blueprint really nicely describes and delineates some high-level roles and responsibilities of a community academic partnership and how both sites can collaborate to deliver care to their patients” – Donald Moore “Ultimately, my hope is that the blueprint, along with some of the additional resources provided with it, will be helpful in bringing these new therapies closer to home for all of our patients... improving the access to care for this emerging drug class.” – Donald Moore Donald Moore, PharmD, BCPS, BCOP, DPLA, FCCP Clinical Oncology Pharmacy Manager Division of Pharmacy Atrium Health Levine Cancer Charlotte, NC Resources: ACCC Best Practices for Expanding Access to BsAbs - https://www.accc-cancer.org/home/learn/precision-medicine/treatment/bispecific-antibodies/best-practices-bispecific-antibodies ACCC Operational Insights in Delivery of BsAbs - https://www.accc-cancer.org/home/learn/precision-medicine/treatment/bispecific-antibodies/bispecific-antibodies-in-solid-tumors ASCO Use of BsAbs in Community Practices - https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e13575 AJMC Obstacles to Optimal Transition Between Academic and Community Centers - https://www.ajmc.com/view/obstacles-to-optimal-transitions-of-care-between-academic-and-community-settings-when-utilizing-bispecific-antibodies ASH Multidisciplinary Provider Insights for Promotion of BsAbs in the Community - https://ashpublications.org/blood/article/138/Supplement%201/4033/481457/Multidisciplinary-Provider-Insights-to-Promote
Dr. Chris Holsinger shares the new guideline from ASCO on transoral robotic surgery (TORS) for patients with oropharyngeal squamous cell carcinoma. He reviews the evidence-based recommendations on baseline assessment, the role of TORS in HPV-positive and HPV-negative disease and in the salvage/recurrent setting, which patients are eligible or ineligible for TORS, and the role of adjuvant therapy. He discusses the importance of multidisciplinary collaboration and shared decision-making between patients and their clinicians. Read the full guideline, “Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline.” TRANSCRIPT This guideline, clinical tools, and resources are available at asco.org. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Chris Holsinger from Stanford University, lead author on “Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline.” Thank you for being here today, Dr. Holsinger. Dr. Chris Holsinger: Thanks, Brittany. We've been working together for years on these guidelines and what a pleasure to get to meet you at least virtually today. Brittany Harvey: Yes, it's great to have you on. And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Holsinger, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So let's jump into this important guideline. Dr. Holsinger, to start us off, can you provide an overview of both the scope and purpose of this guideline? Dr. Chris Holsinger: Absolutely. And again, thanks for the opportunity to be here, Brittany. I appreciate the invitation to participate in the ASCO Guidelines and to work with the great people on this paper that's now out there. I think it's a really important guideline to be published because it really talks about surgery, specifically transoral robotic surgery, a minimally invasive technique, as a new way to treat head and neck cancer. Why that's so important is that what is now known as head and neck cancer is completely different than what we saw even 25 years ago. Around the turn of the century, some really thoughtful epidemiologists working at Hopkins and UW in Seattle started to see this connection between the human papillomavirus and head and neck cancer. And since then we've seen this precipitous rise in the number of throat cancers specifically due to HPV. The results from the American Cancer Society showed last year that head neck cancer, in particular these cancers of the oropharynx, actually were one of the few cancers that still had an increasing incidence, I think it was around 2.5% per year. And other studies have shown that almost 50% of the cases we're seeing across the United States now are actually HPV-mediated throat cancers. That's bad news because we're seeing this rise in cases, but it's good news in the sense that this is a cancer that is highly curable and I think opens up a lot of different treatment avenues that we didn't have a couple of decades ago. And when patients are facing a mortality risk that's two or three times lower than the formerly HPV-negative smoking-driven cancers, it really behooves us as clinicians, as oncologists to think about treatment selection in a completely different way. And for years, the only function-sparing option, surgery certainly was not, was radiation therapy with concurrent cisplatin chemotherapy. In 2009, the FDA approved the use of surgical robotics using a transoral approach, a minimally invasive approach to resect the primary tumors and to perform neck dissection. And so now when patients walk in the door, they not only have this gold standard option in the path of radiation therapy with chemo, but also frontline surgery. And with some recent publications, especially the ECOG 3311 study, there's some really good evidence that for HPV-mediated throat cancers, we can actually de-escalate the intensity of adjuvant therapy when we start with surgery first. So who we choose that option for, which patients want that option - these are all really important new questions that we try to grapple with in these guidelines. Brittany Harvey: That background is really key for setting the stage for what we're about to talk about today. And so next I'd like to review the key recommendations across the clinical questions that the panel addressed. So you just talked about the importance of treatment selection. So to start that off, first, what is recommended for baseline assessment for patients with oropharyngeal squamous cell carcinoma who are being considered for transoral robotic surgery? Dr. Chris Holsinger: So I think here we tried in the guidelines to really standardize the workup and approach of this disease, in general, but with a strong focus on who might be a good surgical candidate. As I mentioned in the introduction, I mean, this is a disease that is very new. Our workup is in flux. And so what we tried to do, especially in items 1.2 and 1.3, is to really standardize and confirm that the tumor that we're dealing with, which oftentimes presents in a metastatic lymph node, is in fact associated with the human papillomavirus. So how biopsy is done, how high risk HPV testing is performed, whether you're doing that with an in situ hybridization, a DNA based study, or a p16 immunohistochemical study. And we try to tackle these issues first to really make sure that the patient population we're considering is actually indeed eligible for this kind of treatment de-escalation with surgery. Brittany Harvey: Understood. So it's important to consider which patients could be eligible for TORS upfront. So what is the role of TORS in patients with HPV-positive oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: Yeah, exactly. So I think first of all, surgery is ideally suited, and the robot is FDA approved for early-stage cancers - T1 and T2 cancers that are amenable to a minimally invasive approach. And we really try to emphasize, especially in our patient selection section of the guideline, who is really an ideal candidate for this. It's not just the T1 and T2 tumor. It's a tumor that is lateralized so that we can maybe consider managing the neck concurrently just on the side of the tumor, rather than doing bilateral neck dissection for most patients. Which patients might get the best functional outcome is a really critical component of this. And in fact, that actually goes back to a guideline that we didn't have time to chat about earlier, which is that we think every head neck cancer patient, whether or not they're being considered for transoral robotic surgery or frontline radiation therapy with cisplatin, every patient should have a pre-treatment assessment by a speech and swallowing expert. They're called different names across the country: speech language pathologists, speech pathologists, etc. But having a really good functional assessment of the patient's ability to swallow before treatment selection is really critical. And why that's important with frontline surgery is that there's a period of about one or two weeks after which that patient really needs intensive rehabilitation. And so for every patient being considered by TORS, we want to work really hand in hand with that speech pathologist to do pre-habilitation and then immediate post-operative rehab and then long longitudinal rehabilitation so that if radiation is needed down the road in a month, that patient just hopefully sails through this de-escalated treatment that we're offering. Brittany Harvey: Great. I appreciate you describing which patients can be considered for transoral robotic surgery. So beyond that, which patients with HPV-positive oropharyngeal squamous cell carcinoma aren't really good candidates for TORS? Dr. Chris Holsinger: We talked about that sort of ideal patient, but you know, we're not always living in an ideal world. And so I think it's important, and I'm really happy about the multidisciplinary discussions that led to these final guidelines because I think it helped engage radiation oncologists, medical oncologists, and surgeons around who's maybe not a good candidate for this because radiation therapy, with or without cisplatin chemotherapy, remains a good option for many of these patients. But I think the consensus, especially among the surgeons in this group, were that patients with tumors were more endophytic - that's the old fashioned oncology and surgical oncology term that refers to tumors that seem to not be as evident on the surface and have more of an infiltrative deep growth pattern - these are not ideal tumors. Whereas an exophytic tumor that's growing upwards, that's more readily seen on flexible endoscopy during a routine clinic assessment, or frankly, better seen on imaging, those exophytic tumors are better suited to a surgical approach because the surgeon has a better chance when he or she sees the tumor to get a good margin. When we can appreciate not just the surface mucosal margins that need to be taken, but also have a better chance to appreciate their depth. And with those infiltrative tumors, it's much harder to really understand how to get that deep margin, which in many cases is always the hardest. And so that's a long way to say that surgical decision making, patient selection is really critical when it comes to offering TORS as a multidisciplinary group. And then there are a few other things that we can quickly talk about before we move on to discussing adjuvant therapy. But I think there are some relative contraindications to patients who might have tumors arising in a palatine tonsil or tonsillar pillar, but which might grow significantly into the soft palate, such that a major palatal resection would be needed to get a good margin. For T1 and T2 tumors, we're not sure that that is an ideal candidate. And the other relative contraindication, but it's a hard and fast contraindication in my personal practice, is patients with extensive nodal disease. I think a patient who has preoperative extranodal extension, matted nodes, clinically and on MRI, you know pre-op they're going to need intensive post operative concurrent chemoradiation post-op that's maybe not the best patient for TORS, although there are some select cases where that that might make sense. But that's a quick overview of patient selection for TORS, Brittany. Hopefully, that's helpful. Brittany Harvey: That's definitely helpful. I think it's really important to consider not only who is eligible, but who isn't eligible for this de-escalation of treatment, and I appreciate you clarifying some of that. So then you've just also mentioned adjuvant therapy along with multidisciplinary discussion. So what is recommended regarding adjuvant therapy for patients who have resected HPV-positive oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: Definitely. And I think the post-operative discussion has to begin with great pre-op planning. And pre-op planning is really anchored in a really robust multidisciplinary team. So, we spoke earlier about the critical importance of getting speech language pathology involved initially, but they're part of a much larger team that includes not just a surgeon, but medical oncologist, a radiation oncologist and a dental oncologist - all of these specialties, and I could think of several others if we had time to chat further - this should also be really engaged in the care of these patients. But great decision making regarding adjuvant therapy really begins with a robust multidisciplinary consultation pre-op and we try to emphasize that in the guidelines. But just to return and answer your question very directly, I think adjuvant therapy is really the critical piece in getting that great functional outcome for a patient with HPV-mediated throat cancer. And I think traditionally patients who have a variety of different risks, based on a large study done again by the ECOG group, ECOG 3311, we showed that by stratifying patients based on their surgical pathology rather than on an estimate of disease extent, we can better stratify adjuvant therapy. And so the low risk patient is a patient with good margins and of course, good margin, we could spend another two hours discussing that. But good margins are greater than at least 1 to 3 millimeters superficially and a clear deep margin. Patients with lymph node metastases that are less than 3 cm and a single lymph node can sometimes be observed but most patients don't fall into that low risk category. Most patients fall into an intermediate risk where the margin is good and it's clear, but it might be close. That depends if you're talking about the superficial mucosal margin or the deep. But more often than not, we spend a lot of time considering the extent of lymph node involvement as it pertains to how adjuvant therapy is delivered. And I think for patients with less than 4 lymph nodes traditionally without extranodal extension, radiation therapy will suffice for adjuvant therapy after TORS. And the question of dose then comes up. Are we talking 50 Gray, the experimental arm that showed real promise in the ECOG 3311 trial, or 60 Gray or more traditional dose? And that is a topic definitely for another podcast, which we should do with a radiation oncologist online. I don't want to get into the weeds with that, but I refer you to our guidelines and Bob Ferris and Barbara Burtness' paper from JCO in 2021 for further details about that. But then for patients with positive margins with more than four lymph nodes, but especially patients with extranodal extension, the role of radiation therapy and chemotherapy is really absolutely critical. Because these patients and while they only accounted for around 20% to 30% of patients that we're seeing in this new era of TORS, they're the ones that we're really focusing on how can we do better because their overall survival is still good, it's 90%, but it's not as good as the patients we're seeing with a low and intermediate risk. So that's a brief overview there. Brittany Harvey: I appreciate that overview. And yes, we'll refer listeners to the full guideline, which is linked in the show notes of this episode to learn more about the intricacies of the radiation therapy that you mentioned. So then we've talked a lot about patients with HPV-positive disease, but what is the role of TORS in patients with HPV-negative disease? Dr. Chris Holsinger: I think TORS still has a role for these patients. Our colleague in India, Surender Dabas, has a really nice series that shows that for HPV-negative patients, this is a way for early stage cancers to potentially escalate the intensity of treatment for a disease that does worse than this new HPV-positive we're seeing in the US. So I think there's a good signal there. I think more study needs to be done and I think those studies, in fact, are underway in India and other countries. I hope that we can, as an oncology community here in the United States, also tackle this disease, which is still a significant part of the disease we face in head and neck oncology. Brittany Harvey: Yes, we'll look forward to more data coming out for HPV-negative disease. So then, the last clinical question that the guideline panel addressed: What is the role of TORS in the salvage or recurrent setting? Dr. Chris Holsinger: So we wrap up the guidelines tackling this topic. It's definitely something for the experienced TORS surgeon in consultation with that multidisciplinary team. Oftentimes, we are still seeing many patients who need salvage surgery and I think, while TORS alone could be a really effective treatment option, TORS with a microvascular reconstruction is oftentimes what is needed for these patients who, with recurrence, do often present with an RT 2, 3, 4 tumor. In my own practice, I found that using TORS as a way to minimize the superficial mucosal extent and then delivering that tumor through a traditional lateral pharyngotomy, then neck dissection and then having a microvascular flap inset done after that really provides the best possible chance for good long term function and of course control of the tumor. Here, I definitely refer the listener to some great work done out of the Royal Marsden with Vin Paleri, who we're happy to have on our TORS guideline panel for his RECUT study that really grapples in some detail with these very issues. Brittany Harvey: Excellent. And so we've covered a lot of the recommendations here that were made by the panel and you've touched a little bit about how this changes things for clinicians in practice. But what should clinicians know as they implement these new recommendations? Dr. Chris Holsinger: One thing as we close, I hope that in the future we can really start to grapple with this concept of patient selection. I think these guidelines help establish that TORS is a great oncologic option with - really the only option for treatment de-escalation in the here and now. Radiation therapy and cisplatin concurrent chemotherapy is going to be an option that is such an important choice for patients. And I think where I hope the field goes in the future is figuring out which patient wants one of these options. And I think certain patients really want that tumor taken out and others just the idea of surgery is not something that makes sense for them. How we in the context of a multidisciplinary team, really engage that patient, elicit their treatment preferences and then through considering treatment eligibility criteria that we've spelled out here for surgery and can be spelled out for chemo RT, bringing all that together in a formal shared decision making process is really where I hope the field will be going in the next few years. And hopefully these guidelines help to pave the way there. Brittany Harvey: Definitely the aspect of care by a multidisciplinary team and talking with patients to go through shared decision making is key to implementing these guidelines. So then, in that same vein, what do these recommendations mean for patients with oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: I think the central take home message for patients should be that especially if you have a T1 and T2 tumor, it's really important to have that consultation with a surgeon who knows how to do TORS and has a busy practice, but then also having an honest discussion up front about what the functional outcomes would be both with surgery and also chemo RT. And I think just knowing all those different options, that multidisciplinary treatment selection process is going to be that much more robust. And I think more right decisions will get made and we'll see less decisional regret down the road, which I think is a long term goal of our field. Brittany Harvey: Absolutely. That discussion of preferences is key. So then to wrap us up, you touched on this a little bit earlier in talking about ongoing research and data, particularly in the field of HPV-negative disease, but what are the outstanding questions regarding TORS in this patient population? Dr. Chris Holsinger: Yeah, I think that in addition to this work around shared decision making, I really hope that we'll embrace shared decision making in the context of future clinical trial. I think where we are now is you have surgeons saying, “Hey, TORS and 50 gray is a great option. Why aren't we doing that?” And then our colleagues, perhaps across the aisle, if I can use a political metaphor, are saying, “Well, where's the comparative data? Can we even do a randomized clinical trial between surgery and radiation?” Well, Christian Simon in Lausanne in Switzerland is trying to do this in a small pilot study being led by the EORTC, and I would encourage American investigators to consider something analogous. But I think how we solve this question of I think treatment choice is going to be pivotal for any such trial to ever be done. And then finally, I think, how will the changing treatment landscape around immunotherapy change this? There's some really provocative data that dates back to 1996 in a JCO paper from Ollivier Laccourreye and the University of Paris experience that showed induction chemotherapy followed by function preserving surgery in the larynx was a really powerful strategy for organ preservation, and that has never been followed up in the United States. And so especially with the upcoming presentation of KEYNOTE-689, will we be doing neoadjuvant approaches for patients and then following them by minimally invasive surgery or lower dose radiation? I think these are going to be some exciting new areas of study and I can't wait to see how this might evolve so we can refine the treatment - still get those great outcomes, but reduce those late toxicity. Brittany Harvey: Yes. We'll look forward to this ongoing research to continue to move the field forward. So, Dr. Holsinger, I want to thank you so much for your time to develop this important guideline. It's been great to have you on the podcast to discuss it today. Dr. Chris Holsinger: Well, thanks a lot Brittany. It's nice to finally meet you. Brittany Harvey: Likewise. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
In the past five years, the use of immunotherapeutic agents for advanced cancers has emerged as a promising alternative to tyrosine kinase inhibitors and chemotherapy, making it an exciting time to be practicing oncology. In this episode, Dr. Tyler Sandow interviews oncology experts about the landscape of advanced hepatocellular carcinoma (HCC) and the current state of immunotherapy treatments. He is joined by medical oncologists Dr. Jonathan Mizrah, Dr. Lingling Du, and Dr. Adam Burgoyne, as well as interventional oncologist Dr. Zachary Berman. Physicians, nurses, nurse practitioners, and physician assistants can follow this link to earn CME / CE credits for completing an accredited learning activity related to this discussion: https://www.cmeuniversity.com/course/take/125737 --- This podcast is supported by an educational grant from: AstraZeneca https://www.astrazeneca.com/our-therapy-areas/oncology.html With additional support from: Boston Scientific https://www.bostonscientific.com/en-US/medical-specialties/interventional-radiology/interventional-oncology.html --- SYNPOSIS Drs. Burgoyne and Mizrahi provide a primer on immunotherapy and explain how they communicate the principles of this treatment to their patients. Dr. Du discusses the Imbrave clinical trial and how recent studies have shown improved overall survival when immunotherapeutic agents are used, especially when multiple agents targeting various pathways are employed. When choosing between different regimens, the doctors consider factors such as the patient's underlying liver function, symptom burden, and prior treatments. Importantly, the doctors also discuss contraindications to immunotherapy, including a history of organ transplant, autoimmune disease, and poor performance status—all of which put patients at high risk for deterioration with this treatment. The treatment of patients with poor liver function remains controversial, as underlying cirrhosis may prevent the recovery of liver function. Dr. Berman outlines recent clinical trials studying the effects of transarterial chemoembolization (TACE) combined with immunotherapy. Finally, the doctors discuss the future of HCC treatment and the benefits of continued innovation in both interventional and medical oncology. --- TIMESTAMPS 00:00 - Introduction to Immunotherapy 04:32 - Notable Clinical Trials 13:39 - HCC Etiology and Immunotherapy Outcomes 18:43 - Contraindications for Immunotherapy 23:05 - Adverse Effects from Treatment 25:14 - Combination Therapy 36:22 - Considerations for Immunotherapy Dosing 40:26 - The Future of HCC Treatment --- RESOURCES Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma, IMbrave150 Trial (Finn et al, 2020): https://pubmed.ncbi.nlm.nih.gov/32402160/ Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma, HIMALAYA Trial (Abou-Alfa et al, 2022): https://evidence.nejm.org/doi/full/10.1056/EVIDoa2100070 Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial (Yau, 2022): https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00604-5/abstract Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW (Galle, 2024): https://ascopubs.org/doi/10.1200/JCO.2024.42.17_suppl.LBA4008 Randomized Phase 3 LEAP-012 Study: Transarterial Chemoembolization With or Without Lenvatinib Plus Pembrolizumab for Intermediate-Stage Hepatocellular Carcinoma Not Amenable to Curative Treatment (Llovet, 2022): https://pubmed.ncbi.nlm.nih.gov/35119481/ Find this episode on BackTable.com for more resources.
