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Dr. Doug Johnson, clinical director of the melanoma program and assistant professor of medicine at Vanderbilt University Medical Center, discusses the management of immune-related adverse events refractory to standard therapies. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT [INTRO MUSIC PLAYING] Welcome to the ASCO University Weekly Podcast. My name is Doug Johnson. I'm the clinical director of the melanoma program, assistant professor of medicine at Vanderbilt University Medical Center. Today we'll discuss management of immune-related adverse events refractory to standard therapies. As a background to today's discussion, immune checkpoint inhibitor are active therapies and FDA approved in 15 different cancer types. Responses in patients who do respond can be quite durable. And these are enhanced further by combining immune checkpoint inhibitors-- specifically combining anti PD-1, or nivolumab or pembrolizumab, with anti CTLA-4, ipilimumab. The side effect from these treatments, called immune-related adverse events, are caused by unleashing T cells not only against tumor but against host tissues. These inflammatory toxicities can affect any organ and may occasionally be life threatening. The cornerstone of managing immune-related adverse events in patients involves corticosteroid treatment, which are usually effective. More clinically severe events are treated with high-dose steroids. For example, prednisone or methylprednisolone, 1 to 2 milligrams per kilogram per day. And less severe side effects may be managed by dose withholding, symptomatic management, or low-dose steroids-- 0.5 milligrams per kilogram or less. In addition, certain side effects have fairly well-established second line treatments. For example, patients with colitis that does not improve with steroids within three days should be considered for infliximab treatment. Similarly, hepatitis that fails to improve should also receive mycophenolate mofetil. For more information about steroid dosing, definitions of mild versus severe toxicities, and established second line treatments for refractory toxicities, please visit the ASCO Clinical Guidelines for managing immune checkpoint inhibitor toxicities. So, as I mentioned, corticosteroids and established second line regimens are fairly effective. So what is the problem? What is the knowledge gap? Well, again, though most events fail to respond to corticosteroids, a subset fails to improve and requires even additional treatment regimens. Actually, approximately 1% of patients treated with combination ipilimumab and nivolumab actually experience fatal toxicities. Further, a small subset of patients develop chronic toxicities, such as neuropathy or arthritis, those developing more effective treatment regimens and more effectively using the treatment regimens we have is a real unmet need. So let's talk about the data. Well, first of all, even the data for steroids for using steroids for these immune-related toxicities, as well as the fairly well-established second line treatments, like infliximab and mycophenolate, are largely based on anecdotal evidence and clinical experience. Thus, the data for use of additional agents on top of that for the very refractory toxicities are even more limited. But with that being said, let's discuss some approaches. First, some general principles. Most immune therapy toxicities have a similar syndrome that's encountered outside of immune checkpoint inhibitor treatment. For example, immune checkpoint inhibitor colitis is quite similar to inflammatory bowel disease. Thus, we consider agents with activity in those situations. Some immune toxicities actually appear virtually identical to their non-immune checkpoint inhibitor analog, including Guillain-Barre syndrome, myasthenia gravis, immune thrombocytopenic purpura, and several others. Again, these are managed with steroids plus appropriate disease-specific management. For example, IVIg or plasmapheresis for patients that have Guillain-Barre syndrome, in addition to steroids. Now, let's go into a few specifics. What about colitis that's refractory to steroids and infliximab? Well, there are a number of case reports that show activity of the integrin inhibitor, vedolizumab, in colitis that does fail to respond to steroids and infliximab. It's important to keep in mind that this agent has a fairly slow onset, and improvement may be seen over a few weeks, similar to the experience in patients who have Crohn's disease. How about pneumonitis refractory to steroids? Well, second line options here are less well established, but guidelines suggest either infliximab, mycophenolate, or IVIg as appropriate options. And if of these fails to work after a few days, it's reasonable to add a second agent. Moving to hepatitis, if steroids and mycophenolate do not improve liver function, there've been anecdotal reports of anti-thymocyte globulin reversing even full-minute presentations. We generally avoiding anti-TNF alpha agents here, like infliximab, since they can actually rarely cause liver failure on their own. Finally, myocarditis. This is a very challenging toxicity with a fatality rate as high as 50% in serious cases. We generally treat this very aggressively upfront when symptomatic and when associate with arrhythmias with very high doses of steroids-- up to 1 gram of methylprednisolone daily. Plus either mycophenolate, IVIg, or even ATG. Really, the best upfront regimen is not well defined. To sum it up, immune checkpoint inhibitor to transformative treatments in some patients that produce durable responses. Their toxicities are usually manageable. But as we use these agents more often in the clinic, we'll increasingly see refractory and unusual toxicities that provide a clinical challenge. Understanding how to manage these events will be a key challenge for oncologists moving forward. Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on immune therapy and the treatment of toxicities, please visit the ASCO Guidelines, as well as the Comprehensive eLearning Center at university.asco.org [OUTRO MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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

Daniel G. Haller, MD, of the University of Pennsylvania joins David H. Henry, MD, to talk about the best ways to read and review the scientific literature.  And Ilana Rachel Yurkiewicz, MD, talks about chaos and opportunity. Show notes  By Hitomi Hosoya, MD, PhD, Resident in the department of internal medicine, University of Pennsylvania Health System - If you are a peer reviewer of a manuscript submitted to a journal, you should be unbiased, consistent, constructive, and focused on the research. COPE guideline is a good resource. - If you are a reader of a published article, it is important to ensure that the abstract has the same conclusion as the body of the article. - If you are a clinical practitioner and wondering how to apply findings of published data, the editorial section is a good source. - If you are a trainee and wondering how to stay up-to-date, Oxford Textbook of Oncology or ASCO University are recommended. Reference: https://bit.ly/2xkGTcq  Contact us: podcasts@mdedge.com   

Dr. Daniel George is Professor of Medicine and Surgery, Director of GU Oncology for the Duke Cancer Institute, and Co-Chair of the DCI Center for Prostate and Urologic Cancers. Dr George’s primary areas of interest are in drug development and optimizing care for patients with GU cancers, particularly prostate and kidney cancers. In this week's episode, Dr. George presents two contrasting cases with nephrectomy as a possible treatment path. Can you determine the best course of treatment for each patient? If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT Welcome to the ASCO University Weekly Podcast. My name is Dr. Daniel George. And I'm a professor of medicine and surgery at Duke University. I'm also the director of GU oncology at the Duke Cancer Institute and co-chair of the DCI Center for Prostate and Neurologic Cancers. Today we'll discuss two similar cases of patients presenting with metastatic renal cell carcinoma in our multidisciplinary management options. Without any standard screening procedures, 20% to 30% of kidney cancer patients today present with metastatic disease. Historically, debulking nephrectomy has been our standard of care. And this has been based on old trials from the interferon era of treatments. Since then, many drugs have been approved for the management of patients with metastatic renal cell carcinoma, many of which have improved the progression free survival and overall survival of patients with metastatic disease, which may have had an impact on the landscape and role for debulking nephrectomy. Furthermore, metastatic kidney cancer patients can be risk stratified. There's a number of criteria used. But historically the most commonly used criteria has been the Memorial Sloan Kettering Cancer Center criteria. Which included five factors, including KPS score less than 70, a calcium score greater than 10, A serum hemoglobin of less than the lower limit of normal, and LDH greater than 1.5 times the upper limit of normal, or having their primary tumor in place, meaning no prior nephrectomy. If patients had zero of these factors they were considered good risk with the best survival. Patients with one or two of these factors are considered intermediate risk. And patients with three or more of these factors historically have been very poor risk, with median survivals of six months or less. The Carmena Study was a prospective, multi-center, randomized, non inferiority trial comparing upfront nephrectomy followed by sunitinib therapy, compared to upfront sunitinib therapy alone in patients with metastatic renal cell carcinoma amenable to cytoreductive nephrectomy. We'll get to these results in a moment. But the study population included, importantly, patients with e cog performance status zero or one. And 40% plus of these patients were considered poor risk, with the average sum of metastatic tumor burden being greater than five centimeters. So now, let's get to some modern cases. The first case we'll discuss is George. He's an 83-year-old man who presented with gross hematuria and a hemoglobin of 13.8 in the normal range. A CT scan revealed an eight centimeter right renal mass and multiple pulmonary mets, up to two centimeters in size. His e cog performance status is zero. And his calcium was 8.4, and LDH was normal as well. Our second case, for comparison, is Philip, a 76-year-old man who was found to have a 16 centimeter