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Dr. Kathleen Horst, Dr. Rachel Jimenez, and Dr. Yara Abdou discuss the updated guideline from ASTRO, ASCO, and SSO on postmastectomy radiation therapy. They share new and updated recommendations on topics including PMRT after upfront surgery, PMRT after neoadjuvant systemic therapy, dose and fractionation schedules, and delivery techniques. They comment on the importance of a multidisciplinary approach and providing personalized care based on individual patient characteristics. Finally, they review ongoing research that may impact these evidence-based guidelines in the future. Read the full guideline, “Postmastectomy Radiation Therapy: An ASTRO-ASCO-SSO Clinical Practice Guideline” at www.asco.org/breast-cancer-guidelines" TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-01747  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Kathleen Horst, expert panel chair from Stanford University; Dr. Rachel Jimenez, expert panel vice chair from Massachusetts General Hospital; and Dr. Yara Abdou, ASCO representative from the University of North Carolina, authors on "Postmastectomy Radiation Therapy: An American Society for Radiation Oncology, American Society of Clinical Oncology, and Society of Surgical Oncology Clinical Practice Guideline." Thank you for being here today, Dr. Horst, Dr. Jimenez, and Dr. Abdou. Dr. Kathleen Horst: Thank you for having us. Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Horst, Dr. Jimenez, and Dr. Abdou who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. Then to dive into the content that we are here today to talk about, Dr. Horst, could you start us off by describing what prompted the update for this joint guideline between ASTRO, ASCO, and SSO, and what is the scope of this 2025 guideline on postmastectomy radiation therapy? Dr. Kathleen Horst: Thank you. This joint guideline was last updated in 2016. Over the past decade, the treatment of breast cancer has evolved substantially. Newer systemic therapy regimens have increasingly personalized treatment based on tumor biology, and local therapy management has explored both the de-escalation of axillary surgery and more abbreviated courses of radiation therapy. Given these advances, it was important to revisit the role of postmastectomy radiotherapy in this modern era of breast cancer therapy. This updated guideline addresses four key questions, including postmastectomy radiation therapy after upfront surgery as well as after neoadjuvant systemic therapy. It also reviews the evolving role of various dose and fractionation schedules and optimal treatment techniques and dose constraints. Brittany Harvey: Excellent. I appreciate that background, Dr. Horst. So then, next, Dr. Jimenez, I would like to review the recommendations of this guideline across those four key questions that Dr. Horst just mentioned. So first, what does the panel recommend for PMRT for patients who received initial treatment with mastectomy? Dr. Rachel Jimenez: The panel provided pretty strong consensus that patients with positive lymph nodes or patients with large tumors involving the skin or the chest wall should receive postmastectomy radiation. However, the panel also recognized that the omission of postmastectomy radiation may be appropriate for select patients who have positive lymph nodes and have an axillary lymph node dissection if they have a low nodal burden and other favorable clinical or pathologic features. For patients without lymph node involvement at the time of surgery and no involvement of the skin or chest wall, postmastectomy radiation was not advised by the panel. Brittany Harvey: Understood. It is helpful to understand those recommendations for that patient population. Following that, Dr. Abdou, what are the key recommendations for PMRT for patients who received neoadjuvant systemic therapy before mastectomy? Dr. Yara Abdou: When we think about PMRT after neoadjuvant treatment, the key point is that the initial stage of presentation still matters a lot. So for example, if a patient comes in with more advanced disease, say a large primary tumor, like a clinical T4, or more extensive nodal disease, like an N2 or N3 disease, those patients should get PMRT, no matter how well they respond to neoadjuvant therapy, because we know it reduces the risk of recurrence and that has been shown pretty consistently. On the other hand, if there are still positive lymph nodes after neoadjuvant treatment, basically residual nodal disease, PMRT is also strongly recommended because the risk of local-regional recurrence is much higher in that setting. The gray area is the group of patients who start with a lower burden of nodal disease, such as N1 disease, but then become node negative at surgery. For those patients, we tend to individualize the decision. So if the patient is young or has triple-negative disease, or if there is a lot of residual disease in the breast even though the nodes are cleared, then radiation is probably helpful. But if everything has melted away with pCR in both the breast and the nodes, then it may be safe to omit PMRT in those patients. For patients with smaller tumors and no nodal involvement to begin with, like a clinical T1-T2 N0, if they are still node negative after neoadjuvant treatment, then PMRT is generally not recommended because their baseline recurrence risk is low. And finally, if the margins are positive and cannot be re-excised, then PMRT is recommended after neoadjuvant therapy. Brittany Harvey: Yes, those distinctions are important for appropriate patient selection. So then, Dr. Horst, we have just reviewed the indications for PMRT, but for those patients who receive PMRT, what are the appropriate treatment volumes and dose fractionation regimens? Dr. Kathleen Horst: The guideline addresses coverage of the chest wall and regional nodes with a specific discussion of the data regarding internal mammary nodal irradiation, which has been an area of controversy over many years. The guideline also reviews the data exploring moderate hypofractionation, or shorter courses of radiation therapy. The task force recommends utilizing moderate hypofractionation for the majority of women requiring postmastectomy radiation, which is likely to have a large impact on clinical practice. This recommendation is based on the evolving data demonstrating that a 3-week course of radiotherapy after mastectomy provides similar oncologic outcomes and minimal toxicity for most patients compared to the standard 5-week treatment course. Brittany Harvey: Thank you for reviewing that set of recommendations as well. So then, Dr. Jimenez, to wrap us up on the key questions here, what delivery techniques are recommended for treating patients who receive PMRT? Dr. Rachel Jimenez: So this portion of the guideline is likely to be most helpful for radiation oncologists because it represents the most technical part of the guideline, but we do believe that it offers some important guidance that has, to this point, been lacking in the postmastectomy radiation setting. So first, the panel recommends that all patients should undergo 3-dimensional radiation planning using CAT scan based imaging, and this includes contouring. So contouring refers to the explicit identification, using a drawing interface on the CAT scan imaging, by the radiation oncologist to identify the areas that are targeted to receive radiation, as well as all of the nearby normal tissues that could receive unintended radiation exposure. And we also provide radiation oncologists in the guideline with suggestions about how much dose each target tissue should receive and what the dose limits should be for normal tissues. Additionally, we make some recommendations regarding the manner in which radiation is delivered. So for example, we advise that when conventional radiation methods are not sufficient for covering the areas of the body that are still at risk for cancer, or where too high of a dose of radiation would be anticipated to a normal part of the body, that providers employ a technique called intensity modulated radiation therapy, or IMRT. And if IMRT is going to be used, we also advise regular 3-dimensional imaging assessments of the patient's body relative to the treatment machine to ensure treatment fidelity. When the treatments are delivered, we further advise using a deep inspiration breath-hold technique, which lowers the exposure to the heart and to the lungs when there is concern for cardiopulmonary radiation exposure, and again, that image guidance be used along with real-time monitoring of the patient's anatomy when those techniques are employed. And then finally, we advise that patients receiving postmastectomy radiation utilize a bolus, or a synthetic substance placed on the patient's skin to enhance radiation dose to the superficial tissue, only when there is involvement of the skin with cancer or other high-risk features of the cancer, but not for every patient who receives postmastectomy radiation. Brittany Harvey: Understood. And then, yes, you just mentioned that section of the guideline is probably most helpful for radiation oncologists, but I think you can all comment on this next question. What should all clinicians, including radiation oncologists, surgical oncologists, medical oncologists, and other oncologic professionals, know as they implement all of these updated recommendations? Dr. Rachel Jimenez: So I think one of the things that is most important when we consider postmastectomy radiation and making recommendations is that this is a multidisciplinary panel and that we would expect and encourage our colleagues, as they interpret the guidelines, to employ a multidisciplinary approach when they are discussing each individual patient with their surgical and medical oncology colleagues, that there is no one size fits all. So these guidelines are intended to provide some general guidance around the most appropriate techniques and approaches and recommendations for the utilization of postmastectomy radiation, but that we recognize that all of these recommendations should be individualized for patients and also represent somewhat of a moving target as additional studies, both in the surgical and radiation oncology realm as well as in the systemic therapy realm, enter our milieu, we have to adjust those recommendations accordingly. Dr. Kathleen Horst: Yeah, I would agree, and I wanted to comment as a radiation oncologist, we recognize that local-regional considerations are intertwined with systemic therapy considerations. So as the data evolve, it is critical to have these ongoing updates in a cross-disciplinary manner to ensure optimal care for our patients. And as Dr. Jimenez mentioned, these multidisciplinary discussions are critical for all of us to continue to learn and understand the evolving recommendations across disciplines but also to individualize them according to individual patients. Dr. Yara Abdou: I could not agree more. I think from a medical oncology perspective, systemic therapy has gotten much better with adjuvant CDK4/6 inhibitors, T-DM1, capecitabine, and immune therapy. So these are all newer adjuvant therapies, so the baseline recurrence risks are lower than what they were in the trials that established PMRT. So the absolute benefit of radiation varies more now, so smaller for favorable biology but still relevant in aggressive subtypes or with residual disease. So it is definitely not a one-size-fits-all. Brittany Harvey: Yes, I think it is important that you have all highlighted that multidisciplinary approach and having individualized, patient-centric care. So then, expanding on that just a little bit, Dr. Abdou, how will these guideline recommendations affect patients with breast cancer? Dr. Yara Abdou: So basically, reiterating what we just talked about, these guidelines really move us towards personalized care. So for patients at higher risk, so those with larger tumors, multiple positive nodes, or residual nodal disease after neoadjuvant therapy, PMRT remains essential, consistently lowering local-regional recurrence and improving survival. But for patients at intermediate or lower risk, the recommendations support a more selective approach. So instead of a blanket rule, we now integrate tumor biology, response to systemic therapy, and individual patient factors to decide when PMRT adds meaningful benefit. So the impact for patients is really important because those at high risk continue to get the survival advantage of radiation while others can be spared the unnecessary treatment and side effects. So in short, we are aligning PMRT with modern systemic therapy and biology, making sure each patient receives the right treatment for their situation. Brittany Harvey: Absolutely. Individualizing treatment to every patient will make sure that everyone can achieve the best outcomes as possible. So then, Dr. Jimenez, to wrap us up, I believe Dr. Horst mentioned earlier that data continues to evolve in this field. So in your opinion, what are the outstanding questions regarding the use of PMRT and what are you looking to for the future of research in this space? Dr. Rachel Jimenez: So there are a number of randomized phase III clinical trials that are either in active accrual or that have reported but not yet published that are exploring further de-escalation of postmastectomy radiation and of axillary surgery. And so we do not yet have sufficient data to understand how those two pieces of information integrate with each other. So for example, if you have a patient who has a positive lymph node at the time of diagnosis and forgoes axillary surgery aside from a sentinel lymph node biopsy, we do not yet know that we can also safely forgo radiation entirely in that setting. So we expect that future studies are going to address these questions and understand when it is appropriate to simultaneously de-escalate surgery and radiation. Additionally, there is a number of trials that are looking at ways in which radiation could be omitted or shortened. So there is the RT CHARM trial, which has reported but not yet published, looking at a shorter course of radiation. And so we do make recommendations around that shorter course of radiation in this guideline, but we anticipate that the additional data from the RT CHARM study will provide further evidence in support of that. Additionally, there is a study called the TAILOR RT trial, which looks at forgoing postmastectomy radiation in patients who, to Dr. Abdou's point, have a favorable tumor biology and a low 21-gene recurrence score. And so we are going to anticipate the results from that study to help guide who can selectively forgo postmastectomy radiation when they fall into that favorable risk category. So there are a number of questions that I think will help flesh out this guideline. And as they publish, we will likely publish a focused update on that information to help provide context for our colleagues in the field and clarify some of these recommendations to suit the latest data. Brittany Harvey: Absolutely. We will look forward to those de-escalation trials and ongoing research in the field to build on the evidence and look for future updates to this guideline. So I want to thank you for your work to update these guidelines, and thank you for your time today, Dr. Horst, Dr. Jimenez, and Dr. Abdou. Dr. Rachel Jimenez: Thank you. Dr. Yara Abdou: Thank you. Dr. Kathleen Horst: Thank you. Brittany Harvey: And then finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Listen to ASCO's Journal of Clinical Oncology Art of Oncology article, "Brown Paper Bags” by Dr. Stephanie Graff, who is an Associate Professor of Medicine at Brown University and Director of Breast Oncology at Brown University Health in Providence Rhode Island. The article is followed by an interview with Graff and host Dr. Mikkael Sekeres. Dr Graff shares how she handled receiving a gift from a patient. TRANSCRIPT Narrator: Brown Paper Bags, by Stephanie Graff, MD, FACP, FASCO  Minor demographic features of the patients described have been altered to honor their privacy “Why are you being weird about opening the bag?” he asks.  The gift that William brought me is still sitting on the edge of the clinic examination room counter, the proverbial elephant in the room. He presented it to me the moment I entered the examination room, excited as a child giving their first Christmas gift. I have demurred, stating I will open it later. I have tried to avoid opening the bag, explaining that I do not like opening gifts in front of people. William is as tenacious about me opening this gift right now as he is about facing his disease. I treat William for male breast cancer. I have always called him William because it is what the electronic medical record says as his preferred name. It is his first name, and when I verified on our first meeting what he preferred to be called, he said “William is fine,” but just like the Sheryl Crow song says, “I'm sure it's Bill or Billy or Mack or Buddy.” 1 William is electric. He lights up the examination room, engages my staff while playfully ribbing them, and has a laugh that reverberates down the hallway. He comes to each visit with a colorful story about the events that have transpired since our last appointment, vividly painting images of his children and grandchildren and his life outside the clinic walls. He swells with pride discussing his grown children like a new mother showing off photos of her baby. “Ryan just finished the most beautiful presentation deck for work. You should see it. Those slides! I bet he would show it to you.” Ryan works in banking or finance or insurance—I cannot remember—but I confess I never took William up on the offer to see the slide deck.  Abruptly, William stands up, moving faster than an elderly patient with metastatic cancer should be able to move. In a single swift movement, he grabs the brown paper bag from where I abandoned it on the counter and drops it in my lap. “Open it!” I sigh deeply, carefully unroll the top, and peek in. “I got those for the mister!” he exclaims. Inside is a bag of Werther's hard caramels. As relief floods me, I laugh a deep, slow laugh of appreciation for this 70-something man and his ability to brighten the world around him in the most surprising ways. During our last clinic visit, he told me hard caramels take the chemotaste out of his mouth, and I had confessed that my husband is also Werther's devotee, but prefers the soft chews. William made a case then and there for the hard caramels and told me I should try to get “Mr Dr Graff” to make the change. He approached the soft caramel versus hard caramel discussion with the intensity of a high school debate champion. Needless to say, the Graff household now alternates our caramels—enjoying both hard caramels and soft chews. “Seriously. What gives with you and the bag?” he probes again. I recognize that William is not going to let this go. He is too astute and persistent. So, I decided to tell him the whole truth about gifts from patients and brown paper bagsThat first year as an oncology fellow, after months on inpatient consults, I finally started outpatient clinics just as the holidays season began. The patients, many of whom had deep and long relationships with the attending oncologists—the same relationships I was eager to build, the relationships that drove me to oncology as a profession—brought in gift after gift, homemade cookies, handmade quilts, and jars of homemade jam. It was rarely something elaborate as the patients knew the faculty could not accept anything too over the top, but it often showed the same tender thoughtfulness that you show a dear friend or favorite relative. Their favorite coffee. A T-shirt of a favorite band. Or something jovial, like a rival sports team or college's coffee mug. It was during this time of the busy holidays, maybe the second week of December, in my own fellow's clinic, that one of my patients with solid tumor arrived with a small brown paper bag. He of course had synchronous primary malignancies that in no way aligned for a simple plan of care and was experiencing dreadful side effects, which seemed to be the way of fellow's clinic. I had been seeing him quite often, pouring every ounce of my nascent skills into trying to help him through his treatment. He handed me the bag, and in my enthusiasm and naivety and holiday spirit, I bubbled with excitement thinking “oh, he brought me a little gift!” But my own thoughts were pouring over him saying “I brought this in for you because…” and as he was saying the rest, I tore open the bag, all the while with my eyes on him as he spoke, and plunged my hand into the bag, grabbing the…what exactly…cloth something…to hear him saying….  “…because I wanted you to see how bad this diarrhea is! Pure liquid. Bloody. Constant. I can't even make it to the bathroom,” he was saying. Yes. I was holding—in my bare hand—his soiled, blood-stained underwear. Merry Christmas. I have not excitedly torn open a mystery gift or plunged my hand into a bag since. This is not a lesson that took more than one time to learn. In retrospect, perhaps my patient did give me a tremendous gift that day. I was given a true under-standing of his side effects, of what it means to have grade 3 diarrhea, hemorrhoidal bleeding, and fecal incontinence. If there was any chance I did not believe patients before that day, I have always believed patients since—no need to bring me evidence in a little brown bag. Thanks. I'm good. By this point in my retelling of the story, William was nearly doubled-over in laughter, red-faced, and barely able to breathe or stay in his chair. Thus, our little ritual began. William continued to bring me gifts in brown paper bags at every visit for the rest of his time as my patient. Always small tokens. A pocket pack of Kleenex during cold season. A can ofsoup “to warm my hands,” which are perpetually cold during physical examinations. A small handmade Christmas ornament. Sometimes, he would put a bag inside a bag, inside a bag…laughing like an evil super villain, while I nervously unpacked his brown paper bags of torture. William elected to go to hospice care appropriately, living a few months with a good quality of life with home hospice. A few weeks after his passing, his son arrived at the registration desk and asked to speak with me. When I went to the front of the clinic to invite him back, to hug him, and tell him how much his father mattered to all of us at the cancer center, he handed me a brown paper bag. “He insisted” was all William's son said. I opened it, genuinely concerned what I might find this time, nervously peeking into the bag. It was a copy of William's obituary, thanking the cancer center for all the care we had shown him and for inviting him to be part of our lives as much as we were a part of his. This is the greatest gift—the gift of impact. Of knowing my care mattered, of knowing we were truly on the same care team. I carry my patients and their families with me through life, recalling their anecdotes, wisdoms, and warnings at just the right moments. I save their precious words in a box of cards I keep at my desk. I also have a collection of hilarious, insightful, peculiar, and profound assortment of little gifts that made a patient think of me—a curio of curiosities, a microcosm of my career. I think this is why patients give these small tokens in the first place—to make tangible the gratitude, the emotion, and the bond that is ex-changed between the patient and the oncologist. In giving, we are connected. Gifts speak for us when the weight of emotion and the vulnerability of truth are too much. A gift says “you matter in my life” as much as a gift says “I want you to feel how life altering the diarrhea I have been experiencing at home has been.” I have received both those gifts. They have changed me. So, I do not know—I am thinking maybe it is time I go back to plunging my hand straight in? Because in the end, somewhere down there at the bottom, that is where all the good stuff is hidden. Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I am your host, Mikkael Sekeres. I am Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. Today, I am so excited to be joined by Dr. Stephanie Graff, Associate Professor of Medicine at Brown University and Director of the Breast Oncology Program at Brown University Health in Providence, Rhode Island, to discuss her Journal of Clinical Oncology article, "Brown Paper Bags." Our guests' disclosures will be linked in the transcript. Stephanie, I am so excited to have you here. Welcome to our podcast, and thank you for joining us. Dr. Stephanie Graff: It is such an honor to be here and to discuss this with you. Mikkael Sekeres: Stephanie, I have to say, I feel like I know you so well because I have read your writing over years, and there is an intimacy to how you write and an honesty to it where I really feel as if we are sitting together over a table drinking an International House of Coffee mocha blend, talking about our recent trip to Paris. But I am not sure all of our listeners know you quite as well, so I am wondering if you can tell us a little bit about yourself. Dr. Stephanie Graff: Sure. So I am on the JCO Art of Oncology editorial board, and live in Providence. So you and I have many shared interests. I love to write and I love to read, and I think that how you described my writing reflects my communication. I think that I tend to be really honest and open with patients about, about everything, about both myself and their disease. And I think that that is really what you are capturing in my story writing. I am an avid reader. I read just nonstop and write a variety of different styles of writing. I have written several breast cancer related texts, obviously academic papers. I have confessed to you in the past that I write poetry, but it is for myself. It is very unlikely to end up in the pages of JCO. I like writing stories like this when I feel like a story has been percolating in my mind for a while. Mikkael Sekeres: Boy, there is a lot of jumping off points I want to take from what you just said, of course. Maybe we can start with your writing process. What triggers a story and how do you face the dreaded blank page? Dr. Stephanie Graff: I think it is different for different stories. Often, it is something that has been the struggle or the relived experience that I keep turning over. And I find that like when I am walking my dog in the morning or when I am running on the treadmill, that sometimes the same moments keep coming back up in my mind: a difficult patient encounter, a heartwarming patient encounter, a challenging conflict with a peer or colleague. Those are the things that I keep going back to. And I think that as I go back to it over time, I craft that narrative. And crafting the narrative is also what helps me work through the story and cement it as a lesson that I learned from or that becomes a memory that is important to me, and ultimately makes it easy to just sit down and write, which is often, I do just sit down and write the whole story and it comes out pretty much in the form I end up submitting. But I think that that is because I have spent so much pre-contemplative thought before I get to pen to paper. Sometimes it is, with this story, and I think I had said this in my original cover letter with "Brown Paper Bags," one of my nurses, my nurse practitioner, actually had gotten a gift from a patient that was actually wildly inappropriate for her, both as a gift from a patient and for her as an individual. And she had like brought it back to our shared workspace and was like, "Guys, like, what do I do with this?" And it prompted all of us to share our stories of like really fantastic things that patients have given us, really weird things that patients have given us, and just to end up laughing hysterically about the funny moments and getting a little teary-eyed thinking about the way that we hold on to some of those memories. Mikkael Sekeres: I love that whole description. First of all, starting with your writing process. I think we all come out of a room sometimes where we have been meeting with a person, and our stomach just turns. There is something that did not sit right with us about the interaction or there is something that was really special about the interaction. And I think if we are thoughtful people and thoughtful doctors, we ruminate over that for a while and think to ourselves, “What was it that was really special about that, that really worked that I can actually apply to other patients?” Or, “What was it that did not work, that something that went south where I probably need to change my behavior or change how I am entering an interaction so that does not happen again?” Dr. Stephanie Graff: Yeah, I think about it like those, you know, I am sure you have the same experience I do that a lot of your early childhood memories are actually photos of your early childhood that you can remember more clearly because you have the picture of them, and certainly the same is true for my own children. But I think that having that description, that powerful visual description of a photograph from a moment, helps you cement that memory and treasure it. And I think that the same is true with writing, that when we have an experience that if we are able to make it tangible, write about it, turn it into a song, turn it into a poem, turn it into a piece of art, whether that is, you know, an interpretive dance or a painting, whatever your expression is, that is going to be something that becomes a more concrete memory for you. And so regardless of whether it is a good memory or a bad memory, I think sometimes that that is how we learn and grow. Mikkael Sekeres: I think that is spot on. I believe there are some theories of memory also that talk about accessing the memory over and over again so that you do not lose it and you do not lose the connections to it. And those connections can be other memories or they can be anything that occurred with our five senses when the event actually occurred. Dr. Stephanie Graff: Yeah. That- so one of my favorite books is Audrey Niffenegger's book called The Time Traveler's Wife. Have you read that? It is- the gentleman has a, you know, genetic condition in the fictional book that makes him travel in time and he like leaves his body, his clothes are on the floor and travels back and he is drawn to moments that are important to him. So he is drawn back constantly to the moment he met his wife, he is drawn back constantly to the moment his parents died. And I think that that is true, right? Our memory takes us back to those really visceral, important moments over and over again. Mikkael Sekeres: So you mentioned before, one of the jumping off points I wanted to explore a little bit more was when someone gets an unusual gift and brings it back to the workroom and there is that moment when everyone looks at it and the person says exactly what you said, "What do I do with this?" Right? And it is interesting that it is even a question because sometimes there is a really weird gift and there are certain people who would just immediately put it in the trash, but as oncologists, we do not, do we? Dr. Stephanie Graff: No. Mikkael Sekeres: That is not an option, but we want to know what it is we can do with it. So I do not know if you can remember any particularly unusual gifts you received or your colleagues received during that conversation and then what do you do with them? Dr. Stephanie Graff: Yeah, I think that sometimes they are, I mean, honestly, like the truth is is that I have them, right? Like they are all over my life, these little trinkets and doodads, even to the point that sometimes I give gifts that are inspired by my patients, too. Like two Christmases ago, I gave all of my colleagues as their Christmas gift these blown glass octopuses because one of my patients was obsessed with octopi and it like had led to several conversations, and they have obviously eight arms, we all know that, but they have numerous hearts, they have this very complex, empathetic brain, they are thinking and feeling, very cool, cool animals if you really start to learn and read about them. And I really started to think both about how much we had all kind of rallied around this one patient and her unique love of octopi, but also like how much that animal represents what it means to practice team based care, to have this larger than life heart, to feel like you are more than one brain, like you have eight arms because you work with these really great people. So I wrote that much more eloquently than I am doing right now in a card for my team and gave them these glass octopuses for Christmas. And so, you know, I think that our patients, it is not always even a physical gift. Sometimes it is just sharing their stories that ends up staying with us. Mikkael Sekeres: And that must not have been that long after the documentary was released about the man who had this special relationship with an octopus as well. So do you save the gifts given to you by patients? Why or why not? Dr. Stephanie Graff: So, obviously we get a lot of things like food and we just eat that, right? I am sure your clinic is a collection of boxes of chocolates and, so in Rhode Island, there is a lot of Portuguese patients and so we get a lot of like Portuguese bread and things like that too, which is delicious. So we have all sorts of food all the time and that just gets eaten. I do save patients'- and I realize we are not on camera for our viewing audience, but I have bizarrely, so one patient gave me this red devil, which is amazing because Adriamycin, which is obviously a really common breast cancer drug, is called the "red devil." And this is kind of a famous folk art carving by Alexander Girard. I think the actual real one is in Philadelphia at their art museum, but she was like, "You gave me the red devil, so I am going to give you the red devil." And like, I think that is hilarious. Like, I will save that forever. But I have so many other patients that have given me like little angels because I like meant a lot to them or helped them through this difficult moment. And I have all of those things, right? And so I have this kind of funny little shelf of angels and devils in my office, which is, I think, amusing. And then, obviously I wrote about the brown paper bags. You know, that patient filled it with little things like butterscotches and a can of soup and an instant hot cocoa mix. It was stuff that like you can realistically use. It kind of comes and goes. It is not necessarily something that you have forever. I had all three of my children during my time, one in fellowship and two as a practicing oncologist, and I was practicing in the Midwest then. I have a wealth of absolutely gorgeous quilts, baby quilts, that were made by my patients for my kids. And I have saved every single one of those. I can tell you which patient made it for which child because those are just such heirlooms to me. Yeah, lots of really great things. I am curious about you. You have to have these treasures too in your life. Mikkael Sekeres: Oh, absolutely. Isn't it remarkable that people in the face of life threatening illnesses, and I probably have a patient population specializing in acute leukemia and myelodysplastic syndromes where their illness is often more acute than, than your typical patient in your patient population even, but even during those times, I am always so moved how people take the time to ask about us and want to know about our lives as physicians and take the time to give a gift. And sure, I have my own shelf of curios, I think that is how you refer to it in your essay, from patients and it is very meaningful. There was one patient I treated who was a baseball fan. We were both living in Cleveland at the time. I am a Yankees fan. Both my parents are from the Bronx, so they raised me the right way, of course, even though I was raised in Providence, Rhode Island. And she was a Red Sox fan, and every time she came to visit me, she would wear red socks. It became this ongoing joke. She would wear her red socks and I would remember to wear my Yankees socks. So when we reached the five year mark, she was cured of her leukemia, she gave me a framed box of red socks to hang up. So, yeah, we have these stories and they are immediately evocative of the person we took care of and built a relationship, hopefully a long term relationship with. Gift giving in oncology can be nuanced at times. Why do you think patients give gifts and why are they meaningful to us as caregivers? Dr. Stephanie Graff: I mean, I think that gift giving at its heart is sometimes just a more comfortable way to express emotion for so many patients, right? And humans, right? We give gifts to celebrate births, weddings, birthdays, anniversaries, major holidays, right, for our own friends and family. And so it makes sense that that cultural or social tradition exists where we give gifts to acknowledge and celebrate that someone is important and a part of our life. And so often, I think it is just a way for a patient to say, "You have been here for me, I see you, I see the work you do, I appreciate you." So it is a way to say thank you that to any individual patient feels bigger than just the words. Obviously, I want to say as- if any patient stumbles onto this podcast, just the words are more than enough and we do not even need that. Like it is my greatest honor to care for the patients that allow me to enter their lives and care for them. Like, I do not need them to tell me thank you. I certainly do not need them to give me a gift, but I think that is a big part of why patients do it. But I think another part of it is that in many ways, you know, we have all seen that when somebody is diagnosed with cancer, that they have this real reckoning with their family and friends where people that they thought were very good friends do not know how to show up for them. And so sometimes they see these shifting dynamics in their friend groups, especially maybe for our younger patients or mid aged patients that just their friends are so busy. There is lots that goes on, right, that I think that often the gift is saying, "Thank you for showing up." We were a constant in their life during that time and for many of my patients, they do not have that constancy from the other people in their life. And so again, if anyone stumbles onto this podcast and someone in your life that you love is diagnosed with cancer, the most important thing that any of us can do for someone battling a chronic illness is just show up. And I often tell people even uninvited, like, show up and offer to take their laundry back to your house, show up and drop off a meal because I think that the people saying, "Well, let me know what I can do," is not helpful because it is really awkward to tell people what to do when you are battling an illness. Mikkael Sekeres: That notion of presence is just so important and you enunciated it beautifully. When my patients say to me, "Oh, I want to get you something," I always respond the same way that you do. I always say, "Your good health is the greatest gift that I could hope for," and just the, just the words and the presence are enough. I wanted to end quoting you to yourself and asking you to reflect on it. You write, "I carry my patients and their families with me through life, recalling their anecdotes, wisdoms, and warnings at just the right moments." Stephanie, what are those moments when you lean on the anecdotes and wisdom of your patients? Dr. Stephanie Graff: Patients will say things to me about - oh gosh, I will get all teary thinking about it - you know, patients say things to me who are my, you know, stage four metastatic patients about what has mattered to them in life. And it makes it so easy for me to leave that thing undone and go home at the end of the day because none of them say, "It really mattered to me that I spent that extra hour at work or that I got that promotion or that raise." I am in the habit of, when I meet patients for the first time and they are at a visit with their husband or their wife or their partner, I will ask how long they have been together. And when patients tell me that it has been decades, 40, 50, 60 years, I will ask what the secret is, because I am at 17 years of marriage and I'd love to see 63, which is my record for a patient story. And my one patient during a visit, the wife and I were talking and I asked how long they had been married. We had already had a pretty long visit at that point when it came up, and the whole visit, the husband had just sat in the corner, very quiet, had not said a word. For all I know, he could have been nonverbal. And she said, "Oh, we have been married 60 years." And I said, "Oh my gosh, what is the secret?" And before she could even open her mouth, he goes, "Separate bathrooms." I think about it all the time. Like any time I am like annoyed with my husband getting ready in the morning, I am like, "Yep, separate bathrooms. It is the key to everything." Bringing those little moments, those little things that patients say to you that just pop back up into your mind are so wonderful. Like those rich little anecdotes that patients share with you are really things that stay with you long term. Mikkael Sekeres: So it does not surprise me, Stephanie, that you and I have settled on the same line of questioning with our patients. I wrote an Art of Oncology piece a few years ago called exactly that: "What I Learned About Love From My Patients," asking the exact same question. It was a fascinating exploration of long term marriage from people who say, "Oh, you have to have a sense of humor," which you always hear, to some things that were just brutally honest where somebody said, "Well, I could not find anybody better, so I just settled," right? Because they are in the oncologist's office and sometimes people will speak very dark truths in our clinics. But my favorites were always the people where I would ask them and the husband and wife would turn to each other and just hold hands and say, "I do not know, I just love her." And I always thought to myself, that is the marriage for me. Dr. Stephanie Graff: My husband and I trained together. He was a fellow when I was a resident. So we had one rotation together in our entire careers and it was in cardiology. Like he was like the fellow on cardiovascular ICU and I was the resident on cardiology. And the attending had been prodding this woman who had heart disease about how she needed to be more physically active and said something to the extent to the patient about how he could tell that she was more of a couch potato, that she really needed to get more active. Mind you, this is a long time ago. And her husband, I mean, they are older patients, her husband boldly interrupts the attending physician and says, "She may be a couch potato, but she is my sweet potato." And my husband and I every once in a while will quip, "Well, you are my sweet potato" to one another because we still, we both remembered that interaction all these years later. Like, that is love. I do not know what else is love if it is not fighting for your wife's honor by proclaiming her your ‘sweet potato'. Mikkael Sekeres: Well, I cannot say just how much of a treat it has been to have you here, Stephanie. This has been Stephanie Graff, Associate Professor of Medicine at Brown University and Director of the Breast Oncology Program at Brown University Health in Providence, Rhode Island, discussing her Journal of Clinical Oncology article, "Brown Paper Bags." If you have enjoyed this episode, consider sharing it with a friend or colleague or leave us a review. Your feedback and support helps us continue to have these important conversations. If you are looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres. Thank you 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.   Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review.    Guest Bio: Stephanie Graff, MD, FACP, FASCO is an Associate Professor of Medicine at Brown University and Director of Breast Oncology at Brown University Health in Providence Rhode Island   Additional Reading: What My Patients Taught Me About Love, by Mikkael Sekeres    