Florian Dobler and Nathalie Alexander from the Laboratory for Gait Analysis in St. Gallen, Switzerland, join the show to discuss their recent research on the impact of obesity on femur development. The conversation spans several of their gait-related studies on lower extremity rotation and the effects of femoral and tibial osteotomies. Your hosts are Carter Clement from Children's Hospital of New Orleans and Tyler McDonald from University of South Alabama. Music by A. A. Aalto. References: 1) Body Mass Index is Related to Femoral Anteversion, Hip Rotation During Gait, and Passive Hip Range of Motion in Children and Adolescents. Dobler et al. JPO, Oct 2024. PMID: 39482988. 2) Effect of femoral derotational osteotomy in patients with idiopathic increased femoral anteversion on joint loading and muscular demands. Alexander et al. JCO, Aug 2024. PMID: 39391579. 3) Compensatory gait deviations in patients with increased outward tibial torsion pre and post tibial derotation osteotomy. Alexander et al. Gait & Posture, 2020. PMID: 31981934. 4) Does pathologically increased or decreased tibial torsion affect muscle activations during walking in typically developing adolescents? Alexander et al. Journal of Biomechanics, 2021. PMID: 34509912.
Listen to ASCO's Journal of Clinical Oncology Art of Oncology article, "You Don't Bring Me Flowers” by Dr. Kathryn Cappell, who is an Assistant Research Physician at the National Cancer Institute. The article is followed by an interview with Cappell and host Dr. Mikkael Sekeres. Dr Cappell shares the difficulty in protecting oncology patients without taking away things that bring them joy. TRANSCRIPT Narrator: You Don't Bring Me Flowers, by Kathryn Cappell, MD, PhD Easter morning dawned a beautiful spring day in Washington, DC. Soft sunlight and a cool breeze streamed through my bedroom window. My children woke up early, and I listened to their shouts of delight as they found their baskets, brimming with grass and chocolate eggs wrapped in pink and purple foil. Later that morning, I drove to a local hospital where I was rounding. Cherry blossom trees bursting with pink flowers bloomed throughout our peaceful neighborhood, and their showers of pollen had coated my car windows in a soft dusting of green. I put my arm out the car window and caught the heavy scent of flowers as fresh air flooded in. The fifth patient on my rounds, Evelyn, had been in the hospital for 22 days. This morning, as the charge nurse, Frances, and I entered the room, I noticed a vase brimming full of bright pink flowers beside her bed. Evelyn caught my eye and looked guiltily at her lovely bouquet. “I know it's against the rules,” she said, “but my son brought them, and they make me so happy.” Fresh flowers were indeed against ward policy. Theoretically, flowers could introduce fungal spores that could float through the air and lodge into the vulnerable lungs of our neutropenic patients. Evelyn was not the only patient who had received flowers. On that Easter day, the elevator area outside the oncology ward bloomed with forbidden flowers mistakenly brought by other loving sons. Frances kindly offered to take a picture of the flowers for Evelyn and print it out. Frances explained that this way she could still enjoy the picture while protecting herself and other patients on our ward. I found myself unsure; I wanted Evelyn to have the joy of the flowers during her long hospitalization. I could picture her son, a lumbering man in his 60s, carefully selecting the flowers last night. He was a quiet man, and I got the impression that bringing flowers was a way for him to share his feelings about his mother. Evelyn had been separated from her family for almost a month and was isolated in a hospital room without the ability to even open a window to enjoy a fresh breeze. She had maintained her gentle and positive attitude throughout, bravely battling complications from chemotherapy. The flowers probably brought her a little chance to savor the beauty of Spring and reflect on the love from her son. I did not want to take that from her. Still, I knew the importance of ward policies and protecting our vulnerable patients. I dislike taking things from my patients, but I have been diligently doing so for most of my career. As a medical student and resident, I remember oncology patients struggling to tolerate a neutropenic diet devoid of many fresh fruits and vegetables. A generation of doctors advised patients that the neutropenic diet was necessary to protect them from infections. I recall one young boy with leukemia repeatedly asking for fresh blueberries and the medical team insisting he follow the neutropenic diet. He eventually got sicker and died; I am not sure if he ever got a blueberry. I think of him with a lingering tension that we did him wrong by taking away something that could have brought him joy before he died. This is particularly true because the neutropenic diet has now been largely debunked.1 The modern oncology patient enjoys the blueberries that only 20 years ago we would have assiduously removed from the room. Like the neutropenic diet, there is little evidence that fresh flowers pose a significant infection risk. Fungal spores could theoretically also come into the ward on fresh fruits and the dusttracked in on employee shoes, yet we ban neither of these. The CDC hospital infection control recommendations note that there are minimal evidence-based studies in this area but cautiously recommend against flowers in areas where immunosuppressed patients are located. The lack of evidence is reflected in varying hospital policies regarding flowers; some major medical centers ban flowers on the oncology ward and others do not. I stood before Evelyn with her pink flowers, as she implored me to overrule the policy and allow her to keep them. Bright sunlight shone in through her window and the room felt stuffy and closed, in stark contrast to the lovely outdoor scene. The flowers did add a hint of beauty to an otherwise sterile-appearing room. The vase that held these was clean and the water crystal clear. If we tested the flowers and water, would it be brimming with fungus that would subsequently endanger Evelyn and others on the ward? Who knew? In the absence of evidence, I followed the rules. Evelyn's face fell as I concurred with Frances that it was ward policy to not allow flowers in the room. She was too polite to argue, and though she looked disappointed, her demeanor toward Frances and me did not change. Frances took a picture of the flowers and brought the picture back to Evelyn. The flowers were carefully moved to the oncology elevator lobby. I finished my rounds, put in orders, wrote my notes, and went home to my children. The afternoon was as lovely as when I went into work that morning. My kids rushed at me as I got out of the car, eager for a promised afternoon Easter Egg hunt. My son climbed on the apricot tree in front of our house, and little flower petals fell to the ground as the branches shook from his weight. He was still at an age where he would often pick dandelions in the yard and tuck these carefully behind my ear. It is his simple way of expressing love and it makes me feel cherished. I pictured him, a grown man, bringing flowers to me in the hospital someday, and how painful it might be to have those taken away. I could not quite shake the feeling I had made the wrong decision. I mentally reassured myself that it was hospital policy to take away Evelyn's flowers, and after all, it was for her own protection. Was it not? Dr. Mikkael Sekeres: Hello and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the oncology field. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. Today, we're joined by Dr. Katy Cappell, Assistant Research Physician at the National Cancer Institute. In this episode, we will be discussing her Art of Oncology article, “You Don't Bring Me Flowers.” At the time of this recording, our guest has no disclosures. Katy, welcome to our podcast and thank you so much for joining us. Dr. Kathryn Cappell: Thank you. Dr. Mikkael Sekeres: It's such a delight to have you here. Can you just start by giving us a little bit of your background? Dr. Kathryn Cappell: I've been practicing mainly in hematologic malignancies, and at the time of the writing of this article, I was an Assistant Research Physician at the National Cancer Institute. Before that, I trained at University of Miami, actually, where you work, for my bachelor's. Then I went to University of North Carolina for an M.D. Ph.D., and then I was at Stanford for my residency, followed by NCI for my fellowship. Dr. Mikkael Sekeres: That's great. I didn't know about your University of Miami connection. I feel like I have to throw up a U to you on our video recording here. Dr. Kathryn Cappell: Yes. Your screen looks very recognizable from my undergrad. Dr. Mikkael Sekeres: Well, it's great to be reunited then with you. I was wondering if I could ask you to talk a little bit about your writing process. When did you start writing and when do you find the time to write? Dr. Kathryn Cappell: Yeah. So this is actually my first story that I've written in a long time, probably in 20 years. Dr. Mikkael Sekeres: Wow. Dr. Kathryn Cappell: I started writing this story because when I was rounding at this hospital, I always noticed the flowers being absent in rooms. And I liked to chart my notes at the nurse's station where a lot of patients would come and check in. And when they were checking in, I'd often hear people getting their flowers taken away and moved to the lobby. So I've been thinking about the piece for a long time, just from rounding and while I was listening to all these conversations about patients losing their flowers. So that's where it came from. And it's my first piece. Dr. Mikkael Sekeres: That's really amazing. It's a phenomenon we witness all the time when people with all of the best intentions bring things into patients who are in the hospital for three or four weeks, like those patients who are getting treatment for acute leukemia or those who are undergoing a transplant to try to make their room more recognizable and more homelike for them. And then we often see those things whisked away because of hospital policies. Dr. Kathryn Cappell: Yeah, definitely. Dr. Mikkael Sekeres: When you're writing, does an essay all come out at once or do you revisit it? So how do you refine your writing to transform it into a work of art? Dr. Kathryn Cappell: This piece, I started writing, probably, actually a year ago. It took me a long time to get started, to the point where I was thinking about it for a long time, thinking about the piece, for almost a year. I can remember that because I started thinking about it at ASH 2023, and I hadn't really finished it till ASH 2024. And during that time, a lot was going on in my head about how I would structure the piece. And then once I had started writing it, I went through multiple revisions before I got the courage to submit one to JCO. Dr. Mikkael Sekeres: I love how you frame it in terms of the courage to submit to JCO. I just read a post from Adam Grant, who's an economist and writes about kind of our actions in the workplace, and he mentioned the point that we often will put something off out of fear. It's not some kind of deliberate action on our part to avoid doing something that we don't want to do. It's really fear and fear of failure and fear of anxiety that prevents us from doing something. So you talk about courage. I think the flip side of courage is fear. Describe what that's like, that first moment that you decide, “Okay, I'm going to write a piece, and I want to write something that's public, that other people will see.” Dr. Kathryn Cappell: Yeah. I think most people, when they write, it's a very personal thing to share something that you've written, especially if you've been thinking about it in your mind for quite a long time. That's actually part of the reason I don't write very often is because of that. And I think you're right that it comes from fear of sharing it. So I started out by, I was just going to write this for myself. And then as I got more comfortable with it over time, I decided, “Well, I might as well share this piece to see what happens.” Dr. Mikkael Sekeres: Did you bounce the idea off of friends or colleagues to kind of see what their reaction would be before you kept taking those steps that eventually led to a completed piece and submitting it to JCO? Dr. Kathryn Cappell: Yes, I did bounce it off a friend who had the same experience in the same hospital with flowers getting taken away from patients. So I checked to see if other people had had the kind of same reaction to it as I had. Dr. Mikkael Sekeres: That's great. It's always helpful to have a cadre of supportive readers when you first start writing - people who are going to talk about what's great about your piece and then give you advice that you can trust that's more helpful in revising it. Dr. Kathryn Cappell: Yes. Dr. Mikkael Sekeres: I love how in this piece you explore the tension we face as hematologist-oncologists between recommending what we feel is medically appropriate for our patients and feeling as if we've taken away some of their agency and some of their liberty. Can you discuss this in a little more detail? Dr. Kathryn Cappell: You'd think that the hardest thing about being a hematologist-oncologist would be knowing all the drugs and knowing what you should do, but I think that that's actually one of the easier parts. The harder part is these kind of interactions that arise because I think they have an emotional component to them and that makes it harder to do, day in and day out, dealing with those things. I mean, I think hospital policies are important and they're there to protect people. So I think, in the end of the story, I did do what the hospital policy said to do. And I think that that's in some ways important to make sure we have a good environment for everybody on the ward. But I think it's really painful as a doctor to have to make those decisions where it impacts someone's agency and someone's joy and what they're getting out of a day to day life, especially when they're in the hospital for a really long time. Dr. Mikkael Sekeres: Was there something that you could do to make up for it? So sometimes we'll take something away like beautiful flowers for fear of introducing infection in a ward where people are immunocompromised. But we can make up for it by saying, “Okay, but we're okay with you bringing food in from the outside.” Dr. Kathryn Cappell: Yeah. So the nurse in the story, I mean, she definitely was trying to make up for it. She was a very sweet nurse with helping me. She went and printed out the picture of the flowers, which I think is one thing you can do, but another thing I've seen a lot of patients do and family members do is bring in paper flowers. They decorate the room in other ways, which I think makes it meaningful and