left renal mass incidentally on a spine MRI. This was confirmed by CT scan, along with some pulmonary nodules measuring up to 1.8 centimeters, as well as enlarged mediastinal lymph nodes up to two centimeters, and an eight millimeter liver lesion. His calcium score was 10.4. And his hemoglobin was 12.5, which was below the limit of normal. He had a normal LDH and an absolutely zero performance status. So for these two cases, we have four choices. The first choice is for both cases a nephrectomy followed by systemic treatment, our historical approach. The second is systemic therapy first, with plus or minus a subsequent nephrectomy for both cases. Our third choice would be to treat case number one with a nephrectomy, followed by systemic therapy, and case number two with systemic therapy first. And our fourth option would be systemic therapy first for case one and a nephrectomy first for case two. Now, to me, when I look at these cases, the correct answer is three. Nephrectomy first for case one, and systemic therapy first for case two. Let me explain. Even though these cases are fairly similar in age, gender, performance status, and had the presence of a large primary tumor, for case one this is an intermediate risk patient. This patient has lung only disease that's relatively low volume, a good performance status, and normal labs. In addition, he's symptomatic with gross hematuria. For these reasons, a debulking nephrectomy is really indicated. And because of his good performance status, he's very likely to recover well from the surgery, despite the fact that he's 83 years old. Case two is subtly different. This is actually a poor risk patient. Even though his e cog performance status is zero, he has an elevated calcium, a decreased hemoglobin, and he's got his primary tumor still in place. That puts him into a poor risk category. And some of these patients never recover from surgery well enough to get systemic therapy. He also has multi organ involvement, involving his lungs and nodes, and possibly even his liver. This is a patient that really mirrors the patient population of Carmena. Based upon this, I think systemic therapy first is a reasonable treatment option for this patient. If we actually look at the results of Carmena, the study confirmed that sunitinib therapy alone, systemic therapy, was non inferior, and actually trended towards improved survival compared to cytoreductive nephrectomy followed by sunitinib. The results suggest that for poor risk or for high volume metastatic patients, that systemic therapy first should be the standard of care. But, importantly, not included in a Carmena study were patients that had low volume metastatic disease and intermediate risk features, or good prognosis. These patients not included in the Carmena study might still benefit first from a debulking or cytoreductive nephrectomy. So thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the role of cytoreductive nephrectomy, including additional patient cases and opportunities for self-evaluation, visit the Comprehensive eLearning Center at university.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Yosef Landman is a graduate of the Sackler School of Medicine, Tel Aviv University. He is currently a medical oncology resident at Davidoff Cancer Center, Rabin Medical Center in Petach Tiqva, Israel. In today's episode, he discusses the recent approval of larotrectinib for tumor-agnostic treatment of advanced solid tumors containing NTRK gene fusion. Dr. Landman, a co-author on the journal paper Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion (Clinical Breast Cancer, June 2018), provides background on the recent approval as well as a case-based example of larotrectinib treatment. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

Dr. Ian Flinn, Medical Oncologist specializing in hematologic malignancies at Tennessee Oncology, discusses the recent FDA approval of duvelisib for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT (Intro Music Playing) As a background to today's discussion, the PI3K are a family of lipid kinases that sit at the crossroads of numerous signaling events that drive many malignancies, including certain lymphomas, and chronic lymphocytic leukemia. There are four isoforms of the PI3K-- alpha, beta, delta, and gamma. Isoform specific inhibitors are attractive because they may lead to efficacy without the toxicity of pan inhibitors. Idelalisib, which is a delta isoform inhibitor, was the first PI3K inhibitor be approved for lymphoma in CLL. The delta isoform is a particular interest in B cell malignancies because its expression is normally restricted to cells of a hematopoietic origin. In data from gene knockout models, show that it has a key role in B cell signaling, development, and survival. Selective targeting of the delta isoform should not alter insulin signaling, which is mediated by the ubiquitously expressed alpha isoform. However, narrow targeting could lead to mechanisms of resistance to upregulation of other isoforms. This has been demonstrated in mantle cell lymphoma where the alpha isoform is expressed in relapse patients. Duvelisib is a dual inhibitor of both the delta and gamma isoforms of the PI3K. Inhibiting the gamma isoform may be important because of its inhibitory effect, not only