JCO fellow Dr. Ece Cali speaks with JCO Associate Editor Dr. Thomas E. Stinchcombe to discuss the JCO article "Phase 2 Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B)", that was simultaneously released at the IASLC 2025 World Conference on Lung Cancer. TRANSCRIPT Dr. Ece Cali: Hello, and welcome to our series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's most important oncology meetings. I am your host, Dr. Ece Cali, JCO editorial fellow, and I am joined by Dr. Tom Stinchcombe, JCO associate editor, to discuss the Journal of Clinical Oncology article and 2025 World Conference on Lung Cancer abstract presentation, “Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non–Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations.” The WU-KONG1B trial is a multinational, phase II study that investigated the efficacy and safety of different doses of sunvozertinib in patients with metastatic non-small cell lung cancer and EGFR exon 20 insertion mutations after progression on platinum based chemotherapy. Tom, before we dive into the results, could you walk us through the rationale for this study, and how does it fit into the current treatment options for patients with EGFR exon 20 insertion? Dr. Tom Stinchcombe: Thank you, Dr. Cali. I think the clinical context is always important. We have known that EGFR exon 20 insertions exist and that they are resistant to our currently available EGFR tyrosine kinase inhibitors, and I think there have been attempts in the past to develop a tyrosine kinase inhibitor, but there is a very narrow therapeutic window between the dose you need to inhibit the EGFR mutation in the cancer and the EGFR receptor on normal tissues, most notably the mucosa, the gut, and the skin. And so, our previous attempts have failed largely because the dose required was not tolerable for patients and they could not really stay on the drug for a long time or they were not very active. And so, I think there was a real desire to develop an EGFR tyrosine kinase inhibitor, and then, historically, the standard had been a platinum based doublet as the standard of care. And more recently, platinum based doublet with amivantamab has proven to be superior to platinum based chemotherapy alone. I think the context is also important that amivantamab is not necessarily available in all the countries, and so, there are patients who do not have access to amivantamab. Going to the rationale, I think that this drug had shown preliminary promise of having activity but without that being encumbered by those EGFR wild type toxicities, and, therefore, it was really explored in this larger study. Dr. Ece Cali: And what are some key findings from this trial? Dr. Tom Stinchcombe: So, I think that we should look at the study design. It is a little quirky, for lack of a better term, in that there is a randomization to 200 versus 300 mg, and then, there was a nonrandomized cohort of 300 mg. So, when you look at the study, if you are a purist, you will just look at the randomized patients. If you are sort of an aggregator, you look at all patients. So, it shows reporting on three cohorts, but I think the key findings are that the 200 mg and the 300 mg treatments had similar toxicities in terms of response rate, duration of response, and progression free survival. And as you know going through the review, there was a lot of queries from the reviewers as to which would be the preferred dose, and to me, I think this really illustrates a dose finding component to a trial design because there is a lot of debate about what the minimal effective dose is or the optimal dose. And in this case, having the two dose cohorts did provide us some valuable efficacy and toxicity information. And then, when I look at the study, I want to make sure it reflects my patient population, and about a quarter of patients had brain metastases, and about 15% had previous amivantamab, and about 5% to 10% had another EGFR tyrosine kinase inhibitor. Dr. Ece Cali: And what is the objective response rate and the duration of response? These are pretty good numbers for this patient population. Dr. Tom Stinchcombe: In the 200 mg cohort, it was about 46%. The duration of response was around 11 months, and the PFS was around 8 months. The 300 mg cohort was 46%, duration of response 9.8, and the median PFS is 6.9 months, and I think that this is greater activity than we have seen with our previous attempts at EGFR tyrosine kinase inhibitors. Dr. Ece Cali: And based on these data, FDA granted accelerated approval for sunvozertinib very recently at 200 mg once daily dosing in this setting. So, that is a major step forward for our patients. Dr. Stinchcombe, how does this impact your clinical practice, and what side effects should oncologists be watching for if they prescribe this medication? Dr. Tom Stinchcombe: So, I think it was very interesting that they chose the 200 mg dose, which I think was more tolerable, and when we kind of look at this, there still was a rate of diarrhea, all grade, rash, paronychia, which are the EGFR related toxicities. There can be some decreased appetite, stomatitis, and then, it can lead to some lab abnormalities, like increased CPK and creatinine that physicians have to be aware of. You know, how it will affect my practice is that all these patients had received a platinum based chemotherapy as the first line therapy. I think that this would become my preferred second line therapy for patients outside the context of a trial because of the activity and the tolerability. Dr. Ece Cali: And lastly, several other tyrosine kinase inhibitors are being evaluated for EGFR exon 20 insertion, including in the frontline setting. So, what are some of the outstanding questions in this space, and what data should our listeners keep an eye on moving forward? Dr. Tom Stinchcombe: I think you are right that now, there is going to be another EGFR tyrosine kinase that may become available in the next year, and there is another drug, furmonertinib, that is being investigated. I think, for the clinical question, is, well, can we move these into the first line setting? And actually, the development path has two ways of doing this. There is EGFR tyrosine kinase compared to platinum based chemotherapy, and then, platinum based chemotherapy with an EGFR tyrosine kinase versus platinum based chemotherapy, and both have their merits and strengths. And so, I think it is going to be very interesting as we see if those first line trials, one, can they be demonstrated to be superior to platinum based chemotherapy, and then by what magnitude and what the side effects are. But I think we are hoping that in the next couple of years, we will have an additional first line option for our patients. Dr. Ece Cali: Yeah, it is always great to have more options for our patients. Thank you, Dr. Stinchcombe, for speaking about the JCO article, “Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations.” Join us again for the latest JCO simultaneous publications. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of World Lung Conference. 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.  

The 5-year+ follow-up from CARTITUDE-1 has people asking if cilta-cel can cure multiple myeloma? We discuss this data and the broad comparison to the other BCMA-targeting CAR-T product, idi-cel and a recent comparison on plasma cell leukemia. CARTITUDE-1 Long-Term F/U: https://doi.org/10.1200/JCO-25-00760 Cilta-cel & ide-cel in plasma cell leukemia: https://doi.org/10.1182/bloodadvances.2025016966

Listen to ASCO's JCO Oncology Practice Art of Oncology article, "No Versus Know: Patient Empowerment Through Shared Decision Making” by Dr. Beatrice Preti, who is an Assistant Professor at Emory University. The article is followed by an interview with Preti and host Dr. Mikkael Sekeres. Dr Preti explores the challenges which may prevent oncologists from fully engaging with patients during shared decision making. TRANSCRIPT Narrator: No Versus Know: Patient Empowerment Through Shared Decision Making, by Beatrice T.B. Preti, MD, MMed, FRCPC  During a recent clinic, I saw three patients back-to-back, all from minority backgrounds, all referred for second opinions, all referenced in the notes for being different forms of difficult. Refused chemo, refused hospice, read one note. Refused surgery and chemo, read another, unsure about radiation. Yet, despite the documented refusals (I prefer the term, decline), they had come to my clinic for a reason. They were still seeking something. As an oncologist trained in a program with a strong emphasis on shared decision making between physician and patient, I approach such situations with curiosity. I consider optimal shared decision making a balance between the extremes of (1) providing a patient complete choice from a menu of treatment options, without physician input, and (2) indicating to a patient the best course of treatment, in the eyes of the physician.1 This is a balance between beneficence (which can often turn paternalistic) and patient autonomy and requires a carefully crafted art. Many of my consults start with an open question (Tell me about yourself…?), and we will examine goals, wishes, and values before ever touching on treatment options. This allows me to take the knowledge I have, and fit it within the scaffold of the patient in front of me. A patient emphasizing quantity of life at all costs and a patient emphasizing weekly fishing trips in their boat will receive the same treatment option lists, but with different emphases and discussions around each. Yet, many physicians find themselves tending toward paternalistic beneficence—logical, if we consider physicians to be compassionate individuals who want the best for their patients. All three patients I saw had been offered options that were medically appropriate, but declined them as they felt the options were not right for them. And all three patients I saw ended up selecting a presented option during our time together—not an option that would be considered the best or standard of care, or the most aggressive treatment, but an option that aligned most with their own goals, wishes, and values. This is of particular importance when caring for patients who harbor different cultural or religious views from our own; western medicine adopts many of its ideas and professional norms from certain mindsets and cultures which may not be the lenses through which our patients see the world. Even when a patient shares our personal cultural or religious background, they may still choose a path which differs from what we or our family might choose. It is vital to incorporate reflexivity in our practice, to be mindful of our own blinders, and to be open to different ways of seeing, thinking, and deciding. I will admit that, like many, I do struggle at times when a patient does not select the medically best treatment for themselves. But why? Do we fear legal repercussions or complaints down the road from not giving a patient the standard of care (often the strongest treatment available)? Do we struggle with moral distress when a patient makes a choice that we disagree with, based on values that we ourselves do not hold? Do we lack time in clinics to walk patients through different options, picking the method of counseling that allows the most efficiency in packed clinical systems? Is it too painful a reminder of our mortality to consider that, especially in the setting of terminally ill patients, aiming for anything other than a shot at the longest length of life might be a patient's preference? Or are we so burnt out from working in systems that deny us sufficient choice and autonomy (with regards to our own work, our own morals, and our own lives) that, under such repeated traumas, we lose touch with the idea of even having a choice? I have a number of patients in my clinic who transferred care after feeling caught between one (aggressive) treatment option and best supportive care alone. They come looking for options—an oral agent that allows them to travel, a targeted therapy that avoids immunosuppression, or a treatment that will be safe around dogs and small children. They are looking for someone to listen, to hold their hand, to fill in the gaps, as was told to me recently, and not skirt around the difficult conversations that both of us wish we did not have to have. Granted, some of the conversations are challenging—requests for ivermectin prescriptions, for example, or full resuscitation efforts patients with no foreseeable chance of recovery (from a medical standpoint) to allow for a possible divine miracle. However, in these cases, there are still goals, wishes and values—although ones that are not aligned with evidence-based medical practice that can be explored, even if they are challenging to navigate. As my clinic day went on, I spoke with my patients and their loved ones. One asked the difference between hospice and a funeral home, which explained their reluctance to pursue the former. Another asked for clarification of how one treatment can treat cancer in two different sites. And yet still another absorbed the information they requested and asked to come back another day to speak some more. All questions I have heard before and will continue to hear again. And again. There is no cure for many of the patients who enter my GI medical oncology clinic. But for fear, for confusion, perhaps there is. Cancer wreaks havoc on human lives. Plans go awry, dreams are shattered, and hopes are crushed. But we can afford some control—we can empower our patients back—by giving them choices. Sometimes, that choice is pitiful. Sometimes, it is an explanation why the most aggressive treatment option cannot be prescribed in good faith (performance status, bloodwork parametres), but it is a choice between a gentle treatment and no treatments. Sometimes it is a choice between home hospice and a hospice facility. I teach many of the learners who come through my clinic about the physician's toolbox, and the importance of cultivating the tools of one's specific specialty and area of work. For some (like surgeons), the tools are more tangible—physical skills, or even specific tools, like a particular scalpel or retractor. For others, like radiologists, it might be an ability—to recognize patterns, for example, or detect changes over time. For those of us in medical oncology, our toolbox can feel limiting at times. Although we have a handful of treatments tied to a specific disease site and histology, these often fall short of what we wish we could offer, especially when studies cite average survivals in months over years. But one of our most valuable tools—more valuable, I would argue, than any drug—is the communication we have with our patients, the way we can let them know that someone is there for them, that someone is here to listen, and that someone cares. Furthermore, the information we share—and the way we share it—has the potential to help shape the path that our patient's life will take moving forward—by empowering them with information to allow them to make the decisions best for them.2 Although having such conversations can be difficult and draining for the oncologist, they are a necessary and vital part of the job. My clinic team knows that we can have up to six, seven such conversations in the course of a half-day, and my clinic desk space is equipped for my between-patient routine of sips of tea and lo-fi beats, a precious few moments left undisturbed as much as possible to allow a bit of recharging. By finding a safe space where I can relax for a few moments, I can take care of myself, enabling me to give each of my patients the time and attention they need. When patients thank me after a long, difficult conversation, they are not thanking me for sharing devastating, life-altering news of metastatic cancer, prognoses in the order of months, or disease resistant to treatment. They are thanking me for listening, for caring, for seeing them as a person and affording the dignity of choice—autonomy. I have had patients make surprising decisions—opting for no treatment for locally-advanced cancers, or opting for gentle treatment when, medically, they could tolerate stronger. But by understanding their values, and listening to them as people, I can understand their choices, validate them, and help them along their journey in whatever way possible. Providing a choice affords a suffering human the right to define their path as long as they are able to. And we can give patients in such situations support and validation by being a guide during dark days and challenging times, remembering that medically best treatment is not always the best. When a patient says no to offered options, it does not (necessarily!) mean they are rejecting the expertise of the physician and care team. Rather, could it be a request to know more and work together with the team to find a strategy and solution which will be meaningful for them?   Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. 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 Beatrice Preti, Assistant Professor at Emory University, Adjunct Professor at Western University, and PhD candidate with Maastricht University, to discuss her JCO Oncology Practice article, "No Versus Know: Patient Empowerment Through Shared Decision-Making." At the time of this recording, our guest has no disclosures. Beatrice, thank you so much for contributing to JCO Oncology Practice and for joining us to discuss your article. Beatrice Preti: Well, thank you so much for having me today. Mikkael Sekeres: It's an absolute treat. I was wondering if we could start with sort of a broad question. Can you tell us about yourself? What was your journey like that landed you where you are right now? Beatrice Preti: Oh goodness, that's a very loaded question. Well, I am originally from Canada. I did all my training in Canada at a couple of different schools, McMaster, Queens, Western University. Before medicine, I was always interested in the arts, always interested in writing, always interested in teaching. So that's something that's really, I guess, come forth throughout my medical practice. During my time at Western, I trained as a gastrointestinal medical oncologist, so that's my clinical practice. But on the side, as you've noted, I've done some work in medical education, got my Masters through Dundee, and now doing my PhD through Maastricht in the Netherlands, which I'm very excited about. Mikkael Sekeres: That's fantastic. What's your PhD in? Beatrice Preti: Health Professions Education. Mikkael Sekeres: Wonderful - can never get too much of that. And can I ask, are you at the stage now where you're developing a thesis and what's the topic? Beatrice Preti: Yeah, absolutely. So the program itself is almost exclusively research based. So I'm thinking of more of a social psychology side, looking at impression management and moral distress in medical trainees, and really along the continuum. So what we're looking at is when people act in ways or feel that they have to act in ways that aren't congruent with what they're feeling inside, why they're doing that and some of the moral tensions or the moral conflicts that go along with that. So a good example in medicine is when you're with a patient and you have to put on your professional face, but inside you might be squirming or you might be scared or worried or anxious or hungry, but you can't betray that with the patient because that would be unprofessional and also unfair to the patient. Mikkael Sekeres: Wow, that's absolutely fascinating. How does that change over the course of training? So how does it change from being a medical student to a resident or fellow to a junior faculty member? Beatrice Preti: So I'm only one year into the PhD, so I don't have all the information on this as yet. Mikkael Sekeres: You don't have all the answers yet? What are you talking about? Beatrice Preti: Yeah, they're telling me I have to finish the PhD to get all the answers, but I think that we certainly are seeing some kind of evolution, maybe both in the reasons why people are engaging in this impression management and the toll it takes on them as well. But stay tuned. It might take me a couple of years to answer that question in full. Mikkael Sekeres: Well, I just wonder as a, you know, as a medical student, we go into medical school often for reasons that are wonderful. I think almost every essay for somebody applying to medical school says something about wanting to help people, right? That's the basis for what draws us into medicine. And I wonder if our definition of what's morally right internally changes as we progress through our training. So something that would be an affront to our moral compass when we start as a medical student may not be such an affront later on when we're junior faculty. Beatrice Preti: Yes, definitely. And I think there's a lot of literature out there about coping in the medical profession because I think that by and large, especially in the lay community, so premedical students, for example, but even within our own profession as well, we don't really give enough credence to the impact a lot of the things that we do or witness have on us personally. That lack of insight doesn't allow us to explore coping mechanisms or at least think things through, and oftentimes what we're seeing is a survival instinct or a gut reaction kick in rather than something that we've carefully thought through and said, you know, “These situations are stressful for me, these situations are difficult. How can I cope? How can I make this more sustainable for me, knowing that this is an aspect of medicine that really isn't escapable.” Mikkael Sekeres: What a fascinating topic and area to be studying. I can't wait for all of the findings you're going to have over the course of your career. But oncology is a field that's, of course, rife with these sorts of conflicts. Beatrice Preti: Yeah, definitely. Mikkael Sekeres: I'm curious if you can talk a little bit about your own story as a writer. You say you've always been a writer. How long have you been writing reflective pieces? Beatrice Preti: Oh, goodness. So there's certainly a difference between how long I've been writing reflective pieces and how long I've been writing good reflective pieces. I can vaguely remember, I think being perhaps 10 years old and writing in school one recess period, sort of both sides of a loose leaf piece of paper, some form of reflection that would have ended up straight in the rubbish bin. So that was probably when it started. Certainly in medical school, I published a fair bit of reflective writing, poetry. That continued through residency, now as a junior attending as well. Mikkael Sekeres: Well, you're excellent at it and I can't see any rubbish can that would accept your pieces for the future. If you feel comfortable doing so, can you tell us what prompted you to write this particular piece? Beatrice Preti: Yes. So this piece was written Friday night around 9:00, 10:00 at night, literally at the end of the clinic day that I described. Coming on the heels of talking about coping, I think for many people in medicine, writing is a coping mechanism and a coping strategy that can be quite fruitful and productive, especially when we compare it to other potential coping strategies. Sometimes it's certainly difficult to write about some of the things we see and certainly it's difficult sometimes to find the words. But on this particular night, the words came quite easily, probably because this is not an isolated incident, unfortunately, where we're seeing patients coming for second opinions or you're encountering patients or you're encountering people who you are not directly treating in your everyday life, who express frustrations with the health care system, who express frustrations with not feeling heard. I think all you have to do is open social media, Facebook, Reddit, and you'll see many, many examples of frustrated individuals who felt that they weren't heard. And on one hand, I'm not naive enough to think that I've never left a patient encounter and had that patient not feeling heard. I'm guilty of many of the same things. Sometimes it's nothing that we've done as physicians, it's just you don't develop a rapport with the patient, right? But it made me think and it made me wonder and question, why is there this mismatch? Why are there so many patients who come seeking someone who listens, seeking a solution or a treatment that is maybe not standard, but might be a better fit for them than the standard? As you know, oncology is very algorithmic, and certainly, as many of the the fellows and residents who come into my clinic learn, yes, there are guidelines and yes, there are beautiful flow charts that teach us if you have this cancer, here's the treatment. But for me, that's only half of the practice of oncology. That's the scientific side. We then have the art side, which involves speaking to people, listening to them, seeing them as people, and then trying to fit what we're able to do, the resources we have, with what the patient's goals are, with their wishes or desires are. Mikkael Sekeres: I completely agree with you. I think sometimes patients come to our clinics, to an examination room, and they look at it as a place to be heard, and sometimes a safe space. You'll notice that, if you've been practicing long enough, you'll have some couples who come in and one of our patients will say something and the partner will reflect and say, "Gee, I never heard you say that before. I never knew that." So if people are coming in expecting to be heard in a safe space, it's almost nowhere more important to do that when it comes to treating their cancer also. Beatrice Preti: Yes. And as I say again to many of our learners, different specialties have different tools to treat or help alleviate sickness, illness, and suffering. For example, a surgeon has quite literal tools. They have their hands, they have their eyes, they're cutting, they're performing procedures. By and large, especially in medical oncology, we are quite limited. Certainly I have medications and drugs that I can prescribe, but in the world of GI oncology, often these are not going to lead to a cure. We are talking about survival in the order of months, maybe a year or two if we're very lucky. So the tool that we have and really the biggest, best treatment that we can give to our patients is our words and our time, right? It's those conversations that you have in clinic that really have the therapeutic benefit or potential for someone who is faced with a terminal illness and a poor prognosis more so than any drug or chemotherapy that I can give as a physician. Mikkael Sekeres: I love the notion that our words and our time are our tools for practicing medicine. It's beautiful. You mentioned in your essay three patients who, quote, and you're very deliberate about using the quote, "refused" because it's a loaded term, "refused" recommended medical intervention such as chemotherapy or surgery. Can you tell us about one of them? Beatrice Preti: Ah, well, I would have to be quite vague. Mikkael Sekeres: Of course, respecting HIPAA, of course. We don't want to violate anything. Beatrice Preti: But I think that was another thing too on this day that struck me quite a bit that it was three patients back to back with very similar stories, that they had been seen at other hospitals, they had been seen by other physicians - in one case, I think a couple of different physicians - and had really been offered the choice of, “Here is the standard of care, here is what the guidelines suggest we do, or you can choose to do nothing.” And certainly in the guidelines or in recommended treatment, you know, doublet chemotherapy, triplet therapy, whatever the case may be, this is what's recommended and this is what's standard. But for the patient in front of you, you know, whose goal may be to go to the beach for two months, right? “I don't want to be coming back and forth to the cancer center. Can I take a pill and maybe get blood work a few times while I'm there?” Or you have a patient who says, “You know, I tried the chemotherapy, I just can't do it. It's just too strong. And now they've told me I have to go to hospice if I'm not going to take the recommended treatment.” While in the guideline this may be correct for this patient who's in front of you, there may be another option which is more, in quotes, “correct”, because, is our goal to kill as many cancer cells as we can? Is our goal to shrink the cancer as much as we can? Is our goal even to eke out the maximum survival possible? As an oncologist, I would say no. Our goal is to try to line up what we can do, so the tools, the medications, the chemotherapies, the drugs that we do have in our tool kit, and the symptom medications as well, and line those up with what the patient's goals are, what the patient's wishes are. For many people, I find, when faced with a terminal illness, or faced with an illness with poor prognosis, their goal is not to eke out the last breath possible. They start to look at things like quality of life. They start to look at things like hobbies or travel or spending time with family. And oftentimes, the best way to facilitate that is not by doing the most aggressive treatment. Mikkael Sekeres: In my memory, you evoke an essay that was written for JCO's Art of Oncology by Tim Gilligan called "Knuckleheads" where he had a patient who was, big quotes, "refusing" chemotherapy for a curable cancer. And one of his colleagues referred to the patient as a knucklehead and they asked Tim to see the patient to try to suss out what was going on. And Tim, he used one of our tools. He talked to the person and it turns out he was a seasonal construction worker and it was summer and he was a single dad where the mother of his children wasn't involved in their care at all. And the only way he had to make money during the year was the work he did during the summer because he couldn't work in the winter. So for very primal reasons, he needed to keep working and couldn't take time to take chemotherapy. So they were able to negotiate a path forward that didn't compromise his health, but also didn't compromise his ability to make a living to support his family. But again, like you say, it's that people bring to these interactions stories that we can't even imagine that interfere with our recommendations for how they get cared for. Beatrice Preti: That's a beautiful example of something that I really do try to impress on my learners and my team in general. When someone comes to you and if a recommendation is made or even if they are skeptical about a certain treatment pathway, there is always a ‘why'. One of the challenges and one of the things that comes with experience is trying to uncover or unveil what that ‘why' is because unless you address it and address it head on, it's going to be very difficult to work with it, to work with the patient. So as you said, it's common people have family obligations, job obligations. Oftentimes as well, they have personal experience with certain treatments or certain conditions that they're worried about. Perhaps they had a loved one die on chemotherapy and they're worried about toxicities of chemo. And sometimes you can talk through those things. That needs to be considered, right? When we talk about shared decision-making, you, the patient, and it might be an experience that the patient has had as well that are all in the room that need to be taken into account. Mikkael Sekeres: You invoke the phrase "shared decision-making," which of course, you talk about in your essay. Can you define that for our listeners? What is shared decision-making? Beatrice Preti: Oh, goodness. There are different definitions of this and I am just cringing now because I know that my old teachers will not be happy regardless of what definition I choose. But for me, shared decision-making means that the decision of what to do next, treatment along the cancer journey, etc., is not decided by only one person. So it is not paternalism where I as the physician am making the decision. However, it's not the patient unilaterally making their own decision as well. It's a conversation that has to happen. And oftentimes when I'm counseling patients, I will write down what I see as potential treatment options for this patient and we will go through them one by one with pros and cons. This is usually after an initial bit where I get to know the patient, I ask them what's important to them, who's important in their life, what kind of things do they enjoy doing, and trying to weave that into the counseling and the discussion of the pros and cons. Ultimately, the patient does make the choice, but it's only after this kind of informed consent or this informative process, I guess, so to speak. And for me, that is shared decision-making where it's a conversation that results in the patient making a decision at the end. Mikkael Sekeres: You know, it's so funny you use the word ‘conversation'. I was going to say that shared decision-making implies a conversation, which is one of the reasons I love it. It's not a monologue. It's not just us listening. It's a back and forth until you know, we figure each other out. Beatrice Preti: Yes. Mikkael Sekeres: I wonder if I could ask you one more question. In your essay, you ask the question, "Do we struggle with moral distress when a patient makes a choice that we disagree with based on values that we ourselves do not hold?" Do you think you can answer your own question? Beatrice Preti: So this is getting to my academic work, and my PhD work that we spoke a little bit about in the beginning. I think it's something that we need to be mindful of. Certainly in my training, certainly when I was less experienced, there would be a lot of moral distress because we are not all clones of each other. We are people, but we have our own beliefs, we have our own backgrounds, we have our own experiences. There are times when people, and not just in medicine, but certainly in medicine, certainly patients make decisions that I don't quite understand because they are so different from what I would make or what I would choose for myself or for a family member. On the flip side, I think I've gotten myself, and I've had enough experience at this point in my career, to be able to separate that and say, you know, “But this is someone who has clearly thought things through and based on their own world view, their own perspectives, their own life experiences, this is the choice that's best for them.” And that's certainly something that I can support and I can work with a patient on. But it takes time, right? And it takes very deliberate thought, a lot of mindfulness, a lot of practice to be able to get to that point. Mikkael Sekeres: Well, I think that's a beautiful point to leave off with here. We've been talking to Beatrice Preti, who is an assistant professor at Emory University and an adjunct professor at Western University, and a PhD candidate with Maastricht University to discuss her JCO Oncology Practice article, "No Versus Know: Patient Empowerment Through Shared Decision-Making." Beatrice, thank you so much for joining me today. Beatrice Preti: Absolutely. Mikkael Sekeres: If you've enjoyed this episode, consider sharing it with a friend or a colleague or leave us a review. Your feedback and support helps us continue to have these important conversations. If you're looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen, and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres for JCO Cancer Stories: The Art of Oncology. 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 Beatrice Preti is an Assistant Professor at Emory University Additional Material: Knuckleheads, by Dr Timothy Gilligan and accompanied podcast episode.  