still nice for people. And I think the nurses on our ward did a great job doing that too. They decorate the rooms and try to still keep a very nice environment. Dr. Mikkael Sekeres: That's terrific. What other things do family members do to try to make the room more of a home environment? Dr. Kathryn Cappell: Bringing in their own blankets for people so they have their own comforter on the bed is a big one. Bringing in pictures of family members, putting them on the walls, on the windows. Bringing in food from home I think is very important. Dr. Mikkael Sekeres: I completely agree. And there was a recent study looking at neutropenic precautions in a transplant unit and whether or not those actually improved the outcome of patients, and it turns out it didn't. So we've had these incredibly restrictive diets for patients that I think we can feel much more comfortable now relaxing and allowing people their comfort foods, which you, as a University of Miami graduate know, here involves a lot of Cuban food. Dr. Kathryn Cappell: Yeah, definitely. But I think that that neutrophenic diet is a great parallel to that. We start instituting things that kind of take away people's agency in something that brings them joy, but we might not have that great of evidence for it. And it really does impact people's happiness, I think, in a lot of ways and comfort in the hospital. Dr. Mikkael Sekeres: Yeah. And that's so important for getting through this ordeal of being in the hospital sometimes for weeks. You start and end the essay writing about your family, and this beautifully illustrates the freedom that they and you have compared to your patients who are confined to the hospital on a lovely holiday weekend. How do you navigate what must feel almost like survivor's guilt of being free from the hospital when others aren't, and being able to shift your focus to the joy of being around your children enjoying their holiday. Dr. Kathryn Cappell: Yeah, I think children help you focus it themselves. When I come home, they're pretty focused on what they want. They want their Easter egg hunt in the morning. They need their Easter baskets. So that alone brings you back into a different world. I come back, and suddenly I'm thinking about where the Easter eggs are going to go. That helps me a lot doing that. But I also think most people in oncology, most onc physicians, it is a difficult separation. You do think about your patients outside of work hours. That is something that's hard to do. But I'd say my children actually help me with that, getting my mind onto something different because they're just so active and they have so much going all the time. Dr. Mikkael Sekeres: It's interesting how you frame that also, how your children help you. I remember distinctly one time my daughter asked me, “How was work?” And I said, “Oh, it was a hard day because I had to tell somebody some bad news.” And she very deliberately said to me, “You need to separate what you tell us at home from what happens at work. We don't want to hear your sad stories.” Dr. Kathryn Cappell: Oh, that's a sad story in itself. Dr. Mikkael Sekeres: Well, it is, right? But it was kind of very helpful to me to realize that, yes, we do have to- we have to compartmentalize, not only for our own health, but also for the health of our family. We've chosen this path in our lives, which is this incredible opportunity to be around people who have a cancer diagnosis at a pivotal point in their lives. But our family hasn't necessarily made that same choice. Dr. Kathryn Cappell: The children don't understand it 100%. Dr. Mikkael Sekeres: Do you feel as if hematologists-oncologists are better at compartmentalizing maybe than other professionals in medicine? Dr. Kathryn Cappell: I'm not sure. I feel like a lot of medicine has those sad points that are difficult. So I think psychiatry is a good example of that. That's hard to, I think probably, very difficult to compartmentalize. So I'm not sure. I think other physicians also have difficulties with it. But I do think we see a lot of difficult scenarios more than other groups. So that could make it that we're better at compartmentalizing. Dr. Mikkael Sekeres: You mentioned in your essay, you refer to your patient's lumbering son. I love that phrase, the lumbering son who brings her the flowers. Do you think it helps to see that backstory to what's going on in your patients' lives? There's a risk of almost too much empathy, of knowing too much about it, and therefore having an even more difficult time separating yourself. Dr. Kathryn Cappell: For me, I think it helps with patient care a lot to know their family so you know where they're going back when they leave the hospital. You kind of know what helps, you know what they value. So I think in a lot of ways it does help for patient care to know what they're coming from in terms of family members. I do think sometimes getting too involved and knowing too much about the situation and attaching to it emotionally can make it hard to be objective. So I think that it's important to keep some distance there in terms of being able to make good decisions for your patients as well. Dr. Mikkael Sekeres: You mention looking at people's rooms and seeing the photos up on the wall. I always think we worry about the patients most who don't have any photos up on the wall and what kind of support system they're going back to when they're discharged from the hospital. Dr. Kathryn Cappell: Yeah, I definitely agree. That's definitely something I think about as well. Dr. Mikkael Sekeres: You end this beautiful essay by asking the question, and I'm quoting you now, “I couldn't quite shake the feeling I'd made the wrong decision. I mentally reassured myself that it was hospital policy to take away Evelyn's flowers. And after all, it was for her own protection, wasn't it?” And I'm wondering, I'm going to put you on the spot a little bit, Katy, can you answer your own question? Dr. Kathryn Cappell: Boy, I'm not sure if I can still. I think that's part of where the tension in the piece arises from. I think when you're in a hospital, you're working as a team, and part of the thing I think about is nurses are an important part of that team and they structure the ward. So I don't think it's just my decision. I think it's a hospital decision as a team. And I do think there's a component of fairness. If you're going to say it to one patient, that's the policy, it should be the policy to all patients. So in some ways I reassure myself about that. But in the other side of me, it still makes me a little sad. Dr. Mikkael Sekeres: Yeah, it's well stated. I'm wondering that the hospital in which you work changed their policy or did your previous position change their policy? Dr. Kathryn Cappell: I haven't actually mentioned this story to them yet or asked them to change their policy. I do feel it's pretty common at the different hospitals. I've worked at seeing a policy similar to this, so I haven't asked. Dr. Mikkael Sekeres: Well, Katy, I want to thank you for joining us today on the podcast. Your writing is elegant, the tale that you tell resonates with all of us, and it's been just delightful getting to know you even better. Dr. Kathryn Cappell: Great to meet you as well. Thank you for having me on. Dr. Mikkael Sekeres: Until next time, thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all of ASCO's shows at asco.org/podcasts. Thank you again. 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. Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr. Kathryn Cappell is Assistant Research Physician at the National Cancer Institute.
In this JCO Article Insights episode, Ece Cali summarizes findings from the JCO article, "Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study." TRANSCRIPT Ece Cali: Hello and welcome to the JCO Article Insights. I'm your host Ece Cali and today we will be discussing the Journal of Clinical Oncology article the “Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study.” Despite significant advances in non-small cell lung cancer treatment over the past decades, second line treatment options for non-small cell lung cancer without actionable genomic alterations have remained largely unchanged since 2000. Many clinical trials failed to demonstrate improved overall survival compared to docetaxel based regimens. TROPION-Lung01 is a global open label randomized phase 3 trial comparing the efficacy and safety of Dato-DXd to docetaxel in patients with previously treated advanced or metastatic non-small cell lung cancer. Dato-DXd is an antibody drug conjugate targeting TROP2 and delivering deruxtecan, a DNA topoisomerase 1 inhibitor, as its payload. The trial is designed with dual primary endpoints of progression free survival, as assessed by blinded independent central review, and overall survival. The initial PFS results were presented at ESMO in 2023 and this article reports more detailed data and overall survival analysis of the trial. In the TROPION-Lung01, 299 patients were randomly assigned to receive Dato-DXd and 305 patients to receive docetaxel. Patients were stratified by the presence of actionable genomic alterations, histology, treatment with PD-1/PD-L1 immunotherapy as the last line of therapy, and geographical region. The baseline characteristics of the patient population were overall balanced between the treatment arms. I'd like to highlight a couple of key points here. The median age was 63 years in the Dato-DXd and 64 years in the docetaxel arm. Similar to the many clinical trials in the thoracic oncology field, this is younger than the median age of lung cancer diagnosis in the US, which is around 70. African American and Hispanic patients were underrepresented in this trial with 41% of patients identifying themselves as white and 39% as Asian. The Ddocetaxel arm had a slightly higher percentage of male patients, 69% versus 61%. The majority of the trial population, 73%, had adenocarcinoma. Patients with actionable genomic alterations were included in this trial if they received one or more targeted therapy and platinum based chemotherapy prior to the enrollment. 17% of the trial population had an actionable genomic alteration in this trial. When it comes to the efficacy results in the full analysis set, the PFS improvement was statistically significant. The median PFS was reported as 4.4 months for the Dato-DXd, and 3.7 months for the docetaxel arm with the hazard ratio of 0.75 and a P value of 0.004. However, after a median follow up of 23 months, the trial did not meet its primary endpoint of overall survival. The median overall survival was 12.9 months for patients treated with Dato-DXd and 11.8 months for patients treated with docetaxel with the hazard ratio of 0.94 and a P value of 0.53. Objective response was a secondary endpoint and the confirmed objective response rate was 26% with Dato-DXd, and 13% with docetaxel. Now let's take a closer look at some of the subgroup analyses. Exploratory analyses of key subgroups in TROPION-Lung01 demonstrated differences in efficacy based on histology. In the nonsquamous subgroup, Dato-DXd showed a longer progression free survival of 5.5 months compared to 3.6 months with docetaxel with a hazard ratio of 0.84. However, in the squamous subgroup, Dato-DXd performed worse with a progression free survival of 2.8 months compared to 3.9 months with docetaxel corresponding to a hazard ratio of 1.32. A similar trend was observed in the overall survival analyses, though confidence intervals crossed 1 in both histology subsets, in this case, the differences observed were not statistically significant. In the nonsquamous subset, the median overall survival was 14.6 months with Dato-DXd and 12.3 months with docetaxel with a hazard ratio of 0.84. In the squamous subset, both arms had shorter survival compared to the nonsquamous subset. The median overall survival with Dato-DXd was almost two months shorter, so 7.6 months, compared to 9.6 months with docetaxel corresponding to a hazard ratio of 1.32. While these analyses suggest the potential survival benefit for Dato-DXd in nonsquamous subset, this trial was not powered to test this hypothesis hence these analyses remain exploratory. Another subgroup analysis of note was the group with actionable genomic alterations. Patients with actionable genomic alterations achieved a median PFS of 5.7 months with Dato-DXD and 2.6 months with docetaxel corresponding to a hazard ratio of 0.35. Similarly, the median overall survival was longer in patients with actionable genomic alterations by almost six months, with a median overall survival of 15.6 months with Dato-DXd and 9.8 months with docetaxel corresponding to a hazard ratio of 0.65. Now, let's talk about safety. Grade 3 or higher treatment related adverse events occurred in 26% of patients with Dato-DXd and 42% with docetaxel. The most common adverse event of any grade seen in the Dato-DXd arm were stomatitis seen in 47% of patients, nausea in 34%, and alopecia in 32%. Treatment related interstitial lung disease occurred in 8.8% of patients on Dato-DXd and 4.1% of patients on docetaxel. Of note, grade 5 drug related ILD was more frequent with Dato-DXd. Seven patients on Dato-DXd and one patient on docetaxel died secondary to drug related ILD in this trial. In summary, TROPION-Lung01 aims to address an unmet need for patients with previously treated non-small cell lung cancer. For this population, the treatment options remain limited with poor survival outcomes. TROPION-Lung01 is a positive trial by design due to clinically modest improvement in PFS. However, the lack of overall survival improvement is disappointing. Exploratory subgroup analyses suggest Dato-DXd may offer survival advantage in specific subsets such as nonsquamous non-small cell lung cancer and patients with actionable genomic alterations. However, these findings require further validation in a prospective trial since TROPION-Lung01 was not designed to address these questions. The data from this trial alone is not sufficient to argue for a change in clinical practice. However, it informs how the future trials using this drug should be tailored. This highlights the importance of studying potential predictive biomarkers earlier in the drug development and incorporating these biomarkers prospectively into the clinical trial designs. Due to the lack of overall survival benefit in this trial, the biologic license application for accelerated approval of Dato-DXd for patients with previously treated nonsquamous non-small cell lung cancer was voluntarily withdrawn. New BLA was submitted for Dato-DXd for patients with previously treated advanced EGFR positive non-small cell lung cancer. This BLA is based on data from TROPION-Lung05, TROPION-Lung01 and TROPION-PanTumor01. Of note, the results of TROPION-Lung05 trial have been just published in JCO. This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts. 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.