in the malignant cell, but also in the micro-environment, which provides important survival signals to malignant cells. Both idelalisib and copanlisib, an inhibitor of the delta and alpha isoforms, are currently FDA approved for third line follicular cell lymphoma. And idelalisib is approved in combination with rituximab in relapse CLL. On September 24, 2018, the Food and Drug Administration granted approval for duvelisib for patients with relapsed refractory chronic lyphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma after at least two prior therapies. The approval of duvelisib in CLL was based on the DUO trial, a large international randomized phase III trial comparing duvelisib, at 25 milligrams orally, twice daily, to ofatumumab, given according to the package label. The results of the duo trial have been published in Blood. In a subset analysis of 196 patients receiving at least two prior therapies, the median progression pre-survival was 16.4 months in the duvelisib arm, and 9.1 months in the ofatumumab arm, with a hazard ratio of 0.40. The overall response rate of 78% with duvelisib was twice the 39% seen with ofatumumab. The follicular lymphoma indication is based on the Dynamo trial, a single arm multi-center trial of duvelisib, which enrolled 83 patients with follicular lymphoma who are refractory to rituximab and to either chemotherapy or radioimmunotherapy. The overall response rate, determined by an independent response committee, was 42%. Of the 35 responding patients, 15, or 43%, maintained responses for at least six months. And 6, or 17%, maintained responses for at least 12 months. The most common adverse reactions with an instance of greater than or equal to 20% were diarrhea, or colitis, neutropenium, rash, fatigue, pyrexia, cough, nausea, upper respiratory tract infection, pneumonia, muscle skeletal pain, and anemia. Over the last decade, we've seen substantial advances in the treatment of low grade lymphoma and CLL, especially in the front-line setting. Unfortunately for patients with relapse and refractory disease, new agents are needed. The approval of duvelisib is an important addition to our armamentarium for these patients. And we'll have an immediate impact. However, to have its greatest effect, strategies will need to be devised to move this drug earlier in the natural history of these diseases. Such approaches might include alternative dosing and scheduling, as well as combination regiments. Duvelisib is a novel PI3K inhibitor and is differentiated from other PI3K inhibitors, because it targets both the delta and gamma isoforms. Consequently, it is being studied in a broader array of diseases, including T cell malignancies, where promising activity has been seen. (Outro Music Playing) Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on drug approvals visit the comprehensive e-learning center at university.asco.org.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello, and welcome to the ASCO Guidelines Podcast Series. Is my name Shannon McKernin and today, I'm interviewing Dr. Elena Stoffel from the University of Michigan, lead author of "Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion.” Thank you for being here today, Dr. Stoffel. I'm delighted to join you. So first, can you tell us what a professional clinical opinion is and why this topic is so important to ASCO? Well, a provisional clinical opinion is a statement that ASCO puts out when we are seeing trends that are relevant to the care of our patients but that may not necessarily have the level of evidence needed to include in a true clinical guideline. This particular provisional clinical opinion that deals with the management of patients with pancreatic cancer and their families is based on some new data that has been published regarding the prevalence of inherited factors influencing pancreatic cancer risk. So what are the key statements of this Provisional Clinical Opinion or also known as a PCO? This particular provisional clinical opinion, which is about just the inherited susceptibility to pancreatic cancer, was prompted by several recent publications, which found that the prevalence of genetic predisposition among patients with pancreatic cancer was much higher than we had originally anticipated. And this is relevant because in talking about pancreatic cancer as one of the deadliest cancers in both in the United States and worldwide, we are very interested in finding ways to reduce the morbidity from this cancer to patients and their families. And this particular provisional clinical opinion addresses the role that genetic risk assessment should have in the care of pancreatic cancer patients and also the role for clinical genetic testing, as well as the risks and benefits of pancreatic cancer screening for at risk family members. What considerations are there for having these conversations with patients and their families? Well, many times when we see families affected with cancer, one of the questions they have is what is the likelihood that this will happen to other individuals in our family and what can we do to prevent cancers in other family members. And I think what's important here is that review of the data from multi-gene panel genetic testing in unselected individuals diagnosed with pancreatic cancer identified