Host Davide Soldato and guest Dr. John K. Lin discuss the JCO article "Racial and Ethnic Disparities Along the Treatment Cascade Among Medicare Fee-For-Service Beneficiaries with Metastatic Breast, Colorectal, Lung, and Prostate Cancer." 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 of the latest articles published in the Journal of Clinical Oncology. I'm your host, Dr. Davide Soldato, a medical oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by Dr. Lin, assistant professor in the Department of Health Services Research at the University of Texas MD Anderson Cancer Center. Dr. Lin and I will be discussing the article titled, "Racial and Ethnic Disparities Along the Treatment Cascade Among  Medicare Fee-for-Service Beneficiaries With Metastatic Breast, Colorectal, Lung, and Prostate Cancer." Thank you for speaking with us, Dr. Lin. Dr. Lin: Thank you so much for having me. I appreciate it. Dr. Davide Soldato: So, just to start, to frame a little bit the study, I just wanted to ask you what prompted you and your team to look specifically at this question - so, racial and ethnic disparities within this specific population? And related to this question, I just wanted to ask how this work is different or builds on previous work that has been done on this research topic. Dr. Lin: Yeah, absolutely. Part of the impetus for this study was the observation that despite people who are black or Hispanic having equivalent health insurance status - they all have  Medicare Fee-for-Service - we've known that treatment and survival differences and disparities have persisted over time for patients with metastatic breast, colorectal, lung, and prostate cancer. And so, the question that we had was, "Why is this happening, and what can we do about it?" One of the reasons why eliminating racial and ethnic disparities in survival among Medicare beneficiaries with metastatic cancer has been elusive is because these disparities are occurring along a lot of dimensions. Whether or not it's because the patient presented late and has very extensive metastatic cancer; whether or not the patient has had a difficult time even seeing an oncologist; whether or not the patient has had a difficult time starting on any systemic therapy; or maybe it's because the patient has had a difficult time getting guideline-concordant systemic therapy because, more recently, these treatments have become so expensive. Disparities, we know, are occurring along all of these different facets and areas of the treatment cascade. Understanding which one of these is the most important is the key to helping us alleviate these disparities. And so, one of our goals was to evaluate disparities along the entire treatment cascade to try to identify which disparities are most important. Dr. Davide Soldato: Thank you very much. That was very clear. So, basically, one of the most important parts of the research that you have performed is really focusing on the entire treatment cascade. So, basically, starting from the moment of diagnosis up to the moment where there was the first line of treatment, if this line of treatment was given to the patient. So, I was wondering a little bit, because for this type of analysis, you used the SEER-Medicare linked database. So, can you tell us a little bit which was the period of time that you selected for the analysis? Why do you think that that was the most appropriate time to look at this specific question? And whether you feel like there is any potential limitation in using this type of database and how you handled this type of limitations? Dr. Lin: Yeah, absolutely. It's a great question. And I want to back up a little bit because I want to talk about the entire treatment cascade because I think that this is really important for our research and for future research. We weren't the first people to look at along the treatment cascade for a disease. Actually, this idea of looking along the treatment cascade was pioneered by HIV researchers and has been used for over a decade by people who study HIV. And there are a lot of parallels between HIV and cancer. One of them is that with HIV, there are so many areas along that entire treatment cascade that have to go right for somebody's treatment to go well. Patients have to be diagnosed early, they have to be given the right type of antiretrovirals, they have to be adherent to those antiretrovirals. And if you have a breakdown in any one of those areas, you're going to have disparities in care for these HIV patients. And so, HIV researchers have known this for a long time, and this has been a big cornerstone in the success of getting people with HIV the treatment that they need. And I think that this has a lot of parallels with cancer as well. And so, I am hoping that this study can serve as a model for future research to look along the entire treatment cascade for cancer because cancer is, similarly, one of these areas that requires multidisciplinary, complex medical care. And understanding where it is breaking down, I think, is crucial to us figuring out how we can reduce disparities. But for your question about the SEER-Medicare linked database, so we looked between 2016 and 2019. That was the most recent data that was available to us. And one of the reasons why we were excited to look at this is because there were some new treatments that were just released and FDA-approved around 2018, which we were able to study. And this included immunotherapy for non–small cell lung cancer, and then it also included androgen receptor pathway inhibitors, the second-generation ones, for prostate cancer. And the reason why this is important is because for some time, as we have developed these new therapies, there's been a lot of concern that there have been disparities in access to these novel therapies because of how expensive they are, particularly for the Medicare population. And so one of the reasons why we looked specifically at this time period was to understand whether or not, in more recent years, these novel therapies, people are having increasing disparities in them and whether or not increasing disparities in these more expensive, newer therapies is contributing to disparities in mortality. That being said, obviously, we're in 2025 and these data are by now six years old, and so there are additional therapies that are now available that weren't available in the past. But I think that, that being said, at least it's sort of a starting point for some of the more important therapies that have been introduced, at least for non–small cell lung cancer and prostate cancer. And the database, SEER-Medicare, is helpful because it uses the population cancer registry, which is the SEER registry cancer registry, linked to Medicare claims. So, any type of medical care that's billed through Medicare, which is going to basically be all of the medical care that these patients receive, for the most part, we're going to be able to see it. And so, I think that this is a really powerful database which has been used in a lot of research to understand what kind of care is being received that has been billed through Medicare. So, one of the limitations with this database is if there is care that's received that was not billed through Medicare, we're not going to be able to see that. And this does not happen probably that frequently, particularly because most patients who have insurance are going to be receiving care through insurance. However, we may see it for some of the oral Part D drugs. Some of those drugs are so expensive that patients cannot pay for the coinsurance during that time. And it's possible that some of those drugs patients were getting for free through the manufacturer. We potentially missed some of that. Dr. Davide Soldato: So, going a little bit into the results, I think that these are very, very interesting. And probably the most striking one is that when we look at the receipt of any type of treatment for metastatic breast, colorectal, prostate, and lung cancer - and specifically when we look at guideline-directed first-line treatments - you observed striking differences. So, I just wanted you to guide us a little bit through the results and tell us a little bit which of the numbers surprised you the most. Dr. Lin: So, what we were expecting is to see large disparities in receiving what we called guideline-directed systemic therapy. And guideline-directed systemic therapy during this time kind of depended on the cancer. So, we thought that we were going to see large disparities in guideline-directed therapy because these were the more novel therapies that were approved, and thus they were going to be the more expensive therapies. And so, what this meant was for colorectal cancer, this was going to be any 5-FU–based therapy. For lung cancer, this was going to be any checkpoint inhibitor–based therapy. For prostate cancer, this was going to be any ARPI, so this was going to be things like abiraterone or enzalutamide. And for breast cancer, this was going to be CDK4 and 6 TKIs plus any aromatase inhibitor. And so, for instance, for breast, prostate, and lung cancer, these were going to be including more expensive therapies. And so, what we expected to see was large disparities in receiving some of these more expensive, novel therapies. And we thought we were going to see fewer disparities in receiving some of the cheaper therapies, such as aromatase inhibitors, 5-FU, older platinum chemotherapies for lung cancer, and ADT for prostate cancer. We were shocked to find that we saw large racial and ethnic disparities in seeing some of the older, cheaper chemotherapies and hormonal therapies. So for instance, for breast cancer, 59% of black patients received systemic therapy, whereas 68% of white patients received systemic therapy. For colorectal, only 23% of black patients received any systemic therapy versus 34% of white patients. For lung, only 26% of black patients received any therapy, whereas 39% of white patients did. And for prostate, only 56% of black patients received any systemic therapy versus 77% of white patients. And so, we were pretty shocked by how large the disparities were in receiving these cheap, easy-to-access systemic therapies. Dr. Davide Soldato: Thank you very much. So, I just wanted to go a little bit deeper in the results because, as you said, there were striking differences even when we looked at very old and also cheap treatments that, for the majority of the patients that were included inside of your study, were actually basically available for a very small price to these patients who had the eligibility for Medicare or Medicaid. And I think that one of the very interesting parts of the research was actually the attention that you had at looking how much of these disparities could be explained by several factors. And actually, one of the most interesting results is that you observed that low-income subsidy status was actually a big determinant of these disparities in terms of treatment. So, I just wanted to guide us a little bit through these results and then just your opinion about how these results should be interpreted by policymakers. Dr. Lin: Yeah, absolutely. I'm going to explain a little bit about what low-income subsidy status is and dual-eligibility status. Some of the listeners may not know what low-income subsidy status or dual-eligibility status is. Low-income subsidy status is part of Medicare Part D. Medicare Part D is an insurance benefit that allows patients to receive oral drugs. So these are drugs that are dispensed through the pharmacy, such as the CDK4/6 inhibitors, as well as second-generation ARPIs in our study. For patients who have Medicare Part D and whose income is low enough - falls below a certain federal poverty level threshold - those patients will receive their oral drugs for much cheaper. And this is really important for some of these more novel therapies because for some of these more novel therapies, if you don't have low-income subsidy status, you may be paying thousands of dollars for a single prescription of those drugs. Whereas if you have low-income subsidy status, you may be paying less than $10. And so that difference, greater than $1,000 or $2,000 versus less than $10, one would think that the patient who's paying less than $10 would be much more likely to receive those therapies. So that's low-income subsidy status. Low-income subsidy status, importantly, doesn't apply for infused medications like immunotherapy. But it's important to know that most people with low-income subsidy status - about 88% - are also dual-eligible. What dual-eligible means is that they have both Medicare and Medicaid. Medicare being the insurance that everybody has in our study who's greater than 65. And Medicaid is the state-run but federally subsidized insurance that patients with low incomes have. And so patients who are dual-eligible - and about 87% of those with low-income subsidy status are dual-eligible - those patients have both Medicaid and Medicare, and they basically pay next to nothing for any of their medical care. And that's because Medicare will reimburse most of the medical care and the copays or coinsurance are going to be covered by Medicaid. So Medicaid is going to pick up the rest of the bill. So, most of the patients who have low-income subsidy status who are dual-eligible, these patients pay almost nothing for their medical care - Part B or Part D, any of their drugs. And so, one would expect that if cost were the main determinant of disparities in cancer care, then one would expect that dual-eligibles, most of them would be receiving treatment because they're facing minimal to no costs. What we found is that when we broke down the racial and ethnic disparity by a number of factors - including LIS status/dual eligibility, age, the number of comorbidities, etcetera - what we found was that the LIS or dual-eligibility status explained about 20% to 45% of the disparities that we saw in receiving treatment. And what that means is despite these patients paying next to nothing for their drugs, these are the most likely patients to not be treated for their cancer at all. So they're most likely to basically be diagnosed, survive for two months, see an oncologist, and then never receive any systemic therapy for their cancer. And this is not just chemotherapies for colorectal or lung cancer. This includes cheaper, easier-to-tolerate hormonal therapies that you can just take at home for breast cancer, or you can get every six months for prostate cancer, that people who even have poorer functional status are able to take. However, for whatever reason, these dual-eligible or LIS patients are very unlikely to receive treatment compared to any other patient. The low likelihood of treating this group of patients, that explains a large portion of the racial and ethnic disparities that we see. Dr. Davide Soldato: And one thing that I think is very interesting and might be of potential interest to our listeners is, did you compare survival outcomes in these different settings? And did you observe any significant differences in terms of racial and ethnic disparities once you saw that there was a significant difference when looking at both receipt of any type of treatment and also guideline-directed treatments? Dr. Lin: We saw that there were large disparities in survival by race and ethnicity when you look overall. However, when you just account for the patients who received any systemic therapy at all - not just guideline-directed systemic therapy - those differences in survival essentially disappeared. And so, what that suggests is that if black patients were just as likely to receive any systemic therapy at all as white patients, we would expect that the survival differences that we were seeing would disappear. And this is not even just looking at guideline-directed systemic therapy. This was looking just at systemic therapy alone. And so, while guideline-directed systemic therapy should be a goal, our research suggests that if we are to close the gap in disparities in overall survival among black and white patients, we must first focus on patients just receiving any type of treatment at all. And that should be the very first focus that policymakers, that leaders in ASCO, that health system leaders, that physicians, that we should focus on: just trying to get any type of treatment to our patients who are poorer or black. Dr. Davide Soldato: Thank you very much. And this was not directly related to the research that you performed, but going back to this very point - so, increasing the number of patients that receive any kind of systemic treatment before looking at guideline-directed treatments - what would you feel would be the best way to approach this in order to decrease the disparities? Would you look at interventions such as financial navigation or maybe improving referral pathways or providing maybe more culturally adapted information to the patients? Because in the end, what we see is disparities based on racial and ethnicity. We see that we can reduce these disparities if we get these patients to the treatment. But in the end, what would you feel is the best way to bring patients to these types of treatments? Dr. Lin: I think the most important thing is to understand that these disparities are not primarily happening because of the high cost of cancer treatment. These disparities are happening because of other social vulnerabilities that these patients are facing. And so these vulnerabilities could be a lot of things. It could be mistrust of the medical system. It could be fear of chemotherapy or other treatments. It could be difficulty taking time off of work. It could be any number of things. What we do know is when we've looked at the types of interventions that can help patients receive treatment, navigation is probably the most effective one. And the reason why I think that is because when patients don't receive treatment because of social vulnerability, I sort of look at social vulnerability like links in a chain. Any weakest link is going to result in the patient not receiving treatment. This may be because they have a hard time taking time off of work. This may be because they had a hard time getting transportation to their physician. It may be because they had an interaction with a physician, but that interaction was challenging for the patient. Maybe they mistrusted the physician. Maybe they're worried about the medical system. If any of these things goes wrong, the patient is not going to be treated. The patient navigator is the only person who can spot any of those weak links within the chain and address them. And so, I think that the first thing to do is to get patient navigation systems in place for our vulnerable patients throughout the United States. And this is incredibly important because in Medicare, patient navigation is reimbursable. And so this is not something that's ‘pie in the sky'. This is something that's achievable today. The second thing is that it's really important that we see these vulnerabilities happening for patients who are dual-eligible, who have both Medicare and Medicaid. One of the reasons why this is important is because there has been a lot of research outside of what we've done that has shown vulnerabilities for dual-eligible patients who have Medicare for a number of different diseases. And the reason why is because, although patients are supposed to have the benefits of both Medicare and Medicaid, usually these two insurances do not play nicely together. It creates a huge, bureaucratic, complex mess and maze that most of these patients are unable to navigate. And so many of these patients are unable to actually receive the full reimbursement from both Medicare and Medicaid that they should be getting because those two insurers are not communicating well. And so the second thing is that national cancer organizations need to be supporting policies and legislation that is already being discussed in Congress to revamp the dual-eligible system so that it facilitates these patients getting properly reimbursed for their care from both Medicare and Medicaid and these systems working together well. The third thing is that Medicaid itself has many benefits that can allow patients to receive care, like they have transportation benefits so that patients can get to and from their doctor's appointments with ease. And so I think this will be additionally very, very helpful for patients. The last thing is, you know, it's possible that future innovations such as telemedicine and tele-oncology and cancer care at home can also make it easier for some of these patients who may be working a lot to receive care. But what I would say is that our study should be a call for healthcare delivery researchers to start piloting interventions to be able to help these patients receive systemic therapy. And so what this could look like is trying to get that care navigation and implement that in clinics so that patients can be receiving the care that they need. Dr. Davide Soldato: Thank you very much. That was a very clear perspective on how we can tackle this issue. So, I just wanted to close with a sort of personal question. I was wondering what led you to work specifically in this research field that is very challenging, but I think it's particularly critical in healthcare systems like in the United States. Dr. Lin: Yeah, absolutely. One of the most important things for me as an oncologist and a researcher is being able to know that all patients in the United States - and obviously abroad - who have cancer should be able to receive the kind of care that they deserve. I don't think that patients, because their incomes are lower or because their skin looks a certain color or because they live in rural areas, these shouldn't be determinants of whether or not cancer patients are receiving the care that they need. We can develop and pioneer the very best treatments and breakthroughs in oncology, but if our patients are not receiving them - if only 20% of our patients with colon cancer or lung cancer are receiving any type of systemic therapy, who are black - this is a big problem. But this is something that I think that our system can tackle. We need to get these breakthroughs that we have in oncology to every single cancer patient in America and every single cancer patient in the world. I think this is a goal that all oncologists should have, and I think that this is something that, honestly, is achievable. I think that research is a powerful tool to give us a lens into understanding exactly why it is that certain patients are not getting the care that they deserve. And my goal is to continue to use research to shed light on why our system is not performing the way that we all want it to be. Dr. Davide Soldato: Circling back to your research, actually the manuscript that was published was supported by a Young Investigator Award by the American Society of Clinical Oncology. So, was this the first step of a more broad research, or do you have any further plans to go deeper in this topic? Dr. Lin: Yeah, absolutely. First, I want to thank the ASCO Young Investigator Award for funding this research because I think it's fair to say that this research would not have happened at all without the support of the ASCO YIA. And the fact that ASCO is doing as much as it can to support the future generation of cancer researchers is incredible. And it's a huge resource, and having it come at the time that it did is critical for so many of us. So I think that this is an unbelievable thing that ASCO does and continues to do with all of its partners. For me, yeah, this is definitely a stepping stone to further research.  Medicare Fee-for-Service is only one part of the population. I want to spread this research and extend it to patients who have other types of insurances, look at other types of policies, and also try to conduct some of the cancer care delivery research that's needed to try to pilot some interventions that can resolve this problem. So hopefully this is the first step in a broader series of studies that we can all do collectively to try to eliminate racial and ethnic disparities in cancer care and survival. Dr. Davide Soldato: So, I think that we've come at the end of this podcast. Thank you again, Dr. Lin, for joining us today. Dr. Lin: Thank you so much. It was a pleasure to be a part of this. Dr. Davide Soldato: So, we appreciate you sharing more on your JCO article, "Racial and Ethnic Disparities Along the Treatment Cascade Among Medicare Fee-for-Service Beneficiaries With Metastatic Breast, Colorectal, Lung, and Prostate Cancer." 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 JCO Article Insights episode, Dr. Joseph Matthew interviews authors Dr. Yang Zhang and Dr. Haiquan Chen about their recently published JCO article, "Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma" TRANSCRIPT Joseph Mathew: Welcome to the Journal of Clinical Oncology Article Insights episode for the August issue of the JCO. This is Joseph Mathew, editorial fellow for JCO, and today, it is my pleasure to have with us Dr. Haiquan Chen and Dr. Yang Zhang, authors of the recently published manuscript, "Phase 3 Study of Mediastinal Lymph Node Dissection for Ground-Glass Opacity-Dominant Lung Adenocarcinoma," which we will be discussing today. Dr. Chen is the Director of the Institute of Thoracic Oncology at Fudan University and the Chief of Thoracic Surgery at Fudan University Shanghai Cancer Center, where he is also the Head of Thoracic Oncology MDT and the Director of the Lung Cancer Center. Dr. Chen is a surgeon-scientist and a pioneer in developing individualized surgical strategies for early-stage non-small cell lung cancer. Dr. Zhang is a surgical oncologist and a member of the team which Dr. Chen leads at the Fudan University Shanghai Cancer Center. Welcome Dr. Chen and Dr. Zhang. Thank you very much for accepting our invitation and joining us today as part of this podcast episode. To summarize the salient points, this study presented the interim analysis of a multi-center, open-label, non-inferiority, randomized controlled trial investigating the necessity of systematic mediastinal lymph node dissection at the time of segmentectomy or lobectomy in patients with clinical stage T1N0M0 ground-glass opacity-dominant invasive lung adenocarcinoma, as defined by a consolidation-to-tumor ratio of 0.5 or less on thin-section computed tomography and a maximum tumor diameter of 3 cm or less. Eligible participants with intraoperatively confirmed invasive adenocarcinoma on frozen section analysis were randomized to either the systematic mediastinal lymph node dissection arm or to no mediastinal lymph node dissection. In the latter experimental group, mediastinal lymph nodes comprising the N2 nodal stations were not dissected, and the hilar nodes were variably addressed at the discretion of the operating surgeon. The primary endpoint of the trial was disease-free survival at 3 years. Secondary endpoints included perioperative outcomes, the status of lymph node metastasis in the systemic lymph node dissection arm, and 3-year overall survival. Before the trial reached its accrual target, a pre-planned interim safety analysis set for the time point when enrollment reached 300 patients was performed. It was noted that while none of the patients in either arm had nodal metastasis on postoperative pathological evaluation, lymph node dissection-related intraoperative and postoperative complications were more commonly observed in the systematic lymph node dissection arm, including one life-threatening episode of massive bleeding. Since this met the predefined criteria for trial termination, and in accordance with the principle of non-maleficence, further recruitment was stopped and the trial terminated. Although the 3-year disease-free survival and the overall survival for the enrolled patients were comparable, operative outcomes, including the duration of surgery, blood loss, chest tube duration, length of postoperative stay, and the rate of clinically significant complications, were significantly lower in the experimental arm compared with the systematic lymph node dissection group. The authors concluded that for well-selected patients, mediastinal nodal dissection could be omitted without adversely affecting oncological outcomes, representing a significant shift in current surgical practice, given that guidelines the world over recommend systematic lymph node dissection or sampling for all invasive lung cancers. In summary, this study addressed a clinically relevant question with regard to the extent of nodal dissection, especially in the light of recent evidence recommending less extensive parenchymal dissections for early-stage non-small cell lung cancer, with the findings suggesting that invasive lung adenocarcinoma associated with ground-glass opacities of consolidation-to-tumor ratio up to 0.5 was an excellent predictor of tumor biology, and in clinical T1N0M0 lesions, a reliable predictor of negative mediastinal lymph node involvement. So Dr. Chen and Dr. Zhang, could you tell us some more about what led you to do this research and the challenges which you faced while recruiting patients for this trial? Dr. Yang Zhang: Dr. Mathew, thank you for your summary. The current clinical guidelines recommend systematic lymph node dissection or sampling for every patient with early-stage lung cancer, regardless of their lymph node status. And in our clinical practice, we observe that this procedure causes a lot of surgical complications including chylothorax and recurrent laryngeal nerve injury. Furthermore, dissecting the tumor-draining lymph nodes actually may potentially damage the body's anti-tumor immunity. So, Dr. Chen proposed the concept of selective lymph node dissection, which we aimed to dissect the metastatic lymph nodes, while at the same time we try to preserve as many uninvolved lymph nodes as possible. So previously, we have conducted a series of retrospective studies to identify reliable predictors of nodal negative status in certain mediastinal zones, and we have performed a prospective observational phase 2 clinical trial to validate that the six criteria we proposed are 100% in predicting node-negative status. And this forms the basis for our phase 3 clinical trial. Dr. Haiquan Chen: This trial is only one of the series of trials. The meaning of this trial you already said. And for a long time, from the surgeon's point of view, we considered minimally invasive surgery. It minimizes the size of the incision and minimizes the number of the holes we made. So, the true and the high-impact of minimally invasive, we make a concept of minimal dissection, that means organ-level minimally invasive. So we proposed the concept of minimally invasive 3.0, that means minimal incision, minimal dissection (that means organ-level minimal), and systemic minimally invasive. So at first, we judged from the point of minimally invasive surgery. As long as immunotherapy is widely used in the clinical practice, we know immunotherapy, that means you use drugs to stimulate and activate the lymph node site. If we dissect all the metastatic lymph nodes, cut them out, how can we restimulate that lymph node site? So, from minimally invasive trauma and second, from the functional aspect, to try to save as many uninvolved lymph nodes as possible. Joseph Mathew: Thank you, Dr. Chen. That's a very interesting concept that you alluded to even in the discussion of this paper, as to the potential role of the non-metastatic lymph nodes as immune reservoirs. So, coming back to this paper, were there any challenges which you faced while recruiting patients for this trial? Dr. Haiquan Chen: The criteria is very clear. That means invasive adenocarcinoma, that means most of the centimeter is 3.0 centimeter and also CTR ratio less than 0.5. And we can see that, you know, we did study about that. Even the invasive component of the subsolid nodule, it's bigger than the solid part. That means even the pure GGO, we can find out that there's still some invasive component. From this point of view, pure GGO and subsolid GGO, from this part of invasive carcinoma, that means it's a special clinical subtype that we, from retrospective study and also prospective study, we find out this group of patients, there are no mediastinal lymph node metastasis. So I think it's very important for this kind of group that we can avoid doing the mediastinal lymph node dissection. And we can do organ-level minimally invasive surgery. And also, we try to keep the patient's immune function as normal as possible. Dr. Yang Zhang: Well, Dr. Mathew, we believe that the biggest challenge when we are enrolling these patients is that there needs to be a paradigm shift in the mind because systematic lymph node dissection has long been the standard of care. And some patients may misunderstand. Before the enrollment, we have to give them informed consent, but if the patient hears that they may be enrolled in the no-lymph-node-dissection group, they may feel that they do not receive radical, curative-intent surgery. So we believe, as Dr. Chen has said, after the release of our results, the no-lymph-node dissection may be incorporated in the future guideline for those patients without lymph node involvement, we can just omit the lymph node dissection. Joseph Mathew: The study described two pre-planned interim points during the course of subject enrollment when the data was analyzed. So Dr. Chen and Dr. Zhang, could you please explain a little more about these two interim points of analysis that were planned and the rationale behind it? Dr. Yang Zhang: When conducting this trial, we have two concerns. One is if there is any lymph node metastasis, there may be omission of metastatic lymph nodes not dissected in the no-lymph-node-dissection group. And there is another concern is that if all these lymph nodes are uninvolved, then dissecting these lymph nodes may cause life-threatening complications. So, we set the 150 interim analysis to ensure that there is no lymph node involvement in this group. And the other early termination criteria is set because if there is no lymph node involvement found in both groups, then a severe complication which is life-threatening is unacceptable because it threatens the patient's safety. Joseph Mathew: So, although you did briefly allude to in the paper, what was the basis for selecting DFS as the primary endpoint when the objective of this trial was to assess nodal involvement in this subset of tumors? Dr. Yang Zhang: Well, previously, we have done a series of retrospective studies and one prospective phase 2 trial. And in these studies, we have identified that GGO-dominant lung adenocarcinoma, even if it's invasive, it has no lymph node involvement. So this phase 3 trial was primarily designed to compare the survival outcomes. But as the trial went on, as Dr. Chen has concerns that if the patients have no lymph node metastasis at all, it may be unfair to dissect the lymph nodes for patients enrolled in the systematic lymph node dissection group. So there is one life-threatening complication that happens due to dissecting the lymph nodes and injury to the superior vena cava, which leads to massive bleeding. It is at this point that we decided to terminate this trial for patient safety concerns. Joseph Mathew: Yeah, that's a very fair point. So you made sure that the ethical considerations were kept intact. So another point was, there was a mention in the study of the historical data from your institution suggesting a 3-year disease-free survival of 96.6% for patients with clinical T1N0M0 ground-glass opacity-dominant invasive lung adenocarcinoma. So could you please elaborate on the patterns of recurrence which you noted for this group of patients who had developed a recurrence? Dr. Haiquan Chen: Yeah, I think over 90% 3-year DFS, that's the least. From our retrospective data for this kind of group of patients, their DFS is so good. To the best of my knowledge, almost 100%. So this is very conservative, 94, 90% is very conservative. I think the trial eventually would have been positive. It's a special clinical subtype, even for invasive adenocarcinoma, their prognosis is much better than the other type of invasive adenocarcinoma. Joseph Mathew: So this question may be slightly outside the purview of this study, but in your clinical practice, would you advocate either segmentectomy or lobectomy for all patients meeting the trial criteria, that is, lesions measuring 3 cm or less with a CTR of up to 0.5? Or is there a subgroup of patients you would recommend a wedge dissection for? Dr. Haiquan Chen: I think CTR ratio is one parameter and also the location is another very important parameter. So we put it together to make a decision, the patient should do a lobectomy or segmentectomy. Even for an ongoing trial, for even the patient, invasive adenocarcinoma, we can do in the right location, even wedge, it can achieve enough negative margin in the ongoing trial to verify the comparable result for the patient, we can do the wedge dissection. So not just the CTR ratio, that's not the only parameter to make a decision on what kind of procedure we'll do. Joseph Mathew: Yeah, great point, Dr. Chen. So from my perspective, this study was a well-designed, randomized control trial based on a relevant and clinically valid research question. So what, in your opinion, are the main strong points of this study? Dr. Yang Zhang: We believe that this study represents the first randomized clinical trial published, yet, regarding the topic of selective lymph node dissection. It basically offers the highest level of evidence. We believe our results should be incorporated in the future clinical guideline. Joseph Mathew: Given the increasing incidence of these lesions, I think it was- a randomized control trial in this arena was much awaited. And the other point is that GGO-dominant lung adenocarcinomas, the specific clinical guidelines are not very clear. So I think your study brought out that lymph node dissection for these tumors which satisfy the eligibility criteria could be omitted safely. Important consideration here is that the conclusions of the trial were based on an interim analysis, and this analysis was not planned for an early assessment of the primary endpoint. In other words, the study was not adequately powered to detect a significant difference in DFS at 3 years. So Dr. Chen and Dr. Zhang, what do you perceive are the most important limitations of this study which you feel should be addressed in future research? Dr. Haiquan Chen: So the surgery now is more individualized. I think the surgery from the last two decades, from the maximum tolerable intervention to minimum effective treatment, there's a big shift. So I think that the consensus, we can preserve normal lung parenchyma as much as possible. For the lymph nodes, I think that the big shift, we should shift it to keep as many as uninvolved lymph nodes as possible. So that's very important, not just to reduce the intraoperative trauma, but also to keep the immune environment as normal as possible. Joseph Mathew: Another point was the limited long-term follow-up data to determine the actual impact of omitting lymph node dissection on local-regional disease control. So is any future follow-up planned to assess the long-term survival outcomes for the 302 patients which were enrolled in this trial? Dr. Haiquan Chen: Yeah, I think that's very important for us. This trial we terminated just because if we keep the trial going, it's unfair for the mediastinal lymph node dissection group. We tried to just stop here, and we shifted to the single-arm trial. So, 2 or 3 years, this trial and another trial, they will give our final result to demonstrate more if selective mediastinal lymph nodes have a better result than ever before. And we will support the mediastinal lymph node dissection. That's one way. And the American College just asked me, how can we put this policy into clinical practice in the United States? Because most of the patients they meet have solid tumors. So we have another trial, try to figure out how we can make sure before and intraoperative the lymph node status is negative or positive, and then we can solve that problem and put this policy into clinical practice in the Western society. Joseph Mathew: Great. So that would be something we should all be looking forward to. So, this brings me to the final point of discussion on future research in this field. Dr. Chen, you commented in the paper that future studies should focus on improving the reproducibility of CTR evaluation. What are your thoughts on this subject? Dr. Haiquan Chen: The CTR ratio, the concept from the JCOG 0201, just a concept from that prospective study, the phase 2 study, only subgroup analysis they give the concept of CTR ratio and the diameter. How can we reproduce? In our group and also I believe in Japan and in China, in Korea, and in our daily practice, I think CTR ratio is not a big issue. There are two very important things. One, you make sure the CTR ratio, not in a common CAT scan, but in a high-resolution CAT scan. So the imaging, that's the first thing. And the second, not from the single section and a two or three section, you make sure that your calculation is accurate. That's not just the single section, you make sure that you got the conclusion, the CTR ratio is the same number. We make sure that totally we, from the top to the bottom of the whole lesion, we make sure that the CTR ratio is accurate. Joseph Mathew: Thank you, Dr. Chen. I think that would involve training our radiologists also to be aware of the CTR ratio and how it should be interpreted. So another very interesting concept which you had alluded to in the discussion was the potential role of non-metastatic lymph nodes as immune reservoirs. So how do you think we could preserve these nodes and do you think sentinel node biopsies would play a role in future? Dr. Yang Zhang: Actually, Dr. Chen has also led some basic research on this topic. We are investigating the immunological role of the tumor-draining lymph nodes. And our preliminary results have already shown that the tumor-draining lymph nodes of lung cancer, especially those uninvolved lymph nodes, have a vital role in the anti-tumor immunity and also effective response to the current anti-PD-1 immunotherapy. In the future, we believe that by incorporating our clinical evidence and those findings from our basic research, we will be able to provide very strong rationale to support selective lymph node dissection. Joseph Mathew: So lastly, what are the questions that still remain to be answered and what do you perceive as the next step in this field? Dr. Haiquan Chen: I think for the lung cancer surgery, especially for the cT1N0M0, they are more individualized. We can, based on the patient, the location, the CTR ratio, we can do wedge dissection, or segmentectomy, or lobectomy. For the lymph node dissection, we can do no mediastinal lymph node dissection or selective, only to dissect the positive one, or we have to do the systemic mediastinal lymph node dissection. So we can see there are too many combinations. So in the near future, for the surgery perspective, we have it more individualized. In the future, we just try to make sure we do not cut as many as possible. We just make sure that we can avoid over-diagnosis or overtreatment or over-dissected. I think that in the near future, that goal will come true. Joseph Mathew: That's a great point, Dr. Chen. So that would be something also for the thoracic oncology community to work towards. This wraps up today's episode of JCO Article Insights. Dr. Chen and Dr. Zhang, thank you very much for taking the time to join us today in what has been a very insightful session. Dr. Haiquan Chen: Thank you. Dr. Yang Zhang: Thanks. Joseph Mathew: To our audience, thank you for listening. Please stay tuned for more interviews and articles, summaries, and be sure to leave us your comments and ratings. 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.

Malignant Hematology Updates: Venetoclax dosing strategies continue to evolve HMA/Ven + IDH1/2 inhibitors: https://doi.org/10.1200/JCO-25-00640 HMA/Ven + revumenib: https://doi.org/10.1200/JCO-25-00914 Venetoclax + CPX-351: https://doi.org/10.1002/ajh.27723 APOLLO: https://doi.org/10.1200/JCO-25-00535 Iland APOLLO editorial: https://doi.org/10.1200/JCO-25-01496 ctDNA assessment vs. PET in Large B-Cell Lymphoma: https://doi.org/10.1200/JCO-25-01534

In a discussion with CancerNetwork®, Jacob Sands, MD, assistant professor of Medicine at Harvard Medical School, thoracic oncologist at the Dana-Farber Cancer Institute, and investigator of the phase 2 TROPION-Lung05 trial (NCT04484142) and phase 3 TROPION-Lung01 trial (NCT04656652), which supported the accelerated approval of datopotamab deruxtecan-dlnk (dato-DXd; Datroway) in pretreated EGFR-mutant metastatic NSCLC in June 2025, discussed safety and efficacy considerations for the agent's use.1-3 He began by outlining a combined cohort of the TROPION-Lung05 and TROPION-Lung01 trials, which collectively showed an efficacy benefit with dato-DXd in patients with EGFR-mutant disease vs docetaxel. In the combined cohort, the median progression-free survival with dato-DXd reached 5.8 months, and the median overall survival was 15.6 months. Additional efficacy data revealed an objective response rate of 45% (95% CI, 35%-54%) and a median duration of response of 6.5 months (95% CI, 4.2-8.4).  Furthermore, Sands highlighted the most common toxicities observed with dato-DXd in this population, which included stomatitis, interstitial lung disease (ILD), and ocular toxicities. He also reviewed management strategies to mitigate their incidence and severity. Specifically, remedies include prophylaxis, oral hygiene, and dose reductions for stomatitis; using preservative-free eye drops and ophthalmology visits for ocular toxicity management and prevention; and monitoring for any incidence of high-grade ILD. He then touched upon next steps for research in this disease state, including the phase 2 ORCHARD trial (NCT03944772) evaluating dato-DXd with osimertinib (Tagrisso) in the second-line setting after progression on osimertinib and the phase 3 TROPION-Lung15 trial (NCT06417814), which is evaluating chemotherapy vs dato-DXd alone or with osimertinib.4,5 Sands concluded by discussing the implications for toxicity management in patients who experience responses that exceed median outcomes, suggesting that the toxicity profile may be more severe for this group. Emphasizing the broadness of outcomes with any drug, he expressed that patients with experiences that deviate from the observed median outcome are an important consideration for clinical practice. References Sands J, Ahn MJ, Lisberg A, et al. Datopotamab deruxtecan in advanced or metastatic non-small cell lung cancer with actionable genomic alterations: results from the phase II TROPION-Lung05 study. J Clin Oncol. Published online January 6, 2025. doi:10.1200/JCO-24-01349 Ahn MJ, Tanaka K, Paz-Ares L, et al. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III TROPION-Lung01 study. J Clin Oncol. Published online September 9, 2024. doi:10.1200/JCO-24-01544  FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. News release. FDA. June 23, 2025. Accessed July 29, 2025. https://tinyurl.com/mtay7ab9 Yu HA, Goldberg SB, Le X, et al. Biomarker-directed phase II platform study in patients with EGFR sensitizing mutation-positive advanced/metastatic non-small cell lung cancer whose disease has progressed on first-line osimertinib therapy (ORCHARD). Clin Lung Cancer. 2021;22(6):601-606. doi:10.1016/j.cllc.2021.06.006 A study to investigate the efficacy and safety of dato-DXd with or without osimertinib compared with platinum based doublet chemotherapy in participants with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (TROPION-Lung15). ClinicalTrials.gov. Updated July 16, 2025. Accessed July 29, 2025. https://tinyurl.com/56z3dmsp