HOPA Pharmacy Outcomes & Practice-Based Collaboration Survey: https://www.surveymonkey.com/r/MXNVRBR Dexamethasone Dosing Intensity in Multiple Myeloma: https://doi.org/10.1182/blood.2024025939 Talquetamab + Teclistamab: https://doi.org/10.1182/blood.2024025939 postMONARCH: https://doi.org/10.1200/JCO-24-02086
We say thank you to current Cancer Stories host, Dr. Lidia Schapira, and welcome Cancer Stories new host, Dr. Mikkael Sekeres. TRANSCRIPT Dr. Lidia Schapira: Hello and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the field of oncology. I'm your host, Dr. Lidia Schapira, a Professor of Medicine at Stanford University, and with me today is Dr. Mikkael Sekeres, who is a Professor of Medicine and the Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center in Miami. In this episode, we will be discussing his new role as the host for the JCO Cancer Stories: The Art of Oncology podcast. Mikkael, welcome to our podcast and thank you for joining me today. Dr. Mikkael Sekeres: Lidia, what an absolute delight it is to be here with you. And I have to confess, it's also intimidating to think about taking this over from you, given the amazing job you've done over the past few years. Dr. Lidia Schapira: Well, thank you so much for that. This podcast originated as a bit of a dare. When Steve Cannistra, back in 2017, said ‘no' to some idea that I had for changing or expanding the section and issued the dare of why don't you do a podcast instead? And back in 2017, I had no idea. And we were less used to podcasts, so I trained myself. And then this beautiful new form sort of emerged just from my idea and dream of giving our listeners and our readers something new to chew on and to reflect on. Dr. Mikkael Sekeres: Well, it turned out to be prescient, didn't it? I can't tell you how many people I know, especially here in Miami, where we do tend to get caught in traffic and have a long commute time. I'm sure that never happens to you in Palo Alto. Dr. Lidia Schapira: Of course not. Dr. Mikkael Sekeres: But people listen to a lot of podcasts and it's a great way to catch up on personalities and on books and on the news. So good for you. I'm so happy you took the dare and ran with it. Dr. Lidia Schapira: Yes. And the first thought I had was to make it a bit artsy. So we started, for the first couple of years of rounding up everybody we knew who was an actor or had a voice that they used for their art or trade and asked them to read the essays or poems before we had the conversation with the author. Now, we have our own voice actor, so we know what we're going to get every week, and we're not looking for people and knocking on doors and asking very busy actors to donate their time. So it has evolved, as has the writing really. So I wondered if you can reflect a little bit on how you see this section both in the journal and also the conversations we're having in this podcast change and evolve over the years. Dr. Mikkael Sekeres: Let's be honest, we're both writers, right? So as a writer, you're always looking for an outlet for your work. And there aren't a lot of outlets in medical journals. Yet there's this huge audience of doctors and nurses and pharmacists and social workers who read these journals and have this incredible experience with this deluge of humanity we see every single day. So this is an incredible thing, that Art of Oncology was even created a couple decades ago and provided this outlet for people. And what I have noticed is that people have become more daring. So let's play on the dare that you took up to even start this podcast. They've become more daring in what they're willing to write about and in how vulnerable they're willing to be in print. I've seen this in my own career, in my own writing, where 20 years ago I came out of fellowship and very cautiously started to write about some of the experiences that I had. But it was cautious and used more professional language and didn't get into some of the vulnerabilities that we face in treating patients and that we experience in ourselves and in our colleagues. But I think people have been willing to share more of themselves, particularly in the last decade. Dr. Lidia Schapira: I totally agree with you. And one of the things that I've noticed is that we have younger writers and younger authors who are now taught, even during their medical training and postgraduate work, that writing as a way of processing emotionally difficult experiences or sharing interesting thoughts or coming together as a community is really important to create the kind of community of thoughtful practitioners that we need to sustain us while we do this difficult work. So we are having more and more submissions and published work from very young colleagues, trainees. And I find it very interesting, sort of this multi-generational way of expressing the contact with very ill patients and sometimes very moving to think back on the first time you gave bad news for those of us who may have done it a hundred thousand times. Dr. Mikkael Sekeres: So I think you're spot on about this. We're getting younger authors. We're getting folks who are early career, mid career. Now, we're receiving essays from folks who are at the end of their career and want to reflect on that career. And people we wouldn't have expected would write these vulnerable essays either. I wonder if some of the pieces we're getting from younger authors stems from the fact that fellowship programs are finally paying attention to the experience of being a fellow and being a trainee. Dr. Lidia Schapira: Oh, my goodness. It was staring at them all this time. I think when you were a fellow a long time ago, you were one of the advocates of having fellows talk to one another about their experience, right? Dr. Mikkael Sekeres: You have an incredible memory. During our fellowship, we started a Balint Physician Awareness Group. So there's this movement started by the Ballint, a husband and wife team to start to get healthcare providers to reflect on their experience and share that experience with each other to build a community of support. And we started this in our fellowship. And you can imagine the initial reaction to this among the fellowship directors was, “Why do you need that? What do you think you're doing? There's no place for that.” Dr. Lidia Schapira: “And we need our time to train them on the science.” This is maybe an extra. Right? I think many of us have felt that trying to advance anything that deals with humanism or the human side of providing care is considered maybe optional. And I think you and I have been pushing against that for a long time. Dr. Mikkael Sekeres: I think that's exactly right. What I think legitimized it a little bit is we got funding for it from The Schwartz Foundation. We then actually published a study looking at it in JCO because the fellows in our program spent time at two different hospitals. So it was by design, this crossover study where half the fellows got the intervention of the Balint group and half didn't. And it turns out, lo and behold, they actually felt better and had a better experience as a fellow when they had the intervention. Dr. Lidia Schapira: Yeah. It's so interesting that we had to turn it into a randomized control trial or whatever design you picked, but you needed to fit it into the section of the journal that respected the logic and process of scientific research. But that brings me to another point, I think, that we have talked about so much, but I think it's important for us to share with listeners. And that is that the section of the journal that we've created now, it used to be When the Tumor Is Not the Target, and we've shortened the title. The Art of Oncology is not a section for papers that address research or where there is no methods and results section. It is intentionally meant to be different from the rest of the journal. Is that how you see it, too? Dr. Mikkael Sekeres: Oh, my word. Absolutely. And our reviewers occasionally will have a submission that is more of a classic article in how it's structured, and our reviewers will push against it. And sometimes we're able to get back to the author and say, could you write this in a different way, something that's more reflective of Art of Oncology? I think it's meant to be, I don't want to say a break from the way other articles are written, but maybe a different style, a different way of using your brain and reading these articles. And we've seen that they're popular. Sometimes they are the most read article, even in JCO, in a given week, which, of course, we share with each other and gloat a little bit when that happens. Dr. Lidia Schapira: Yes, and it doesn't have to be the article that made you cry. It can also be the article that made you think. That's been my intention as the editor for this section for the last 10 years. I've tried to be very intentional instead of bringing to our readership articles that delve into different parts of this lived experience of giving care. Some are moving more towards ethical conflicts. Some are moving more towards the emotional labor of the work. But some bring out different voices and different perspectives. And I'm proud to say that the submissions we get really come from all over the world. So I wonder, Mikkael, as you're entering into this role now, your decade as editor for this section and host for our podcast is how you view the editorial process. How does your team help the authors bring their best article forward? Dr. Mikkael Sekeres: I took the lead from you, and I'm not saying that just to blow wind in your sail, but you have always given feedback to authors, whether it's a request for a revision and acceptance or turning a piece down. That's been helpful, that's been thoughtful, that's been empathic. And in the end, I know that your goal has always been with these reviews, to give the author advice moving forward. I've tried to take a page out of your book by doing that as well. I go into every piece you shared with me that you do the same thing. When I get a submission, I look at it and I'm so excited about what could be there, what truth this could reveal, what angle of thinking about something that I've never thought about before. And our reviewers go into it the same way as well. These are folks who have read hundreds, if not thousands of essays. They themselves are readers. They're writers. They've had submissions accepted to Art of Oncology. They're looking for pieces that reflect a great truth that we all realize sometimes it's a great truth that no one wants to talk about, and this is the first time somebody's talking about it. Those are the best pieces. When you read it and say, “I thought the same thing,” Or, “I had the exact same experience and no one's ever talked about it before.” We're looking for good writing. We're looking for pieces that are focused on a patient. And you and I have both given talks on narrative medicine. And one of the slides I have in my talk is to remind people that the patient is the most important person in the room and to make that piece focused on the patient's experience and, of course, the writer's reaction to that experience. But in the end, it's all about our patients and their experience. And we're looking for, as you mentioned, perspectives that we haven't seen before. So we want to hear from people who are in training. We want to hear from people in different stages of their careers, people who practice in different settings, people who bring different cultural backgrounds to their own perspective on the practice of oncology. Dr. Lidia Schapira: And if I may point something out to our listeners, you are an artist in being able to bring the bedside verbatims to the page and make them live. I've always admired that in your writing, Mikkael. Can you tell us a little bit about your process for writing and how the role of the editor varies or is different from the role of the writer? Because I've learned a lot about editing, and I think the editor is an interpreter, in a way. I'm fascinated. I was brought up in a household where we spoke four languages, and I was always fascinated by trying to find the right word in a language and struggling with all of that. And I think some of my love for editing, which is different from my love for writing or reading, comes from that, from trying just to find the right word or trying to respect the voice of the author and make it even better or more artistic. Can you tell us a little bit about your process and your relationship to language and writing and editing? Dr. Mikkael Sekeres: It's great to hear you come from a family where you spoke four languages. I am an unfortunate monoglot. I'm terrible with foreign languages. But I come from a family of English majors. My dad was a journalist for the Providence Journal in Rhode island, then an editor for 10 years. My mom was an English major as well. So I always think that as parents, our job is to impart one employable skill to our kids so they don't live in our basement forever. Dr. Lidia Schapira: That's what my father thought, and that's why I'm a doctor and not a philosopher. Dr. Mikkael Sekeres: We joke that we moved to Miami, so there is no basement they can live in. But I always felt in my family, the employable skill was writing. I grew up and when I went to med school, I think, we put on this armor of the language we're learning, and we're very uncomfortable and nervous about the skills that we have. So we use this language to separate ourselves from our uncertainty around medicine. I distinctly remember at one point talking to my parents and saying something that was very complex, using medicalese. And they said to me, “Why are you talking to us like this? We're your parents. You don't have to use that language. Just use language we can understand.” And that always resonated with me. That was kind of a North Star moment for me. That's what's guided my writing. And I have so much respect for the words that my patients use. And I think that's why I try to incorporate it in my essays as well. I always try to have my patient's voice literally there in their words as a focal point. I think as an editor, we go into a piece and we want to learn something. In the end, essays either educate or entertain, and ideally both. So we want to come out of a piece, we want to be either emotionally moved or we want to learn something and hopefully both things. And if I'm reading a piece as an editor and one of those two criteria have been satisfied, then I think it's a piece that's worth giving feedback to and advising revision. But I'm curious. I want to turn this a little bit, Lidia, because you're the one who always asks the questions. Dr. Lidia Schapira: I love asking questions. Dr. Mikkael Sekeres: So I'd like to ask you a question. When did you get started as a writer and a reader? And has that interest and skill changed over the course of your career? Dr. Lidia Schapira: Yes, I must say, I've always been a reader. That's my idea of heaven is a place with an enormous amount of books and a good espresso machine, just to give you an idea. So books have always provided companionship to me. They've provided community. I'm very happy living in a world of ideas, and I love art, and I love the sound of words and beautiful words put together beautifully. So that's basically reading and thinking, to me, are very closely aligned. And I also love and come from a culture, a society where conversation was valued. And I'm very sad that we don't anymore. We don't converse in our typical academic settings because we're so busy, and our language is mostly turned into units of efficiency. So I love the idea of communicating through language. Words, spoken words, things we listen to, things we read, things we write. My relationship to writing has been very undisciplined and inconsistent. And for all the years that I was an editor for this section, I found myself sort of inhibited from writing. And from the moment that I passed the baton on to you, I've been gushing. So I'm working on a book, and hopefully it'll be the first of several. But I've sort of kept my writing very private, and I've only been able to do it when I have a lot of time and no pressure. I'm not the kind of disciplined writer who can set aside time every day to write. I just can't do that. I need to be totally empty and free and be able to disagree with myself and erase a thousand words written on a page because they're just not good enough and start again. Dr. Mikkael Sekeres: I'm fascinated by that comment that you just made. What is it about being an editor that you feel has inhibited you from writing? Dr. Lidia Schapira: I think I was just busy. I was busy, again, immersing myself in the words that I needed to respond to and in the creative process of transforming essays into their best possible publishable form. And I think that's how I've interpreted the work of editors. I have tremendous respect for editors. I now need one to help me with my own work. But I think editors play an incredible role. And I am very happy that you view this role as something that is joyful. And I know that you have the amazing talent to do it. So I'm just very happy that we've made this transition. Dr. Mikkael Sekeres: Can I suggest that you've been giving as an editor also, because I think that your guidance to authors is precious? It's so valuable. Writers are so desperate to have that kind of caring advice. And I wonder if you've devoted all of your creative juices to doing that for the past 10 years at the expense of not being able to write yourself. So I'm so thrilled that you have the opportunity now. I will be the first person to buy your book, to write a review for your book. I can't wait to read it. Dr. Lidia Schapira: We've got a blurber. So now I need a good editor and a therapist, and I'm on my way. So on that note, I think it's time for us to end this lovely conversation, although we could go on for a long time. For our listeners. I want to thank you for having listened to me all these years, and I'm delighted that Dr. Sekeres will continue this wonderful program. And I look forward to listening while I drive, while I walk, and while I just simply am. Thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all of the ASCO shows at asco.org/podcasts. And thank you Mikkael. Dr. Mikkael Sekeres: Thank you so much, Lidia. 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. Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr. Mikkael Sekeres is a Professor of Medicine and the Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center in Miami.
Dr. Evan Yu presents the new evidence-based guideline on genetic testing for metastatic prostate cancer. He discusses who should receive germline and somatic testing with next-generation sequencing technologies, what samples are preferred for testing, and the therapeutic & prognosistc impacts of genetic testing. Dr. Yu emphasizes the need for awareness and refers to areas of active investigation and future research to improve personalized therapies for patients with metastatic prostate cancer. Read the full guideline, “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline” at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02608 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Evan Yu from the University of Washington and Fred Hutchinson Cancer Center, lead author on “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline”. Thank you for being here today, Dr. Yu. Dr. Evan Yu: Thanks for having me on. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline, including Dr. Yu, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, Dr. Yu, to start us off on the content of this guideline, could you first provide an overview of both the purpose and scope of this guideline? Dr. Evan Yu: Yeah, absolutely. So I think the one key thing to recognize is that prostate cancer is the highest incidence of all cancers in males. Additionally, it's the second highest cause of mortality in males, and that's about 35,000 deaths in 2024. So with that being said and done, it's a disease where we need to do better. And part of that is recognizing that we now have many targeted therapies, precision medicine type of therapies, but unlike a lot of other cancers out there, prostate cancer patients are not always getting sequencing, next generation DNA sequencing, let's say, to identify both inherited and also spontaneously develop what we call somatic mutations in their tumor. And I suspect that's partially because other cancers like breast cancer, we're so used to- in the first line, you present the patient, you throw out their estrogen receptor status, progesterone receptor status, HER2, ER/PR HER2; in lung cancer it's EGFR, ALK, ROS1, etc. In things like prostate cancer, things like BRCA2 have major important patient treatment implications and potentially family counseling and downstream cascade testing implications. But it hasn't made their way into that first-line presentation yet. And for that reason, there are some studies out there that show that testing in the community may be as low as 15% of patients with metastatic prostate cancer. We want to bring awareness to that and hopefully increase testing down the road so that we can better help our patients with metastatic prostate cancer. Brittany Harvey: Absolutely. It's important to get these targeted therapies to the patients who can benefit most. Using that context, I'd like to next review the key recommendations of this guideline across the six clinical questions that the panel addressed. So, starting with: Who should receive germline testing with next generation sequencing technologies? Dr. Evan Yu: Yeah. We think that it's common enough that everyone with metastatic prostate cancer should receive germline genetic testing. And the reason for that is there have been studies that have looked at this and have shown that 12% of men with metastatic prostate cancer have some sort of inherited germline mutation in a gene, mostly DNA repair genes. But 12% have something that is inherited and that loved ones, first degree relatives, siblings, offspring might have also inherited. Now, most of these are in the DNA repair genes, but that being said and done, there's not only treatment implications for the patient, where there are newer drugs that that patient could get treated with, but other loved ones that might have inherited these gene mutations, that these things can cause other cancers as well - not just prostate cancer, but breast cancer, endometrial cancer, ovarian cancer, pancreatic cancer. So, it's very important to test, with as high of an incidence as 12%, to test, and if you identify it in a patient, it's our job to talk to the patient about it and talk to them about the pros and cons of family counseling and talking to their loved ones and potentially having their loved ones get tested. Because if they test positive, then their doctors may want to know and may screen them very, very aggressively and differently for a whole host of other cancers. And the whole idea is you find the cancer very early and cure the patients before the cancer really takes hold and has the ability to spread so we can save a lot of lives down the road. Brittany Harvey: Absolutely. This germline testing is important not just for the patient, but has wider implications for their families as well, as you mentioned. So then, beyond those recommendations for germline testing, which patients should receive somatic testing with next-generation sequencing technologies? Dr. Evan Yu: So let's talk a little bit about somatic testing. So germline again, as we know, is inherited. The patient inherited it in every single cell in their body, then it becomes very easy, many of these are cancer predispositions for them to lose the other allele and then to have biallelic loss and then develop the cancer. Now, somatic just means it spontaneously occurred. Certainly, it's not going to occur in every cell in the body, but you can get one hit, lose one allele and then lose the other allele. And if that gene is truly carcinogenic and leading to that cancer, then that can have implications potentially for treatment as well. So we recommend that all patients with metastatic prostate cancer also undergo somatic