pathogenic germline variants in 1 out of every 10 individuals. And this is really important because when you think about it, if 1 out of every 10 patients with pancreatic cancer develop their cancer in the setting of a genetic predisposition syndrome, this has tremendous implications for management both for them as well as for their family members. One of the most common inherited cancer syndromes identified in families affected with pancreatic cancer is hereditary breast ovarian cancer associated with mutations of BRCA1 and BRCA2. As you know, there are definite screening recommendations we make for individuals who carry these genetic alterations. And certainly if a family member is diagnosed with a genetic alteration, then that has an impact for cancer screening and management. Furthermore, there are emerging data about the utility of pancreatic cancer screening in high risk individuals. And while there's still some controversy about how to screen individuals at risk for pancreatic cancer, certainly there are some emerging data suggesting that this may have a role for early detection. And finally, the panel included a discussion section on the limitations of the research and future directions. So what are the key points of this section? I think that what we're learning is with genetic testing, and particularly with multi-gene panel testing, we are we often find unexpected results. Certainly variants of uncertain significance are not uncommon when multi-gene panel tests are used. And being able to interpret the clinical significance of some of these genetic test results can pose some challenges, especially for clinicians who don't have specific expertise in genetics. Certainly being able to deal with the volumes of patients who need genetic testing who are also battling pancreatic cancer, we want to make sure that we have the resources to be able to offer genetic testing to everyone who needs it. And finally, in talking about screening for pancreas cancer, while there are some studies that have demonstrated that screening with MRIs and/or endoscopic ultrasounds has led to early detection and down staging of cancers in some cases, larger studies are needed to be able to refine more specifically who and how to screen individuals at risk for pancreas cancer. Great. Thank you so much for taking your time today to discuss this PCO with us, Dr. Stoffel. Thank you very much for having me. And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. If you've enjoyed what you heard today, please rate and review the podcast and refer the show to a colleague.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Scott Morgan from the Ottawa Hospital and University of Ottawa, lead author on "Hypofractionated Radiation Therapy for Localized Prostate Cancer: an ASTRO, ASCO, and AUA Evidence-Based Guideline.” Thank you so much for being here today, Dr. Morgan. It's my pleasure, Shannon. I'm happy to take part in the podcast and hopefully share the highlights of the guideline with your listeners. So first, can you give us a general overview of what this guideline covers? Yeah. So the guideline covers really hypofractionated external beam radiation therapy, which is a treatment for localized prostate cancer, and for the non-radiation oncology folks in your audience, I think it's important to begin by placing the guideline sort of in its context and going over some of the terminology that we use as radiation oncologists. So external beam radiotherapy, it's a standard treatment-- standard local treatment option for men with localized prostate cancer. It gives outcomes which are really equivalent to those of radical prostatectomy or brachytherapy, which are the other two standard local treatment options. And traditionally, it's given in small daily fractions over several weeks and the usual daily fraction size is 1.8 to 2 Gray per day. And this is called conventional fractionation. And that really translates into a course of about seven and a half to nine weeks of treatment. And so that total dose which is delivered in those daily treatments, five days a week, is about 76 to 80 Gray. And that's what we call conventional or standard fractionation. And there's a theoretical framework in radiation medicine and there's some evidence to accompany that that suggests that prostate cancer is quite sensitive to radiation fraction size. And just to give a brief primer, for any tissue, cancerous or non-cancerous, there's a sensitivity to fraction size and it's characterized by something called the alpha-beta ratio. And for prostate cancer, that's felt to be low compared to most other cancers, the alpha-beta ratio, and indeed, it's thought to be lower than the adjacent dose-limiting normal structure, which is the rectum. And so an implication of that is that hypofractionation, and by that we mean daily fraction size of more than 2 Gray, might improve the therapeutic ratio of radiation therapy in localized prostate cancer. Now the guideline-- and I think it's important to emphasize this-- it draws a distinction between what we call moderate hypofractionation and ultra-hypofractionation. Clearly, fraction size is a continuous variable, so any subdivision that we might make is necessarily a bit arbitrary, but it turns out that at least in clinical practice, there's been