Dr. Joseph McCollom and Dr. Ramy Sedhom discuss precision palliative care, a new strategy that aims to align palliative care delivery with patient and caregiver needs instead of diagnosis alone. TRANSCRIPT ADN Podcast Episode 8-22 Transcript: What Is Precision Palliative Care? Rethinking a Care Delivery Problem Dr. Joseph McCollom: Hello and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Joseph McCollom. I'm a GI medical oncologist and palliative oncologist at the Parkview Packnett Family Cancer Institute here in Fort Wayne, Indiana. So, the early benefits of palliative care for patients with cancer have been well documented, but there are challenges in terms of bandwidth to how do we provide this care, given the workforce shortages in the oncology field. So today, we'll be exploring a new opportunity known as precision palliative care, a strategy that aims to align care delivery with patient and caregiver needs and not just diagnosis alone. Joining me for this discussion is Dr. Ramy Sedhom. He is the medical director of oncology and palliative care at Penn Medicine Princeton Health and a clinical assistant professor of medicine at the University of Pennsylvania Perelman School of Medicine. Our full disclosures are available in the transcript of this episode.  Dr. Sedhom, it's great to have you on the podcast today. Thank you so much for being here. Dr. Ramy Sedhom: Thank you, Joe. It's a pleasure to be here and lucky me to be in conversation with a colleague and friend. Yes, many of us have heard about the benefits of early palliative care. Trials have shown better quality of life, reduced symptoms, and potentially even improved survival. But as we know, the reality is translating that evidence into practice, which is really, really challenging. So Joe, both you and I know that not every patient can see palliative care, or I'd even argue should see palliative care, but that also means there are still many people with real needs who still fall through the cracks. That's why I'm really excited about today's topic, which we'll be discussing, which is precision palliative care. It's a growing shift in mindset from what's this patient's diagnosis or what's this patient's prognosis, to what matters most for this person in front of me right now and what are their individual care needs. I think, Joe, it's very exciting because the field is moving from a blanket approach to one tailored to meet people where they actually are. Dr. Joseph McCollom: Absolutely, Ramy. And I think from the early days when palliative care was kind of being introduced and trying to distinguish itself, I think one of the first models that came to clinicians' eyes was Jennifer Temel's paper in The New England Journal of Medicine in 2010. And her colleagues had really looked at early palliative care integration for patients with advanced non–small cell lung cancer. And in that era – this is a pre-immunotherapy era, very early targeted therapy era – the overall prognosis for those patients are similar to the population I serve as a GI medical oncologist, pancreatic cancer today. Typically, median overall survival of a year or less. And so, a lot of her colleagues really wanted her to track overall survival alongside quality of life and depression scores as a result of that. And it really was a landmark publication because not only did it show an improvement of quality of life, but it actually showed an improvement of overall survival. And that was really, I think, revolutionary at the time. You know, a lot of folks had talked about if this was a drug, the FDA would approve it. We all in GI oncology laugh about erlotinib, which got an FDA approval for a 2-week overall survival advantage. And so, it really kind of set the stage for a lot of us in early career who had a passion in the integration of palliative care and oncology. And I think a lot of the subsequent ASCO, NCCN, COC, Commission on Cancer, guidelines followed through with that. But I think what we realized is now we're kind of sitting center stage, there's still a lot of resource issues that if we sent a referral to palliative care for every single patient diagnosed with even an advanced cancer, we would have a significant workforce shortage issue. And so, Ramy, I was wondering if you could talk a little bit about how do we help center in on who are the right patients that are going to have the greatest benefit from a palliative care specialist intervention? Dr. Ramy Sedhom: Thanks, Joe. Great question. So you mentioned Dr. Temel's landmark 2010 trial published in the New England Journal of Medicine. And it is still a game changer in our field. The results of her work showed not only improved quality of life and mood, but I think very surprisingly at the time, a survival benefit for patients with lung cancer who had received early palliative care. That work, of course, has helped shape national guidelines, as you've shared, and it also helped define early, as within 8 weeks of diagnosis. But unfortunately, there remains a disconnect. So in clinical practice, using diagnosis or stage as the only referral trigger doesn't really match the needs that we see show up. And I think unfortunately, the other part is that approach creates a supply demand mismatch. We end up either referring more patients than palliative care teams can handle, or at the opposite extreme, we end up referring no one at all. So, I actually just wanted to quickly give, for example, two real world contrasts. So one center that I actually have friends who work in, tried as a very good quality improvement incentive, auto-refer all patients with stage IV pancreas cancer to palliative care teams. And while very well intentioned, they saw very quickly that in a two-month period, they had 30 new referrals. And on the palliative care side, there were only 15 available new patient slots. On the other hand, something that I often see in practice, is a situation where, for example, consider the case of a 90-year-old with a low-grade B-cell lymphoma. On paper, low-risk disease, but unfortunately, when you look under the microscope, this gentleman is isolated, has symptoms from his bulky adenopathy, and feels very overwhelmed by many competing illnesses. This is someone who, of course, may benefit from palliative care, but probably doesn't check the box. And I think this is where the model of precision palliative care steps in. It's not really about when was someone diagnosed or what is the prognosis or time-based criteria of their cancer, but it's really fundamentally asking the question of who needs help, what kind of help do they need, and how urgently do we need to provide this help? And I think precision palliative care really mirrors the logic and the philosophy of precision oncology. So just like we've made strides trying to match therapies to tumor biology, we also need to have the same attention and the same precision to match support to symptoms, to context of a patient situation and their caregiver, and also to their personal goals. So I think instead of a blanket referral, we really need to tailor care, the right support at the right moment for the right person to the right care teams. And I think to be more precise, there's really four core elements to allow us to do this well. So first, we really need to implement systematic screening. Let's use what we already have. Many of our centers have patient reported outcomes. The Commission on Cancer motivates us to use distress screening tools. And the EHR is there, but we do very little to flag and to surface unmet care needs. We have seen amazing work from people like Dr. Ethan Bash, who is the pioneer on patient-reported outcomes, and Dr. Ravi Parikh, who used to be my colleague at Penn, now at Emory, who show that you could use structured data and machine learning to identify some of these patient needs in real time. The second piece is after a systematic screening, we really need to build very clear referral pathways. One very good example is what the supportive care team at MD Anderson has done, of course, led by Dr. Eduardo Brera and Dr. David Huey, where they have, for example, designed condition-specific triggers. Urgent referrals, for example, to palliative care for severe symptoms, where they talk about it like a rapid response team. They will see them within 72 hours of the flag. But at the same time, if the unmet need is a caregiver distress, perhaps the social work referral is the first part of the palliative care intervention that needs to be placed. And I think this helps create both clarity and consistency but also it pays attention to that provider and availability demand mismatch. Third, I really think we need to triage smartly. As mentioned in the prior example, not every patient needs every team member of the palliative care team. Some benefit most from the behavioral health intervention. Others might benefit from chaplaincy or the clinician for symptom management. And I think aligning intensity with complexity helps us use our teams wisely. Unfortunately, the greatest barrier in all of our health care systems is time and time availability. And I think this is one strategic approach that I have not yet seen used very wisely. And fourth, I really think we need to embrace interdisciplinary care and change our healthcare systems to focus more on value. So this isn't about more consults or RVUs. I think it's really about leveraging our team strengths. Palliative care teams or supportive care teams usually are multidisciplinary in their core. They often have psychologists, social workers, sometimes they have nurse navigators. And I think all of these are really part of that engine of whole person care. But unfortunately, we still are not set up in care delivery systems that unfortunately to this day still model fee for service where the clinician or the physician visit is the only quote unquote real value add. Hopefully as our healthcare systems focus more on delivery and on value, this might help really embrace the structure to bring through the precision palliative care approach. Dr. Joseph McCollom: No, I love those points. You know, we talk frequently in the interdisciplinary team about how a social worker can spend 5 minutes doing something that I could not as a physician spend an hour doing. But does every patient need every member every time? And how do we work as a unified body to deliver that dose of palliative care, specialized palliative care to those right patients and match them? And I think that perfect analogy is in oncology as a medical oncologist, frequently I'm running complex next-generation sequencing paneling on patients' tumors, trying to find out is there a genetic weakness? Is there a susceptibility to a targeted therapy or an immunotherapy so that I can match and do that precision oncology, right patient to the right drug? Similarly, we need to continue to analyze and find these innovative ways like you've talked about, PROs, EHR flags, machine learning tools, to find those right patients and match them to the right palliative care interdisciplinary team members for them. I know we both get to work in oncology spaces and palliative and supportive spaces in our clinical practice. Share a little bit, if you could, Ramy, about what that looks like for your practice. How do you find those right patients? And how do you then intervene with that right palliative oncology dose? Dr. Ramy Sedhom: So Joe, when I first started in this space as a junior faculty, one thing became immediately clear. I think if we rely solely on physicians to identify the patients for palliative care, we're unfortunately going to be very limited by what we individually, personally observe. And I think that's what reflects the reality that many patients have real needs that go unseen. So over the past few years, I've really worked with a lot of my colleagues to really work the health system to change that. The greatest partnership I've personally had has been working with our informatics team to build a real time EHR integrated dashboard that I think helps us give us a broader view of patient needs. What we really think of as the population health perspective. Our dashboard at Penn, for example, pulls in structured data like geriatric assessment results, PHQ-4 screens, patient reported outcomes, whether or not they've been hospitalized, whether or not these hospitalizations are frequent and recurrent. And I think it's allowed us to really move from a reactive approach to one that's more proactive. So let me give you a practical example. So we have embedded in our cancer care team, psycho-oncologists. They share the same clinic space, they're right down the hall. And we actually use this shared dashboard to review weekly trends in distress scores and patient reported outcomes. And oftentimes, if they see a spike in anxiety or worsening symptoms like depression, they'll reach out to me and say, “Hey, I noticed Mrs. Smith reported feeling very anxious today. Do you think it'd be helpful if I joined you for her visit?” And I think that's how we could really use data and teamwork to offer and maximize the right support at the right time. Like many of our other healthcare systems, we also have real-time alerts for hospitalizations. And I think like Dr. Temel's most recent trial, which we'll discuss at some point, I'm sure, it's another key trigger for vulnerability. I think whenever someone's admitted or discharged, we try to coordinate with our palliative care colleagues to assess do they need follow-up and in what timeline. And we know that these are common triggers, progression of disease, hospitalizations, drops in quality-of-life. And it's actually surprisingly simple to implement once you set up the right care structures. And I think these systems don't just help patients, which is what I quickly learned. They also help us as clinicians too. Before we expanded our team, I often felt this weight, especially as someone dual trained in oncology and palliative medicine, as trying to be everything to everyone. I remember one patient in particular, a young woman with metastatic breast cancer who was scheduled for a routine pre-chemo visit with me. Unfortunately, on that day, she had a very dramatic change in function. We whisked her down to x-ray and it revealed a pretty large pathologic fracture in her femur. And suddenly what was scheduled as a 30-minute visit became a very complex conversation around prognosis, urgent need for surgery and many, many life changes. And when I looked at my Epic list, I had a full waiting room. And thankfully, because we have embedded palliative care in our team, I was able to bring in Dr. Collins, the physician who I work with closely, immediately. She spent the full hour with the patient while I was able to continue seeing other patients that morning. And I think that's what team-based care makes possible. It's not just more hands on deck but really optimizing the support the patient needs on each individual day. And I think last, we're also learning a lot from behavioral science. So many institutions like Penn, Stanford, Massachusetts General, they've experimented with a lot of really interesting prompts in the EHR. One of them, for example, is the concept of nodes or the concept of prompt questions. Like, do you think this patient would benefit from a supportive care referral? And I think these low-level nudges, in a sense, can actually really dramatically increase the uptake of palliative care because it makes what's relevant immediately salient and visible to the practicing physician. So I think the key, if I had to maybe finish off with a simple message: It's not flashy tech, it's not massive change against staffing, but it's having a local champion and it's working smarter. It's asking the questions of how can we do this better and setting up the systems to make them more sustainable. Dr. Joseph McCollom: I appreciate you talking about this because I think a lot of folks want to put the wheels on in some way and they don't know where to get started. And so I think some of the models that you've been able to create, being able to track patients, screen your population, find the right individuals, and then work within that team to be able to extend, I think when you have an embedded palliative care specialist in your clinic, they expand your practice as a medical oncologist. And so you can make that warm handoff. And that patient and that caregiver, when they view the experience, they don't view you as a medical oncologist, someone else as a palliative care specialist, they view that team approach. And they said, "The team, my cancer team took care of me." And I think we can really harness a lot of the innovative technological advancements in our EHR to be able to prompt us in this work. I know that Dr. Temel had kind of set the stage for early palliative care intervention, and you did mention her stepped palliative care trial. Where do you see some of the future opportunities as we continue to push the needle forward as oncologists and palliative care specialists? What do you see as being the next step? Dr. Ramy Sedhom: So for those who are not familiar with the stepped palliative care trial, again, work by Dr. Temel, I think it's really important to explain not just the study itself, but I think more importantly, what it's representing for the future of our field. First, I really want to acknowledge Dr. Temel, who is a trailblazer in palliative oncology. Her work has not only shaped how we think about timing and delivery, but really about the value of supportive care. And more importantly, I think for all the young trainees listening, she had shown that rigorous randomized trials in palliative care are possible and meaningful. And I think for me, one quick learning point is that you could be an oncologist and lead this impactful research. And she's inspired many and many of us. Now let's quickly transition to her study. So in this trial, the stepped palliative care trial, patients with advanced lung cancer were randomized into two groups. One group followed the model from her landmark 2010 New England Journal of Medicine paper, which was structured monthly palliative care visits, again, within eight weeks of diagnosis. The second group, which is in this study, the intervention or the stepped palliative care group, received a single early palliative care visit. Think of this as a meet and greet. And then care was actually stepped up. If one of three clinical triggers happened. One, a decline in patient reported quality of life as measured by PROs. Two, disease progression, or three, hospitalization. And the findings which were presented at ASCO 2024 were striking. Clinical outcomes, very similar between the two groups. And this included quality-of-life, end-of-life communication, and resource use. But I think the take-home point is that the number of palliative care visits in the stepped group was significantly lower. So in other words, same impact and fewer visits. This was a very elegant example of how we can model precision palliative care, right sizing patient care based on patient need. So where do we go from here? I think if we want this model to take root nationally, we really need to pull on three key levers: healthcare systems, healthcare payment, and healthcare culture. So from a system alignment, unfortunately, as mentioned too often, the solution to gaps in palliative care is we need more clinicians. And while yes, that's partly true, it's actually not the full picture. I think what we first need to do and what's more likely to be achieved is to develop systems that focus on building the infrastructure that maximizes the reach of our existing care teams. So this means investing in nurse navigation, real-time dashboards with patient-reported outcomes and EHR flags, and again, matching triage protocols where intensity matches complexity. And the goal, as mentioned, isn't to maximize consults, but to really maximize deployment of expertise based on need. The second piece is, of course, we need payment reform. So the stepped palliative care model only works when it allows continuous patient engagement. But unfortunately, current pay models don't reward or incentivize that. In fact, electronic PROs require a very high upfront financial investment and ongoing clinician time with little to no reimbursement. Imagine if we offered bundled payments or value-based incentives for teams that integrated PROs. Or imagine if we reimbursed palliative care based on impact or infrastructure instead of just fee-for-service volume. There is a lot of clear evidence that tele-palliative care is effective. In fact, it was the Plenary at ASCO 2024. Yet we're still battling these conversations around inconsistent reimbursement, and we're always waiting on whether or not telehealth waivers are gonna continue. So I think most importantly is we really need to recognize the broader scope of what palliative care offers, which is caregiver support, improving navigation, coordinating very complex transitions. To me, and what I've always prioritized as a champion at Penn, is that palliative care is not a nice to have, and neither are all of these infrastructures, but they're really essential to whole person care, and they need to be financially supported. And last, we really need a culture shift. We need to change from how palliative care is perceived, and it can't be something other. It can't be something outside of oncology, but it really needs to be embraced as this is part of cancer care itself. I often see hesitancy from many oncologists about introducing palliative care early. But it doesn't need to be a dramatic shift. I think small changes in language, how we introduce the palliative care team, and co-management models can really go a very long way in normalizing this part of patient care. And I'm particularly encouraged, Joe, by one particular innovation in this space, which is really the growth of many startups. And one startup, for example, is Thyme Care, where I've seen them working with many, many private practices across the country, alongside partnerships with payers to really build tech-enabled navigation that tries to basically maximize triage support with electronic PROs. And to me, I really think these models can help scale access without overwhelming current care teams. So precision palliative care, Joe, in summary, I think should be flexible, scalable, and really needs to align based on what patients need. Dr. Joseph McCollom: No, I really appreciate, Ramy, you talking about that it really takes a village to get oncology care in both a competent and a compassionate way. And we need buy-in champions at all levels: the system level, the administrative level, the policy level, the tech level. And we need to change culture. I kind of want to just get your final impressions and also make sure that we make our listeners aware of our article. We should be able to have this in the show notes here as well to find additional tools and resources, all the studies that were discussed in today's episode. But, Ramy, what are some of your kind of final takeaways and conclusions? Dr. Ramy Sedhom: Before we wrap up, I just want to make sure we highlight a very exciting opportunity for residents considering a future in oncology and palliative medicine. Thanks to the leadership of Dr. Jamie Von Roen, who truly championed this cause, ASCO and the ABIM (American Board of Internal Medicine) have partnered to create the first truly integrated palliative care oncology fellowship. Trainees can now double board in just two years or triple board in three with palliative care, oncology, and hematology. And I think, Joe, as you and I both know, it's incredibly rewarding and meaningful to work at this intersection. To close our message, if there's one message I think listeners should carry with them, it's that palliative care is about helping people live as well as possible for as long as possible. And precision palliative care simply helps us do that better. We need to really develop systems that tailor support to individual need, value, and individual goals. Just like our colleagues in precision oncology mentioned, getting the right care to the right patient at the right time, and I would add in the right way. For those who want to learn more, I encourage you to read our full article in JCO, which is “Precision Palliative Care As a Pragmatic Solution for a Care Delivery Problem.” Joe, thank you so, so much for this thoughtful conversation and for your leadership in our field. And thank you to everyone for listening. Thank you all for being champions of this essential part of cancer care. If you haven't yet joined the ASCO Palliative Care Communities of Practice, membership is free, and we'd love to have you. Dr. Joseph McCollom: Thank you, Ramy, not only for sharing your insights today, but the pioneering work that you have done in our field. You are truly an inspiration to me in clinical practice, and it is an honor to call you both a colleague and friend.  And thank you for our listeners for joining us today. If you value the insights that you've heard on the ASCO Daily News Podcast, please subscribe, rate, and review wherever you get your podcasts. Thanks again. 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. Follow today's speakers:   Dr. Joseph McCollom @realbowtiedoc Dr. Ramy Sedhom @ramsedhom Follow ASCO on social media:   @ASCO on X (formerly Twitter) ASCO on Bluesky  ASCO on Facebook   ASCO on LinkedIn   Disclaimer: Dr. Joseph McCollom: No relationships to disclose Dr. Ramy Sedhom: No relationships to disclose

When is Y90 the right treatment for metastatic disease? Join Drs. Tyler Sandow, Zach Berman and host Kavi Krishnasamy in the conclusion of Dosimetry University where they discuss the complexities of treating different variations of metastatic disease and review how they've approached complicated cases with Y90. --- SYNPOSIS The interventional oncologists first outline the types of metastases that they treat, including colorectal, lung, cholangiocarcinoma, breast, gastric, RCC, and melanoma. The doctors then discuss the potential for Y90 to provide palliative relief by reducing tumor-related pain. The conversation also covers key differences between treating liver-dominant and liver-only disease, along with their algorithm for patients not on systemic chemotherapy.The episode then covers advanced concepts in Y90, such as sub-ablative dosing, the possibility of creating an abscopal effect, and how radiation thresholds change depending on treatment goals. They outline their approach to partition dosimetry, using SPECT/CT to calculate tumor-to-normal ratios, and explain how they modify particle counts and microsphere activity, using flow augmentation based on tumor vascularity. Additional discussion includes the impact of mutation status, prior lines of chemotherapy, and tumor response criteria like RECIST 1.1 and mRECIST. The experts conclude with a case series that illustrates decision-making around when to consider Y90, thermal ablation, TACE, or alternative approaches—even in complex cases like sphincter of Oddi dysfunction. The session underscores the nuanced nature of advanced dosimetric techniques and the evolving landscape of interventional oncology. --- TIMESTAMPS 00:00 - Introduction 01:30 - Types of Metastases Treated with Y9002:50 - Liver-Dominant vs. Liver-Only Disease 07:20 - Sub-Ablative Dosing and the Abscopal Effect09:55 - Tips for Partition Dosimetry 15:30 - Clinical Factors in Treatment Planning23:50 - Choosing Ablation, Resection, or Y90 for mCRC30:27 - Case Series: Colorectal Metastases, Biliary Complications, and more46:00 - Final Thoughts: The Evolving Field --- RESOURCES RECIST 1.1 and mRECIST Criteria:https://pmc.ncbi.nlm.nih.gov/articles/PMC9161105/ COLLISION Trial:https://ascopubs.org/doi/10.1200/JCO.2024.42.17_suppl.LBA3501 BackTable Episode on COLLISION Trial:https://www.youtube.com/watch?v=NQLKcv1BRVM FOXFIRE, SIRFLOX, FOXFIRE-Global:https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30457-6/fulltext

Is one outdated warning label standing between millions of women and safe, effective care? In this episode of BackTable Urology, Dr. Yahir Santiago-Lastra, a urologist specializing in female pelvic medicine and reconstructive surgery at UC San Diego, joins host Dr. Suzette Sutherland to discuss the black box warning on vaginal estrogen, its historical context, and the ongoing advocacy efforts to update outdated FDA guidelines. --- SYNPOSIS The conversation covers the importance of low-dose vaginal estrogen in treating genitourinary syndrome of menopause (GSM), the fear surrounding hormone therapy due to misinterpreted data from the Women's Health Initiative (WHI) study, and the inequities faced in women's health, particularly in the context of hormone replacement therapies. They discuss the legislative and advocacy strategies needed to enact change, emphasizing the role of professional societies, legislative efforts, patient advocacy, and industry support in overcoming the barriers to updating the black box warning. --- TIMESTAMPS 00:00 - Introduction03:43 - History Behind the Estradiol Black Box Warning13:44 - The FDA Citizen Petition18:18 - Gender Inequity in Medicine24:05 - The Role of Organizational Guidelines in Patient Advocacy28:51 - Vaginal Estrogen for Genitourinary Syndrome of Menopause (GSM)32:57 - Medicare Spending and Legislative Advocacy44:56 - Recap and Future Directions --- RESOURCES (TRAVERSE Trial) Cardiovascular Safety of Testosterone-Replacement Therapyhttps://www.nejm.org/doi/full/10.1056/NEJMoa2215025 Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Studyhttps://doi.org/10.1093/jnci/djac112 (ASCO Study) Use of local estrogen therapy among breast cancer patients in SEER-MHOS databasehttps://doi.org/10.1200/JCO.2025.43.16_suppl.578 Vaginal estrogen use in breast cancer survivors: a systematic review and meta-analysis of recurrence and mortality riskshttps://doi.org/10.1016/j.ajog.2024.10.054

In this JCO Article Insights episode, Michael Hughes summarizes “International Myeloma Society and International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma" by Avet-Loiseau et al. published on June 09, 2025 along with an interview with author Dr Nikhil C. Munshi, MD. TRANSCRIPT Michael Hughes: Welcome to this episode of JCO Article Insights. This is Michael Hughes, JCO's editorial fellow. Today I am interviewing Dr. Nikhil Munshi on the “International Myeloma Society and International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma” by Avet-Loiseau et al. At the time of this recording, our guest has disclosures that will be linked in the transcript. While some patients with multiple myeloma live for decades after treatment, others exhibit refractory or rapidly relapsing disease irrespective of treatment administered. We term this “high-risk myeloma.” Multiple risk stratification systems have been created, starting with the Durie-Salmon system in 1975 and evolving with the advent of novel therapeutics and novel treatment approaches. In 2015, the Revised International Staging System (R-ISS) was introduced, which incorporated novel clinical and cytogenetic markers and remained, until recently, a mainstay of risk stratification in newly diagnosed disease. Myeloma as a field has, just in the past few years, though, undergone explosive changes. In particular, we have seen groundbreaking advances not only in treatments - the introduction of anti-CD38 agents and the advent of cellular and bispecific therapies - but also in diagnostic technology and our understanding of the genetic lesions in myeloma. This has led to the proliferation of numerous trials employing different definitions of high-risk myeloma, a burgeoning problem for patients and providers alike, and has prompted attempts to consolidate definitions and terminology. Regarding cytogenetic lesions, at least, Kaiser et al's federated meta-analysis of 24 therapeutic trials, published here in the JCO in February of 2025 and recently podcasted in an interview with associate editor Dr. Suzanne Lentzsch, posited a new cytogenetic classification system to realize a shared platform upon which we might contextualize those trial results. This article we have here by Dr. Avet-Loiseau, Dr. Munshi, and colleagues, published online in early June of this year and hot off the presses, is the definitive joint statement from the International Myeloma Society (IMS) and the International Myeloma Working Group (IMWG). What is high-risk multiple myeloma for the modern era? The IMS and IMWG Genomics Workshop was held in July 2023 and was attended by international myeloma experts, collaborating to reach consensus based on large volumes of data presented and shared. The datasets included cohorts from the Intergroupe Francophone du Myélome (IFM); the HARMONY project, comprised of multiple European academic trials; the FORTE study, findings from which solidified KRd as a viable induction regimen; the Grupo Español de Mieloma Múltiple (GEM) and the PETHEMA Foundation; the German-Speaking Myeloma Multicenter Group (GMMG); the UK-based Myeloma XI, findings from which confirmed the concept of lenalidomide maintenance; Emory 1000, a large, real-world dataset from Emory University in Atlanta; the Multiple Myeloma Research Foundation Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile (CoMMpass) dataset; and some newly diagnosed myeloma cohorts from the Mayo Clinic. Data were not pooled for analyses and were assessed individually - that is to say, with clear a priori understanding of whence the data had been gathered and for what original purposes. Consensus on topics was developed based on the preponderance of data across studies and cohorts. In terms of results, substantial revisions were made to the genomic staging of high-risk multiple myeloma, and these can be sorted into three major categories: A) alterations to the tumor suppressor gene TP53; B) translocations involving chromosome 14: t(14;16) (c-MAF overexpression), t(14;20) (MAFB overexpression), and t(4;14) (NSD2 overexpression); and C) chromosome 1 abnormalities: deletions of 1p or additional copies of 1q. In terms of category A, TP53 alterations: Deletion of 17p is present in up to 10% of patients at diagnosis and is enriched in relapsed or refractory disease. This is well-documented as a high-risk feature, but the proportion of the myeloma cells with deletion 17p actually impacts prognosis. GEM and HARMONY data analyses confirmed the use of 20% clonal cell fraction as the optimal threshold value for high-risk disease. That is to say, there must be the deletion of 17p in at least 20% of the myeloma cells on a FISH-analysis of a CD138-enriched bone marrow sample to qualify as high-risk disease. TP53 mutations can also occur. Inactivating mutations appear to have deleterious effects similar to chromosomal losses, and the biallelic loss of TP53, however it occurs, portends particularly poor prognosis. This effect is seen across Myeloma XI, CoMMpass, and IFM cohorts. Biallelic loss is rare, it appears to occur in only about 5% of patients, but next-generation sequencing is nevertheless recommended in all myeloma patients. Category B, chromosome 14 translocations: Translocation t(14;16) occurs in about 2% to 3% of patients with newly diagnosed disease. In the available data, primarily real-world IFM data, t(14;16) almost always occurs with chromosome 1 abnormalities. Translocation t(4;14) occurs in about 10% to 12% of newly diagnosed disease, but only patients with specific NSD2 alterations are, in fact, at risk of worse prognosis, which clinically appears to be about one in every three of those patients. And so together, the CoMMpass and Myeloma XI data suggest that translocation t(4;14) only in combination with deletion 1p or gain or amplification of 1q correlates with worse prognosis. Translocation t(14;20) occurs in only 2% of newly diagnosed disease. Similar to translocation t(4;14), it doesn't appear to have an effect on prognosis, except if the translocation co-occurs with chromosome 1 lesions, in which case patients do fare worse. Overall, these three translocations - t(14;16), t(4;14), and t(14;20) - should be considered high-risk only if chromosome 1 aberrations are also present. In terms of those chromosome 1 aberrations, category C, first deletions of 1p: Occurring in about 13% to 15% of newly diagnosed disease, deletion 1p eliminates critical cell checkpoints and normal apoptotic signaling. In the IFM and CoMMpass dataset analyses, biallelic deletion of 1p and monoallelic deletion of 1p co-occurring with additional copies of 1q denote high-risk. In terms of the other aberration in chromosome 1 possible in myeloma, gain or amplification of 1q: This occurs in up to 35% to 37% of newly diagnosed disease. It upregulates CKS1B, which is a cyclin-dependent kinase, and ANP32E, a histone acetyltransferase inhibitor. GEM and IFM data suggest that gain or amplification of 1q - there was no clear survival detriment to amplification - is best considered as a high-risk feature only in combination with the other risk factors as above. Now, in terms of any other criteria for high-risk disease, there remains one other item, and that has to do with tumor burden. There has been a consensus shift, really, in both the IMS and IMWG to attempt to develop a definition of high-risk disease which is based on biologic features rather than empirically observed and potentially temporally dynamic features, such as lactate dehydrogenase. Beta-2 microglobulin remains an independent high-risk indicator, but care must be taken when measuring it, as renal dysfunction can artificially inflate peripheral titers. The consensus conclusion was that a beta-2 microglobulin of at least 5.5 without renal failure should be considered high-risk but should not preclude detailed genomic profiling. So, in conclusion, the novel 2025 IMS-IMWG risk stratification system for myeloma is binary. It's either high-risk disease or standard-risk disease. It's got four criteria. Number one, deletion 17p and/or a TP53 mutation. Clonal cell fraction cut-off, remember, is 20%. Or number two, an IGH translocation - t(4;14), t(14;16), t(14;20) - with 1q gain and/or deletion of 1p. Or a monoallelic deletion of 1p with 1q additional copies or a biallelic deletion of 1p. Or a beta-2 microglobulin of at least 5.5 only when the creatinine is normal. This is a field-defining work that draws on analyses from across the world to put forward a dominant definition of high-risk disease and introduces a new era of biologically informed risk assessment in myeloma. Now, how does this change our clinical approach? FISH must be performed on CD138-enriched samples and should be performed for all patients. Next-generation sequencing should also be performed on all patients. Trials will hopefully now begin to include this novel definition of high-risk multiple myeloma. It does remain to be seen how data from novel therapeutic trials, if stratified according to this novel definition, will be interpreted. Will we find that therapies being evaluated at present have differential effects on myelomas with different genetic lesions? Other unanswered questions also exist. How do we go about integrating this into academic and then community clinical practice? How do we devise public health interventions for low-resource settings? To discuss this piece further, we welcome the esteemed Dr. Nikhil Munshi to the podcast. Dr. Munshi is a world-renowned leader in multiple myeloma and the corresponding author on this paper. As Professor of Medicine at Harvard Medical School, Director of the Multiple Myeloma Effector Cell Therapy Unit, and Director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center of the Dana-Farber Cancer Institute, he has presided over critical discoveries in the field.  Thank you for joining us, Dr. Munshi. Dr. Nikhil Munshi: Oh, it's my pleasure being here, Michael, to discuss this interesting and important publication. Michael Hughes: I had a few questions for you. So number one, this is a comprehensive, shall we say, monumental and wide-ranging definition for high-risk myeloma. How do you hope this will influence or impact the ways we discuss myeloma with patients in the exam room? And how do we make some of these components recommended, in particular next-generation sequencing, feasible in lower-resource settings? Dr. Nikhil Munshi: So those are two very important questions. Let's start with the first: How do we utilize this in our day-to-day patient care setting? So, as you know well, we have always tried to identify those patients who do not do so well with the current existing treatment. And for the last 30 years, what constitutes a myeloma of higher risk has continued to change with improvement in our treatment. The current definition basically centers around a quarter of the patients whose PFS is less than 2 to 3 years. And those would require some more involved therapeutic management. So that was a starting point of defining patients and the features. As we developed this consensus amongst ourselves - and it's titled as “International Myeloma Society, International Myeloma Working Group Consensus Recommendation” - this IMS-IMWG type of recommendation we have done for many years, improvising in various areas of myeloma care. Now, here, we looked at the data that was existing all across the globe, utilizing newer treatment and trying to identify that with these four-drug regimens, with transplant and some of the immunotherapy, which group of patients do not do as well. And this is where this current algorithm comes up. So before I answer your question straight, “How do we use it?” I might like to just suggest, “What are those features that we have identified?” There are four features which constitute high-risk disease in the newer definition. Those with deletion 17p with 20% clonality and/or TP53 mutation. Number two, patients with one of the translocations - t(4;14), t(14;16), or t(14;20) - co-occurring with 1q amplification or deletion 1p32. And that's a change. Previously, just the translocation was considered high-risk. Now we need a co-occurrence for it to be called high-risk. The third group is patients having biallelic deletion 1p32 or monoallelic deletion 1p32 along with 1q amplification. And finally, patients with high beta-2 microglobulin, more than or equal to 5.5 mg/dL, with normal creatinine less than 1.2 mg/dL. And the question, “How do we use this?” There are multiple areas where we incorporate high-risk features in our treatment algorithm. One of the first areas is where we would consider the induction regimen. If a patient has a high-risk disease, we would definitely consider a four-drug regimen rather than a three-drug regimen, although we are beginning to incorporate four-drug for all groups. That's one important thing. Number two, those are the patients where we do consider consolidation with transplant or maybe in the new world, considering some of the immunotherapeutic consolidation more early or more aggressively. Number three, these are the patients who get a little bit more maintenance therapy. So normally, lenalidomide might end up being our standard maintenance regimen. In patients who have high-risk disease, we incorporate either addition of daratumumab or the anti-CD38 targeting antibody and/or addition of proteasome inhibitor, either bortezomib or carfilzomib. So you would have multi-drug maintenance therapy in these patients. And in high-risk patients, we follow them with maintenance longer periods of time. One very critically important point to keep in mind is that to get the better outcome in high-risk disease, we must try to get them into MRD negativity because there is clear data that patients who do achieve MRD negativity, despite having high-risk disease, have a much superior outcome. They become near to standard-risk disease. And so, in high-risk patients, I would try to do whatever various options I have to try and get them into MRD-negative status. And when these patients relapse, we do not wait for the classic progression criteria to be met before we intervene. We would propose and suggest that we intervene earlier before the disease really blasts off. And so there are a number of areas in our setting where this high-risk definition will help us intervene appropriately and also with appropriate aggressiveness to achieve better outcome, to make this similar to standard-risk disease. Michael Hughes: Thank you, Dr. Munshi. And thoughts on how to really integrate this not only into academic centers but also lower-resource settings? Dr. Nikhil Munshi: So that's a very important question, Michael. And when we were developing this consensus, we were very cognizant of that fact. So wherever available, I think we are recommending that over a period of next 2, 3, 5 years, we should begin to switch over to sequencing-based methods because two components of this definition, one is TP53 mutation, which we cannot do without sequencing, and also reliably detecting deletion 1p requires sequencing-based method. So in the low-resource countries - and there are many in this world, and also even in our own country, patients may not be able to afford it - the older method with FISH or similar such technology, which is more affordable, is also acceptable for current time. They may miss a very small number of patients, maybe 2% to 3%, where these finer changes are not picked up, but a majority of this would be captured by them. So the current practice might still be applicable with some limitation in those patient populations, and that's what we would recommend. What is happening, fortunately, is that actually sequencing-based method is becoming cheaper. And in many centers, it is cheaper to do the sequencing rather than to do the FISH analysis. And so my hope is that even in low-resource centers, sequencing might be more economical in the end. It's, I think, the access to technology, which is a little bit limited currently, but it's hopefully becoming available soon. Michael Hughes: Thank you, Dr. Munshi. And staying for a minute and looking at the multiple myeloma subsets which might be missed by this really still very broad-ranging high-risk definition, at least by prior risk stratification systems, right, there is this group of patients who have standard-risk cytogenetics by R-ISS or R2-ISS, but they have primary refractory disease or they relapse early. We call these, as you are well aware, functionally high-risk disease. What proportion of previously FHR, functionally high-risk, myeloma patients do you expect to be captured by this novel definition? Dr. Nikhil Munshi: So I think the newer definition - and we can look at it both ways, but the newer definition should capture most of the functionally high-risk definition. To put it differently, Michael, there are patients who we know are, as you mentioned, functionally high-risk. Those are the patients who might have plasma cell leukemia, those who might have extramedullary disease, those who might not respond to our four-drug induction. If you don't respond to the four-drug induction, almost by definition, they are high-risk. However, a majority of them have one of the abnormalities that we are describing here. There would be a very small proportion which may not have. And if they do not have, we know one of the important components of this definition here is also that the genome, we know, keeps on evolving. So there may be a very small clone with the high-risk feature which was not obvious in the beginning. Following treatments or following relapse, that clone predominates, and now the patient's disease becomes high-risk.  So the definition would incorporate or would capture these functional high-risk patients, but as you said, in countries where resources are not available, using this functional high-risk would also be helpful and advantageous. Sometimes LDH ends up being a high-risk. In our studies, LDH has not come out to be high-risk anymore because the features we are describing captures most of those patients, but those alternatives, older, can still be considered if other newer techniques are not available. Michael Hughes: Got you. And in terms of these older definitions, yes, that incorporate tumor burden, these empirical observations about how myeloma presents, do you foresee any additional tumor burden indicators being added to future definitions of high-risk disease? Or do you instead see this particular definition as a major waypoint on the journey towards a fully biologically grounded definition of high-risk disease? Dr. Nikhil Munshi: I think your second part is what is going to happen. I think the tumor burden-related definition is being now replaced by the biological or genomic-based definition. And I think at some point, it will be quite fully replaced. One component not here, and it is because one thing, we don't have enough data; number two, we don't know how it will pan out, is also the influence of the microenvironment on the risk definition. For example, the immune system, the immune function, etc. But not enough data exists to suggest how it would change the current definition. So in future, would a definition be totally genomic or it could be more integrative? And my personal guess is that it would be more integrative and that some immune features might come into the picture, especially now that we are using immune-based therapy as a very important component of treatment - CAR T-cells, bispecific, and antibody-based treatments. What role the immune system plays in either supporting tumor or what role suppression of the anti-tumor immunity plays? They all will be important how patient outcomes end up being, and which in turn could translate into how patient's risk stratification might happen. So I think the older tumor burden-related definitions probably will become things of the past. What we have currently proposed and consensus developed is the new path forward, and over time, some microenvironmental influences, if defined and found to be important, may get some more incorporation if it compares favorably with the genomic features. Michael Hughes: Thank you, Dr. Munshi for that enlightening response.  To conclude the podcast, I'd like to look to the future and to the immediate future, what are the next steps for high-risk disease definition between now and discussing an integrated genomic-microenvironment-based definition? Will we see attempts to refine? Will we see a multi-level system, things like this? Dr. Nikhil Munshi: Yeah, so I think the current definition will be here to stay for the next 10 years or so. I think this has been developed using a large amount of data, so we do believe that this will remain fine. It has been validated now within the last six months by a few of the other studies. So there won't be a quick change. But we will try to, all of us will try to innovate. And as you very rightly bring up, the areas of research would include looking at the expression or transcriptomic component. Does that matter? And we do believe a small number of patients will have transcriptomic changes, not looked at the DNA changes, and may play a role. There are newer components, so long non-coding RNA, for example, is going to be an important component to look at, how it impacts the disease outcome, etc. There are also some of the proteomic-related changes which may become important in our studies. And then as we discussed, microenvironment and immunological changes. So these are the future areas of ongoing research where we all should collect data, and then in the next 5 to 10 years, we'll have another group meeting to see has anything changed or any of the features have become more important.  Most of the time, some of the older features are lost because they are not as critically high-risk, and the newer features come in. And so the historical background for just one second, there was a time when chromosome 13 was considered a high-risk disease. We now don't even mention it because it's not high-risk. The newer treatments have improved the outcome. t(4;14) used to be a high-risk disease. Now by itself today, in this definition by itself is not; it needs to be with something else. And so I think this is a great sign of progress. As we improve the treatment and outcomes, some of the features will become less important, new features will come up, and we'll need to keep on evolving with time and with technology and make it better for patients. Michael Hughes: Thank you so much, Dr. Munshi, for your wisdom, for your sagacity, for your historical perspective as well.  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.  