next-generation sequencing testing. We recognize that at this point in time it's only those with metastatic castration-resistant prostate cancer or hormone-resistant prostate cancer, which is a later disease state where there are drugs that may target those mutations, for instance, like PARP inhibitors, but that early identification for a patient population that's fit and that can benefit from these therapies makes sense so that you know it's in place already and you have your treatments outlined and mapped out for the future. So we recommend it for everybody - somatic testing also for everyone with metastatic prostate cancer. Brittany Harvey: Understood. And then when patients are receiving that somatic testing, what is recommended for somatic testing? Primary tumor archival tissue? Fresh metastatic biopsy tissue? Or circulating tumor DNA testing? Dr. Evan Yu: We recommend that in the initial setting when you're first diagnosed, that archival tissue samples are fine and preferred. But circulating tumor DNA is good when there's no accessible archival tissue, or if the archival tissue, let's say, is very old and it's been sitting around for a long time, or you can't get it anymore because it's many years back when maybe a patient had a prostate needle biopsy. So if it's not accessible, then we recommend ctDNA. We believe that is preferred and also that ctDNA is recommended in a situation where you can't easily biopsy a metastatic site. Sometimes it's just not in a safe area to go after. Sometimes it's just a small lesion. So in general, we recommend tissue when available, and when we think that the tissue sample will yield clean results, if not, then we recommend doing ctDNA at that point in time. Brittany Harvey: So you have described who should get germline and somatic genomic testing. But what are the therapeutic impacts of this germline or somatic testing for single gene genetic variants? Dr. Evan Yu: We pulled this panel together and we met like every single month for like 12 months straight, and part of it was to review the literature. And as part of this literature review, we were able to pull a whole bunch of different trials. I think there was like 1713 papers we identified in the literature search. Eventually, we narrowed it down because with ASCO, we want to present the data with the highest level evidence, level 1 evidence, randomized controlled prospective data. And after reviewing 1713 papers, we narrowed it down to 14 papers. With those 14 papers, if you look at it, there are a lot of things that we think may have implications for treatment or prognosis, but we didn't feel was the highest level of evidence that we could support. So the things that have the highest level of evidence that we can support are certain DNA repair gene alterations, especially BRCA2, and treatment with PARP inhibitors because there are many PARP inhibitor prospective trials that show progression-free survival benefit and even overall survival benefit. And so that's the type of study that achieved the level of evidence that we could include. So I would say BRCA1 and BRCA2 highest level of evidence and PARP inhibitor use also is included in that. Brittany Harvey: Understood. I appreciate you reviewing those therapeutic options. So then, the last clinical question, which you just touched on briefly, but what are the prognostic impacts of germline and/or somatic testing? Dr. Evan Yu: Whenever you do testing, especially if you use panel testing, you find a lot of information. There's a lot of different mutations and some of which are VUSs (variants of unknown significance) where we don't quite know what it means yet, but we can track that, especially if it's germline. But with somatic, we find lots of things that have implications, but maybe just not treatment implications. A perfect example is p53. p53 is one of the most common tumor suppressor gene mutations on all cancers, but in prostate cancer they can occur and they can usually occur late, although there can even be germline inherited p53 alterations. There's no treatment that targets p53 right now, but we know that if you have a p53 mutation that those patients may have more aggressive disease and that prognostic information is important to give to the patient. And I think it's important for future clinical trial design and direction. So we do not recommend making treatment recommendations or changes based on these prognostic only biomarkers at this point in time. But we do recommend that, based on this, we can design intensification trials for those patients who have these poor risk biomarkers and de-intensification trials for patients who may have a good risk biomarker. So for instance, SPOP is a gene where we think these patients may have better outcomes, they might respond better to certain hormonal therapies like abiraterone. I say might because the level of evidence isn't quite there. But what I would say is that these prognostic only biomarkers, we just don't think they cut the mustard yet to be able to make treatment decisions. But we do think that they can drive counseling for the patient and potential selection and trial design for the future to say, “Okay. This is a patient population that has a more aggressive cancer. We need to be more aggressive in treating these patients.” “This patient population might have a less aggressive cancer. Maybe we can de-intensify and say side effects and quality of life may be better for the patients.” Brittany Harvey: Definitely. It's important for thinking through how to personalize care for these patients. So then you've talked about this a little bit in talking through the recommendations, but could you expand on what is the importance of this guideline and how it will impact both clinicians and patients with metastatic prostate cancer? Dr. Evan Yu: Yeah, I think the number one thing is awareness. I think the data's out there and people that are in my field, they know this. But by evidence of the fact that it's not first-line presentation lingo that everyone's talking about things like BRCA status, it means it hasn't necessarily disseminated all the way through. So it's increasing awareness of the fact that both germline and somatic alterations can occur and that these may have impacts on the patient for their treatment and their prognosis, and basically to increase testing for the future. I really think that in the future, there'll be other reasons that we may want to serially even retest and we may find that there may be mutations that develop as mechanisms of resistance that might guide therapy down the road. So we need to get people to start doing this for everyone with metastatic prostate cancer, because someday we might be doing it not just once, but over and over again. Brittany Harvey. Absolutely. We hope this guideline reaches a wide audience and that these recommendations can be put into practice. Finally, you've talked about how not all the data in the field has yet risen to the level of evidence that made it into the guidelines. So what are the outstanding questions in future research areas for both germline and somatic genomic testing for metastatic prostate cancer? Dr. Evan Yu: It was in our discussion, but it clearly- it's not common enough for there to be randomized prospective trials that would reach that level of evidence to make it in this guideline recommendation. But we all know that for any solid tumor, you can get mismatched repair deficiency, microsatellite instability leading to hypermutation or high tumor mutational burden. And that happens in maybe 3 to 5% of patients with metastatic prostate cancer as well. There is evidence and data that these patients can potentially benefit from immunotherapies like pembrolizumab. But again, it's just not common enough for there to be those randomized prospective controlled trials out there. But we mention it because we know it's FDA-approved across all the tumor types, so we felt like we have to mention it because that's something that has treatment implications for the patient. But also, I alluded to this earlier, I think an area of active investigation is the tried and true number one driver of prostate cancer, which is androgen receptor. Testosterone binds to androgen receptors, stimulates it. That's how androgen deprivation therapy works. That's how abiraterone and the amides like enzalutamide, apalutamide, darolutamide, that's how they all work. But even beyond that, we're starting to identify that maybe 15%, 20% of patients with metastatic castration resistant prostate cancer have androgen receptor mutations. And there are newer classes of therapies like androgen receptor degraders like CYP11A1 antagonist that lead to complete adrenal annihilation of other steroid hormones that might promiscuously stimulate these androgen receptor mutants. These things develop as mechanisms of resistance, and in the future, we might want to serially test- and that's an active area of investigation in the future, to say you've been treated, let's say, with androgen deprivation therapy and abiraterone for years. There are certain mutations that might develop as a resistance mechanism. We might need to serially test somebody because you didn't have that mutation earlier on, but later in the disease course you might. And then there might be a new drug X out there that we would want to use. Again, we need the data, we need the randomized prospective controlled trials, but they're happening out there. And somewhere down the road we may rewrite this guideline and have a lot more recommendations to add to it. Brittany Harvey: Yes, we'll look forward to more research in this field to better provide targeted therapies for patients with metastatic prostate cancer across the treatment paradigm. And we'll look forward to report outs from those trials that you mentioned. So I want to thank you so much for your work to develop this guideline and thank you for your time today, Dr. Yu. Dr. Evan Yu: Thank you so much. It's wonderful to be here today. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Host Dr. Davide Soldato and his guests Dr. Ann Wu and Dr. Alexa White discuss the article "Air Pollution and Breast Cancer Incidence in the Multiethnic Cohort Study" and the editorial "Growing Evidence for the Role of Air Pollution in Breast Cancer Development" TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO authors Dr. Anna Wu and Dr. Alexander White. Dr. Wu is a professor of Population and Public Health Sciences at the Keck School of Medicine of UCS, while Dr. White is an investigator in the Epidemiology branch of the Environment and Cancer Epidemiology Group at the National Institute of Health. Today, we will be discussing the article titled, “Air Pollution and Breast Cancer Incidence in the Multiethnic Cohort Study,” and the accompanying editorial. So, thank you for speaking with us, Dr. Wu, Dr. White. Dr. Anna Wu: Thank you for having us. Dr. Alexandra White: Yes, thank you so much for the invitation to be here. Dr. Davide Soldato: So before going in depth about the results of the study that was published in the JCO, I was wondering if you could give us like a brief introduction and a little bit of background about what was known about air pollution as a risk factor for breast cancer and what was the evidence before this study was conducted. Dr. Alexandra White: Okay. I can start with that question. So, there's been research for decades looking at the relationship between air pollution and breast cancer. And it's been a really challenging question to address for a number of reasons. One being that it can be really difficult to assess exposure to air pollution and many previous studies have had really limited information on people's residences over time. But in general, what we thought leading up to this study was that evidence was most consistent that exposure to traffic related pollutants such as nitrogen dioxide was more consistently related to a higher risk of breast cancer. The evidence for fine particulate matter or PM2.5 was less consistent. More recently, there have been a few large, well conducted studies that have supported a positive association. This new study in the multiethnic cohort led by Dr. Wu is really important because it really demonstrated that, in this large study of over 50,000 women in California, that they also do see an association with PM2.5. Dr. Davide Soldato: Thank you very much for the introduction. So, Dr. Wu, we just want to hear a little bit more about the results. So, what was the association that was observed for PM2.5? And specifically, the study that you ran was focused on a very diverse population, a multiethnic cohort, and so I was wondering if you observed any type of differences when you consider the different populations that were included in your study. And if you could also give us a little bit of what was the composition of the women that were enrolled in this cohort. Dr. Anna Wu: Thank you for the question. So, the multiethnic cohort study is a cohort of over 200,000 individuals who were enrolled when they lived in Hawaii or California. For the air pollution studies that we've been conducting, we have focused on primarily the California participants. And in this instance for the breast cancer study, it was based on roughly 56,000 individuals out of- there were about 100,000 because half of them were men and they were not included. Of the California participants, 75% of them were African Americans or Latinos and they were self-identified as these racial ethnic groups when they enrolled in the study. And this was a particularly important consideration for us because in most of the studies that have been published so far on-air pollution and breast cancer, as well as other cancer sites, most of those studies were conducted among whites in the US or whites in Europe. And even if they included non-white populations, the numbers tend to be small so that they were not able to conduct racial ethnic specific analysis. So, we were particularly interested in examining these other racial ethnic groups because we know from other studies that racial ethnic minority groups tend to live in communities of low socioeconomic status and those communities also tend to have higher levels of various types of environmental pollutants. And so, it was important for us to actually try to tease apart these various interrelated factors. So, what we found was that per 10 micrograms per cubic meter, we had a 28% increased risk overall in all participants combined that meet across the racial ethnic groups. We actually did not see any differences or significant differences in the hazard ratios by race ethnicity and they were in general quite compatible with each other. But we did see a stronger finding among the white participants in our study. Dr. Davide Soldato: Thank you, a lot, Dr. Wu. So, I think it's very interesting the fact that in the end you observed that air pollution is a significant risk factor across all the ethnicities that were included in the study. But I think that one very strong point of the manuscript and one very strong point of the analysis was that in the end you also corrected for a series of different factors because we know that the incidence of breast cancer can be modified, for example, by familial history or BMI or smoking habits or also alcohol consumption. And a lot of these risk factors were included in your analysis. And so, I was wondering if you could tell us a little bit whether you observed any significant differences when you observed or included also these risk factors in your analysis, or whether the association for air pollution as a risk factor stands even when we consider all of these other elements. Dr. Anna Wu: Yes. So, we considered all the well-established breast cancer risk factors. And in this situation, we were particularly interested in considering smoking, alcohol intake, use of menopausal hormones, history of diabetes, body mass index, family history, as well as physical activity, because many of these risk factors, such as, for example, diabetes and body mass index, they are risk factors for breast cancer, and air pollution, have also been found to increase risk of these factors. So, in our analysis, we first adjusted for all of these potential confounders in a mutually adjusted manner, so all of them were considered. In addition, we also conducted stratify analysis. So as an example, we stratified the analysis to examine whether the hazard ratio associated with PM2.5 provided comparable risk estimate or hazard ratio estimates for never smokers, former smokers, and current smokers. Although we did not see significant heterogeneity by these various subgroups, we did see a significantly stronger effect of PM2.5 among individuals who did not have a family history of breast cancer. Interestingly, our finding was also stronger among individuals who were never smokers and light alcohol drinkers, even though the results were not significantly different. So, we surmised that maybe individuals who already had a high risk because of other established risk factors for breast cancer, we were less likely to be able to observe the effect of air pollution. But it's important to note that other studies, such as the ones that Dr. White has conducted, have also looked at various subgroups, and I think part of the limitation that all of us have is that once you subdivide the study population, even if you start out with a large sample size, often the sample size gets cut in half or a third. And so, we still lack the statistical power to be able to observe significant differences. But I think it is important to note that, in fact, the hazard ratio estimates are actually quite comparable, but we did see a hint of stronger effects among never smokers, and people who were light alcohol drinkers. So, I think this is an area that we certainly need to continue to investigate since there are other subgroups, such as menopausal status, such as hormone receptor status of breast cancer, that we need to consider in future studies. There's still a lot of work we need to do to sort this out, to actually figure out who are the women who are the most susceptible to the exposures. Dr. Davide Soldato: Dr. White, I would really love a comment from you on this specific area and specifically on what still needs to be done. And related to this, a question actually, for both of you, because I think that from a methodological point of view, there is a lot of work that goes into deciding how we are going to assess the exposure to air pollution. So which type of data are we going to use? Which type of data are we currently using in the epidemiological studies that have been conducted and in the one that we are discussing right now in JCO? And what are the caveats for this data that we are using? Meaning, I think that we use mostly residential addresses, which means that we are looking at the exposure where people actually live, which might not be the place where they spend most of their time. For example, if someone is working, maybe they could be more exposed and have higher exposure when they are at work compared to when they are at home. So, I was wondering if you could give us a little bit of an overview as to what is the methodological standard of care right now in terms of this analysis and what can we do better to refine and understand this specific factor as Dr. Wu was mentioning? Dr. Alexandra White: Yeah, so I'm happy to take a first stab at that question. So, I think it's important to note just how far we've come. I think even a few years ago, air pollution was really not considered a risk factor for breast cancer. And a lot of the work that we've been doing and others have really moved this forward in terms of understanding this as a risk factor. And as I mentioned earlier, there have been a lot of challenges in exposure assessment. And to get to your question, I think that our studies in general are doing better at looking at exposure over more years, residences, more time. We know that cancer takes time to develop, and we can't rely on just a single snapshot of exposure. But as you mentioned, almost all of the studies published have really exclusively focused on residential estimates of exposure. And so, there's a real need to understand the exposures that people are experiencing in other aspects of their life, from their commute to their jobs, to really capture that totality of exposure. And then I think one of the points that Dr. Wu was alluding to as well as we know that breast cancer is a very heterogeneous disease, so risk factors for breast cancer vary by tumor subtypes, by menopausal status at diagnosis. And a lot of studies have really focused on considering breast cancer as a combined outcome, and that might be missing some really important signals where we might have a stronger effect for certain subtypes due to the fact that there's different biologic pathways that are underlying these subtypes or by menopausal status. And so having large study populations where, as we discussed earlier, would really give us the power to look among these smaller groups of women who might be more susceptible and those with younger women, we know that incidence of cancer is rising in young people, and we need to understand the risk factors for that. And most of our studies are really focused on older individuals, so I think that's one important gap, as well as having the power to really look at different differences by tumor subtypes. Dr. Davide Soldato: I think it's very interesting, and I think one point both of you made in the original article and in the accompanying editorial is also the fact that we tend to look at these risk factors in people who are actually aged, while we maybe should be looking at this in an earlier phase of development and potentially during puberty. Do you think that we should design studies that are more focused on this population even though I think that they will take a lot of time to produce significant results? Dr. Alexandra White: Yeah. I think that it is really important to consider how exposure during early life is related to breast cancer risk. We know that exposures during pregnancy or even as early as during puberty might be particularly relevant for breast cancer. And I think a lot of our studies have really been up against the challenge of the fact that exposure monitoring for air pollution really didn't start until the 1990s. And so, it's challenging, especially for these older cohorts, to get back at that time period that might be relevant. But I think that's something that definitely newer cohorts are going to be able to address, and I think it's going to be really important, and also will give us some clues to better understand the important windows of exposure, but also that might provide clues for the biologic pathways as well that are relevant. Dr. Davide Soldato: And just a related question, because I'm not aware of this, but are there right now cohorts that are specifically looking at this in the US or in other parts of the world? If you are aware of that, of course. Dr. Alexandra White: There have been some cohorts that have focused on exposure during these hypothesized windows of susceptibility, but I don't think they've been able to follow those women long enough to develop breast cancer. One of the things that we're working on in the sister study is trying to expand our assessment of air pollution exposure back in time to try to get at these earlier windows of exposure. So, I'm hoping that it's something we'll be able to comment on and at least for some of the women in our cohort who are younger. But I don't know, Dr. Wu, if you're familiar with any other populations that are doing this now? Dr. Anna Wu: Well, NCI funded several new cohorts in the last couple years that are really focused on trying to get a much more refined exposure assessment. So, I know colleagues at University of Michigan that are peers and also Dr. Wei Zheng at Vanderbilt, they are putting together newer cohorts that are younger and also trying to include a range of exposure, not just air pollution, but really environmental exposures. Those cohorts I think have the potential in the future to try to address some of these questions, but again, it will take at least another number of years