really two distinct approaches to hypofractionation that have arisen. And one of these is moderate hypofractionation and that's an approach where the fraction size is modestly higher than 2 Gray per fraction, and in the guideline, it's been defined as a fraction size between 2.4 and 3.4 Gray, whereas ultra-hypofractionation, this is defined in the guideline as a fraction size greater than 5 Gray. And it's also been referred to in the literature as extreme hypofractionation or Stereotactic Body Radiation Therapy, SBRT, or SABR, Stereotactic Ablative Radiation Therapy. But in any case, we are talking here about, with ultra-hypofractionation, with radical courses of treatment that are often delivered over as few as five fractions, often on an alternate day approach over two or two and a half weeks. And so the guideline really was largely motivated by the publication of a number of randomized trials, including four large-scale trials in the past two years that have compared conventionally fractioned radiation therapy and moderately hypofractionated radiation therapy. So that is really what stimulated the guideline, which was the evidence concerning moderately hypofractionated radiation therapy. But at the same time, there has been an increasing use in routine clinical practice that's been observed of ultra-hypofractionated radiotherapy, so the decision was made to make recommendations on it as well. So ASTRO, American Society for Radiation Oncology, in collaboration with ASCO and the AUA, convened a panel of radiation oncologists, medical physicists, urologists, radiation oncology resident, patient representative, and a systematic review of the literature was conducted and their recommendations have been made on the basis of this systematic review. So the aim was to provide recommendations on use of both moderate hypofractionation and ultra-hypofractionation, in particular with reference to oncologic outcomes, toxicity, and quality of life. So we didn't directly consider health economic endpoints, though clearly the very nature of hypofractionation is such that there are potential advantages in terms of cost and convenience for patients. And what are the key recommendations of this guideline? We separated the key recommendations into three main groups and the first set of recommendations pertains to moderate hypofractionation, and these are generally based on the highest-quality evidence. So they could be viewed as the strongest recommendations in the guideline. And the second set of recommendations concern ultra-hypofractionation. They're somewhat less strong given they're based on somewhat weaker evidence. And then the third set of recommendations relate to some of the technical aspects of the planning and delivery of hypofractionated radiation therapy. So, dealing with the moderate hypofractionation recommendations first, arguably the most important recommendation of the guideline is that the panel has recommended that in patients with localized prostate cancer who are candidates for external beam radiation therapy, moderate hypofractionation should be offered. And this is graded as a strong recommendation. It's based on high-quality evidence and it applies to patients across all risk groups. So it applies to patients with low-risk prostate cancer who require active treatment or who have declined active surveillance and it also applies to patients with intermediate-risk or high-risk localized prostate cancer. And why really does it apply to all these groups? It's essentially because these groups are well-represented in the trials of moderate hypofractionation. And the trials have shown that moderate hypofractionation really gives similar outcomes in terms of efficacy to conventional fractionation. Now one caveat I guess that I should say is that the trials generally only looked at radiation therapy to the prostate rather than radiation therapy to the prostate as well as the pelvic lymph nodes. So the panel's recommendations regarding moderate hypofractionation don't apply to the scenario where the clinician has decided to include the pelvic lymph nodes in the radiation therapy volume. The panel also made recommendations with respect to toxicity and quality of life, and specifically, they did recommend that men should be counseled about a small increased risk of acute gastrointestinal toxicity, typically rectal toxicity, with moderately hypofractionated radiation therapy. And they should also be counseled that moderately hypofractionated radiation therapy has a similar risk of late GI toxicity and also has a similar risk of both acute and late GU toxicity compared to conventional fractionation. The only difference was seen in acute GI toxicity. And I think it's probably worth dwelling on this a little bit more. Probably the most granular data on acute GI toxicity comes from the CHHiP trial. This was a trial from the UK. It was far and away the largest randomized trial of moderate hypofractionation versus conventional fractionation. And they followed the amplitude of GI toxicity very carefully over the short and long term and what they did found was that in the early weeks, there was greater peak acute GI toxicity with moderate hypofractionation, but this difference had really disappeared by about 18 weeks after the start of radiotherapy. So