In this episode, we discuss the management of follicular lymphoma with Dr. Gilles Salles from Memorial Sloan Kettering Cancer Center. Here are the articles we discussed: 1. Relevance of Bone Marrow Biopsy in Follicular Lymphoma: https://pubmed.ncbi.nlm.nih.gov/35787017/2. TROG 99.03 (RCT of Systemic Therapy after Involved-Field Radiotherapy in Patients with Early-Stage Follicular Lymphoma): https://pubmed.ncbi.nlm.nih.gov/29975623/3. Long-term follow-up results of RCT comparing early rituximab monotherapy versus watchful waiting for advanced stage, asymptomatic, low tumor burden follicular lymphoma: https://pubmed.ncbi.nlm.nih.gov/40306831/4. RELEVANCE RCT: Lenalidomide plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma: https://ascopubs.org/doi/10.1200/JCO.22.008435. GALLIUM RCT: Obinutuzumab Versus Rituximab Immunochemotherapy in Previously Untreated iNHL. https://pubmed.ncbi.nlm.nih.gov/37404773/https://pubmed.ncbi.nlm.nih.gov/28976863/6. Long-term follow-up of mosunetuzumab in relapsed/refractory FL: https://pubmed.ncbi.nlm.nih.gov/39447094/7. Epcoritamab in relapsed/refractory FL: https://pubmed.ncbi.nlm.nih.gov/38889737/8. Phase 3 inMIND RCT: Tafasitamab plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma: https://ashpublications.org/blood/article/144/Supplement%202/LBA-1/5343199. Long term follow-up results from the Phase 3 PRIMA trial of rituximab maintenance in Follicular Lymphoma: https://ascopubs.org/doi/10.1200/JCO.19.01073

The incidence of early onset colorectal cancer (EOCRC) has been rising prompting the change in change in screening guidelines to 45 years of age for average risk patients. Join us for an in-depth discussion with guest speakers Dr. Andrea Cercek and Dr. Nancy You, where we provide a comprehensive look at the growing challenge of EOCRC. Hosts: - Dr. Janet Alvarez - General Surgery Resident at New York Medical College/Metropolitan Hospital Center - Dr. Wini Zambare – General Surgery Resident at Weill Cornell Medical Center/New York Presbyterian - Dr. Phil Bauer, Graduating Colorectal Surgical Oncology Fellow at Memorial Sloan Kettering Cancer Center  - Dr. J. Joshua Smith MD, PhD, Chair, Department of Colon and Rectal Surgery at MD Anderson Cancer Center - Dr. Andrea Cercek - Gastrointestinal Medical Oncologist at Memorial Sloan Kettering Cancer Center - Dr. Y. Nancy You, MD MHSc - Professor, Department of Colon and Rectal Surgery at MD Anderson Cancer Center Learning objectives:  - Describe trends in incidence of colorectal cancer, with emphasis on the rise of EOCRC. - Identify age groups and demographics most affected by EOCRC. - Summarize USPSTF recommendations for colorectal cancer screening. - Distinguish between screening methods (e.g., colonoscopy, FIT-DNA) and their sensitivity. - Understand treatment approaches for colon and rectal cancer (CRC) - Understand the role of mismatch repair (MMR) status in guiding treatment. - Outline the importance of genetic counseling and testing in young patients. - Discuss racial, ethnic, and socioeconomic disparities in CRC incidence and outcomes. - Describe the impact of cancer treatment on fertility and sexual health. -  Review fertility preservation options. - Identify the value of integrated care teams for young CRC patients. References: 1.         Siegel, R. L. et al. Colorectal Cancer Incidence Patterns in the United States, 1974–2013. JNCI J. Natl. Cancer Inst. 109, djw322 (2017). https://pubmed.ncbi.nlm.nih.gov/28376186/ 2.         Abboud, Y. et al. Rising Incidence and Mortality of Early-Onset Colorectal Cancer in Young Cohorts Associated with Delayed Diagnosis. Cancers 17, 1500 (2025). https://pubmed.ncbi.nlm.nih.gov/40361427/ 3.         Phang, R. et al. Is the Incidence of Early-Onset Adenocarcinomas in Aotearoa New Zealand Increasing? Asia Pac. J. Clin. Oncol.https://pubmed.ncbi.nlm.nih.gov/40384533/ 4.         Vitaloni, M. et al. Clinical challenges and patient experiences in early-onset colorectal cancer: insights from seven European countries. BMC Gastroenterol. 25, 378 (2025). https://pubmed.ncbi.nlm.nih.gov/40375142/ 5.         Siegel, R. L. et al. Global patterns and trends in colorectal cancer incidence in young adults. (2019) doi:10.1136/gutjnl-2019-319511. https://pubmed.ncbi.nlm.nih.gov/31488504/ 6.         Cercek, A. et al. A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers. J. Natl. Cancer Inst. 113, 1683–1692 (2021). https://pubmed.ncbi.nlm.nih.gov/34405229/ 7.         Zheng, X. et al. Comprehensive Assessment of Diet Quality and Risk of Precursors of Early-Onset Colorectal Cancer. JNCI J. Natl. Cancer Inst. 113, 543–552 (2021). https://pubmed.ncbi.nlm.nih.gov/33136160/ 8.         Standl, E. & Schnell, O. Increased Risk of Cancer—An Integral Component of the Cardio–Renal–Metabolic Disease Cluster and Its Management. Cells 14, 564 (2025). https://pubmed.ncbi.nlm.nih.gov/40277890/ 9.         Muller, C., Ihionkhan, E., Stoffel, E. M. & Kupfer, S. S. Disparities in Early-Onset Colorectal Cancer. Cells 10, 1018 (2021). https://pubmed.ncbi.nlm.nih.gov/33925893/ 10.       US Preventive Services Task Force. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 325, 1965–1977 (2021). https://pubmed.ncbi.nlm.nih.gov/34003218/ 11.       Fwelo, P. et al. Differential Colorectal Cancer Mortality Across Racial and Ethnic Groups: Impact of Socioeconomic Status, Clinicopathology, and Treatment-Related Factors. Cancer Med. 14, e70612 (2025). https://pubmed.ncbi.nlm.nih.gov/40040375/ 12.       Lansdorp-Vogelaar, I. et al. Contribution of Screening and Survival Differences to Racial Disparities in Colorectal Cancer Rates. Cancer Epidemiol. Biomarkers Prev. 21, 728–736 (2012). https://pubmed.ncbi.nlm.nih.gov/22514249/ 13.       Ko, T. M. et al. Low neighborhood socioeconomic status is associated with poor outcomes in young adults with colorectal cancer. Surgery 176, 626–632 (2024). https://pubmed.ncbi.nlm.nih.gov/38972769/ 14.       Siegel, R. L., Wagle, N. S., Cercek, A., Smith, R. A. & Jemal, A. Colorectal cancer statistics, 2023. CA. Cancer J. Clin. 73, 233–254 (2023). https://pubmed.ncbi.nlm.nih.gov/36856579/ 15.       Jain, S., Maque, J., Galoosian, A., Osuna-Garcia, A. & May, F. P. Optimal Strategies for Colorectal Cancer Screening. Curr. Treat. Options Oncol. 23, 474–493 (2022). https://pubmed.ncbi.nlm.nih.gov/35316477/ 16.       Zauber, A. G. The Impact of Screening on Colorectal Cancer Mortality and Incidence: Has It Really Made a Difference? Dig. Dis. Sci. 60, 681–691 (2015). https://pubmed.ncbi.nlm.nih.gov/25740556/ 17.       Edwards, B. K. et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 116, 544–573 (2010). https://pubmed.ncbi.nlm.nih.gov/19998273/ 18.       Cercek, A. et al. Nonoperative Management of Mismatch Repair–Deficient Tumors. New England Journal of Medicine 392, 2297–2308 (2025). https://pubmed.ncbi.nlm.nih.gov/40293177/ 19.       Monge, C., Waldrup, B., Carranza, F. G. & Velazquez-Villarreal, E. Molecular Heterogeneity in Early-Onset Colorectal Cancer: Pathway-Specific Insights in High-Risk Populations. Cancers 17, 1325 (2025). https://pubmed.ncbi.nlm.nih.gov/40282501/ 20.       Monge, C., Waldrup, B., Carranza, F. G. & Velazquez-Villarreal, E. Ethnicity-Specific Molecular Alterations in MAPK and JAK/STAT Pathways in Early-Onset Colorectal Cancer. Cancers 17, 1093 (2025). https://pubmed.ncbi.nlm.nih.gov/40227607/ 21.       Benson, A. B. et al. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. JNCCN 19, 329–359 (2021). https://pubmed.ncbi.nlm.nih.gov/33724754/ 22.       Christenson, E. S. et al. Nivolumab and Relatlimab for the treatment of patients with unresectable or metastatic mismatch repair proficient colorectal cancer. https://pubmed.ncbi.nlm.nih.gov/40388545/ 23.       Dasari, A. et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. The Lancet 402, 41–53 (2023). https://pubmed.ncbi.nlm.nih.gov/37331369/ 24.       Strickler, J. H. et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 24, 496–508 (2023). https://pubmed.ncbi.nlm.nih.gov/37142372/ 25.       Sauer, R. et al. Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer. N. Engl. J. Med. 351, 1731–1740 (2004). https://pubmed.ncbi.nlm.nih.gov/15496622/ 26.       Cercek, A. et al. Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol. 4, e180071 (2018). https://pubmed.ncbi.nlm.nih.gov/29566109/ 27.       Garcia-Aguilar, J. et al. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J. Clin. Oncol. 40, 2546–2556 (2022). https://pubmed.ncbi.nlm.nih.gov/35483010/ 28.       Schrag, D. et al. Preoperative Treatment of Locally Advanced Rectal Cancer. N. Engl. J. Med. 389, 322–334 (2023). https://pubmed.ncbi.nlm.nih.gov/37272534/ 29.       Kunkler, I. H., Williams, L. J., Jack, W. J. L., Cameron, D. A. & Dixon, J. M. Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer. N. Engl. J. Med. 388, 585–594 (2023). https://pubmed.ncbi.nlm.nih.gov/36791159/ 30.       Jacobsen, R. L., Macpherson, C. F., Pflugeisen, B. M. & Johnson, R. H. Care Experience, by Site of Care, for Adolescents and Young Adults With Cancer. JCO Oncol. Pract. (2021) doi:10.1200/OP.20.00840. https://pubmed.ncbi.nlm.nih.gov/33566700/ 31.       Ruddy, K. J. et al. Prospective Study of Fertility Concerns and Preservation Strategies in Young Women With Breast Cancer. J. Clin. Oncol. (2014) doi:10.1200/JCO.2013.52.8877. https://pubmed.ncbi.nlm.nih.gov/24567428/ 32.       Su, H. I. et al. Fertility Preservation in People With Cancer: ASCO Guideline Update. J. Clin. Oncol. 43, 1488–1515 (2025). https://pubmed.ncbi.nlm.nih.gov/40106739/ 33.       Smith, K. L., Gracia, C., Sokalska, A. & Moore, H. Advances in Fertility Preservation for Young Women With Cancer. Am. Soc. Clin. Oncol. Educ. Book 27–37 (2018) doi:10.1200/EDBK_208301. https://pubmed.ncbi.nlm.nih.gov/30231357/ 34.       Blumenfeld, Z. How to Preserve Fertility in Young Women Exposed to Chemotherapy? The Role of GnRH Agonist Cotreatment in Addition to Cryopreservation of Embrya, Oocytes, or Ovaries. The Oncologist 12, 1044–1054 (2007). 35.       Bhagavath, B. The current and future state of surgery in reproductive endocrinology. Curr. Opin. Obstet. Gynecol. 34, 164 (2022). 36.       Ribeiro, R. et al. Uterine transposition: technique and a case report. Fertil. Steril. 108, 320-324.e1 (2017). 37.       Yazdani, A., Sweterlitsch, K. M., Kim, H., Flyckt, R. L. & Christianson, M. S. Surgical Innovations to Protect Fertility from Oncologic Pelvic Radiation Therapy: Ovarian Transposition and Uterine Fixation. J. Clin. Med. 13, 5577 (2024). 38.       Holowatyj, A. N., Eng, C. & Lewis, M. A. Incorporating Reproductive Health in the Clinical Management of Early-Onset Colorectal Cancer. JCO Oncol. Pract. 18, 169–172 (2022). ***Behind the Knife Colorectal Surgery Oral Board Audio Review: https://app.behindtheknife.org/course-details/colorectal-surgery-oral-board-audio-review Please visit https://behindtheknife.org to access other high-yield surgical education podcasts, videos and more.   If you liked this episode, check out our recent episodes here: https://app.behindtheknife.org/listen

In this episode, CancerNetwork® spoke with breast oncologists Heather McArthur, MD; Erika Hamilton, MD; Hope Rugo, MD; and Paolo Tarantino, MD, PhD, about advances in breast cancer. These developments included recent drug approvals and ongoing research for therapeutic approaches, particularly in the areas of antibody-drug conjugates (ADCs) and CDK4/6 inhibitors, based on presentations they gave at the 25th Annual International Congress on the Future of Breast Cancer (IBC) East in New York City. Initially, McArthur, Komen Distinguished Chair in Clinical Breast Cancer Research at the Harold C. Simmons Comprehensive Cancer Center, discussed immunotherapy use in high-risk triple-negative and HER2-positive disease, the evolving role of adjuvant CDK4/6 inhibition in HER2-negative breast cancer, and potentially transformative advancements in early breast cancer treatment.  She highlighted the FDA approval for pembrolizumab (Keytruda) in early-stage triple-negative breast cancer, promising clinical trials in estrogen receptor (ER)–positive high-risk early-stage breast cancer, and data from an investigator-initiated trial to treat HER2-positive disease. Additionally, she highlighted an 8.5% improvement in pathological complete response with pembrolizumab added to immunotherapy in the phase 3 KEYNOTE-756 trial (NCT03725059), adding that a further event-free survival benefit may complicate the landscape for CDK4/6 inhibition based on lung and liver toxicities associated with the coadministration of these inhibitors with immunotherapy.1 McArthur expressed further excitement for ADC-based combinations for triple-negative disease, as well as in the high-risk residual disease setting. In addition, she highlighted potential advancements in de-escalation strategies and further considerations for ADCs in the HER2-positive and hormone receptor (HR)–positive spaces. Then, Hamilton, director of Breast Cancer and Gynecologic Cancer Research at the Sarah Cannon Research Institute, highlighted emerging therapies for early breast cancer, as well as her use of datopotamab deruxtecan-dlnk (dato-DXd; Datroway) and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) given their recent approvals in various breast cancer subtypes. She also touched upon challenges with respect to the implementation of new therapies for early breast cancer into clinical practice. She initially highlighted new data from the phase 3 VERITAC-2 trial (NCT05654623) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.2 Specifically, findings showed that vepdegestrant, an oral proteolysis-targeting chimera (PROTAC), exhibited an efficacy advantage over fulvestrant (Faslodex) in patients with ESR1-mutant ER-positive, HER2-negative advanced or metastatic disease. Moreover, she highlighted data from the phase 3 DESTINY-Breast09 (NCT04784715) of T-DXd in various combinations for patients with HER2-positive metastatic breast cancer.3 Hamilton further highlighted her implementation of T-DXd into clinical practice, citing her use of the agent in patients with metastatic disease, including those with HER2-low and HER2-ultralow breast cancer. She further differentiated dato-DXd from T-DXd, suggesting that they were different classes of drugs due to their different targets: TROP2 vs HER2. She concluded by highlighting an unmet need regarding sustained benefit from endocrine therapy in HR-positive disease, as well as for ADC sequencing and mechanisms of resistance. Afterward, Rugo, division chief of Breast Medical Oncology, Women's Cancer Program Director, and professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, discussed efficacy and safety considerations for CDK4/6 inhibitors in early breast cancer treatment. Specifically, she highlighted their high tolerability despite adverse effects and costs associated with their use. Rugo further touched upon a reduction of recurrence rates associated with CDK4/6 inhibition, although longer-term follow-up data were warranted to optimize the duration of therapy and elucidate survival outcomes. Finally, Tarantino, a research fellow at the Dana-Farber Institute, concluded by discussing sequencing strategies for ADCs, as well as which breast cancer settings or patient populations will experience the greatest impact with this treatment modality. Tarantino discussed his use of the “sandwich strategy,” where he switches the mechanism of action of treatment after using a TOPO1 ADC. Furthermore, Tarantino highlighted data from the DESTINY-Breast09 and phase 3 ASCENT-04 (NCT06100874) trials, which displayed the enhanced efficacy of 2 ADC combination therapies.4 He concluded by discussing future considerations for combining multiple ADCs. References 1. Cardoso F, O'Shaughnessy J, Liu Z, et al. Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2- breast cancer: a randomized phase 3 trial. Nat Med. 2025;31(2):442-448. doi:10.1038/s41591-024-03415-7 2. Hamilton E, De Laurentiis M, Jhaveri K, et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: results of the global, randomized, phase 3 VERITAC-2 study. J Clin Oncol. 2025;43(suppl 17):LBA1000. doi:10.1200/JCO.2025.43.17_suppl.LBA1000 3. Tolaney S, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):LBA1008. 4. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109