before there are a sufficient number of endpoints so that they can actually do these types of studies. Another possibility is that there are a number of big cohort studies in Asia. The age of diagnosis tends to be earlier in Asia. I know that investigators in China are very interested and concerned with the air pollution effects in China. I think there are potentials that in other countries where the age of breast cancer diagnosis is actually younger than in the US and if they establish in a manner that allows them to assess air pollution that they may have opportunities. And I think the other way to try to address this question, whether there are studies where you can actually tap into either biomarkers or pathology samples so you won't be actually studying air pollution in a large population, but you're actually narrowing it down to try to see if you see any signals in a way that would give you some additional clues and insights as to the mechanism. So I think we're going to have to piece together various types of study to try to answer the questions because one type of study like these observational air pollution studies, will allow us to address one slice of the questions that we have and then we need to put together other studies so that we can address other aspects that we're interested in to put it together. Dr. Davide Soldato: Thank you very much both of you. That was very interesting. Coming back to the results of the manuscript, we really focused up until now on PM2.5. But it's true that inside of the study you evaluated different pollutants. So, I was wondering whether you saw a similar association for other pollutants that were included in the study or whether the association for higher risk was observed only for PM2.5. Dr. Anna Wu: The results for NO2, NOx, PM10, and carbon monoxide were actually very compatible with the risk estimates that other studies have published as well as from the meta-analysis. So, I would say that our results from the other pollutants are actually very consistent with other results. I think one difference is that our PM2.5 estimates were based on the satellite-based PM2.5 estimates, whereas all the other pollutants were based on monitoring station estimates from EPA sponsored air monitoring stations. So, they are not measured in the same way. And I think different studies over time have used either monitoring station type measures for other pollutants. And I think we were particularly interested in PM2.5 because the measurement of PM2.5 in the monitoring world didn't start until around 2000. So, studies up until that time were less able to actually provide the assessment of PM2.5 as good as we can for air pollution. There's always misclassification. So, I think it's a matter of how much misclassification in the assessment. But, again, we are really limited in really just having exposure over one part of adult life. Dr. Davide Soldato: Thank you very much. And one potentially related question. We are speaking in general about air pollution, but I think that since we are considering residential addresses, probably we are capturing more either traffic pollution or pollution that comes from probably industries or stuff like that, which is mostly related to residential areas or the place where people live. But I think that in the end we also think about air pollution as something that can come from different forms. And one very interesting point, Dr. White, that you made in your editorial is also that there is a global change also in the way we are faced with air pollution. For example, you made the example of wildfires in your editorial and how this might potentially change exposure to air pollution, maybe for limited times, but with concentrations that are fairly higher compared to what we generally observed. So, I was wondering if you could comment a little bit on that and also, if there is potentially a way to also consider this in future epidemiological studies. Dr. Alexandra White: Yeah, so when we talk about exposure to fine particulate matter, PM2.5, we're assessing exposure to particles that are based on the size of the particle, and we're really not evaluating the types of particles that people are experiencing exposure to. And we know that, in general, that PM2.5 composition really varies geographically due to differing sources of exposure. So, like you were saying, there might be a stronger contribution to industry or from agriculture or from traffic. And so that could really change the PM2.5 exposure profile that individuals experience. And so it could be that this is another really important area that this research needs to consider, which could really help us identify what sources of exposure are most relevant. Wildfires are a really important growing concern. We know that wildfires are increasing in both intensity and duration and frequency, and we really don't understand the long-term health impacts of wildfires. But we know that wildfire associated PM2.5 might be one of the most dominant contributors to PM2.5 moving forward. And although we've seen historic declines in PM2.5 in the US after the Clean Air Act, those declines have really stalled. PM2.5 itself is projected to increase over the next few decades, so understanding different PM2.5 composition profiles and the sources that drive them can really help us identify the most important targets for any potential interventions. And wildfire PM2.5 in particular may be of concern because it's a combustion byproduct, and so it's thought to have more of the components that might, we hypothesize, are most relevant for breast cancer, such as PAHs or polycyclic aromatic hydrocarbons or metals. And so, these components are thought to act as endocrine disruptors, which may be particularly relevant for breast cancer. So, I think understanding this changing landscape of PM2.5 moving forward is going to be really important in understanding how PM2.5 contributes to cancers beyond just breast, but as well as other female hormone driven cancers and all of the cancers really. Dr. Davide Soldato: Thank you very much. So, one closing remark, because I think that in general, we have been really in a field of primary prevention for breast cancer where we were focusing on individual behaviors, for example, smoking cessation, reduction in alcohol intake, reduction of BMI, increase of physical activity. But I think that the evidence that is accumulating in the last three years or so is telling us more and more that we also need to shift the perspective on prevention going not only on individuals, but also as including environmental risk. So, I was wondering, how can we include this new evidence in the policies that we implement and how policymakers should act on the data that we have available right now? Dr. Anna Wu: I think it's really important that this new information is communicated to all the stakeholders, including our policymakers, so that they are, first of all, really aware that any changes and not actually adhering to current guidelines can have long lasting consequences, deleterious consequences. And I think it's important to also note that over 90% of the world actually live in areas where PM2.5 exceeds the limit. We have observed increases in breast cancer in many middle- and low-income countries, so I think it's particularly important to emphasize that this is really not just a western country issue, it is really a global issue. Dr. Alexandra White: I agree. And I would just add to that that air pollution is not something that an individual can really change on their own. There are things you can do, you can monitor air quality, you can try to live in a home that's far away from traffic. But really these are large scale problems that really require large scale solutions. And we know that policy changes can be effective here and that this is something that, in my opinion, is not something that we leave to the individual to change. This is something that we as a society should encourage change for the health of everyone. Dr. Davide Soldato: So, thank you very much again, Dr. Wu, Dr. White, for joining us today on the podcast. Dr. Anna Wu: Thank you. Dr. Alexandra White: Thank you so much for having us. Dr. Davide Soldato: So we appreciate you sharing more on your JCO article and accompanying editorial titled, “Air Pollution and Breast Cancer Incidents in the Multiethnic Cohort Study.” If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts. 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. Hedy Kindler joins us on the podcast to discuss the latest update to the treatment of pleural mesothelioma guideline. She discusses the latest changes to the updated recommendations across topics including surgery, immunotherapy, chemotherapy, pathology, and germline testing. Dr. Kindler describes the impact of this guideline and the need for ongoing research in the field. Read the full guideline update, “Treatment of Pleural Mesothelioma: ASCO Guideline Update” at www.asco.org/thoracic-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02425 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Hedy Kindler from the University of Chicago, lead author on “Treatment of Pleural Mesothelioma: ASCO Guideline Update.” Thank you for being here today, Dr. Kindler. Dr. Hedy Kindler: Thank you so much. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kindler, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this podcast episode, first, Dr. Kindler, can you provide an overview of the purpose and scope of this guideline update on pleural mesothelioma? Dr. Hedy Kindler: The initial ASCO practice guideline on mesothelioma, which we published in 2018, was quite comprehensive, but since that time incredible progress has been made which has truly transformed the management of this disease. So we felt it was really important to update the guideline now, focusing on four key areas: the role of surgery, new systemic treatments, pathologic insights, and germline testing. Brittany Harvey: Great. Thank you for highlighting those key areas of the guideline. And so I'd like to next review the key updated recommendations for our listeners. So starting with what are the new updates for surgery? Dr. Hedy Kindler: So surgery has always been controversial in meso, with significant geographic variation in its use. Now, it's even more controversial. Recent randomized data from the MARS 2 trial, placed in the context of other data we also reviewed in this update, suggest that surgical cytoreduction should not be routinely offered to all patients based solely on anatomic resectability. Surgery should only be offered to highly selected patients with favorable prognostic characteristics. This includes comprehensively staged patients with early-stage epithelioid tumors. Patients should preferably be treated at centers of excellence which have documented low morbidity and mortality, and this should also be done in the context of multimodality therapy and preferably within clinical trials. Brittany Harvey: Understood. I appreciate you reviewing those recommendations for who surgery should be offered to. So following those, what are the main recommendations for immunotherapy for treating pleural mesothelioma? Dr. Hedy Kindler: So for a disease in which for 16 years there was only one FDA-approved regimen, pemetrexed and platinum, the pace of recent changes in systemic therapy has been a welcome change with the FDA approval of doublet immunotherapy in October of 2020 and the approval of chemo immunotherapy just a few months ago in September of 2024. Now that we have choices, we've tried to help clinicians determine the optimal treatment regimen for the individual patient. Doublet immunotherapy with ipilimumab and nivolumab should be offered as a first-line systemic option to any mesothelioma patient. For patients with non-epithelioid histology, doublet immunotherapy is hands down the recommended regimen based on the dramatic improvement in survival from 8.8 to 18.1 months for immunotherapy compared with chemo. For patients with previously untreated epithelioid mesothelioma, either ipilimumab-nivolumab immunotherapy or platinum-pemetrexed chemotherapy are reasonable options. Therapy can be individualized based on the patient's comorbidities, acceptance of differing toxicities. and treatment goals. Chemoimmunotherapy with pembrolizumab, pemetrexed, and carboplatin is a newer treatment option for patients with newly diagnosed pleural mesothelioma. This regimen is noteworthy for its very high objective response rate of 62%. Brittany Harvey: It's great to have those new options to improve outcomes for patients. Beyond the chemoimmunotherapy recommendation that you just described, what are the highlights for chemotherapy recommendations? Dr. Hedy Kindler: So pemetrexed platinum-based chemotherapy with or without bevacizumab still plays a role in this disease and should be offered as a first-line treatment option in patients with epithelioid histology. This regimen is not recommended in patients with non-epithelioid disease unless they have medical contraindications to immunotherapy. Pemetrexed maintenance chemotherapy following pemetrexed-platinum chemotherapy is not recommended. Brittany Harvey: Thank you for reviewing those recommendations as well. So then next, what are the important changes regarding pathology? Dr. Hedy Kindler: Well, one fun fact is that we've changed the name of the disease. It's no longer malignant mesothelioma. Now it's just mesothelioma. Since the non-malignant mesothelial entities have been renamed, all mesos are now considered malignant, so there's no need to use the prefix malignant in the disease name. Mesothelioma should be reported as epithelioid, sarcomatoid, or biphasic because these subtypes have a clear prognostic and predictive value. Knowing the subtype helps us decide on whether chemotherapy or immunotherapy is the optimal treatment for a patient, so it must be reported. Additionally, within the epithelioid subtype, histologic features, including nuclear grade, some cytologic features, and architectural patterns should be reported by pathology because they have prognostic significance. Pathologists have recently identified a premalignant entity, mesothelioma in situ, which can be found in patients with long standing pleural effusions and should be considered in the differential diagnosis. In the appropriate clinical setting, additional testing, including BAP1 and MTAP IHC should be performed. Brittany Harvey: Definitely. These pathologic recommendations are important for treatment selection. So in that same vein, in the final section of the recommendations, what are the updated recommendations from the panel regarding germline testing? Dr. Hedy Kindler: This is one of our most important recommendations, that universal germline testing should be offered to all mesothelioma patients. The proportion of patients with mesothelioma who have pathogenic or likely pathogenic germline variants is similar to other diseases in which universal germline genetic testing and counseling are now the standard of care. This is most commonly observed in the tumor suppressor gene BAP1 and this not only affects cancer risk in patients and their family members, but also has key prognostic significance. For example, pleural mesothelioma patients with BAP1 germline mutations who receive platinum-based chemotherapy live significantly longer, 7.9 years compared to 2.4 years for those without these mutations. Thus, we recommend that all patients with mesothelioma should be offered universal germline genetic counseling and/or germline testing. Brittany Harvey: So there were a large amount of new and updated recommendations in this update. So in your view Dr. Kindler, what is the both importance of this update and how will it impact both clinicians and patients with pleural mesothelioma? Dr. Hedy Kindler: Even as we were researching and writing this update, new data kept emerging which we needed to include. So it's clearly a time of great progress in the management of this disease. We've comprehensively reviewed and analyzed the extensive emerging data and provided clinicians with a roadmap for how to incorporate these new advances into their management of this disease. Brittany Harvey: Absolutely, that is key for optimal patient care. So you've just mentioned emerging data and rapid evidence generation, so what future research developments are being monitored for changes in the treatment of pleural mesothelioma? Dr. Hedy Kindler: Despite these recent advances in disease management, mesothelioma continues to be a lethal cancer, and there's clearly a need to develop better treatments. This includes ongoing studies of novel immunotherapeutic agents such as bispecific antibodies, cell therapy using chimeric antigen receptors targeting mesothelioma tumor antigens, and precision medicine approaches to target tumor suppressor genes. Finally, strategies for early cancer detection and prevention are vital for individuals predisposed to develop mesothelioma due to BAP1 and other germline mutations, as well as for those who are occupationally or environmentally exposed to asbestos. Brittany Harvey: Absolutely. We'll look forward to these new updates to continue development in the field. So thank you so much for this mountain of work to update this guideline, and thank you for your time today, Dr. Kindler. Dr. Hedy Kindler: Thank you so much. It's been a pleasure. Thank you for asking me to do this. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
In this JCO Article Insights episode, Giselle de Souza Carvalho provides a summary on "Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies" by Bhardwarj, et al and "US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations" by Dilawari et al published in the Journal of Clinical Oncology. TRANSCRIPT Giselle Carvalho: Hello and welcome to JCO Article Insights episode for the December issue of the Journal of Clinical Oncology. I'm your host Giselle Carvalho, Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers and one of the ASCO Editorial Fellows at JCO this year. Today, I will be discussing two articles. The first one is “Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies,” and the second one is the “US FDA Approval Summary on Capivasertib with Fulvestrant for HR-positive HER2-negative Locally Advanced or Metastatic Breast Cancer with PIK3CA/AKT1/PTEN Alteration.” As we know, 65% to 70% of all breast cancers are HR-positive HER2-negative and this is also the most common subtype of metastatic breast cancer. The current standard of care for frontline therapy of patients with luminal metastatic disease is a CDK4/6 inhibitor in combination with endocrine therapy. However, as new endocrine and targeted therapies gain approval, choosing the best systemic therapy upon disease progression after frontline therapy is a topic of ongoing debate. Nearly 40 to 50% of HR-positive breast cancers have actionable genomic alterations and molecular testing should be a routine recommendation for patients with metastatic HR-positive HER2-negative disease. This can be performed repeating tissue biopsy at the time of progression or from archival tissue. Treatment options after progression on CDK4/6 inhibitors include alpelisib in combination with fulvestrant in patients with PIK3CA mutant tumors as seen in the SOLAR-1 trial, or capivasertib with fulvestrant in patients with a tumor mutation in (PI3K)–AKT–PTEN pathway as seen in the CAPItello-291 study, which will be discussed further. In approximately 30% of patients, progression on frontline endocrine plus CDK4/6 inhibitor treatment is caused by endocrine resistance, frequently involving activating mutations in ESR1. For those tumors, elacestrant, an oral SERD is an option as demonstrated in the EMERALD trial. For patients with a BRCA mutation, PARP inhibitors represent another option. If no mutations are detected, everolimus, an mTOR inhibitor, can be used based on the BOLERO-2 results. The phase 2 MAINTAIN and PACE trials, along with the phase 3 postMONARCH trial support changing the endocrine therapy backbone with or without switching the CDK4/6 inhibitor. In less resourced areas, fulvestrant monotherapy is still an option to delay cytotoxic chemotherapy, though its efficacy is limited when used as a single agent. Finally, after progression on at least one line of chemotherapy, antibody drug conjugates including sacituzumab govitecan or trastuzumab deruxtecan may be an option. Now focusing on the PI3K AKT PTEN signaling pathway, activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN occur in approximately half of luminal breast cancers. In June 2023, the CAPItello-291 trial was published and treatment with fulvestrant plus capivasertib, a PTEN AKT inhibitor, demonstrated a 3.6 month PFS benefit compared to fulvestrant alone, regardless of the presence of AKT pathway alterations. However, for those with tumors without AKT pathway alteration, an exploratory analysis showed that although there was a numerical improvement in PFS, it did not meet statistical significance, indicating that the biomarker positive population primarily drove the positive results noted in the overall population. Therefore, capivasertib plus fulvestrant was approved by the US FDA in November 2023 exclusively for patients with PI3K/AKT1/PTEN tumor alterations after progression on an aromatized inhibitor with or without a CDK4/6 inhibitor. The approved schedule of capivasertib is slightly different from that of other agents used in breast cancer. It is 400 milligrams taken orally twice a day for four days per week every week in a 28-day cycle in combination with fulvestrant. Diarrhea, rash and hyperglycemia were the most commonly reported grade three or four adverse events in the interventional group. I would like to highlight that even though the CAPItello trial excluded patients with glycosylated hemoglobin levels higher than 8% or those diagnosed with diabetes who required insulin, hyperglycemia occurred in 19% of biomarker positive patients treated with capivasertib, with nearly 2% of this population experiencing grade 3 or 4 hyperglycemia and some patients experiencing life threatening outcomes such as diabetic ketoacidosis. By way of comparison, hyperglycemia of any grade was three times higher with alpelisib therapy in the SOLAR-1 trial, occurring in 64% of the patients and grade three or higher hyperglycemia was seen in 37% of the patients. Diarrhea was the most common treatment related adverse event experienced by 77% of the biomarker positive population. Prompt use of the antidiarrheal drugs when needed, such as loperamide must be encouraged as untreated diarrhea can lead to dehydration and renal injury. Cutaneous rash occurred in 56% of the biomarker positive population in the interventional group and 15% experienced a grade 3 or 4 rash. Nearly half of the patients with cutaneous adverse reactions required treatment and this was the leading reason for dose reduction of capivasertib. In the biomarker positive population, the improvement in medium PFS were 4.3 months by investigator assessment. Overall survival data from the CAPItello-291 trial is still immature, but quality of life data was recently published in September this year and was assessed by the 30 item QLQ C30 questionnaire and the QLQ BR23, the breast module. According to Oliveira et al, global health status and quality of life were maintained for a longer period with capivasertib fulvestrant than with placebo fulvestrant except for symptoms of diarrhea which were significantly worse in the capivasertib group. The median time of deterioration of global health status and quality of life was twice as long in the capivasertib group being almost 25 months versus 12 months in the placebo fulvestrant group. These data reinforced the use of capivasertib in combination with fulvestrant for the treatment of HR-positive HER2-negative advanced breast cancer patients with PIK3CA/AKT1/PTEN tumor alterations who have progressed after an aromatase inhibitor-based therapy with or without a CDK4/6 inhibitor. Thank you for listening to JCO Article Insights. This is Giselle Carvalho. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. See you next time. 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.