within a few months, there was no difference, and afterwards, there was no consistent difference in long-term GU or GI toxicity across these trials. Now I guess I should mention that, at the current time, that the median follow-up of most of these trials is between five and six years, so arguably, the last word hasn't been written. The panel also offered conditional recommendations on particular moderate hypofractionation regimens. There were multiple different regimens that were evaluated but most were not compared head-to-head. And the panel preferred two particular regimens-- 60 Gray and 20 fractions over four weeks or 70 Gray and 28 fractions over five and a half weeks, as these were the two regimens that were evaluated in the largest populations. And of these two, likely the strongest evidence supports 60 Gray and 20 fractions, given it was used in two different trials and it was used across all risk groups and with or without concomitant hormonal therapy. So those were the recommendations regarding moderate hypofractionation. So moving to ultra-hypofractionation, again, this is talking about fraction size of at least 5 Gray, typically a course of as few as five fractions over perhaps two or two and a half weeks. I think it's important to say that, at the time we were preparing this guideline, there were no published efficacy or toxicity data from randomized trials comparing ultra-hypofractionation and conventional fractionation. So the strengths of the recommendations made by the panel is correspondingly lower than was the case for moderate hypofractionation. But having said that, there are several prospective non-randomized studies that have been published and have documented safe delivery of ultra-hypofractionation for appropriately-selected patients and pretty good biochemical control and low toxicities have been observed in these studies. But again, relatively few have follow-up beyond five years. So what the panel recommended was that in men with low-risk prostate cancer-- and the bulk of the data to date for ultra-hypofractionation has been in this group-- panel conditionally recommended that in those who decline active surveillance and choose active treatment with radiation therapy, that ultra-hypofractionation may be offered as an alternative to conventional fractionation. Again, this is a conditional recommendation. In men with intermediate-risk prostate cancer, the panel has conditionally recommended that ultra-hypofractionation may be offered as an alternative to conventional fractionation but it's strongly recommended in this group that these patients be treated as a part of a clinical trial-- and there are several clinical trials ongoing-- or as part of the multi-institutional registry. And then finally, in patients with high-risk localized prostate cancer, there was really insufficient comparative evidence for the panel to suggest offering this outside of a clinical trial or outside of a registry. Regarding particular regimens, that the panel again made a conditional recommendation that a schedule of 35 Gray to 36.25 Gray and five fractions delivered to the planning target volume could be offered and that it recommended against consecutive daily treatments for this schedule. So I think it's again important to note that compared to moderate hypofractionation, the ultra-hypofractionation literature is really substantially less mature and it is evolving rapidly. And therefore, a short-term update of this guideline to address new data pertaining specifically to ultra-hypofractionation is likely going to be necessary. And then I mentioned there was a third set of recommendations and these pertain to the technical aspects of planning and delivering radiation therapy. And these probably are not of core interest to your audience, but briefly, the guideline recommends that in the planning of hypofractionated radiotherapy, that normal tissue constraints and target volumes derive from published reference standards the use and that image guidance and intensity modulation at one form or another are recommended in delivering hypofractionated radiotherapy. Great. Thank you for the overview of those guideline recommendations. So why is this guideline so important and how will it change practice? Yeah. I guess the first point to make is that the guideline potentially can inform the care of a very large number of patients. Across North America, about 200,000 patients a year are diagnosed with prostate cancer and its far and away that the most prevalent non-dermatologic cancer in men and it's the third-leading cause of cancer death in men, at least in North America. So the vast majority of those 200,000 men are diagnosed with localized disease at the time of presentation and therefore they're potentially treatable with radiation therapy and therefore the guideline is relevant to these patients. Prior to the publication of the trials that motivated this guideline, the overwhelming majority of these men who chose external beam radiotherapy as their primary treatment have been treated with conventionally fractionated therapy. In other words, seven and a half to nine weeks of treatment. And already, since the publication of these trials-- the trials of moderate hypofractionation-- we're talking really about moderate hypofractionation because