Dr. Lyudmila Bazhenova is back on the podcast to discuss the latest update of the living guideline on therapy for stage IV NSCLC without driver alterations. She shares the studies the Expert Panel reviewed in the first- and second-line settings, including NIPPON, HARMONi-2, and DUBLIN-3. Although these studies do not impact the existing guideline recommendations, Dr. Bazhenova provides context and comments on ongoing trials that will influence the next iteration of the living guideline. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1” at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-01062 Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on "Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1." It's great to have you back on the show today, Dr Bazhenova. Dr. Lyudmila Bazhenova: It's my pleasure to be here. Brittany Harvey: And then before we discuss this guideline update, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bazhenova, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, Dr. Bazhenova, this living clinical practice guideline for systemic therapy for patients with stage IV non–small cell lung cancer without driver alterations is updated on an ongoing continuous basis. So what prompted this latest update to the recommendations? Dr. Lyudmila Bazhenova: Living ASCO guidelines are designed to keep pace with rapidly evolving evidence that impacts treatment of our patients with lung cancer. As a committee, we are tasked with regular review of the published literature and determine if the new data warrants changes to existing recommendations. So in this recently published update, we evaluated new trials related to treatment of patients with metastatic lung cancer without driver alterations. Brittany Harvey: Excellent. Thank you for that explanation of the process. So, you just mentioned that the panel reviewed new trials for this update. So, which particular updated evidence did the panel review on first-line treatment options for patients with good performance status across histology and PD-L1 expression status, and how did this impact the recommendations? Dr. Lyudmila Bazhenova: For the first-line treatment option for patients without driver alterations, two studies met our criteria for review. One was the NIPPON trial from Japan, the second was the HARMONi trial. None of those two trials resulted in change in our guidelines, but I think they are giving us some additional information that would be useful for the way we treat patients with non–small cell lung cancer without driver alterations. For example, if we take those patients, we currently have several treatment options as a first line. One is monotherapy immunotherapy. You can give pembrolizumab as an example, and that was based on the KEYNOTE-024 and KEYNOTE-042 trials. Then we have a platinum doublet plus immunotherapy, and there are several trials that did that pathway. And then we have also an option of giving our patients dual IO immunotherapy combination, such as CheckMate 9LA and POSEIDON. At this point, we do not have any randomized trials comparing those three treatment modalities head-to-head. And the NIPPON trial was interesting to us because it was the first trial to compare CheckMate 9LA regimen, which is again, dual immunotherapy plus chemo, versus KEYNOTE-189 or KEYNOTE-407, which is a chemotherapy plus immunotherapy. And as a result of the study, while chemotherapy plus ipilimumab-nivolumab led to numerically higher overall survival, the difference was not statistically significant. And what is concerning in that trial is that we saw a higher number of treatment-related death occurring in nivolumab and ipilimumab arm compared to the pembrolizumab-chemotherapy arm. As a matter of fact, the trial was terminated early because of the increased risk of death. If you look at the treatment-related death in CheckMate 9LA, the 9LA study reported the treatment-related death to be 2%, and then in the NIPPON trial, the treatment-related death was 7%. Why is that happening? It's really difficult to say. The study was done in Japan. Maybe there is some pharmacogenomic differences between global population and Japan population. But certainly the higher rate of adverse events needs to be taken into account. Another interesting thing about this trial is that it did not show any differences in a subset analysis for patients with squamous histology as well as PD-L1 negative tumor. So while this does not change our current guidelines and CheckMate 9LA treatment still remains an appropriate treatment option, it kind of raises the possibility that this combination could be associated with a higher toxicity. And we do have a randomized US-based trial that is ongoing, and we are hoping that eventually we will be able to answer that question after the trial will be completed. The second trial we reviewed is HARMONi-2. So HARMONi-2 was a randomized, double-blind study which is conducted primarily in China, looking at bispecific PD-L1 and VEGF antibody called ivonescimab. And that took patients who were PD-L1 positive, as defined as more than 1% expression, and patients were randomized to pembrolizumab versus bispecific ivonescimab. And the study was positive. It showed improvement in median progression-free survival of 11 months versus almost 6 months in bispecific versus pembrolizumab. There were, however, higher grade 3 events in the ivonescimab arm. At this point, we are not changing our recommendations because this trial was done in an ex-US population, and we are awaiting a similar trial ongoing in the United States before we change recommendations and decide if ivonescimab needs to be included in our guidelines. Brittany Harvey: This context is very helpful when clinicians think through the data behind these options. And it's important that the panel reviews this evidence, even if it doesn't prompt a change to the recommendations. And we'll await results of those trials that you mentioned to further inform this guideline. So then beyond those studies for first line, what updated evidence did the panel review for second-line and subsequent treatment options for patients with good performance status, and how did this impact the recommendations? Dr. Lyudmila Bazhenova: So for second line, only one trial met the criteria, and that was DUBLIN-3. DUBLIN-3 is a phase 3 single-blind randomized trial comparing docetaxel versus docetaxel plus plinabulin. And the study enrolled patients with second or third line. They have to have had platinum-based chemotherapy and progressed. Plinabulin is an interesting compound. It's a small molecule tubulin binder that prevents polymerization of tubulin and appears to impact dendritic cell maturation and T-cell activation. This study enrolled 559 patients, randomly assigned them to two groups. And one important information about this study is that was a study that was envisioned before immunotherapy became a standard mainstream treatment for first-line therapy. And only 20% of patients had prior PD-1 exposure. So therefore, the results of that study need to be taken into context of this population no longer existing in the United States because we use PD-L1 inhibitors in the first line. And we saw that interesting in the plinabulin arm had lower rates of neutropenia but higher rates of serious adverse events. And at this point, we are not changing our guidelines for mainly two reasons. Number one, low number of patients that received prior treatment with first-line immune checkpoint inhibitors, as well as a modest overall survival benefit of this trial. Brittany Harvey: Understood. I appreciate you describing that study as well and why that evidence didn't prompt a change to those particular recommendations. So then, what should clinicians know as they implement this living guideline, and how does this new evidence impact clinicians and patients? Dr. Lyudmila Bazhenova: At this point, none of the studies that we reviewed resulted in a change in guidelines. We are still waiting for more global results from some of the studies that I highlighted. It shows that there's still a lot of questions we need to be answering in those patients. And I'm hoping that with future clinical trials, we will be able to definitively maybe recommend one treatment over another. But at this point, all the treatments that I mentioned before remain appropriate for patients with stage IV non–small cell lung cancer without driver alterations. Brittany Harvey: Definitely. And then you just mentioned that there's still a lot of outstanding questions in this field. You've mentioned a couple different studies where we're awaiting evidence. Beyond those that you already mentioned, what is the panel examining for future updates to this living guideline? Dr. Lyudmila Bazhenova: Right now, our next task is to come up with a full guidelines update. ASCO have certain rules for the guidelines committee members. And so we are gearing for a full guideline update, which hopefully will be ready by the end of 2025. Brittany Harvey: Excellent. We'll look forward to that full update of the living guideline, and we'll still await results of these ongoing trials to further inform this living guideline. So I want to thank you so much for your work to rapidly and continuously update this living guideline, and thank you for the time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: My pleasure. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Joshua Reuss joints that podcast to discuss the latest changes to the living guideline on stage IV NSCLC with driver alterations. He discusses the new evidence for NSCLC with EGFR mutations and NRG1 fusions and how this impacts the latest recommendations from the panel. He shares ongoing research that the panel will review in the future for further updates to this living guideline, and puts the updated recommendations into context for clinicians treating patients with stage IV NSCLC. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2025.1” at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-01061 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Joshua Reuss from Georgetown University, co-chair on "Therapy for Stage IV Non–Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2025.1." It's great to have you here today, Dr. Reuss. Dr. Joshua Reuss: Thank you. Happy to be here. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Reuss, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So to dive into what we're here today to talk about, Dr. Reuss, this living clinical practice guideline for systemic therapy for patients with stage IV non–small cell lung cancer with driver alterations is updated on an ongoing basis. So what prompted this latest update to the recommendations? Dr. Joshua Reuss: Yes, thank you. It's very important that we have living guidelines that are continuously updated. We obviously don't live in a static environment where things are non-changing, and we really need to apply the most up-to-date and current evidence to treat our patients with the most effective strategies, the most groundbreaking strategies. And so to have guidelines that can be disseminated, particularly these ASCO guidelines, to treating providers is incredibly important. So, with any of these updates, we review ongoing studies, published work, for the quality of evidence to see if it's something that warrants making adjustments to our guidelines or at least incorporating the information so that providers can review it and incorporate this into their own personal decision-making. So in this particular update, we reviewed evidence particularly pertaining to EGFR-mutated non–small cell lung cancer and non–small cell lung cancer harboring an NRG1 fusion. Brittany Harvey: Yes, certainly there's a lot of new evidence in the advanced non–small cell lung cancer field, and so we appreciate the panel's continuous review of this evidence. So then you just mentioned two separate areas where the panel reviewed new evidence. So starting with that first one, what updated evidence did the panel review on first-line treatment options for patients with EGFR alterations, and how did this impact the recommendations? Dr. Joshua Reuss: Yes, so advanced EGFR-mutated non–small cell lung cancer, at least with classical activating alterations - that is our exon 19 deletions and our exon 21 L858R mutations - is something that's really evolved rapidly in the last few years. You know, for many years, we basically, for the frontline treatment setting, were saying, "Okay, we have a targeted therapy, osimertinib. We're going to give that, and we're going to see what effect we can get out of that," with, you know, a median time of duration of treatment response averaging around 18 months, knowing that there are some that that's a lot longer and some that are a lot shorter. But recently, we've seen a lot of data emerging on combination strategies. The guideline has already been updated to incorporate two of these combinations: osimertinib with chemotherapy based off of the FLAURA2 trial, and then the combination of amivantamab with lazertinib based off of the MARIPOSA trial. And that was data on progression-free survival that was published and led to those particular recommendations. Now, more recently, we've seen data come out in smaller, randomized studies for other combinations. And more recently, we reviewed the RAMOSE study. So this was a phase II, open-label, randomized trial for patients with tyrosine kinase inhibitor–naive and really, treatment-naive advanced EGFR-mutated non–small cell lung cancer harboring one of these two classical EGFR alterations, randomized to either osimertinib alone or osimertinib with the combination of ramucirumab, which is an anti-VEGF agent. There's been a lot of data, preclinical and clinical, for the role of VEGF blockade, particularly in EGFR-mutated non–small cell lung cancer, so exploring the combination of this for synergy in the frontline setting really made a lot of sense. So again, this was a phase II trial that randomized patients prospectively to one of these two regimens. The population here is really what we typically see with EGFR-mutated non–small cell lung cancer, predominantly a younger population - median age on this study was 65 - predominantly female - 71% female - and predominantly nonsmokers. Now, what this study showed was that at a median follow-up of 16.6 months, the progression-free survival favored the combination arm with a median progression-free survival of 24.8 months with the combination of osimertinib plus ramucirumab versus 15.6 months for osimertinib alone, for a hazard ratio of benefit of 0.55. The landmark one- and two-year endpoints for progression-free survival also favored the combination arm, and response rates were relatively comparable between groups, with overall adverse events being more frequent in the combination group, specifically high blood pressure, proteinuria, and epistaxis, which are our common adverse events related to VEGF-blocking agents. So, it's good to see data in this space. Now, of note, though, this was a phase II study, so not a phase III level of evidence. In addition, when looking at the population, this was a randomized, multicenter study, but it was a US-only population. There was also some imbalance in the number of visits between arms, so the combination arm was seen more frequently than the arm that got osimertinib alone. Now, the imaging assessments were no different, but obviously this could lead to potential confounding, at least in timing of awareness of potential side effects and and things being brought to the attention of investigators. So very promising data here, but because, you know, of this being a phase II study, this actually led to no changes in the guideline at this time. Brittany Harvey: Understood. Yes, as you mentioned prior, it's important to understand the full body of evidence and to review the trials even when it doesn't impact the recommendations. Dr. Joshua Reuss: And I will say that, you know, there is an ongoing phase III study looking at a very similar combination. It's the phase III ECOG-ACRIN trial of the combination of osimertinib plus bevacizumab versus osimertinib alone in this specific population. So, you know, I think we will see phase III–level data for a combination of VEGF with osimertinib, but again, promising phase II data that did not lead to a change in the recommendation at this time. Brittany Harvey: Absolutely. We'll look forward to that ongoing trial to learn more about combination in this patient population. So then moving to that second patient population that you mentioned earlier where the panel reviewed evidence, what is the updated evidence and recommendation for patients with NRG1 fusions? Dr. Joshua Reuss: Yeah, so this was an exciting update that we made more recently with this unique iteration of the living guidelines. So, NRG1 fusions, this is perhaps a newer kid on the block in terms of driver alterations that has been known to be identified in non–small cell lung cancer among other solid tumors. It is very rare, occurring in less than 1% of solid tumors, but something that we know is a unique oncogenic pathway that can lead to oncogenesis and cancer development, including in non–small cell lung cancer. So up until now, unfortunately, there have not been targeted therapies that target this unique alteration. It's somewhat different than other driver alterations where there's a top-level signaling change in a protein. This is more of a ligand alteration that then alters, that then enables activation of more classical pathways, but again, through upregulation of a unique ligand. So a slightly different pathway but something that we know should be able to be targeted to promote patient survival for those with NRG1 fusions. So the therapy here is a therapy called zenocutuzumab. It's an IgG1 bispecific antibody against HER2 and HER3. So it prevents the downstream dimerization and signaling that occurs as a result of this NRG1 fusion and upregulation of the NRG1 signal. This was, as you can imagine with a rare alteration, a large phase II registrational study that examined this in advanced solid tumors containing the NRG1 fusion. This is the NRG1 registrational trial. And this study enrolled patients with advanced solid tumors who had progressed on prior therapy. Patients were treated with zenocutuzumab 750 milligrams IV every two weeks. Among 158 response-evaluable solid tumor patients, the response rate was 30%, median duration of response of 11.1 months, and a median progression-free survival of 6.8 months. Now, in those with non–small cell lung cancer, that made up 93 response-evaluable patients, very similar outcomes there: a response rate of 29%, median duration of response of 12.7 months, and a median progression-free survival of 6.8 months. This therapy did appear to be well tolerated. The most common higher-grade emergent side effects - grade 3 or higher - were anemia occurring in 5% and elevated liver numbers occurring in 3%. So this is a subsequent-line study, so this led to the updated recommendation that clinicians may offer zenocutuzumab in the subsequent-line setting for patients with advanced non–small cell lung cancer who harbor NRG1 fusions. So I think this does speak toward the incredible importance of next-generation sequencing and molecular testing for patients, particularly to include testing that looks at the RNA. These large fusions can sometimes be very challenging to detect on DNA sequencing platforms alone, so it's important to, if you have a high level of suspicion for an alteration like this, perhaps some of the mucinous adenocarcinomas where it's been challenging to find a driver alteration, and it's someone who is a never-smoker, really would want to include molecular testing that assesses the RNA level and not just the DNA. Brittany Harvey: Absolutely. It's important to have all the biomarkers available so that clinicians are able to use that to inform their decision-making. So then, given these changes in the guideline, what should clinicians know as they implement this latest living guideline update? And how do these changes impact patients? Dr. Joshua Reuss: Yeah, I think talking in reverse order of what we just discussed here, there is a new guideline update for NRG1 fusions. So I think making sure that that's being evaluated, that clinicians are testing for that and really looking for that result that should be incorporated in in most next-generation large sequencing assays to get that result, but it's very important that that is not overlooked now that we do have a therapy that's available in the subsequent-line setting, though it is important to note that patients with NRG1 fusions, at least the limited data that there is suggests that the efficacy to standard chemoimmunotherapy regimens is overall poor. So physicians unfortunately might be facing this question for second-line therapy in patients with NRG1 fusions sooner rather than later. For the former, for EGFR-altered non–small cell lung cancer and how do we incorporate VEGF-containing regimens into these patients? Our guideline top-level update did not change based off of review of this new study, but it's important for clinicians to know what other combinations may exist. You know, there are phase III studies looking at this combination in the frontline setting. And of course, there is data on other bispecific molecules that incorporate VEGF in the subsequent-line setting, particularly a combination that includes the VEGF/PD-1 bispecific antibody ivonescimab that's being studied in the HARMONi-A trial for patients with EGFR-mutated advanced non–small cell lung cancer, for which we hope to get some more definitive data in the coming months. Brittany Harvey: Definitely. And then you've just mentioned a few ongoing trials where we're looking for evidence to inform future updates. But thinking beyond that, into the future, what is the panel examining for future updates to this living guideline? Dr. Joshua Reuss: It's a very exciting time to be in the world of treating advanced non–small cell lung cancer, particularly patients with driver alterations, because there is so much evolving data that's changing our practice in real time, again highlighting the importance of these living guideline updates. I'd say there's many things that we're excited to see. You know, a lot of the combination regimens in EGFR-mutated non–small cell lung cancer for which there are approvals and current recommendations in our guideline, particularly osimertinib plus chemotherapy and amivantamab plus lazertinib - those are the two approved combination strategies in the front line - we are now seeing the emergence of overall survival data for those combinations. So obviously that is something that's going to be very important for the committee to review and incorporate into guideline updates. There are several new therapies coming down the road for other driver populations. We recently saw an approval for taletrectinib for ROS1 fusion–positive non–small cell lung cancer, so it's going to be important that the committee reviews the data and the publications regarding that therapy. And then there are other novel therapies that we're looking to see updated data on. There are multiple antibody-drug conjugates, which take the potent power of a chemotherapy molecule and attempt to make that targeted with an antibody targeting to a unique feature on the cancer cell. And there are several antibody-drug conjugates that are in development at various levels of promise in this space, particularly in EGFR-mutated non–small cell lung cancer, and I anticipate seeing some emerging data for that coming up in the near future as well. So really, lots to be excited in the space and lots for our committee to review to give guidance on so that these patients can really receive the top-level care wherever they are being treated in the country and throughout the world. Brittany Harvey: Yes, we'll await this new data to continue to provide optimal options for patients with stage IV non–small cell lung cancer with driver alterations. So, Dr. Reuss, I want to thank you so much for your work to rapidly and continuously update and review the evidence for this guideline and thank you for your time today. Dr. Joshua Reuss: Thank you so much. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available on the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this JCO Article Insights episode, host Peter Li summarizes "Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST" by Pérol et al, published April 03, 2025, followed by an interview with first author, Dr Maurice Pérol. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Peter Li: Welcome to this episode of JCO Article Insights. I am Dr. Peter Li, JCO's editorial fellow, and today I am joined by Dr. Maurice Pérol on “Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST,” by Pérol et al. At the time of this recording, our guest has disclosures that will be linked in the transcript. Before we start our interview, I want to give our listeners a quick summary of the TRUST study. For those tuning in, the TRUST study is a phase II, single-arm, open-label, nonrandomized, multicenter trial looking at the efficacy and safety of a novel, next-generation ROS1 TKI, taletrectinib, in advanced ROS1-mutated non–small cell lung cancer. While a relatively rare mutation, the prevalence of ROS1 mutations ranges from 0.9% to 2.6% of patients, with a third of patients presenting with brain mets at diagnosis.Current FDA-approved therapies include crizotinib, entrectinib, and repotrectinib, which have varying degrees of efficacy, in-coming with trade-offs in CNS penetrance and safety with newer generations, particularly in the realm of neurological side effects, highlighting an unmet need in this arena. A total of 273 patients with advanced non–small cell lung cancer with confirmed ROS1 mutation were recruited for this study. 160 patients were TKI-naive, while 113 were TKI-experienced with either crizotinib or entrectinib. Patients with asymptomatic brain mets were also allowed to enroll. In the TKI-naive arm, the median age was 57, with 91% of patients having stage IV disease, 20% having no more than one cycle of chemo, and 23% having brain mets at baseline. In the TKI-experienced arm, the median age was 53, with 97% having stage IV disease, 37% having received prior chemo, and about 50% having brain mets. Furthermore, about 10% of the study population had received entrectinib, while more than 90% had received crizotinib. About 10% had a known G2032R acquired resistance mutation. Taletrectinib was dosed at 600 mg daily until disease progression or unacceptable toxicities. The primary endpoint was overall response rate, with secondary endpoints being disease control rate, duration of response, time to response, and progression-free survival. For those with brain mets, intracranial overall response rate and disease control rate were also assessed. Median follow-up time was about 21 months in both cohorts. In the TKI-naive cohort, the overall response rate was 89%, with 8 patients achieving a complete response. Disease control rate was 95%, with a median duration of response of 44.2 months. Time to treatment response was about 1.5 months. Median progression-free survival was 45.6 months, with 52.6% not having progressed at 3 years. While overall survival data were immature, 66% of patients were still alive at 3 years. In the pretreated cohort, overall response rate was 56%, with 5 patients achieving a complete response. Overall response rate was 53% for those who were crizotinib-pretreated and 80% for the entrectinib-pretreated patients. Disease control rate was 88%, and median duration of response was about 16.5 months. Time to treatment response was also 1.5 months, and median progression-free survival was 9.7 months. Median overall survival was not reached, but 77.5% of patients were still alive at 1 year. Responses were consistently seen across subgroup analyses. 17 TKI-naive and 32 TKI-pretreated patients had measurable brain mets. In the TKI-naive arm, intracranial overall response rate was 77%. Disease control rate was 88%, and duration of response was 15 months. In the TKI-pretreated arm, intracranial overall response was 66%, with one patient achieving complete response. The disease control rate was 94%, and duration of response was about a year. For the 13 patients who had a known G2032R mutation, a 62% response rate was noted. Most common treatment-related side effects were AST/ALT elevation, nausea, and vomiting, with most being grade 1 or 2. Most common neurological side effects were dizziness, dysgeusia, and headache. Again, most were grade 1. QTc prolongation is another important adverse event to note, occurring in about 18% of all patients. Discontinuation rate from treatment was only 7%. There were three treatment-related deaths in this study: one from hepatic failure, one from pneumonia in the naive arm, and one from liver dysfunction in the pretreated arm. Dr. Peter Li: Maurice, thank you so much for joining us today to talk about your paper. Would you mind just giving yourself a brief introduction to the listeners out there of who you are? Dr. Maurice Pérol: So, my name is Maurice Perol. I'm a thoracic oncologist working in the Cancer Center of Lyon in France. And I'm involved in clinical research in thoracic oncology. I've been involved for many years now. Dr. Peter Li: Okay. And for listeners out there, don't forget, he's also the primary author of the paper that we just talked about. So, Maurice, let's begin. Can you tell our listeners what is the significance of your study? Dr. Maurice Pérol: Well, the results of these two large phase II studies - TRUST-I, which has been conducted in China, and TRUST-II, which was a global, worldwide phase II study - so, the results place taletrectinib as the TKI with the most favorable efficacy-tolerability ratio of the available ROS1-targeting TKIs, especially in frontline therapy. And this is based on the response rate, which was very impressive, the CNS penetration with a great CNS activity, the duration of response with a compelling 45 months median PFS in frontline setting. The level of activity in pretreated patients after crizotinib or entrectinib was also impressive and similar to that of repotrectinib, for example, but with a more favorable neurological tolerance profile. The toxicity is mainly represented with grade 1 or 2 transaminase elevation, but without clinical symptoms, and GI toxicity, but mainly grade 1 and 2. The neurological toxicity is low, especially for dizziness, showing that taletrectinib spares TrKB in a large part. And finally, there is also a decrease in toxicity over time, especially for GI toxicity and liver toxicities, which allows a very long and a prolonged administration, which is very important in this setting. Dr. Peter Li: These are all excellent points. Can you tell the listeners if there are any limitations that we should be concerned about, about this study? Dr. Maurice Pérol: Sure. This data comes from single-arm phase II studies. So, this is not comparative data. And a phase III trial, which compares taletrectinib to crizotinib, is ongoing to evaluate the superiority of taletrectinib over the standard of care. Another limitation comes from the lack of systematic brain imaging at each tumor evaluation in patients without brain metastases at baseline, not allowing to assess the intracranial PFS in all patients, and which did not allow us to assess the CNS protective issue from taletrectinib, especially in patients without brain metastases at baseline. Dr. Peter Li: Another question that I have is, with this novel TKI now available, how would you recommend the sequencing of these drugs? Would you start with someone on an alternate TKI and then reserve taletrectinib second line or later? Or would you use it upfront? Or does it depend? Dr. Maurice Pérol: Well, it is a very important question, as we have now different available TKIs. Looking at the efficacy-toxicity balance, I would strongly favor the use of taletrectinib in frontline setting, in first line. The response rate, the CNS activity, the duration of response with a very compelling 45 months median PFS, and moreover, the good tolerance profile over time are strong arguments in favor of giving taletrectinib in frontline. Generally speaking, the use of the most active agent as frontline treatment in lung cancer depending on an oncogenic addiction is probably the best way to improve the patient's outcome. This is true for patients with EGFR mutation, for patients with ALK fusions, and this is probably also true for patients with ROS1 fusion. So, I would probably argue in favor of a frontline use of taletrectinib. Dr. Peter Li: Listeners are going to ask, well, if you use taletrectinib upfront, then what are you going to use second line once they progress? Dr. Maurice Pérol: Well, we have some new compounds which are under development today. For example, the NVL-520, which is a very interesting compound, which seems also to be active in case of resistance mutation. But I do think that we have to use the best-in-class TKI in frontline because, you know, the extension of PFS after acquired resistance you can obtain with a second-line TKI is always shorter than the benefit you can obtain by using the most active agent in frontline. And this is true for the majority of oncogenic addiction in lung cancer. Dr. Peter Li: That makes sense. I also noticed that cognitive impairment wasn't listed in the safety table. Is that not an issue that you've observed at all with taletrectinib, or is it still an issue but less so because, like you mentioned earlier, because of its higher selectivity? Dr. Maurice Pérol: Well, this is a good question because we have some ROS1-targeting TKIs like repotrectinib, entrectinib, and even lorlatinib, with some neurological adverse events and some cognitive issues. Taletrectinib is a very selective ROS1-targeting TKI, and it spares very well the TrKB, for example, explaining that we did not observe any cognitive impairment with taletrectinib in the TRUST study, showing also with the low level of other neurological adverse events, dizziness, dysgeusia, for example, the high selectivity of the compound and the preservation of TrKB. So, this is very important when you consider the long duration of treatment in those patients with ROS1 fusion. If you have to take a drug for more than 2, 3, or 4 years, of course, the neurological adverse events are very important, and they can clearly impair the quality of life. So, this is a very important point, the very low level of neurological toxicity of taletrectinib. Dr. Peter Li: And I think that goes to say why you would favor using it frontline as well compared to entrectinib or repotrectinib. Last question that we have for you is: well, what's next? You mentioned there's a phase III trial comparing it to crizotinib. I think one of the questions that a lot of us would have is: why not compare it to one of the newer agents as a comparator arm? Dr. Maurice Pérol: Well, this is a good question. Crizotinib remains the standard of care in many countries for ROS1-positive advanced non–small cell lung cancer outside of the US, especially in Europe, and in particular in patients who do not have brain metastases at diagnosis. Entrectinib has a better CNS penetration, but it did not achieve a better PFS than crizotinib in phase I/II trials, and clearly, it has a less favorable tolerance profile with weight gain, edema, and neurological adverse events. Repotrectinib has overall a level of activity which seems close to that of taletrectinib. So, it makes it difficult to consider a comparative trial that would, for example, test taletrectinib in comparison with repotrectinib because this kind of study would need a very large number of patients and a very late readout. Considering if you have a median PFS of more than 3 or 4 years, it would be very difficult to have results in before 4-5 years. So, from a pragmatic point of view, the comparison of taletrectinib to crizotinib is probably the best way to evaluate in a phase III setting the level of activity of taletrectinib, especially in the CNS, because this study will probably allow us to assess the CNS protective effect of the compound for patients without brain metastates at baseline. So, I think probably it's a pragmatic study that will allow us to confirm the high level of activity and the good tolerance profile of taletrectinib. Dr. Peter Li: Well, thank you, Maurice, so much for speaking about the JCO article, “Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST,” and for all your valuable input today. 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.  

In this episode, we took a deep dive intro the landscape of menin inhibitors in AML with Dr. Eytan Stein from MSKCC. Here are the key trials and studies we discussed: ELN 2022 AML Classification https://ashpublications.org/blood/article/140/12/1345/485817/Diagnosis-and-management-of-AML-in-adults-2022Predictors of outcomes in adults with AML and KMT2A rearrangements: https://www.nature.com/articles/s41408-021-00557-6DOT1L inhibitor https://ashpublications.org/blood/article/131/24/2661/37193/The-DOT1L-inhibitor-pinometostat-reduces-H3K79AUGMENT 101: https://ascopubs.org/doi/10.1200/JCO.24.00826Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study: https://ashpublications.org/blood/article/doi/10.1182/blood.2025028357/537139/Menin-inhibition-with-revumenib-for-NPM1-mutatedKOMET-001: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00386-3/abstractSAVE trial: https://ashpublications.org/blood/article/144/Supplement%201/216/530724/Phase-I-II-Study-of-the-All-Oral-Combination-ofKOMET-007: https://library.ehaweb.org/eha/2025/eha2025-congress/4159213/harry.erba.ziftomenib.combined.with.intensive.induction.chemotherapy.2872B329.in.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2882%2Aot_id%3D31560%2Amarker%3D5843%2Afeatured%3D19595MEN1 mutations: https://www.nature.com/articles/s41586-023-05755-9 

Listen to Journal of Clinical Oncology's Art of Oncology poem, "Transcription: Phone Call, 2018” by Elane Kim, a student at Harvard College. The poem is followed by an interview with Kim and host Dr. Mikkael Sekeres. Kim shares her poem that lingers in the spaces between words; a mother and daughter navigating illness and memory. TRANSCRIPT Narrator: Transcription: Phone Call, 2018, by Elane Kim Spiculated mass, irregular contours. Can you come to translate these words? Something in the lung. Yes, I am eating well.   Birds, green ones, are nesting outside the window. Singing as if they aren't young but dying. Lately, I have been singing.   Since we last spoke, the snow has melted into pearls. Rare and pale, glittering like it's the last time you'll ever see it. Will you come see it?   In Korea, we say magpies bring good luck. I dreamt of one the last night I slept well. Though you are my daughter, I feel like   a child. In our language, the word for cancer comes from the character for mouth. The fruit you bought is too tough to swallow.   The cough is worse in the mornings and after rain. When you were younger, you loved the rain. If I could do anything,   I would like to see the snow. To see it for the first time again, the cold a shivering afterthought.   Time passes in pieces: one appointment, then the next. Monday, can you ask the doctor   about the prescription? Will it be stronger? Every new day is an empty one.   No appetite. No warmth. I hope I did not give you a rotten body, my body. Will I be stronger? I feel   a shattering inside. Hello? You are breaking up. Remember to eat well, daughter.   Remember to call home.   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 are joined by Elane Kim, a student at Harvard College. In this episode, we will be discussing her Art of Oncology poem, “Transcription: Phone Call 2018.” At the time of this recording, our guest has no disclosures. Elane, what a joy to have you on our podcast. Welcome and thank you for joining us. Elane Kim: Thank you so much for having me - very excited. Dr. Mikkael Sekeres: So am I actually. Elane, I was wondering, I think you may be one of the youngest authors we've accepted a piece from. You had an absolutely gorgeous poem that you submitted to us and we were so thrilled that you chose us for your submission and ultimately that we were able to publish it. Elane Kim: Oh, that's so exciting. Dr. Mikkael Sekeres: So, can we start out with just kind of some general questions about you? Can you tell us about yourself? Where are you from? And walk us through how you reached this point in your career. Elane Kim: I'm originally from California, but I moved to the East Coast for college and I'm also a writer. I love to write fiction and poetry. When I first started writing, I wrote for fun for a really long time, but I started to kind of take it seriously in middle school because I went to this one slam poetry event and I remember I went home and I told my mom, “I am going to be a poet.” And so ever since then, I've been writing poetry and it's been really awesome for me because it's my way of expressing myself and translating my world into words and having a space where I'm able to experiment fearlessly. So I love to write and it's been a journey for me because I started publishing little poems here and there. And now my debut full length is coming out early next year with a small and lovely press. So I'm very excited and also honored to be on this podcast with you. Dr. Mikkael Sekeres: Elane, I can tell you as a parent of a daughter who's a rising senior in college, it's every parent's dream when your child comes home and says, “I want to be a poet.” So the question I wanted to ask is, are you a writer who dipped her toe into medicine or are you an aspiring doctor who dipped her toe into writing? Elane Kim: Oh my gosh, it's hard to say. I really love science, but I also really love writing. So I think maybe it comes from a place of wanting to do both because I also think that, I don't know, I really, really admire doctors for everything they do because from everything I've seen, I feel like medicine is a place where I think you need to have very deep empathy in order to proceed. So I also think writing is a place where you need empathy and so I think maybe a little bit of both. It's sort of hard for me to see which angle. Dr. Mikkael Sekeres: That's okay. You still have a couple years in college and, of course, the rest of your life to figure that out. But I think you're right. We obviously meet a lot of doctors who are writers. That's probably the main phenotype of the sort of person who submits something to the Art of Oncology at JCO. But I've always felt there's a lot of overlap between the two because inherently medicine is about storytelling. A patient comes to us with a story of illness. We tell that story to ourselves, to our colleagues when we're getting consults, and eventually we're trying to find the denouement of that story, where we have an answer for the story of illness. So I think it's great that you're still open to both aspects of this, writing and medicine, and I completely agree with you. I do think there's a lot of overlap between the two. Elane Kim: I think that's really beautiful. Dr. Mikkael Sekeres: Tell us about your journey as a writer then. So you talked about going to a poetry slam, but of course, you had to have gone there with a piece of poetry to participate. So when did you start writing poetry? Elane Kim: I always wrote poetry for fun. I loved making cards and stuff for my parents and my family for every little event. So I was my own like Hallmark factory. So I used to write really silly things and so whenever like people wanted cards or anything, I always had a poem ready. But then I started taking it seriously after this slam poetry event. I feel like slam poetry is very rooted in emotion and performance. And so all the poets there are so awesome and they really like are able to get into character and share their story in a very like raw way, which I thought was so, so awesome. And it was sort of the first time I had seen poetry as less of a vehicle for like a Valentine's Day joke or something and more of an actual story with like a punchline with a lot of character and individuality. And so that was sort of a space where I saw all these poets who were so excited about what they were doing and able to tell a story about something bigger than themselves. And so I think that was kind of a turning point and little middle school me, I was like, “This is totally what I want to do and totally something I want to pursue.” And although I no longer am like strictly in the spoken word space, I still think every single poem should be read aloud and should be shared with people in a space where everyone's listening and everyone's able to gain something new from it. Dr. Mikkael Sekeres: It's beautifully stated. And you know, that notion of reading words aloud is so important and that's advice that I give to some of my mentees even in scientific writing. As they're moving along, I'll actually say to them, “Okay, now read that paragraph or those sentences out loud and tell me if they make sense.” And as they're reading them, they'll often realize, “Wait a second, it's constructed the wrong way. And I'm burying the lead or the grammar doesn't quite work out.” And they rewrite it. So I love the fact that you talk about writing as something that should be read out loud. I think that's true whether you're writing creatively with poems or narrative pieces or even in scientific writing. Can you tell us what prompted you to write “Transcription: Phone Call 2018?” Elane Kim: Kind of like the title suggests, I wrote this poem after I had a phone call with a loved one that really stayed with me because I think there were a lot of, I guess, distances that were traversed through that phone call and it was a little bit more about what was left unsaid as opposed to what was said. So the poem is- it kind of addresses this, but there are language barriers, generational gaps, and also like the weight of illness that's bearing on this conversation that sort of bleeds into everyday life. And so I was thinking a little bit about how people can often carry conversations across physical distance and also emotional distance, especially in immigrant families, for example, where a lot of the times communication is something more emotional or cultural rather than something that's, you know, said through sentences. And so I think that the poem is both like a literal transcription of a phone call that's like spliced up, but also maybe like an emotional transcription where we're trying to preserve this moment of love and tenderness between a mother and a daughter. Dr. Mikkael Sekeres: It's really a terrific piece. I keep saying this over and over again. You captured so much in so few words, which of course, is the goal of poetry. One of the things that I loved about your poem is how you captured the fractured nature of phone calls, particularly if you're hearing bits and pieces on either side of the phone call. You start the poem focusing on otherness. I mean, right out of the gates, on being an outsider. Your first line is “Spiculated mass, irregular contours,” which is some of our medical speak. And then the next line immediately says, “Can you translate these words?” You're already saying the person, the character who's speaking that line doesn't get it, right? It doesn't make sense to them. They need help in figuring it out. Can you talk about this from the perspective of coming from another country or culture and as a neophyte to medical terminology? Elane Kim: Definitely. It's so awesome that you're able to notice all these small details and everything. That's so awesome. Dr. Mikkael Sekeres: It's a testimony to your writing. You're a great writer. Elane Kim: That's so kind of you, but I'm very excited to get to talk about all this. Yeah, like you said, there's like an insider/outsider dynamic. I guess as somebody who might be new to this country, there's also somebody who's new to medicine and how there can be a lot of barriers there where if you don't have somebody who's acting as somebody who can be in both worlds at once and translate these things, then you're sort of left in the dark. And I think the role of translator is very important here because you're not totally in one world or the other. You're kind of this floating being who is in charge of traversing both worlds and bringing, in this case, the mother from one to the next. But because of this, I think that sort of suggests that the person who is receiving the phone call is not totally comfortable in one world or the other world. They're sort of playing this mediator role. And I think that also maybe speaks to belonging in this poem as well. Dr. Mikkael Sekeres: Yeah. It really emphasizes how critical it is, particularly with serious diagnoses in medicine like cancer, that people bring with them another set of ears, or sometimes we'll joke and we'll say they bring an ectopic brain with them, someone else who can listen because it's not only the medical terminology that people trip over, but like you say, it's the emotions of the diagnosis and how receptive people are to the information. So they need somebody else there as another source of truth and another advocate to ask the right questions and also make sure that what the patient is hearing is what's being said and vice versa. So, are there poets who've been particular influences on you and if I could ask, who and how? Elane Kim: When I was first starting out, I really appreciated slam poets and I still do. I love slam poets. I remember I would go home and watch YouTube videos like over and over of these poets performing their work. For example, I really love Sarah Kay. I also really love Hieu Minh Nguyen. Both of them, oh my gosh, so, so awesome. And I think they bring a lot of, especially Sarah Kay, she brings a lot of whimsy into her work and also a lot of naturalistic references and also like scientific references that you wouldn't necessarily expect. Like, she has this one poem about these birds called starlings and when they fly together, they fly in the big shape of another starling, which is really fascinating, but also very poetic. I listened to that. I was like, “Wait, that is so awesome that nature knows to do that.” So things like that, I think I take a lot of inspiration from whenever there's something I learn about in, say, like my bio class. I'm like, “Write that down, write that down.” Because I'm like, “Oh, that could be something I put in my next poem.” But I also really love a lot of Asian and Asian American writers who have been big inspirations to me. I really love Jenny Xie. She has a collection called Eye Level, which blows me away every time I see a poem from it. I also love Chen Chen. He has this one poem, “When I Grow Up I Want to Be a List of Further Possibilities,” and I love that poem. It was one of the first poems I really fell in love with. Dr. Mikkael Sekeres: You've given me and our listeners a list of people to look up and to read. It's great. I'm curious about your writing process. What triggers a poem and how do you face the dreaded blank page on your computer? Elane Kim: So the way you avoid that is you never have it for too long. My method of writing, tried and true, is I have this one document where I collect everything and it's like my scraps and even the most random, like, ‘this would never go in a poem' random like throwaway lines, I put them all in one ginormous document. I don't know what I'm going to do if I lose access to it, to be honest, because it's like many, many pages. Basically, I just collect everything there. Like I will be in class and I will hear someone say something that's like just in a conversation, but I'm like, “Wait, that's kind of poetic.” And I write it down or like walking down the street and I'm looking at the water. I'm like, “Huh, that water looks a lot like this.” And I write that down. And so I have this huge, huge running document that has all these random lines. And so for me, I think writing is less about going into a document and like just type, type, type, type. It's more about for me like, how can I take these fragments and put them into a story? Like these random fragments. How can I tell a story out of these pieces that seem disparate initially? For me, I don't have a blank page for too long. My issue is like, how can I make this random mess of words into something that actually tells a story? But I think that's the most fun part of writing also is like putting together this puzzle. Dr. Mikkael Sekeres: I have to say it's also the most fun part of medicine. We're handed chaos in oncology and we're asked to put it together into a story and hopefully a story with a happy ending. So that's great. Elane Kim: I love that. Dr. Mikkael Sekeres: So you're welcome to write that down in your scraps. Elane Kim: Oh my gosh, it's going in there. Dr. Mikkael Sekeres: So, I wanted to end by actually quoting the end of your poem, which was amazing. And the poem reads like this and one of the characters says, “I feel a shattering inside. Hello? You're breaking up. Remember to eat well, daughter. Remember to call home.” And it's a marvelous, marvelously unsettling ending where both the phone call and the character are breaking up, while the character maintains her concern for her daughter. Do you think she's retaining some control of a cancer that obviously has gone beyond her control by expressing her maternal concerns about her daughter's welfare? Elane Kim: Definitely. I think this poem is a lot about how the mother experiences this loss of control. I think there's a moment where the mother and daughter sort of switch roles during the process of her care. She talks about how she starts to feel like a child again or she starts to feel less like a mother and more like the daughter. But I think at the end of the day, the way she expresses her care for her daughter is the way that she always has through like these small gestures. No matter how sick she is, her first concern is always her daughter and whether, you know, she's getting her meals in and just hearing her voice over the phone is something that she looks forward to. And so I think being able to like put somebody else above yourself even when your body is at its most sick is something that, I don't know, I think I find it very sad, but also I think a lot of mothers would also relate to putting your child above other things in moments of illness. And so I think it's a very poignant moment, but also, yeah, one that kind of rings true. Dr. Mikkael Sekeres: It's a poignant moment in an extremely poignant poem and beautifully written. We've been talking to Elane Kim about her poem, “Transcription: Phone Call 2018.” Elane, I want to thank you so much for joining us today. You are so incredibly accomplished and I can't wait to read all of your future pieces as well. Elane Kim: Oh, thank you so much. Narrator: 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 or follow us 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, thanks 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: Elane Kim is a student at Harvard College.  