Two studies published in the same week reveal how seed oils like canola, corn, soy and cottonseed may increase inflammation, creating a pathway for cancer to thrive. On the flip side, omega-3-rich fish oils show promise in reducing inflammation and bolstering the immune system. Listen in this week as Dee discusses the science behind these findings and their potential impact on your health.References:Aronson, W. J., Grogan, T., Liang, P., Jardack, P., Liddell, A. R., Perez, C., Elashoff, D., Said, J., Cohen, P., Marks, L. S., & Henning, S. M. (2024). High omega-3, low omega-6 diet with fish oil for men with prostate cancer on active surveillance: The CAPFISH-3 randomized clinical trial. Journal of Clinical Oncology, JCO2400608. Advance online publication. https://doi.org/10.1200/JCO.24.00608Soundararajan, R., Maurin, M. M., Rodriguez-Silva, J., Upadhyay, G., Alden, A. J., Gowda, S. G. B., Schell, M. J., Yang, M., Levine, N. J., Gowda, D., Sundaraswamy, P. M., Hui, S., Pflieger, L., Wang, H., Marcet, J., Martinez, C., Bennett, R. D., Chudzinski, A., Karachristos, A., . . . Yeatman, T. J. (2024). Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer. Gut, gutjnl-332535. https://doi.org/10.1136/gutjnl-2024-332535
Dr. Van Morris presents the new evidence-based guideline on systemic therapy for localized anal squamous cell carcinoma. Dr. Morris discusses the key recommendations from the Expert Panel, including recommended radiosensitizing chemotherapy agents, dosing and schedule recommendations, the role of induction chemotherapy and ongoing adjuvant chemotherapy, and considerations for special populations. He emphasizes the importance of this first guideline from ASCO on anal squamous cell carcinoma for both clinicians and patients with stage I-III anal cancer, and ongoing research the panel is looking to for the future. Read the full guideline, “Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02120 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Van Morris from MD Anderson Cancer Center, co-chair on “Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline.” Thank you for being here today, Dr. Morris. Dr. Van Morris: Thank you for having me. On behalf of our committee who put together the guidelines, I'm really excited to be here and talk with you today. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Morris, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this guideline, Dr. Morris, can you provide an overview of both the purpose and the scope of this guideline on stage I to III anal squamous cell carcinoma? Dr. Van Morris: So anal cancer is considered a rare malignancy for patients in the United States and across the world as well. Even though it's not something we see as commonly, for example, as the adjacent colorectal cancer, this still is a cancer that is rising in incidence every year in the United States. And really, despite the presence of the preventative HPV vaccines, which we hope will ultimately prevent and eradicate this cancer, we still expect the incidence to continue to rise in the coming decades before we really start seeing numbers begin to decrease as a result of the vaccine. So this is an alarming trend for which oncologists will continue to see likely more and more cases and new diagnoses every year. So we wanted to review the most recent literature and provide oncologists up to date recommendations for how they can best take care of patients with a new diagnosis of localized anal cancer. Brittany Harvey: Absolutely. I appreciate that background and context to set the stage for this guideline. So then next I'd like to review the key recommendations of this guideline. So starting from the first clinical question, what are the recommended radiosensitizing, doublet or single chemotherapy agents for patients with stage I to III anal cancer? Dr. Van Morris: It's true that really the standard treatment for patients with localized anal cancer has not changed over the last literally half century. When the Nigro regimen was first reported back in 1974, 50 years ago, the standard of care for patients with a new diagnosis of localized anal cancer centers around concurrent chemotherapy and radiotherapy. And we looked at the various randomized control trials and the highest level of evidence which has been reported over the past decades, and really for most patients, the standard of care continues to remain doublet cytotoxic chemotherapy in combination with radiation. We reported that the most commonly, and I think most accepted, regimen here is a combination regimen of 5-FU, intravenous 5-fluorouracil with mitomycin C. And this most commonly is given on a week 1 to 5 regimen. The 5-FU, we recommended a dose of 1000 milligrams per meter squared per day on days 1 to 4 and then on days 29 to 32 of the radiation treatment. And then the mitomycin C, looking at various trials, has been given at a dose of 10 milligrams per meter squared on day 1 and day 29, or alternatively a single dose of mitomycin C at 12 milligrams per meter squared on day 1. I think that the thing that's important for clinicians and patients alike to remember is that this chemotherapy can be very toxic in patients who are undergoing a curative-intent therapy for this diagnosis of localized anal cancer. I think it's just important for oncologists to be watching closely the blood counts for the patients to make sure that the myelosuppression doesn't get too bad. And then in select cases, if that is the case, when the oncologist opts to go for the day 1 and day 29 dosing, it may be prudent, if the myelosuppression is too excessive, to consider withholding that day 29 dose. Brittany Harvey: Great. Thank you for providing those recommendations along with some of those dosing and the schedule recommendations from the expert panel. So are there any other alternate dose or schedule recommendations from the expert panel? Dr. Van Morris: Yeah, but I think that we saw with the ACT II data that was a randomized trial that was done out of the UK that compared 5-FU mitomycin with 5-FU cisplatin as two different doublet cytotoxic regimens, that overall outcomes were very similar between the two regimens in terms of curative outcomes for patients treated whether 5-FU mitomycin or 5-FU cisplatin. So certainly there is evidence supporting the use of cisplatin as a second cytotoxic agent with 5-fluorouracil. In the ACT II study that was given at a dose of 60 milligrams per meter squared on days 1 and 29 along with the 5-FU at the regimen I talked about previously. There is other lower level of evidence data suggesting that even the 5-FU and cisplatin can be given on a weekly schedule and that that can be safe. Actually, at my institution at MD Anderson, that is our standard practice pattern as well. There's also the option when we're thinking about giving pelvic radiation for patients with lower GI cancers, many oncologists in the treatment of localized rectal adenocarcinoma are accustomed to using capecitabine as a chemosensitizer in patients with localized rectal cancer. If I'm giving chemoradiation for a patient with localized anal cancer, can I substitute the intravenous 5-FU with oral capecitabine? And although the evidence is not as strong in terms of available data with regards to randomized controlled trials, there certainly is data that suggests that capecitabine may be an acceptable alternative in lieu of intravenous 5-fluorouracil that would be given at a dose of 825 milligrams per meter squared on days of radiation. But certainly, I think that that's a feasible approach as well and maybe even associated with less hematologic toxicity than intravenous 5-FU would be. Brittany Harvey: Great. It's important to understand all the options that are out there for patients with early-stage anal squamous cell carcinoma. So in addition to those chemoradiation recommendations, what is recommended from the expert panel regarding induction chemotherapy or ongoing adjuvant chemotherapy for this patient population? Dr. Van Morris: When we think about treating patients with lower GI cancers with curative intent therapies, when we think about the more common rectal adenocarcinoma, oncologists may be used to giving chemoradiation followed by subsequent cytotoxic chemotherapy. But actually when you look at the data for anal cancer, really there's not any data that strongly supports the use of either induction chemotherapy prior to chemoradiation or adjuvant post-chemoradiation chemotherapy. The RTOG 98-11 study was a trial which evaluated the role of induction 5-fluorouracil prior to chemoradiation and did not show any survival benefit or improved outcomes with the use of induction chemotherapy in a randomized control trial setting. The ACT II trial, which I referenced earlier, was a 2 x 2 design where patients were either randomized to concurrent chemoradiation with 5-FU mitomycin C or concurrent chemoradiation with 5-FU cisplatin. But then there was a second randomization after chemoradiation where half of the study participants received adjuvant cisplatin 5-fluorouracil after completion of their chemo radiation, or the other half were randomized to the standard of care, which of course would be observation. And what that trial showed was that there was no added benefit with the addition of post-chemoradiation cytotoxic chemotherapy. So we look at these data and say that in general, for the general population of patients with localized stages I to III anal cancer, there really is no supporting data suggesting benefit of either induction chemotherapy or adjuvant chemotherapy. And to that end, really it's concurrent chemoradiation remains the standard of care at this time for patients with a new diagnosis of localized anal cancer. Brittany Harvey: Absolutely. It's just as important to know what is not recommended as it is to know what is recommended for these patients. And so I thank you for explaining the evidence behind that decision from the panel as well. So then, are there any other considerations for special populations that oncologists should consider? Dr. Van Morris: I think so. I think that anal cancer is a disease where we don't see that many patients being diagnosed earlier at a younger age, especially in relation to the alarming trend of early onset colorectal cancer that we're currently seeing right now. So there may be patients who come with a new diagnosis of localized anal cancer who are an octogenarian at an advanced age or may have other significant medical comorbidities. And if that is the case, we get called about this quite frequently from outside institutions. I have an 85 year old who is coming to my clinic with this diagnosis. I don't feel comfortable giving this patient doublet cytotoxics, what options do I have? Especially given other organ dysfunction that may precede this diagnosis. And I think that in that case, there are times when it's okay safely to drop the mitomycin C and opt for single agent 5-fluorouracil as a single cytotoxic agent. So I think that that would be something that we've certainly incorporated into our practice at our institution. There's also an association between various autoimmune disorders, patients on immunosuppression, even persons living with HIV being at higher risk for this virally associated cancer. So I think that, again, if the patient is coming with baseline immunosuppression for these reasons prior to treatment, certainly kind of being in tune to the potential for hematologic toxicity. And watching these patients very closely as they're getting chemoradiation remains really important. Brittany Harvey: Definitely. So, you've just discussed some of those comorbidities and patient characteristics that are important for clinicians to consider when deciding which regimens to offer. So in addition to those, in your view, what is the importance of this guideline and how will it impact clinical practice for clinicians who are reading this guideline. Dr. Van Morris: Chemoradiation remains a very effective option and most patients will be cured with this diagnosis and with this treatment. So it's important to make sure that these patients are able to safely get through their treatment, minimizing treatment delays due to toxicities which may come about because of the treatment, and really help to carry them over the finish line so that they have the best likelihood for achieving cure. So we really hope that these data will provide oncologists with a readily available summary of the existing data that they can refer to and continue to help as many patients as possible achieve and experience a cure. Brittany Harvey: Absolutely. So then to build on that, it's great to have this first guideline from ASCO on anal squamous cell carcinoma. But how will these new recommendations affect patients with stage I to III anal cancer? Dr. Van Morris: I certainly hope it will allow patients and oncologists to know what their options are. It certainly is not a one size fits all treatment approach with regards to the options which are available. Depending on the patient, depending on the various medical conditions that may accompany them, these treatments may need to be tailored to most safely get them through their treatment. Brittany Harvey: I appreciate you describing the importance of this guideline for both clinicians and patients. So what other outstanding questions and future research do you anticipate seeing in this field? Dr. Van Morris: It's a really good question and I think that there is a lot coming on the horizon. Even though the standard treatment has really not changed over the last half century, I think it still remains true that not all patients will achieve cure with a chemoradiation treatment. So a recent trial has completed enrollment in the United States, this is the EA2165 trial led by one of our committee members, Dr. Rajdev and Dr. Eng as well, that's looking at the use of nivolumab anti PD-1 immunotherapy after completion of concurrent chemo adiation. So in that trial, patients were randomized to concurrent chemoradiation followed by either observation or six months of adjuvant anti PD-1 therapy. We're really awaiting the results of that. Hopefully if we see an improvement with the addition of nivolumab following concurrent chemoradiation, our hope would be that more patients would be able to achieve a cure. So we're certainly looking forward to the outcomes of that EA2165 study. And then I think one question that we often get from our patients in the clinics is, “What is the role of circulating tumor DNA in the management of my disease?” And really, to date there have been some series which have shown that we can assess patients or circulating tumor DNA after completion of their concurrent chemo radiation that may need to start about three months after to give time for the radiation to wear off and most accurately prognosticate that. But I think that this will be a powerful tool moving forward, hopefully, not only in the surveillance to identify patients who may be at high risk for recurrence, but ultimately to translate that into next generation clinical trials which would treat patients at higher risk for recurrence by virtue of a detectable circulating tumor DNA result. In doing so, hopefully cure even more patients with this diagnosis. Brittany Harvey: Yes, we'll look forward to these developments and hope to add more options for potential treatment and surveillance for patients with anal cancer. So, I want to thank you so much for your work to develop these guidelines and share these recommendations with us and everything that the expert panel did to put this guideline together. Thank you for your time today, Dr. Morris. Dr. Van Morris: Thank you. And thank you to ASCO for helping to keep this information out there and ready for oncologists for this rare cancer. Brittany Harvey: Absolutely. And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
In this episode of SurgOnc Today®, Dr. Julie Hallet, Chair of the HPB Disease Site Work Group, and Dr. Patricio Polanco, Vice-Chair of the HPB Disease Site Work Group, are joined by Drs. Sajid Khan from Yale School of Medicine and Dr. Cecilia Ethun from UT Southwestern. They will wrap the 2024 HPB year by reviewing the top HPB surgical oncology published this year. References/Resources: #10: AMPLIFY https://www.nature.com/articles/s41591-023-02760-3 #9: Adjuvant therapy for IPMN-derived PDAC - https://ascopubs.org/doi/abs/10.1200/JCO.23.02313 #8: HELIX https://jamanetwork.com/journals/jama/fullarticle/2822555 #7: CAMINO https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00572-7/fulltext #5 : PANDAS/PRODIGE https://www.annalsofoncology.org/article/S0923-7534(24)03884-5/fulltext
The Accelerators (Drs. Matt Spraker and Simul Parikh) host Dr. Donald Abrams, MD, Medical and Integrative Oncologist at the UCSF Oscher Center for Integrative Health. Donald offers a comprehensive review of a very poorly understood topic! We review the history of cannabis regulation in the US and globally, different delivery forms, and Donald's observations throughout his oncology practice. We additionally discuss indications for use in cancer care; is smoking cannabis safer than taking sugary edibles?Of course, we discuss cannabis misinformation. Right now Donald offers the best discussion of this topic that we have seen.We close the episode with a dicussion of CBD, the future, and a bit on studies of psychedelic therapies and melatonin. Don't miss the ASCO Cannabis and Cannabinoids guideline. Here are some other things we discussed during the show:The Marijuana Tax Act and AMA oppositionThe Controlled Substences ActFederal Marijuana Compassionate Use ProgramBraun et al., JCO, National Survey of Medical Oncologists PerceptionsNASEM report on The Health Effects of CannabisTashkin, Annals ATS, Effects of marijana smoking on the lungNabiximolsWaissengren et al, TAMO, Effect of cannabis on oxaliplatin-induced peripheral neuropathyOverview of cannabis for peripheral neuropathy (Cleveland Clinic)Munson et al, JNCI, Antineoplastic Activity of CannabinoidsGuzmán et al., Br J Cancer, Pilot study of CBD for recurrent GBMTwelves et al., Br J Cancer, Phase 1b study of CBD for recurrent GBMBook Rec: The First Cell, Azra RazaPiper et al, Cancers, Regarding cannabinoids and immunotherapyThe Accelerators Podcast is a Photon Media production.
The 1st menin inhibitor, revumenib, is approved for relapsed/refractory acute leukemias. Understanding the Pathway: https://doi.org/10.1200/JCO-24-01265
Dr. Greg Kalemkerian reviews the latest evidence-based rapid update from the Expert Panel on systemic therapy for small cell lung cancer. He discusses the updated recommendations for patients with limited-stage SCLC based on the ADRIATIC trial, and for patients with relapsed SCLC based on the DeLLphi-301 trial. Dr. Kalemkerian shares insights on what these changes mean for clinicians and patients, and highlights new trials in progress to provide more options for patients diagnosed with SCLC. Read the full rapid update, “Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/thoracic-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02245 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Greg Kalemkerian from the University of Michigan, lead author on, “Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update”. Thank you for being here today, Dr. Kalemkerian. Dr. Greg Kalemkerian: Thank you. Thank you for the invitation. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kalemkerian, who has joined us here today, are available online with the publication of the update in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this rapid update, Dr. Kalemkerian, what prompted this update to the Systemic Therapy for Small Cell Lung Cancer Guideline, which was previously published in 2023? Dr. Greg Kalemkerian: So even though the original guideline only came out a year ago, the past year we've seen two significant advances in small cell lung cancer with two reports, one in limited stage with the addition of immunotherapy, the other in the addition of a new immunotherapeutic agent in relapsed small cell lung cancer. Brittany Harvey: It's great to have this new data in the small cell lung cancer space. So based on these new changes, what are the updated recommendations from the expert panel? Dr. Greg Kalemkerian: So the first recommendations have to do with patients with limited-stage small cell lung cancer based on the ADRIATIC trial which added consolidation durvalumab for patients who had not had progression after standard chemotherapy and radiotherapy. And this study demonstrated a significant improvement in overall survival with about a 10% improvement in both 2- and 3-year overall survival, up to a 57% overall survival at 3 years for the patients receiving consolidation durvalumab. And based on those findings, we updated the recommendation for the standard treatment for limited-stage small cell lung cancer such that it included the use of consolidation immunotherapy with durvalumab for up to two years in patients who had had no disease progression, and completion of concurrent chemoradiotherapy for limited-stage small cell lung cancer. Of course, those patients would be those who do not have contraindications to the use of immunotherapy. As a corollary to that recommendation, for patients who have poorer performance status, so performance status of 3 or 4, who had had initial treatment perhaps with sequential chemotherapy and radiotherapy, if their performance status improves with their initial treatment, then it would also be reasonable to add consolidation immunotherapy for those patients as long as their performance status maintains improvement and they have no evidence of progression. The other update of the guidelines had to do with patients with relapsed small cell lung cancer and that was based on the DeLLphi-301 trial which was a phase II study looking at the use of tarlatamab, a bispecific T cell engager, binds to both DLL3 and CD3 in order to increase the immune killing of small cell lung cancer cells. So what this study did was it treated patients who had had at least two prior regimens. So this is third-line or beyond was what the population that this study looked at. And the majority of these patients had already had some immune checkpoint therapy. They all had good performance status and it did allow patients with brain metastases to be included in the study. When we look at the patients who received the approved 10 milligram dose of the drug, the response rate was about 40%. Responses were seen in both patients with sensitive and refractory based on the time since their prior treatment and the median duration of response was 10 months, which is much better than anything we've seen before with relapsed small cell lung cancer patients, remembering that all these patients were also third-line or beyond. So based on the results of the DeLLphi-301 trial, we updated two of the recommendations regarding relapsed small cell lung cancer. In the first one, we stated that in patients with relapsed small cell lung cancer with a chemotherapy free interval of less than 90 days, single agent systemic therapy would be considered standard of care, and that the preferred agents would include topotecan, lurbinectedin, or, now, tarlatamab. We did mention as a qualifying statement that single-agent chemotherapy is preferred over multi-agent chemotherapy. And the second recommendation was that, in patients with relapsed small cell lung cancer with a chemotherapy interval longer than 90 days, the rechallenge with a platinum-based regimen or single-agent chemotherapy was considered standard and the preferred agents for single agent therapy would be topotecan, lurbinectedin, or tarlatamab being added in the recent study. Tarlatamab was approved by the FDA for use in patients with relapsed small cell lung cancer with no stipulations with regard to the treatment. Brittany Harvey: Understood. I appreciate you describing those updated recommendations along with the supporting data for both limited stage small cell lung cancer and relapsed small cell lung cancer. So then, what should clinicians know as they implement these new and updated recommendations into practice? Dr. Greg Kalemkerian: So with regard to the ADRIATIC trial or the consolidation durvalumab being added for limite- stage small cell lung cancer patients, I think the important considerations are that this was done after patients had demonstrated no progression of disease after chemotherapy and radiotherapy, so the initial treatment does not change with platinum-etoposide plus definitive radiotherapy being recommended. The addition of durvalumab is going to be potentially useful in patients generally with good performance status, so performance statuses 0 to 1, and we still have to pay attention to the patients who may have contraindications to immunotherapy, things like interstitial lung disease, autoimmune problems that do occur in patients with small cell lung cancer where they develop paraneoplastic autoimmune syndromes such as Lambert-Eaton myasthenic syndrome. Those patients with those types of preexisting conditions would not be good candidates for immunotherapy use. So still having the tailored treatment to the individual patient is what's most important. The duration of the durvalumab was up to two years and not beyond that, so following those specific guidelines for the use of durvalumab in patients with limited-stage small cell lung cancer. With regard to tarlatamab, tarlatamab is an immunotherapy treatment. So we still do have the exclusions of people who have had prior severe immune-related adverse events, people who have pneumonitis, people who have interstitial lung disease, people with autoimmune neurologic problems we can see with small cell lung cancer, these patients should not be considered good candidates for the use of tarlatamab. The study did include patients who had had treated and asymptomatic brain metastases and there is some evidence that tarlatamab can have some control of brain metastases. So that's not necessarily an exclusion. Tarlatamab does have some other specific considerations to it in that 51% of patients had some evidence of cytokine release syndrome (CRS). Only 1% of those patients had grade 3 CRS. So even though they had frequent fevers and hypotension and hypoxia, it was generally not severe. But this concern for CRS and also for neurologic complications after treatment does require that patients be admitted to the hospital for a 24-hour observation period during the first and second doses. Subsequent to that, patients can be observed for some time after the infusion in the outpatient setting. But they also need to have very clear and strict guidance for when they go home about what things to look for. Looking for fevers, looking for shortness of breath, looking for any neurologic changes. It's a good idea for them to have a caregiver with them in order to observe them during that time. Most of these complications occur during the first or second cycles, but it is a drug that is going to require significant education not only of our staff, but also of the patients in order to ensure that the drug's used safely. Brittany Harvey: Absolutely. For these new options, it's important to tailor cancer treatment to the individual patient and the factors that you mentioned and be mindful of these potential toxicities. So, it's always great to learn of new options for patients. But in your view, how will this update impact patients with small cell lung cancer? Dr. Greg Kalemkerian: Well, clearly we need longer term follow up. So, with regard to the limited-stage small cell lung cancer situation, that's a curative situation. We have been curing patients with limited-stage disease with chemotherapy and radiotherapy for several decades now, but the cure rates were relatively low with about 25%, 30% of people becoming long term survivors. Now the hope is with the durvalumab being added on, that we can increase that number. Thus far, we have three-year survival data with a three-year survival of 57% overall survival and we're hoping that that is maintained over time and that we're not just delaying recurrences, but that we're actually preventing recurrences and helping people live longer, as has been seen with non-small cell lung cancer in stage III disease with the addition of durvalumab to chemoradiotherapy. So hopefully, we will be improving the cure rate of people with limited-stage small cell lung cancer. There are several other trials with immunotherapy in this space coming down the line and we're anxiously awaiting not only long term follow up from ADRIATIC, but also initial data from studies such as KEYLYNK and ACHILLES and NRG-LU005. So all of these studies in the next few years are hopefully going to guide treatment for limited-stage small cell lung cancer and hopefully improve the long term survival outcomes. With regard to tarlatamab, unclear at this point what the long term outcomes are going to be. Is a 40% response rate substantially better than what we've seen before? Well, lurbinectedin also had about a 40% response rate in patients who had sensitive disease, but the duration of response does look longer. And there are some patients now who have been on this study that are doing very well for quite long periods of time with the drug. So, the hope here also is that we will have some small subset of patients who continue to do better for long periods of time. Whether that'll translate into a cure or not, way too early to know, clearly hoping to add another brick in the wall so that we can keep the disease at bay, at least for a longer period of time for these patients. How we will integrate tarlatamab into the regimens is a bit unclear. Whether most of us will start using it as second-line therapy or whether we will use perhaps lurbinectedin or topotecan as second-line and tarlatamab as third-line, we're all going to have to work that out based on the potential toxicities, the logistical complications of using the drug at this point in time. But I do think that it's nice to have more options to add to our armamentarium to treat this very, very challenging and difficult disease. Brittany Harvey: Definitely. So, you've just discussed the need for both longer term follow up here along with some important ongoing trials in this space. So we'll look forward to future readouts of those trials to learn more about caring for patients in small cell lung cancer. So, I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Kalemkerian. Dr. Greg Kalemkerian: Okay. Again, thank you for the invitation, Brittany, and thanks to ASCO for developing the whole guideline structure to help all of us take better care of our patients. Brittany Harvey: Absolutely. And also thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full update, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
A nice editorial succinctly summarizes a framework for thinking about how to incorporate anthracyclines into the treatment of early stage breast cancer patients. Anthracyclines in Early Breast Cancer: The Long Goodbye -https://doi.org/10.1200/JCO-24-01916 10-year Outcomes of READ trial: https://doi.org/10.1200/JCO.24.00836 Bonus - Practical Guide for Testing for Pharmacogenomics: https://doi.org/10.1200/OP.24.00191
In this episode, we discuss the comeback of belantamab mafadotin in multiple myeloma with Dr. Hang Quach, along with some other important abstracts presented at EHA/ASCO 2024. Here are the studies we discussed: 1. DREAMM-7 RCT: Belantamab-Vd vs Daratumumab-Vd in relapsed MM. https://pubmed.ncbi.nlm.nih.gov/38828933/2. DREAMM-8 RCT: Belantamab-Pd vs PVd in relapsed MM. https://pubmed.ncbi.nlm.nih.gov/38828951/3. Long-term follow-up of CASSIOPEIA Trial: https://pubmed.ncbi.nlm.nih.gov/38889735/4. Update on MRD data from PERSEUS Trial: https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.7502
Is your microwave ablation technique up to date? Dr. Ed Kim sits down with guest-host Dr. Kavi Krishnasamy to explore cutting-edge techniques in tumor ablation, with a focus on hepatocellular carcinoma (HCC) treatment with microwave. Dr. Ed Kim is the Director of Interventional Oncology and Professor of Radiology and Surgery in the Division of Vascular and Interventional Radiology at the Mount Sinai Medical Center. --- This podcast is supported by an educational grant from: Varian, a Siemens Healthineers company https://www.varian.com/ --- SYNPOSIS The doctors discuss microwave ablation, radiation segmentectomy, and the decision-making algorithms for choosing appropriate procedures based on lesion characteristics. Dr. Kim touches on the complexities of ablation near the diaphragm and subcapsular lesions, emphasizing the impact of practitioner skill and experience on outcomes. Recent advancements in ablation technologies, software, and device-specific versus device-agnostic applications are also highlighted, along with the importance of post-contrast scans and ultrasound skills. Dr. Kim also delves into emerging technologies such as HistoSonics, augmented reality/virtual reality, and immunotherapy synergies. The doctors underscore the need for a multidisciplinary approach for optimizing patient outcomes and pushing the field toward future innovations. --- TIMESTAMPS 00:00 - Introduction 04:28 - Standardizing Ablation Algorithms 07:51 - Suboptimal Lesion Locations 13:06 - Device Selection and Properties 22:49 - Ablation Planning Software 32:53 - Real-Time Visualization 44:48 - Biopsy and Ablation Techniques 52:14 - Future of Ablation Technology --- RESOURCES Dr. Ed Kim's Publications: https://scholars.mssm.edu/en/persons/edward-kim ACCLAIM Trial: https://www.sio-central.org/ACCLAIM-Trial A multicenter randomized controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF trial): Analysis of overall survival: https://ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.4093 Surgery versus thermal ablation for small-size colorectal liver metastases (COLLISION): An international, multicenter, phase III randomized controlled trial. https://ascopubs.org/doi/10.1200/JCO.2024.42.17_suppl.LBA3501 SIR welcomes results of COLLISION Trial, presented at the 2024 ASCO Annual Meeting: https://www.sirweb.org/media-and-pubs/media/news-release-archive/collision-trial-06032024/ HistoSonics: https://histosonics.com/
Reviewing 3 recent AML publications Double-Dauno (90 mg/m2 vs. 60 mg/m2): https://doi.org/10.1200/JCO.24.00235 AML60+ Risk Stratification: https://doi.org/10.1200/JCO.23.02631 Decitabine-Ven as bridge to Allo HSCT: https://doi.org/10.1016/S2352-3026(24)00241-2
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