In the wake of the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, CancerNetwork® put together an X Spaces discussion hosted by Stephen Liu, MD, and Joshua Sabari, MD, to highlight the most intriguing and practice-changing lung cancer abstracts. Discussed topics ranged from long-term follow-up with commonplace therapies to an analysis of what time of day is the best to administer immunochemotherapy.  Liu, an associate professor of Medicine at Georgetown University, and the director of Thoracic Oncology and head of Developmental Therapeutics at the Georgetown Lombardi Comprehensive Cancer Center, and Sabari, an assistant professor in the Department of Medicine at the NYU Grossman School of Medicine, and the director of High Reliability Organization Initiatives at the Perlmutter Cancer Center, shared expert insights on the latest non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) breakthroughs. Trials of note that they discussed included: The phase 3 DeLLphi-304 trial (NCT05740566) - Tarlatamab (Imdelltra) versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): primary analysis of Ph3 DeLLphi-304.1 The phase 3 IMforte trial (NCT05091567) - Lurbinectedin (Zepzelca; lurbi) + atezolizumab (Tecentriq; atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): primary results of the phase 3 IMforte trial.2 The phase 3 CheckMate 816 trial (NCT02998528) - Overall survival with neoadjuvant nivolumab (Opdivo; NIVO) + chemotherapy (chemo) in patients with resectable NSCLC in CheckMate 816.3 The phase 3 PACIFIC15 trial (NCT05549037) - Randomized trial of relevance of time-of-day of immunochemotherapy for progression-free and overall survival in patients with non–small cell lung cancer.4 The phase 3 Beamion LUNG-1 trial (NCT04886804) - Patient-reported outcomes (PRO) evaluating physical functioning and symptoms in patients with pretreated HER2-mutant advanced non–small cell lung cancer (NSCLC): results from the Beamion LUNG-1 trial.5 The phase 3 ARTEMIA trial (NCT06472245) - Phase 3 trial of the therapeutic cancer vaccine OSE2101 versus docetaxel in patients with metastatic non–small cell lung cancer and secondary resistance to immunotherapy. References Rudin C, Mountzios G, Sun L, et al. Tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): primary analysis of Ph3 DeLLphi-304. J Clin Oncol. 2025;43(suppl 17):LBA8008. doi:10.1200/JCO.2025.43.17_suppl.LBA8008 Paz-Ares L, Borghaei H, Liu SV, et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): primary results of the phase 3 IMforte trial. J Clin Oncol. 2025;43(suppl 16):8006. doi:10.1200/JCO.2025.43.16_suppl.8006 Forde PM, Spicer JD, Provencio M, et al. Overall survival with neoadjuvant nivolumab + chemotherapy in patients with resectable NSCLC in CheckMate 816. J Clin Oncol. 2025;43(suppl 17):LBA8000. doi:10.1200/JCO.2025.43.17_suppl.LBA8000 Zhang Y, Huang Z, Zeng L, et al. Randomized trial of relevance of time-of-day of immunochemotherapy for progression-free and overall survival in patients with non-small cell lung cancer. J Clin Oncol. 2025;43(suppl 16):8516. doi:10.1200/JCO.2025.43.16_suppl.8516 Sabari JK, Nadal E, Hendriks L, et al. Patient-reported outcomes (PRO) evaluating physical functioning and symptoms in patients with pretreated HER2-mutant advanced non-small cell lung cancer (NSCLC): results from the Beamion LUNG-1 trial. J Clin Oncol. 2025;43(suppl 16):8620. doi:10.1200/JCO.2025.43.16_suppl.8620 Liu SV, Guibert C, Tostivint EP, et al. Phase 3 trial of the therapeutic cancer vaccine OSE2101 versus docetaxel in patients with metastatic non-small cell lung cancer and secondary resistance to immunotherapy. J Clin Oncol. 2025;43(suppl 16):TPS8651. doi:10.1200/JCO.2025.43.16_suppl.TPS8651

An expert panel highlights key presentations in multiplemyeloma, lymphoma, and other hematologic malignancies at the 2025 ASCO Annual Meeting.CancerNetwork®, in collaboration with The American Societyfor Transplantation and Cellular Therapy (ASTCT), organized an X Space hosted by Rahul Banerjee, MD, FACP; Taha Al-Juhaishi, MD; and Muhammad Salman Faisal, MD. This expert panel convened to discuss key presentations and abstracts of interest at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting featuring noteworthy developments in modalities like CAR T-cell therapy and transplantation across multiple myeloma, lymphoma, and other disease types.Banerjee is an assistant professor in the Clinical Research Division at the Fred Hutchinson Cancer Center in Seattle, Washington. Al-Juhaishi is the associate director of the Hematopoietic Stem Cell Transplantation and Cell Therapy Program at Oklahoma University Health Stephenson Cancer Center and an assistant professor of medicine at the University of Oklahoma College of Medicine. Faisal is a hematologist/oncologist at Oklahoma University HealthStephenson Cancer Center and serves as an ambassador for ASCO.The group highlighted several late-breaking abstracts,plenary sessions, and poster presentations focused on significant clinical trial data and other findings across the hematologic oncology landscape. Topics of interest included the following:Phase 1b/2 CARTITUDE-1 trial (NCT03548207,NCT05201781)1Long-term follow-up showed that approximately one-third(33%; n = 32) of patients with relapsed/refractory multiple myeloma maintained progression-free status for at least 5 years following a single infusion of ciltacabtagene autoleucel (cilta-cel; Carvykti). An equal likelihood of progression-free survival occurred in patients with high-risk cytogenetics or extramedullary plasmacytomas.With a median follow-up of 61.3 months, the median overall survival (OS) with cilta-cel was 60.7 months (95% CI, 41.9-notevaluable [NE]). Real-world axicabtagene ciloleucel (axi-cel; Yescarta) use2Across inpatient and outpatient treatment settings, safety and efficacy outcomes were comparable for patients who received axi-cel for relapsed/refractory large B-cell lymphoma.Multivariate analysis showed no associations between intended care setting and cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome.Investigators noted that these real-world data support the consideration of axi-cel in appropriate outpatient settings.Phase 1b/2 NEXICART-2 trial (NCT06097832)3Investigators assessed NXC-201, a sterically optimized CAR T construct, as a treatment for patients with relapsed/refractory light chain amyloidosis, a population with no FDA-approved options.Among 12 patients who received the agent at 450x 106 cells, 100% achieved rapid and deep hematologic responses at a median time to first and best response of 7 and 26 days, respectively. With a median follow-up of 121 days (range, 29-289), no hematologic relapses or progression had occurred.References1.     Voorhees P, Martin T, Lin Y, et al. Long-term (≥5 year) remission and survival after treatment with ciltacabtagene autoleucel (cilta-cel) in CARTITUDE-1 patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2025;43(suppl 16):7507. doi: 10.1200/JCO.2025.43.16_suppl.75072.     Furqan F, Hemmer M, Tees M, et al. Trends and outcomes by inpatient and outpatient infusion of axicabtagene ciloleucel (axi-cel) in the US for patients (pts) with relapsed/refractory large B-celllymphoma (R/R LBCL). J Clin Oncol. 2025;43(suppl 16):7023. doi:10.1200/JCO.2025.43.16_suppl.70233.     Landau H, Hughes C, Rosenberg A, et al. Safety and efficacy data from Nexicart-2, the first US trial of CAR-T in R/R light chain (AL) amyloidosis, Nxc-201. J Clin Oncol. 2025;43(suppl 16):7508.doi:10.1200/JCO.2025.43.16_suppl.7508

In the third edition of a special podcast series, CancerNetwork® spoke with Daniel Morgensztern, MD; Mary Ellen Flanagan, NP; and Janelle Mann, PharmD, BCOP, about optimal strategies for incorporating different therapeutic agents into lung cancer care. As part of the latest discussion, the group highlighted the relevant efficacy data, administration protocols, and toxicity management considerations associated with TROP2-directed antibody-drug conjugates (ADCs) in patients with non–small cell lung cancer (NSCLC). Morgensztern is a professor of Medicine and the clinical director of Thoracic Oncology in the Division of Oncology at Washington University School of Medicine in St. Louis. Flanagan is a nurse practitioner in the Division of Thoracic Oncology at Washington University. Mann is a clinical oncology pharmacist at Siteman Cancer Center of Washington University School of Medicine and manager of Clinical Pharmacy Services at Barnes-Jewish Hospital. Morgensztern opened the discussion by highlighting the characteristics of prominent TROP2-targeting ADCs in NSCLC management, which included sacituzumab govitecan-hziy (Trodelvy), datopotamab deruxtecan-dlnk (Datroway), and sacituzumab tirumotecan (sac-TMT). Additionally, he reviewed data from clinical trials assessing these ADCs across different NSCLC populations, including the phase 3 EVOKE-01 trial (NCT05089734) showing a numerical overall survival (OS) improvement with sacituzumab govitecan vs docetaxel. Regarding the safety profiles of these ADCs, Flanagan described the unique toxicities associated with the agents' payloads as well as potential off-target effects. On top of myelosuppression, fatigue, and diarrhea, she stated that these therapies may cause more visceral organ toxicities like keratitis of the eye and interstitial lung disease. According to Flanagan, some prophylactic measures in the event of certain toxicities include frequent salt and baking soda mouth rinses as well as oral dexamethasone.  Mann then outlined the dosing variability considerations and supportive care measures surrounding the use of agents like sacituzumab govitecan. She emphasized continuously re-educating patients about expected toxicities and supportive care strategies as they undergo these infusion-based therapies to help avoid surprise instances of ocular toxicity, diarrhea, and other adverse effects. Reference Paz-Ares LG, Juan-Vidal O, Mountzios GS, et al. Sacituzumab govitecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III EVOKE-01 study. J Clin Oncol. 2024;42(24):2860-2872. doi:10.1200/JCO.24.00733

Listen to ASCO's Journal of Clinical Oncology Art of Oncology article, "A Whipple of Choice” by Dr. Carl Forsberg, who is an Assistant Professor of Strategy and History at Air Force War College. The article is followed by an interview with Forsberg and host Dr. Mikkael Sekeres. Dr Forsberg shares his experience with an uncommon cancer treated by a new therapy for which no directly relevant data were available. Transcript Narrator: A Whipple of Choice, by C. W. Forsberg, PDH I sat across from a hepatobiliary surgeon on a gray October afternoon. “To be frank,” he told me, “we don't know what to recommend in your case. So we default to being conservative. That means a Whipple surgery, even though there are no data showing it will improve your outcome.” The assessment surprised me, diverging from my expectation that doctors provide clear recommendations. Yet the surgeon's willingness to structure our conversation around the ambiguity of the case was immensely clarifying. With a few words he cut through the frustrations that had characterized previous discussions with other physicians. I grasped that with an uncommon cancer treated by a novel therapy with no directly relevant data, I faced a radical choice. My situation that afternoon was worlds away from where I was 5 months earlier, when I was diagnosed with presumed pancreatic cancer at the age of 35. An early scan was suspicious for peritoneal metastasis. The implications seemed obvious. I prepared myself for the inevitable, facing my fate stoically except in those moments when I lingered next to my young son and daughter as they drifted to sleep. Contemplating my death when they were still so vulnerable, I wept. Then the specter of death retreated. Further tests revealed no metastasis. New doctors believed the tumor was duodenal and not pancreatic. More importantly, the tumor tested as deficient mismatch repair (dMMR), predictable in a Lynch syndrome carrier like me. In the 7 years since I was treated for an earlier colon cancer, immune checkpoint inhibitor (ICI) immunotherapy had revolutionized treatment of dMMR and high microsatellite instability tumors. One oncologist walked me through a series of recent studies that showed extraordinary responses to ICI therapy in locally advanced colon and rectal tumors with these biomarkers.1-4 He expressed optimism that my cancer could have a similar response. I embarked on a 24-week course of nivolumab and ipilimumab. After 6 weeks of therapy, a computed tomography (CT) scan showed a significant reduction in tumor size. My health rebounded as the tumor receded. This miraculous escape, however, was bound by the specter of a Whipple surgery, vaguely promised 6 months into my treatment. At the internationally renowned center where I was diagnosed and began treatment with astonishing efficiency, neither oncologists nor surgeons entertained the possibility of a surgery-sparing approach. “In a young, healthy patient like you we would absolutely recommend a Whipple,” my first oncologist told me. A second oncologist repeated that assessment. When asked if immunotherapy could provide a definitive cure, he replied that “if the tumor disappeared we could have that conversation.” My charismatic surgeon exuded confidence that I would sail through the procedure: “You are in excellent health and fitness—it will be a delicious surgery for me.” Momentum carried me forward in the belief that surgery was out of my hands. Four months into treatment, I was jolted into the realization that a Whipple was a choice. I transferred my infusions to a cancer center nearer my home, where I saw a third oncologist, who was nearly my age. On a sunny afternoon, 2 months into our relationship, he suggested I think about a watch-and-wait approach that continued ICI therapy with the aim of avoiding surgery. “Is that an option?” I asked, taken aback. “This is a life-changing surgery,” he responded. “You should consider it.” He arranged a meeting for me with his colleague, the hepatobiliary surgeon who clarified that “there are no data showing that surgery will improve your outcome.” How should patients and physicians make decisions in the absence of data? My previous experience with cancer offered little help. When I was diagnosed with colon cancer at the age of 28, doctors made clear recommendations based on clear evidence. I marched through surgery and never second-guessed my choices. A watch-and-wait approach made sense to me based on theory and extrapolation. Could duodenal tumors treated by ICIs behave that differently from colorectal cancers, for which data existed to make a watch-and-wait approach appear reasonable? The hepatobiliary surgeon at the regional cancer center told me, “I could make a theoretical argument either way and leave you walking out of here convinced. But we simply don't know.” His comment reflects modern medicine's strict empiricism, but it foreclosed further discussion of the scientific questions involved and pushed the decision into the realm of personal values. Facing this dilemma, my family situation drove me toward surgery despite my intuition that immunotherapy could provide a definitive cure. The night before I scheduled my Whipple procedure, I wrote in my journal that “in the face of radical uncertainty one must resort to basic values—and my priority is to survive for my children. A maimed, weakened father is without doubt better than no father at all.” To be sure, these last lines were written with some bravado. Only after the surgery did I viscerally grasp that the Whipple was a permanent maiming of the GI system. My doubts lingered after I scheduled surgery, and I had a final conversation with the young oncologist at the cancer center near my home. We discussed a watch-and-wait approach. A small mass remained on CT scans, but that was common even when tumors achieved a pathological complete response.5 Another positron emission tomography scan could provide more information but could not rule out the persistence of lingering cancer cells. I expressed my low risk tolerance given my personal circumstances. We sat across from one another, two fathers with young children. My oncologist was expecting his second child in a week. He was silent for moments before responding “I would recommend surgery in your situation.” Perhaps I was projecting, but I felt the two of us were in the same situation: both wanting a watch-and-wait approach, both intuitively believing in it, but both held back by a sense of parental responsibility. My post-surgery pathology revealed a pathological complete response. CT scans and circulating tumor DNA tests in the past year have shown no evidence of disease. This is an exceptional outcome. Yet in the year since my Whipple, I have been sickened by my lack of gratitude for my good fortune, driven by a difficult recovery and a sense that my surgery had been superfluous. Following surgery, I faced complications of which I had been warned, such as a pancreatic fistula, delayed gastric emptying, and pancreatic enzyme insufficiency. There were still more problems that I did not anticipate, including, among others, stenoses of arteries and veins due to intraabdominal hematomas, persistent anemia, and the loss of 25% of my body weight. Collectively, they added up to an enduringly dysfunctional GI system and a lingering frailty. I was particularly embittered to have chosen surgery to mitigate the risk that my children would lose their father, only to find that surgery prevented me from being the robust father I once was. Of course, had I deferred surgery and seen the tumor grow inoperable or metastasize between scans, my remorse would have been incalculably deeper. But should medical decisions be based on contemplation of the most catastrophic consequences, whatever their likelihood? With hindsight, it became difficult not to re-examine the assumptions behind my decision. Too often, my dialogue with my doctors was impeded by the assumption that surgery was the obvious recommendation because I was young and healthy. The assumption that younger oncology patients necessarily warrant more radical treatment deserves reassessment. While younger patients have more years of life to lose from cancer, they also have more years to deal with the enduring medical, personal, and professional consequences of a life-changing surgery. It was not my youth that led me to choose surgery but my family situation: 10 years earlier, my youth likely would have led me to a watch-and-wait approach. The rising incidence of cancer among patients in their 20s and 30s highlights the need for a nuanced approach to this demographic.  Calculations on surgery versus a watch-and-wait approach in cases like mine, where there are no data showing that surgery improves outcomes, also require doctors and patients to account holistically for the severity of the surgery involved. Multiple surgeons discussed the immediate postsurgical risks and complications of a pancreaticoduodenectomy, but not the long-term challenges involved. When asked to compare the difficulty of my prior subtotal colectomy with that of a pancreatoduodenectomy, the surgeon who performed my procedure suggested they might be similar. The surgeon at the regional cancer center stated that the Whipple would be far more difficult. I mentally split the difference. The later assessment was right, and mine was not a particularly bad recovery compared with others I know. Having been through both procedures, I would repeat the subtotal colectomy for a theoretical oncologic benefit but would accept some calculated risk to avoid a Whipple. Most Whipple survivors do not have the privilege of asking whether their surgery was necessary. Many celebrate every anniversary of the procedure as one more year that they are alive against the odds. That I can question the need for my surgery speaks to the revolutionary transformation which immunotherapy has brought about for a small subset of patients with cancer. The long-term medical and personal consequences of surgery highlight the urgent stakes of fully understanding and harnessing the life-affirming potential of this technology. In the meantime, while the field accumulates more data, potentially thousands of patients and their physicians will face difficult decisions on surgery verses a watch and- wait approach in cases of GI tumors with particular biomarkers showing exceptional responses to ICI therapy.7,8 Under these circumstances, I hope that all patients can have effective and transparent conversations with their physicians that allow informed choices accounting for their risk tolerance, calculations of proportionality, and priorities.  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 at University of Miami. Today, we are so happy to be joined by Dr. Carl Forsberg, Assistant Professor of Strategy and History at the Air Force War College. In this episode, we will be discussing his Art of Oncology article, "A Whipple of Choice." At the time of this recording, our guest has no disclosures. Carl, it is such a thrill to welcome you to our podcast, and thank you for joining us. Dr. Carl Forsberg: Well, thank you, Mikkael, for having me. I'm looking forward to our conversation. Dr. Mikkael Sekeres: So am I. I wanted to start, Carl, with just a little bit of background about you. It's not often we have a historian from the Air Force College who's on this podcast. Can you tell us about yourself, where you're from, and walk us through your career? Dr. Carl Forsberg: Sure. I was born and raised in Minnesota in a suburb of Minneapolis-St. Paul and then went to undergraduate on the East Coast. I actually started my career working on the contemporary war in Afghanistan, first as an analyst at a DC think tank and then spent a year in Kabul, Afghanistan, on the staff of the four-star NATO US headquarters, where I worked on the vexing problems of Afghanistan's dysfunctional government and corruption. Needless to say, we didn't solve that problem. Dr. Mikkael Sekeres: Wow. Dr. Carl Forsberg: I returned from Afghanistan somewhat disillusioned with working in policy, so I moved into academia, did a PhD in history at the University of Texas at Austin, followed by postdoctoral fellowships at Harvard and Yale, and then started my current position here at the Air Force War College. The War Colleges are, I think, somewhat unusual, unique institutions. Essentially, we offer a 1-year master's degree in strategic studies for lieutenant colonels and colonels in the various US military services. Which is to say my students are generally in their 40s. They've had about 20 years of military experience. They're moving from the operational managerial levels of command to positions where they'll be making strategic decisions or be strategic advisors. So we teach military history, strategy, international relations, national security policy to facilitate that transition to a different level of thinking. It really is a wonderful, interesting, stimulating environment to be in and to teach in. So I've enjoyed this position here at the War College quite a lot. Dr. Mikkael Sekeres: Well, I have to tell you, as someone who's been steeped in academic medicine, it sounds absolutely fascinating and something that I wouldn't even know where to start approaching. We have postdoctoral fellowships, of course, in science as well. What do you do during a postdoctoral fellowship in history and strategy? Dr. Carl Forsberg: It's often, especially as a historian, it's an opportunity to take your dissertation and expand it into a book manuscript. So you have a lot of flexibility, which is great. And, of course, a collegial environment with others working in similar fields. There are probably some similarities to a postdoc in medicine in terms of having working groups and conferences and discussing works in progress. So it was a great experience for me. My second postdoc occurred during the pandemic, so it turned out to be an online postdoc, a somewhat disappointing experience, but nevertheless I got a lot out of the connections and relationships I formed during those two different fellowships. Dr. Mikkael Sekeres: Well, there are some people who used the pandemic as an excuse to really just plow into their writing and get immersed in it. I certainly wrote one book during the pandemic because I thought, “Why not? I'm home. It's something where I can use my brain and expand my knowledge base.” So I imagine it must have been somewhat similar for you as you're thinking about expanding your thesis and going down different research avenues. Dr. Carl Forsberg: I think I was less productive than I might have hoped. Part of it was we had a 2-year-old child at home, so my wife and I trying to, you know, both work remotely with a child without having childcare really for much of that year given the childcare options fell through. And it was perhaps less productive than I would have aspired for it to be. Dr. Mikkael Sekeres: It's terrifically challenging having young children at home during the pandemic and also trying to work remotely with them at home. I'm curious, you are a writer, it's part of your career, and I'm curious about your writing process. What triggers you to write a story like you did, and how does it differ from some of your academic writing? Dr. Carl Forsberg: Yeah. Well, as you say, there is a real difference between writing history as an academic and writing this particular piece. For me, for writing history, my day job, if you will, it's a somewhat slow, painstaking process. There's a considerable amount of reading and archival work that go into history. I'm certainly very tied to my sources and documents. So, you know, trying to get that precision, making sure you've captured a huge range of archival resources. The real narrative of events is a slow process. I also have a bad habit of writing twice as much as I have room for. So my process entailed a lot of extensive revisions and rewriting, both to kind of shorten, to make sure there is a compelling narrative, and get rid of the chaff. But also, I think that process of revision for me is where I often draw some of the bigger, more interesting conclusions in my work once I've kind of laid out that basis of the actual history. Certainly, writing this article, this medical humanities article, was a very different experience for me. I've never written something about myself for publication. And, of course, it was really driven by my own experiences of going through this cancer journey and recovering from Whipple surgery as well. The article was born during my recovery, about 4 months after my Whipple procedure. It was a difficult time. Obviously kind of in a bad place physically and, in my case, somewhat mentally, including the effects of bad anemia, which developed after the surgery. I found it wasn't really conducive to writing history, so I set that aside for a while. But I also found myself just fixating on this question of had I chosen a superfluous Whipple surgery. I think to some extent, humans can endure almost any suffering with a sense of purpose, but when there's a perceived pointlessness to the suffering, it makes it much harder. So for me, writing this article really was an exercise, almost a therapeutic one, in thinking through the decisions that led me to my surgery, addressing my own fixation on this question of had I made a mistake in choosing to have surgery and working through that process in a systematic way was very helpful for me. But it also, I think, gave me- I undertook this with some sense of perhaps my experience could be worthwhile and helpful for others who would find themselves in a situation like mine. So I did write it with an eye towards what would I like to have read? What would I like to have had as perspective from another patient as I grappled with the decision that I talk about in the article of getting a Whipple surgery. Dr. Mikkael Sekeres: So I wonder if I could back up a little bit. You talk about the difficulty of undergoing a Whipple procedure and of recovery afterwards, a process that took months. And this may come across as a really naive question, but as, you know, as an oncologist, my specialty is leukemia, so I'm not referring people for major surgeries, but I am referring them for major chemotherapy and sometimes to undergo a bone marrow transplant. Can you educate us what makes it so hard? Why was it so hard getting a Whipple procedure, and what was hard about the recovery? Dr. Carl Forsberg: Yeah, it was a long process. Initially, it was a 14-day stay in the hospital. I had a leaking pancreas, which my understanding is more common actually with young, healthy patients just because the pancreas is softer and more tender. So just, you know, vast amount of pancreatic fluid collecting in the abdominal cavity, which is never a pleasant experience. I had a surgical drain for 50-something days, spent 2 weeks in the hospital. Simply eating is a huge challenge after Whipple surgery. I had delayed gastric emptying for a while afterwards. You can only eat very small meals. Even small meals would give me considerable stomach pain. I ended up losing 40 lb of weight in 6 weeks after my surgery. Interestingly enough, I think I went into the surgery in about the best shape I had been in in the last decade. My surgeon told me one of the best predictors for outcomes is actual muscle mass and told me to work out for 2 hours every day leading up to my surgery, which was great because I could tell my wife, "Sorry, I'm going to be late for dinner tonight. I might die on the operating table." You can't really argue with that justification. So I went in in spectacular shape and then in 6 weeks kind of lost all of that muscle mass and all of the the strength I had built up, which just something discouraging about that. But just simply getting back to eating was an extraordinarily difficult process, kind of the process of trial and error, what worked with my system, what I could eat without getting bad stomach pains afterwards. I had an incident of C. diff, a C. diff infection just 5 weeks after the surgery, which was obviously challenging. Dr. Mikkael Sekeres: Yeah. Was it more the pain from the procedure, the time spent in the hospital, or psychologically was it harder? Dr. Carl Forsberg: In the beginning, it was certainly the physical elements of it, the difficulty eating, the weakness that comes with losing that much weight so quickly. I ended up also developing anemia starting about two or 3 months in, which I think also kind of has certain mental effects. My hemoglobin got down to eight, and we caught it somewhat belatedly. But I think after about three or 4 months, some of the challenges became more psychological. So I started to physically recover, questions about going forward, how much am I going to actually recover normal metabolism, normal gastrointestinal processes, a question of, you know, what impact would this have long-term. And then, as I mentioned as well, some of the psychological questions of, especially once I discovered I had a complete pathological response to the immunotherapy, what was the point to having this surgery? Dr. Mikkael Sekeres: And the way you explore this and revisit it in the essay is absolutely fascinating. I wanted to start at the- towards the earlier part of your essay, you write, "The surgeon's willingness to structure our conversation around the ambiguity of the case was immensely clarifying." It's fascinating. The ambiguity was clarifying to you. And the fact that you appreciated the fact that the surgeon was open to talking about this ambiguity. When do you think it's the right thing to acknowledge ambiguity in medicine, and when should we be more definitive? When do you just want someone to tell you, “Do this or do that?” Dr. Carl Forsberg: That's a great question, which I've thought about some. I think some of it is, I really appreciated the one- a couple of the oncologists who brought up the ambiguity, did it not at the beginning of the process but a few months in. You know, the first few months, you're so as a patient kind of wrapped up in trying to figure out what's going on. You want answers. And my initial instinct was, you know, I wanted surgery as fast as possible because you want to get the tumor out, obviously. And so I think bringing up the ambiguity at a certain point in the process was really helpful. I imagine that some of this has to do with the patient. I'm sure for oncologists and physicians, it's got to be a real challenge assessing what your patient wants, how much they want a clear answer versus how much they want ambiguity. I've never obviously been in the position of being a physician. As a professor, you get the interesting- you start to realize some students want you to give them answers and some students really want to discuss the ambiguities and the challenges of a case. And so I'm, I imagine it might be similar as a physician, kind of trying to read the patient. I guess in my case, the fact was that it was an extraordinarily ambiguous decision in which there wasn't data. So I think there is an element, if the data gives no clear answers, that I suppose there's sort of an ethical necessity of bringing that up with the patient. Though I know that some patients will be more receptive than others to delving into that ambiguity. Dr. Mikkael Sekeres: Well, you know, it's an opportunity for us to think holistically about our patients, and you as a patient to think holistically about your health and your family and how you make decisions. I believe that when we're in a gray zone in medicine where the data really don't help guide one decision versus the next, you then lean back towards other values that you have to help make that decision. You write beautifully about this. You say, "In the face of radical uncertainty, one must resort to basic values, and my priority is to survive for my children. A maimed, weakened father is without doubt better than no father at all." That's an incredibly deep sentiment. So, how do you think these types of decisions about treatment for cancer change over the course of our lives? You talk a lot about how you were a young father in this essay, and it was clear that that was, at least at some point, driving your decision. Dr. Carl Forsberg: Yeah, I certainly have spent a lot of time thinking about how I would have made this decision differently 10 years earlier. As I mentioned the article, it was interesting because most of my physicians, honestly, when they were discussing why surgery made sense pointed to my age. I don't think it was really my age. Actually, when I was 23, I went off to Afghanistan, took enormous risks. And to some extent, I think as a young single person in your 20s, you actually have generally a much higher risk tolerance. And I think in that same spirit, at a different, earlier, younger stage in my life, I would have probably actually been much more willing to accept that risk, which is kind of a point I try to make, is not necessarily your age that is really the deciding factor. And I think once again, if I were 70 or 60 and my children, you know, were off living their own lives, I think that also would have allowed me to take, um, greater risk and probably led me to go for a watch-and-wait approach instead. So there was a sense at which not the age, but the particular responsibilities one has in life, for me at least, figured very heavily into my medical calculus. Dr. Mikkael Sekeres: It's so interesting how you define a greater risk as watch and wait, whereas a surgeon or a medical oncologist who's making recommendations for you might have defined the greater risk to undergo major surgery. Dr. Carl Forsberg: And I thought about that some too, like why is it that I framed the watch and wait as a greater risk? Because there is a coherent case that actually the greater risk comes from surgery. I think when you're facing a life and death decision and the consequence, when you have cancer, of course, your mind goes immediately to the possibility of death, and that consequence seems so existential that I think it made watch and wait perhaps seem like the riskier course. But that might itself have been an assumption that needed more analysis. Dr. Mikkael Sekeres: Do you think that your doctor revealing that he also had young children at home helped you with this decision? Dr. Carl Forsberg: I think in some ways for a doctor it's important to kind of understand where your patient is in their own life. As a patient, it was interesting and always helpful for me to understand where my physicians were in their life, what was shaping their thinking about these questions. So I don't know if it in any way changed my decision-making, but it definitely was important for developing a relationship of trust as well with physicians that we could have that mutual exchange. I would consider one of my primary oncologists, almost something of a friend at this point. But I think it really was important to have that kind of two-way back and forth in understanding both where I was and where my physician was. Dr. Mikkael Sekeres: I like how you frame that in the sense of trust and hearing somebody who could make similar considerations to you given where he was in his family. One final question I wanted to ask you. You really elegantly at the end of this essay talk about revisiting the decision. I wonder, is it fair to revisit these types of decisions with hindsight, or do we lose sight of what loomed as being most important to us when we were making the decisions in real time? Dr. Carl Forsberg: That's a great question, one that is also, I think, inherent to my teaching. I teach military history for lieutenant colonels and colonels who very well may be required, God willing not, but may be required to make these sort of difficult decisions in the case of war. And we study with hindsight. But one thing I try to do as a professor is put them in the position of generals, presidents, who did not have the benefit of hindsight, trying to see the limits of their knowledge, use primary source documents, the actual memos, the records of meetings that were made as they grappled with uncertainty and the inherent fog of war. Because it is, of course, easy to judge these things in hindsight. So definitely, I kept reminding myself of that, that it's easy to second guess with hindsight. And so I think for me, part of this article was trying to go through, seeing where I was at the time, understanding that the decision I made, it made sense and with what I knew, it was probably the right decision, even if we can also with hindsight say, "Well, we've learned more, we have more data." A lot of historical leaders, it's easy to criticize them for decisions, but when you go put yourself in their position, see what the alternatives were, you start to realize these were really hard decisions, and I would have probably made the same disastrous mistake as they would have, you know. Let's just say the Vietnam War, we have our students work through with the original documents decisions of the Joint Chiefs in 1965. They very frequently come to the exact same conclusions as American policymakers made in 1965. It is a real risk making judgments purely on the basis of hindsight, and I think it is important to go back and really try to be authentic to what you knew at the time you made a decision. Dr. Mikkael Sekeres: What a great perspective on this from a historian. Carl Forsberg, I'd like to thank you, and all of us are grateful that you were willing to share your story with us in The Art of Oncology. Dr. Carl Forsberg: Well, thank you, and it's yeah, it's been a, it's a, I think in some ways a very interesting and fitting place to kind of end my cancer journey with the publication of this article, and it's definitely done a lot to help me work through this entire process of going through cancer. So, thank you. 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. Until next time, thank you so much. 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. Carl Forsberg is a Assistant Professor of Strategy and History at the Air Force War College.

CancerNetwork®, in collaboration with The American Society for Transplantation and Cellular Therapy (ASTCT), organized an X Space hosted by Rahul Banerjee, MD, FACP; Taha Al-Juhaishi, MD; and Muhammad Salman Faisal, MD. This expert panel convened to discuss key presentations and abstracts of interest at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting featuring noteworthy developments in modalities like CAR T-cell therapy and transplantation across multiple myeloma, lymphoma, and other disease types. Banerjee is an assistant professor in the Clinical Research Division at the Fred Hutchinson Cancer Center in Seattle, Washington. Al-Juhaishi is the associate director of the Hematopoietic Stem Cell Transplantation and Cell Therapy Program at Oklahoma University Health Stephenson Cancer Center and an assistant professor of medicine at the University of Oklahoma College of Medicine. Faisal is a hematologist/oncologist at Oklahoma University Health Stephenson Cancer Center and serves as an ambassador for ASCO. The group highlighted several late-breaking abstracts, plenary sessions, and poster presentations focused on significant clinical trial data and other findings across the hematologic oncology landscape. Topics of interest included the following: ·       Phase 1b/2 CARTITUDE-1 trial (NCT03548207, NCT05201781) o   Long-term follow-up showed that approximately one-third (33%; n = 32) of patients with relapsed/refractory multiple myeloma maintained progression-free status for at least 5 years following a single infusion of ciltacabtagene autoleucel (cilta-cel; Carvykti).  o   An equal likelihood of progression-free survival occurred in patients with high-risk cytogenetics or extramedullary plasmacytomas. o   With a median follow-up of 61.3 months, the median overall survival (OS) with cilta-cel was 60.7 months (95% CI, 41.9-not evaluable [NE]). ·       Real-world axicabtagene ciloleucel (axi-cel; Yescarta) use o   Across inpatient and outpatient treatment settings, safety and efficacy outcomes were comparable for patients who received axi-cel for relapsed/refractory large B-cell lymphoma. o   Multivariate analysis showed no associations between intended care setting and cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. o   Investigators noted that these real-world data support the consideration of axi-cel in appropriate outpatient settings. ·       Phase 1b/2 NEXICART-2 trial (NCT06097832) o   Investigators assessed NXC-201, a sterically optimized CAR T construct, as a treatment for patients with relapsed/refractory light chain amyloidosis, a population with no FDA-approved options. o   Among 12 patients who received the agent at 450 x 106 cells, 100% achieved rapid and deep hematologic responses at a median time to first and best response of 7 and 26 days, respectively.  o   With a median follow-up of 121 days (range, 29-289), no hematologic relapses or progression had occurred. References 1. Voorhees P, Martin T, Lin Y, et al. Long-term (≥5 year) remission and survival after treatment with ciltacabtagene autoleucel (cilta-cel) in CARTITUDE-1 patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2025;43(suppl 16):7507. doi: 10.1200/JCO.2025.43.16_suppl.7507 2. Furqan F, Hemmer M, Tees M, et al. Trends and outcomes by inpatient and outpatient infusion of axicabtagene ciloleucel (axi-cel) in the US for patients (pts) with relapsed/refractory large B-cell lymphoma (R/R LBCL). J Clin Oncol. 2025;43(suppl 16):7023. doi:10.1200/JCO.2025.43.16_suppl.7023 3. Landau H, Hughes C, Rosenberg A, et al. Safety and efficacy data from Nexicart-2, the first US trial of CAR-T in R/R light chain (AL) amyloidosis, Nxc-201. J Clin Oncol. 2025;43(suppl 16):7508. doi:10.1200/JCO.2025.43.16_suppl.7508

JCO Editorial Fellow Dr. Ece Cali Daylan and JCO Associate Editor Dr. Thomas Stinchcombe discuss the ASCO 2025 Simultaneous Publication paper "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small-Cell Lung Cancer." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, JCO Editorial Fellow, and I am joined by JCO Associate Editor, Dr. Tom Stinchcombe. In this episode, we will discuss the Journal of Clinical Oncology article and abstract presentation "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer.” NeoADAURA is a randomized global phase III study investigating the efficacy of neoadjuvant osimertinib-containing regimens in patients with resectable EGFR-mutated stage II to IIIB non–small-cell lung cancer. 358 patients were randomized 1:1:1 to receive osimertinib plus chemotherapy, osimertinib monotherapy, or placebo plus chemotherapy in the neoadjuvant setting. The primary endpoint was major pathological response. Osimertinib plus chemotherapy and osimertinib alone demonstrated MPR rates of 26% and 25%, respectively, compared to 2% in the chemotherapy plus placebo arm with a p-value of less than 0.001. Tom, can you please explain to our listeners how you interpret this data? Dr. Thomas Stinchcombe: Great question. Yeah, I think to give a little context, obviously, chemotherapy and immunotherapies preoperatively is becoming the standard of care. However, patients with EGFR-mutant lung cancer generally have not responded to immunotherapy, and many of the trials excluded patients with known EGFR mutation. There have been smaller phase II trials that had looked at EGFR TKIs preoperatively, but none of these were definitive. So I think that this trial is a big trial, and I think some of the strengths are that it has osimertinib alone and chemotherapy with osimertinib arms as compared to the standard of chemotherapy. I think it's going to be really interesting at the meeting to see how this is discussed by the discussant and also what the reaction is to its public presentation. And I think that's largely because there's an alternative paradigm now, surgical resection adjuvant osimertinib, that's available to patients. So I think this will be interesting to see what the reaction is to the induction therapy. For patients with known N2 disease, I've generally given some form of induction therapy prior to surgical resection. So I think that's the subgroup of patients that I'm most likely to employ this approach with based on the results. Dr. Ece Cali: So, in this trial, more than 90% of the patients on the osimertinib-containing regimens underwent curative-intent surgery. So, this speaks to the feasibility of the approach, and the higher MPR rate with osimertinib-containing regimens is encouraging. Event-free survival data is currently immature. You have already touched upon some of the strengths of the trial, but what are the weaknesses and the strengths of this trial? Dr. Thomas Stinchcombe: So, I mean, I think there are some weaknesses. A major pathological response was chosen as an endpoint, and there could be an argument that path CR is more of a prognostic marker. However, the rates of path CR are relatively low, so it would have been very hard to design a trial such as that. And then I think the trial started off as a preoperative trial but effectively became a perioperative trial with preoperative EGFR-TKI, postoperative osimertinib. And so I think it's going to be very hard to determine what the contribution of the components are. And then you've hit on another part that I think is very important when we interpret the data that the maturity on the event-free survival is only 15%, and most people are still on therapy. So the event-free survival, which is an important endpoint, is very immature right now. Dr. Ece Cali: And this trial was designed to compare the neoadjuvant approaches, hence the comparator arm here is neoadjuvant chemotherapy followed by surgery. So, considering the ADAURA trial results with upfront surgery followed by osimertinib as adjuvant, so how do you see this trial's impact on the current clinical practice? Dr. Thomas Stinchcombe: Well, very good question, I think one that we're still struggling with as we kind of look at this data. I think, for me, stage II patients will most likely go to surgery and then get adjuvant osimertinib, and then maybe the N2 patients will get an osimertinib-containing regimen as an induction therapy. I think one of the questions is does it really matter when you get the osimertinib as long as you get it at some point? And I think that's going to be the critical interpretation of some of the data at this point. Dr. Ece Cali: And how do you think this trial shapes the future research for patients with resectable EGFR-mutated lung cancer? Dr. Thomas Stinchcombe: Well, I mean, I think it shows that chemotherapy was really modestly active with an MPR rate of 2%, no pathological responses. And then I think you're going to have to look at an osimertinib plus another targeted therapy component. I think, you know, when I looked at the osimertinib versus the chemo-osimertinib arm, I also was sort of surprised that the MPR rate and the path CR rate were very, very similar. So I think that the question is would a double targeted therapy approach or some other approach matter? And I think it also sets a safety standard. And you touched on this in your comments, that there was not a disparity in terms of the rate of going to surgery or R0/R1 resections. So patients were not having progressive disease events or toxicities that prevented surgery. So I think it does give us good safety data. Dr. Ece Cali: Tom, thank you so much for sharing your insights on the JCO article, "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting, and please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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.

JCO Editorial Fellow Dr. Peter Li and JCO Associate Editor Dr. Andrew Ko discuss the ASCO 25 Simultaneous Publication paper "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Peter Li: Hello, everyone, and welcome to our 2025 ASCO Annual Meeting Series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, JCO Editorial Fellow, and I'm joined by Dr. Andrew Ko, JCO Associate Editor, to discuss the Journal of Clinical Oncology article and abstract presentation "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Now, let's start off with the relevance of this article. Andrew, can you please explain this to our listeners? Dr. Andrew Ko: Sure. Thanks, Peter. So, this was a very large international study evaluating the combination of lenvatinib and pembrolizumab. And just for context, that combination has been approved for use in other solid tumor types. It's FDA approved for renal cell carcinoma, for example, and endometrial carcinoma. But this study was looking specifically at this combination together with a chemotherapy backbone - so either FOLFOX or CAPOX - and comparing that to what at the time was a standard of care, which was just standard chemotherapy by itself. So, this very large study was intending to look at this particular novel combination. And we can get into some of the nuances of this study because the way that the experimental, the combination arm, was designed was perhaps a little bit more on the unusual side and led to maybe some imbalance in terms of how we think about the respective arms. Dr. Peter Li: Okay. We can definitely talk more about that as we go on. So, what are some of the key results of this study, and how do you think this will impact practice in the future? Dr. Andrew Ko: That's a good question. Technically, it was not a positive study. Well, it was positive in the sense that the co-primary endpoints - which included both progression-free survival and overall survival - so, progression-free survival, it did technically meet its endpoint, both in terms of the overall population and the preplanned subgroup analysis of patients who had a PD-L1 CPS of greater than or equal to 1. So, there was a PFS benefit with the experimental combination - the lenvatinib, pembrolizumab, plus chemotherapy - compared to chemotherapy alone. I will say the benefit was on the more modest side. So, if you even look at the medians, it was not a marked difference. If you look at the hazard ratios, they did meet statistical significance. On the other hand, this did not translate into a benefit for overall survival. So, when you ask, "Well, is this going to inform practice?" I'd have to say no. It highlights, I think, that JCO does want to publish articles that aren't necessarily going to be practice-changing, but that I think offer a lot of insights into trial design and important aspects of investigating novel treatments, even if they don't end up moving the needle in routine clinical practice. Dr. Peter Li: I totally agree with you. I mean, it was significant in terms of progression-free survival, but again, not clinically significant. And then overall survival, the interventional arm actually appeared to do slightly worse overall. Can you make some comments on the strengths and the weaknesses of this study, and where do you see us going from here? Dr. Andrew Ko: So, I think a couple of things worth highlighting in this study, very well designed, more than 800 patients in total. So, first of all, as I mentioned at the beginning, the combination was a little bit unique in terms of patients enrolled to the experimental arm got the combination of lenvatinib, pembrolizumab, together with chemotherapy for a very finite duration. So, that period of chemotherapy they received was only three months. And per protocol, patients then just segued to, quote unquote “maintenance treatment” with just the lenvatinib and pembrolizumab combination. Whereas patients on the control arm, meaning chemotherapy alone, would continue chemotherapy basically in perpetuity until their disease progressed or intolerable toxicity. So, there really was an imbalance in terms of, if you think that chemotherapy or continuing chemotherapy beyond that initial three-month period of time may be significant, that could have had some impact on the robustness or the efficacy of the experimental arm. There were some other aspects in terms of perhaps some differences in the rates of post-progression treatment, in other words, patients going on to receive second-line treatment. I think the other very relevant aspect, Peter, in this study was that the control arm - and no fault of the investigators - but the control arm at the time the study was ongoing just consisted of chemotherapy, FOLFOX CAPOX, by itself, without an immune checkpoint inhibitor, right? And we clearly know, based on results of several large phase III studies, and it's now in standard clinical practice, that we routinely use chemotherapy plus an immune checkpoint inhibitor. Certainly for patients with CPS PD-1/PD-L1 scores that are, well, you could argue greater than 1, or perhaps greater than 5 or 10. But the point being that the control arm of the study probably doesn't reflect what is currently used in clinical practice. And that's just always a challenge in clinical trial design, right? That when a study is designed and when it rolls out, you're always at risk in a rapidly changing and moving field that the standard of care may evolve during the lifetime of that particular trial, which is what I think you see in LEAP-015. Dr. Peter Li: Totally understand. And the survival we see from this study is also roughly similar to the combination of immuno-chemotherapy that is the standard of care today, which is, the authors mentioned, 12 to 14 months. Thank you so much, Andrew, for your input and for speaking about the JCO article "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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.

JCO Editorial Fellow Peter Li and JCO Associate Editor Eileen O'Reilly discuss the ASCO 25 Simultaneous Publication paper "Tumor-Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal, Phase 3 PANOVA-3 Study." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Peter Li: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, and I'm joined by JCO Associate Editor Dr. Eileen O'Reilly to discuss the Journal of Clinical Oncology article and abstract presentation "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal, Phase 3 PANOVA-3 Study." Now, let's start with the relevance of the article. Eileen, can you explain this study to our listeners? Dr. Eileen O'Reilly: Thanks very much, Peter, for the invitation today to discuss this. Yes, so this is a positive phase 3 trial that was conducted in locally advanced, unresectable pancreas cancer. Patients were randomized to receive either gemcitabine and nab-paclitaxel, international standard, with or without tumor-treating fields. And this is a device like a battery pack that you would wear with a goal to wear that approximately 18 hours a day. And the primary endpoint of this study was overall survival, with key secondary endpoints of tumor response, progression-free survival, looking at pain-free survival, and distant progression-free survival. So, the primary endpoint was met with a median overall survival of 16.2 months compared to 14.2 months on the intervention versus control arm, with a hazard ratio of 0.82. And so that met the pre-specified boundary. There was not an increase in progression-free survival, but there was an increase in control of pain on the tumor-treating fields study. So, it was a large, global study, community, academic sites, randomized 570 people, and it supports what I think we've seen in other difficult-to-treat malignancies using tumor-treating fields, that there's a signal of interest. Dr. Peter Li: Can you speak to some of the strengths and weaknesses of this study? Dr. Eileen O'Reilly: So, strengths: it was a large study. It included community sites, it included academic sites. It included ECOG performance status 0, 1, and some patients with 2. The intent was locally advanced. It probably is fair to say that there were some patients who had more advanced disease based on early progression, based on relatively high CA 19-9 for a percentage of people. But likely that was, with random assignment, that would have presumably fallen out between the arms. The inclusion of patients with a lower performance status is nice to see in large phase 3 studies in pancreas cancer. So, they would be some of the strengths. So maybe some of the limitations are the fact that it's an open-label study - so, always some biases inherent in that. Acknowledging that the primary endpoint was overall survival, presumably that wouldn't be directly influenced by that. And there was an imbalance of women on the control arm, and women do fare a little better in this disease, so possibly kind of weighted one of the study arms a little bit. But nonetheless, I think it was a rigorously designed and rigorously conducted phase 3 trial. It's always hard to fully interpret the signal in locally advanced disease because of the fact that some patients go on to surgery, some patients have a treatment switch of cytotoxic therapy, some patients will go on to radiation. And the endpoint here of overall survival, to a degree, eliminates some of that. So, the benchmark, I think, was generally high here. Dr. Peter Li: Gotcha. And then with these findings and this positive study, how do you foresee this research being implemented and how it will impact clinical practice moving forward? Dr. Eileen O'Reilly: I think there'll be an educational need to introduce this approach to the community and to the pancreas cancer world. Again, there's a precedent in glioblastoma and data from other diseases, so there's some familiarity with this. I think people always want to understand how it works and why it works, and that's something that we'll look forward to hearing more about mechanistically, and also seeing how it can be built upon. And there's some intriguing data with the combination of tumor-treating fields and immunotherapy that's being evaluated in the PANOVA-4 study. So, we'll stay tuned to hear how that reads out in due course. But I think overall, it'll be educational and learning, managing the cutaneous impacts or some skin irritation effects from this, and building on this signal in locally advanced disease. Dr. Peter Li: Well, thank you so much, Eileen, for your time and for speaking about the JCO article, "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal, Phase 3 PANOVA-3 Study." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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.

JCO Editorial Fellow Dr. Ece Cali Daylan and JCO Associate Editor Dr. Grant McArthur discuss the ASCO 2025 Simultaneous Publication paper "A Phase II (Alliance A091802) Randomized Trial of Avelumab Plus Cetuximab vs. Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma (cSCC)." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, and I'm joined by JCO Associate Editor Dr. Grant McArthur. Today, we will discuss Journal of Clinical Oncology article and abstract presentation "A Phase II Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma." Let's start with a brief overview of the clinical trial. This is a randomized phase II trial that compared avelumab plus cetuximab to avelumab in PD-1/PD-L1 antibody-naive patients with advanced cutaneous squamous cell carcinoma. This is a cooperative group study conducted in the United States. Sixty patients were randomized one-to-one and stratified by PD-L1 and HIV status. The primary endpoint was progression-free survival. Patients on the cetuximab plus avelumab arm had a median PFS of 11.1 months, while patients on the avelumab arm had a median PFS of 3 months, corresponding to a hazard ratio of 0.48 with a p-value of 0.018. Grade III or higher treatment-related adverse events occurred in 48% of the patients on the combination arm versus 21% of patients on the avelumab arm. Dr. McArthur, can you please explain to our listeners how you interpret this data? Dr. Grant McArthur: These results are very important because they provide proof of concept for inhibiting PD-L1 as a target when combined with EGFR, so inhibiting PD-L1 with avelumab and inhibiting EGFR with cetuximab, in a randomized trial with a very significant impact in terms of efficacy. So, what this does is it provides proof of concept for inhibiting those targets in cutaneous squamous cell carcinoma of the skin. Avelumab is not approved for cutaneous squamous cell carcinoma of the skin, and so further studies would need to be done, particularly asking the question about combination with the approved PD-1 agents cemiplimab and pembrolizumab. Dr. Ece Cali: I still find the difference in median PFS with various PD-1/PD-L1 inhibitors striking in this context. In this trial, avelumab, as you mentioned, the PD-L1 inhibitor, demonstrated a median PFS of 3 months, whereas PD-1 inhibitors cemiplimab and pembrolizumab have demonstrated longer median PFS in other trials. So, what are some potential reasons for this, and do you think this difference impacts the interpretation of the results here? Dr. Grant McArthur: So, the obvious reason for the differences is that avelumab targets PD-L1, where pembrolizumab and cemiplimab inhibit PD-1, so there could be simply a difference in the target to explain those differences in progression-free survival. However, as you point out, cross-trial comparisons, one has to do with caution because you can, in different phase II studies, enroll different patient populations, which would impact the progression-free survival. So, we have to be cautious about that interpretation. However, given that cemiplimab and pembrolizumab are the approved agents, I think they are the logical ones for further clinical development. Nonetheless, this is still a very important proof-of-concept trial showing that there is a strong clinical signal when you combine EGFR inhibition with inhibition of PD-L1 versus PD-L1 alone. Dr. Ece Cali: I want to highlight some of the safety data presented in this trial as well. The treatment discontinuation rate due to adverse events was much higher in the combination arm, reaching 31% compared to the 14% in the single-agent avelumab arm. The most common grade III adverse events were infusion reaction, rash, and diarrhea in the combination arm. So, these adverse events may affect patients' quality of life significantly. So, what are your thoughts on this, Dr. McArthur? Dr. Grant McArthur: So, the safety data is important. What we're seeing is safety related to each individual agent. So, we have diarrhea and skin rash from the cetuximab, and the infusion reactions is a common toxicity of avelumab. I think what's important, given this is proof of concept inhibiting these targets going forward to further studies, is that agents such as cemiplimab and pembrolizumab have a very low infusion reaction rate. So, the treatment discontinuations due to infusion reaction are unlikely to be an issue with cemiplimab and pembrolizumab when further clinical trials are done. Of course, there is still the issue of diarrhea and skin rash. Now, that can be managed in many patients with EGFR inhibition, you know. However, one would have to await safety data from a significant patient cohort with a combination of cetuximab with either cemiplimab or pembrolizumab, of course, to assess the clinical impact of those safety signals. But I would expect there to be definitely rash and diarrhea as predominant toxicities with those other combinations as well. Dr. Ece Cali: And lastly, I think we touched upon this a little bit, but how do you think this trial impacts the clinical practice, and what are some outstanding questions that need to be addressed in this field in light of the data from this trial? Dr. Grant McArthur: So, the most important outstanding question is - of course, we've already alluded to in our conversation - regarding using anti-PD-1 agents such as pembrolizumab or cemiplimab. So, that needs to be undertaken. Clearly, a randomized trial would be required combining cetuximab with those agents because they are quite active as single agents with impressive response rates and PFS. So, that is the way forward. There's other important clinical questions as well, though. So, patients that get locally aggressive or metastatic cutaneous squamous cell carcinoma of the skin are often immunosuppressed. And so, we do need data in patients that are immunosuppressed, either due to treatment of immune-related disorders - and also organ transplantation. We see a lot of cutaneous squamous cell carcinoma in organ transplant patients. So, these are important patient subsets that would also need to be investigated in further clinical development. However, overall, you know, this is a strong signal, hazard ratio of less than 0.5, and very worthy of further investigation in randomized trials of inhibiting these targets. Dr. Ece Cali: This was a great discussion. Thank you so much for your insight, Dr. McArthur, for speaking about the JCO article "A Phase II Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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.

JCO Editorial Fellow Dr. Lauren Shih and JCO Associate Editor Dr. Stephanie Wheeler discuss the ASCO 25 Simultaneous Publication paper "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Lauren Shih: Hello, and welcome to our 2025 ASCO annual meeting series where we cover some of the top JCO papers published simultaneously with their abstract presentations at this year's meeting. I'm your host, Dr. Lauren Shih, JCO editorial fellow, and I'm joined by JCO Associate Editor Dr. Stephanie Wheeler to discuss the Journal of Clinical Oncology article and abstract presentation "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare." Let's start with the relevance of the article. Dr. Wheeler, can you explain this to our listeners? Dr. Stephanie Wheeler: Thank you so much. Let's get right into it. So this article is really about understanding different types of Medicare plans and what we should expect to see in terms of their use of low-value treatments for cancer patients. So, as Medicare really is focused on trying to limit the use of low-value cancer treatments, we really need to better understand the drivers of variability. So we know that many cancer patients have multiple treatment options available to them. We also know that the vast majority of older adults beyond age 65 are insured by Medicare, and about half of them are on Medicare Advantage plans, which are serviced by private insurance. And private insurance companies in this case are receiving capitated payments for Medicare beneficiaries to manage their service utilization and reduce costs. So, with respect to Medicare Advantage versus the traditional fee-for-service Medicare, it's not really been known to what extent low-value treatments are differentially used by these types of plans for cancer patients. And so that was really the focus of this article. What the authors found is that across six different types of treatments, in general, the folks who were enrolled in Medicare Advantage plans had reduced use of low-value treatment. So that's a good sign for Medicare beneficiaries. And although the relative difference in that use was somewhat low, this translates to a significant number of Medicare enrollees across the country not receiving these low-value treatments. And of course, this translates to considerable savings at the society level. Dr. Lauren Shih: Are there any additional key results that we should review? Dr. Stephanie Wheeler: Yeah. So I'll tell you just a little bit more about the methods and also their findings. So they looked at six different low-value treatments, and this was in, again, 100% of national Medicare enrollees from 2015 through 2021. So the six low-value treatments that they examined were the use of G-CSFs among patients receiving low-risk chemotherapy and denosumab for those who had castration-sensitive prostate cancer. Then they also looked at four high-cost treatments, including using nab-paclitaxel instead of paclitaxel for patients with breast or lung cancer; second, adding bevacizumab to carboplatin plus paclitaxel for ovarian cancer; third, using brand-name drugs instead of generics when generics were available; and fourth, using biologics instead of biosimilars when biosimilars were available. And these are all, by the way, non-recommended treatments according to a variety of guidelines, including NCCN and ASCO's Choosing Wisely guidelines. So they used the Medicare claims data to examine use of these regimens. They also analyzed results by type of Medicare Advantage plan, whether people were enrolled in a health maintenance organization plan, or an HMO, or a preferred provider organization plan, or a PPO. They also looked at the largest Medicare Advantage insurers—including Aetna, Blue Cross Blue Shield, Cigna, Humana, and UnitedHealth—and limited their analyses to those that had complete encounter data. And what they found across the board is that the enrollees in Medicare Advantage plans generally had lower use of these low-value treatments. And the largest differences between Medicare Advantage and traditional Medicare plans were in the outcomes, including G-CSF use and using denosumab for castration-resistant prostate cancer, and then the combination of bevacizumab, carboplatin, and paclitaxel versus carboplatin and paclitaxel. And all of these had a change in use ranging from about 19% change to 24% change in use. This is significant as a field as we look at ways in which different plan organization can influence use of treatments, particularly given the excess cost of cancer care. This is something we really want to pay attention to. So I'd encourage folks to look more closely at the results by treatment type as well as the results by plan type to see a little bit more about what was going on across different plan types. Dr. Lauren Shih: Great. And are there any outstanding questions that need to be answered? Dr. Stephanie Wheeler: Yes, there always are, of course. I think the study has several strengths that are worth noting. First, they have 100% of Medicare enrollees, so there's national coverage there, which is, you know, quite outstanding. They also use an appropriate choice of analysis to help deal with some of the selection. So they use inverse probability of treatment weights, and they control for practice and county indicators to try to get some realistic adjustment for the selection that happens in terms of how patients are enrolled in different Medicare Advantage versus traditional fee-for-Medicare plans. These statistical approaches are a good idea, but they are limited by the observed variables that we can use for these kinds of adjustments. And so any unobserved—confounding or any unobserved factors that would influence selection in these plans aren't going to be captured well. So preferences, for example, that patients may have about different types of plans when they're insuring themselves and their families may not be captured. Second, the data that are used are only encounter data from those plans with complete records. That may mean that smaller Medicare Advantage insurers or those that don't have as comprehensive records are not included. So this may not be reflective of their practice patterns. And then third, of course, this only looked at six different low-value cancer treatments. It remains to be seen whether this kind of finding extends to other types of low-value cancer treatments, and that's an opportunity for future study. Finally, I would say that we don't exactly know why these patterns exist. It could be that Medicare Advantage plans have different approaches to prior authorization. They could have more in-house quality control and management to really understand, among their population for whom they're receiving Medicare Advantage payments, to really look at care quality and assess Choosing Wisely guidelines. We don't know exactly how that's playing out. And so we need additional data to really figure out what's working here and what are opportunities for future policy and payment innovations that can further reduce low-value care. Dr. Lauren Shih: Great. Thank you so much, Dr. Wheeler, for speaking to us about the JCO article, "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare." We really appreciate your insights. Dr. Stephanie Wheeler: Thanks for having me. Dr. Lauren Shih: Join us again for the latest simultaneous publications from the ASCO 2025 Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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, host Michael Hughes summarizes "Co-Occurrence of Cytogenetic Abnormalities and High-Risk Disease in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma" by Kaiser et al, published February 18, 2025, followed by an interview with JCO Associate Editor Suzanne Lentzsch. Transcript Michael Hughes: Welcome to this episode of JCO Article Insights. This is Michael Hughes, JCO's editorial fellow. Today I have the privilege and pleasure of interviewing Dr. Suzanne Lentzsch on the “Co-Occurrence of Cytogenetic Abnormalities and High-Risk Disease in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma” by Dr. Kaiser and colleagues. At the time of this recording, our guest has disclosures that will be linked in the transcript. The urge to identify patients with aggressive disease, which is the first step in any effort to provide personalized medical care, is intuitive to physicians today. Multiple myeloma patients have experienced heterogeneous outcomes since we first started characterizing the disease. Some patients live for decades after treatment. Some, irrespective of treatment administered, exhibit rapidly relapsing disease. We term this ‘high-risk myeloma'. The Durie-Salmon Risk Stratification System, introduced in 1975, was the first formal effort to identify those patients with aggressive, high-risk myeloma. However, the introduction of novel approaches in therapeutic agents—autologous stem cell transplantation with melphalan conditioning, proteasome inhibitors like bortezomib, or immunomodulatory drugs like lenalidomide—rendered the Durie-Salmon system a less precise predictor of outcomes. The International Staging System in 2005, predicated upon the burden of disease as measured by beta-2 microglobulin and serum albumin, was the second attempt at identifying high-risk myeloma. It was eventually supplanted by the Revised International Staging System (RISS) in 2015, which incorporated novel clinical and cytogenetic markers and remains the primary way physicians think about the risk of progression or relapse in multiple myeloma. Much attention has been focused on the canonically high-risk cytogenetic abnormalities in myeloma, typically identified by fluorescence in situ hybridization: translocation t(4;14), translocation t(14;16), translocation t(14;20), and deletion of 17p. Much attention also has been focused on the fact that intermediate-risk disease, as defined by the RISS, has been shown to be a heterogeneous subgroup in terms of survival outcomes. The RISS underwent revision in 2022 to account for such heterogeneity and has become the R2-ISS, published here in the Journal of Clinical Oncology first in 2022. Translocations t(14;16) and t(14;20) were removed, and gain or amplification of 1q was added. Such revisions to core parts of a modern risk-stratification system reflect the fact that myeloma right now is in flux, both in treatment paradigms and risk-stratification systems. The field in recent years has undergone numerous remarkable changes, from the advent of anti-CD38 agents to the introduction of cellular and bispecific therapies, to the very technology we use to investigate genetic lesions. The major issue is that we're seeing numerous trials using different criteria for the definition of high-risk multiple myeloma. This is a burgeoning problem and speaks very much now to a critical need for an effort to consolidate all these criteria on at least cytogenetic lesions as we move into an era of response-adapted treatment strategies. The excellent article by Kaiser and colleagues, published in the February 2024 edition of the JCO, does just that in a far-ranging meta-analysis of data from 24 prospective therapeutic trials. All 24 trials were phase II or III randomized controlled trials for newly diagnosed and relapsed/refractory multiple myeloma. The paper takes a federated analysis approach: participants provided summaries and performed prespecified uniform analyses. The high-risk cytogenetic abnormalities examined were translocation t(4;14), gain or amplification of 1q, deletion of 17p, and translocation t(14;16), if included in the original trials. All of these were collected into zero, single, or double-hit categories, not unlike the system currently present in diffuse large B-cell lymphomas. The outcomes studied were progression-free survival and overall survival, with these analyses adhering to modified ITT principles. The authors also performed prespecified subgroup analyses in the following: transplant-eligible newly diagnosed myeloma, transplant non-ineligible newly diagnosed myeloma, and relapsed/refractory myeloma. They, in addition, described heterogeneity by the I2 statistic, which, if above 50%, denotes substantial heterogeneity by the Cochrane Review Handbook, and otherwise performed sensitivity analyses and assessed bias to confirm the robustness of their results. In terms of those results, looking at the data collected, there was an appropriate spread of anti-CD38-containing and non-containing trials. 7,724 patients were evaluable of a total 13,926 enrolled in those 24 trials: 4,106 from nine trials in transplant-eligible myeloma, 1,816 from seven trials in transplant non-ineligible myeloma, and 1,802 from eight trials in relapsed/refractory disease. ISS stage for all patients was relatively evenly spread: stage I, 34.5%; stage II, 37%; stage III, 24%. In terms of high-risk cytogenetic lesions, double-hit disease was present in 13.8% of patients, and single-hit disease was present in 37.4%. In terms of outcomes, Kaiser and colleagues found a consistent separation in survival outcomes when the cohort was stratified by the number of high-risk cytogenetic lesions present. For PFS, the hazard ratio was for double-hit 2.28, for single-hit 1.51, without significant heterogeneity. For overall survival, the hazard ratio was for double-hit disease 2.94, single-hit disease 1.69, without significant heterogeneity except in patients with double-hit disease at 56.5%. By clinical subgroups, hazard ratios remained pretty consistent with the overall cohort analysis. In transplant-eligible newly diagnosed myeloma, the hazard ratio for progression is 2.53, overall survival 4.17. For transplant non-ineligible, 1.97 progression, 2.31 mortality. Relapsed/refractory disease progression 2.05, overall mortality 2.21, without significant heterogeneity. Of trials which started recruitment since 2015, that is to say, since daratumumab was FDA approved and thus since an anti-CD38 agent was incorporated into these regimens, analysis revealed the same results, with double-hit myeloma still experiencing worse survival by far of the three categories analyzed. Risk of bias overall was low by advanced statistical analysis. In terms of subgroup analysis, double-hit results for transplant-eligible newly diagnosed myeloma may have been skewed by smaller study effects, where the upper bound of the estimated hazard ratio for mortality reached into the 15 to 20 range. In conclusion, from a massive amount of data comes a very elegant way to think about the role certain cytogenetic abnormalities play in multiple myeloma. A simple number of lesions - zero, one, or at least two - can risk-stratify. This is a powerful new prognostic biomarker candidate and, somewhat soberingly, also may confirm, or at least suggests, that anti-CD38 agents are unable to overcome the deleterious impact of certain biologic characteristics of myeloma. Where do we go from here? This certainly needs further a priori prospective validation. This did not include cellular therapies. The very scale at which this risk-stratification system operates, agnostic to specific genetic lesion, let alone point mutations, lends itself also to further exploration. And to discuss this piece further, we welcome the one and only Dr. Suzanne Lentzsch to the episode. Dr. Lentzsch serves as an associate editor for JCO and is a world-renowned leader at the bleeding edge of plasma cell dyscrasia research. Dr. Lentzsch, there are several new investigations which suggest that translocation t(4;14), for example, is itself a heterogeneous collection of patients. There are other studies which suggest that point mutations in oncogenes like TP53, which were not assessed in Kaiser et al., carry substantial detrimental impact. Is this classification system - no-hit, single-hit, double-hit - too broad a look at tumor genetics? And how do you think we will end up incorporating ever more detailed investigations into the genetics of multiple myeloma moving forward? Dr. Suzanne Lentzsch: Michael, first of all, excellent presentation of that very important trial. Great summary. And of course, it's a pleasure to be here with JCO and with you to discuss that manuscript. Let me go back a little bit to high-risk multiple myeloma. I think over the last years, we had a lot of information on what is high-risk multiple myeloma, and I just want to mention a couple of things, that we separate not only cytogenetically high-risk multiple myeloma, we also have functional high-risk multiple myeloma, with an early relapse after transplant, within 12 months, or two years after start of treatment for the non transplant patients, which is difficult to assess because you cannot decide whether this is a high-risk patient before you start treatment. You only know that in retrospective. Other forms of high-risk: extramedullary disease, circulating tumor cells/plasma cell dyscrasia, patients who never achieve MRD positivity, extramedullary multiple myeloma, or even age and frailty is a high risk for our patients. Then we have gene expression and gene sequencing. So there is so much information currently to really assess what is high-risk multiple myeloma, that is very difficult to find common ground and establish something for future clinical trials. So what Dr. Kaiser did was really to develop a very elegant system with information we should all have. He used four factors: translocation t(14;16), t(4;14), gain or amplification of 1q, and deletion of 17p. Of course, this is not the entire, I would say, information we have on high risk, but I think it's a good standard. It's a very elegant system to really classify a standard single-hit, double-hit, high-risk multiple myeloma, which can be used for all physicians who treat multiple myeloma, and especially, it might also work in resource-scarce settings. So, ultimately, I think that system is an easy-to-use baseline for our patients and provides the best information we can get, especially with a baseline, in order to compare clinical trials or to compare any data in the future. Michael Hughes: Thank you, Dr. Lentzsch. To the point that you made about this isn't the full story. There does, as you said, exist this persistent group of functional high-risk multiple myeloma where we see standard-risk cytogenetics, but these patients ultimately either exhibit primary refractory disease or very early relapse despite aggressive, standard aggressive treatment. How do you see risk-stratification systems incorporating other novel biomarkers for such patients? Is it truly all genetic? Or is next-generation sequencing, gene expression profiling, is that the answer? Or is there still a role for characterizing tumor burden? Dr. Suzanne Lentzsch: Excellent question, Michael, and I wish I would have the glass ball to answer that question. I see some problems with the current approach we have. First of all, to do the cytogenetics, you need good material. You only detect and identify what you have. If the bone marrow is of low quality, you have mainly peripheral blood in your bone marrow biopsy, you might not really fully have a representation of all cytogenetic changes in your bone marrow. So I think with a low-quality sample, that you might miss one or the other really cytogenetic high risk. So, having said this, I think circulating tumor cells, that might be something we will look into in the future, because circulating tumor cells are readily available, can be assessed without doing a bone marrow biopsy. And what is even more exciting, in addition to the circulating tumor cells or plasma cells, using them is next-generation sequencing. I think at the moment, we are more in a collection phase where we really try to correlate sequencing with our cytogenetics and especially to establish next-generation sequencing in all of our patients. But I think after that collection phase, maybe in the future, collecting peripheral blood and doing sequencing on peripheral blood samples might be the way to go. In addition, I don't want to forget the imaging. We started with a skeletal survey, and we know that you probably need to lose 30% of the bone before you see a lesion at all. So having imaging, such as diffusion-weighted imaging, whole-body MRI, is also, together with sequencing of the tumor cells, a step into the right direction. Michael Hughes: Thank you, Dr. Lentzsch. Bringing this back to the article at hand, how has Kaiser et al. changed the way we discuss myeloma with patients in the exam room? Dr. Suzanne Lentzsch: I think we have more data on hand. So far, we talked about standard risk and high risk, but I think right now, with a very simple system, we can go into the room and we can tell the patient, "Listen, you don't have any of those cytogenetic abnormalities. I think you have a standard risk. We might give you a simple maintenance treatment with Revlimid." But we might also go into the room and say, "I'm really concerned. You have so-called double-hit multiple myeloma. You have high-risk and at least two of those abnormal cytogenetics which we discussed, and I think you need a more intense maintenance treatment, for instance, double maintenance." I think we know that a high-risk multiple myeloma can be brought into a remission, but the problem that we have is to keep those patients into a remission. So, I think a more intense treatment, for instance, with a double maintenance, or with consolidation after transplant, and a longer and more intense treatment is justified in patients who have that truly high-risk multiple myeloma described here. Michael Hughes: Dr. Lentzsch, thank you so much for your time and your wisdom. Dr. Suzanne Lentzsch: My pleasure. Thank you for having me. Michael Hughes: Listeners, 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.

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

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.  

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

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.  

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    

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/

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.