I think that is where the guideline will have its impact, at least in the short term. In the jurisdiction where I practice in Canada, practice has already substantially changed in light of these trials, and I think a large majority of patients with localized prostate cancer choosing external beam radiation therapy are now typically being treated with a moderately hypofractionated approach, typically a four-week schedule. So it will be interesting to see if a similar change is occurring or will occur over time in the United States, particularly informed or potentially informed in part by this guideline. And then finally, with respect to ultra-hypofractionation, I think again I have to note that this is a very dynamic space in terms of evidence and there are a number of large-scale trials looking at ultra-hypofractionation and comparing it to either conventional fractionation or moderate hypofractionation that are in progress or near to reporting. And so again, an update of the guideline in the short-term as data emerges from these studies will likely be important and it may ultimately influence practice as well on a large scale. And finally, how will these guideline recommendations affect patients? So I think in the short term, that the recommendation that has the potential to impact patients in the greatest way is the recommendation regarding moderate hypofractionation. And the guideline really recommends that this is a management approach that substantially reduces the treatment burden without compromising treatment efficacy and without increasing the risk of long-term side effects. So in my view, the move to moderately hypofractionated radiation therapy is a win for patients with localized prostate cancer who choose radiation therapy as their primary treatment modality. And so moderate hypofractionation really represents about a halving of the overall treatment time in some patients. And those who live, for example, in rural or remote areas and who need to travel considerable distance to have their treatment, a halving of treatment time is significant. But I think even more generally, halving of treatment time is significant for patients regardless of where they live. And clearly there are also benefits potentially in terms of cost and also benefits in terms of for the health care system but those really weren't specifically studied in the guideline. Great. Thank you so much for your time today, Dr. Morgan, and thank you for your work on this important guideline. My pleasure, Shannon, and thank you for having me. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

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

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a moment to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] Hello and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Valerie de Haas from Princess Máxima Center for Pediatric Oncology in the Netherlands, lead author on "Initial Diagnostic Workup of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the CAP and ASH Guideline.” Thank you for being here today, Dr. de Haas. Thank you. So first, can you give us a general overview of what this guideline covers? Well, yes. The laboratory evaluation of patients who are suspected of having acute leukemia is very complex, and it has evolved significantly with the incorporation of advanced laboratory techniques. The traditional backbone of initial workup of AL, of acute leukemia, is composed of ctyomorphology, cytochemistry, immunophenotyping, and molecular cytogenetics. These techniques are the backbone of the initial diagnostic workup of acute leukemia. This is leading to risk stratification and fine tuning of the therapy by molecular signatures. The advanced molecular diagnostics, such as next-generation sequencing, has become more important in the diagnosis and in the risk stratification of acute leukemia. This guideline is meant for both pediatric and adult patients, and it was initially published in 2017. This year, we reviewed this guideline, and we have taken into account two important developments. First, since 2017, we've seen that there are major advances in molecular techniques and also that we can identify and validate new molecular markers. And those two events have contribute to a better risk stratification. And the second development is the effect that the WHO classification was revised in 2017 which also has led to new risk recoveries and refined subclassifications. So what are the key recommendations of this guideline? Well, in total, we have reviewed 27 guideline statements by the ASCO endorsement expert panelists. And discussion points are used to summarize issues that were identified from the updated literature. The ASCO expert panel determined that the recommendations from the guideline as published in 2016 are clear, thorough, and they are based upon the most relevant scientific evidences. We fully endorse the CAP-ASH guideline on initial diagnostic workup of acute leukemia. And we decided to include some discussion points according to clinical practice and according to the updated literature. In fact, we identified four categories of key recommendations. The first one is the initial diagnostics focusing on basic diagnostics and determination of risk parameters. This concerns, in total, about 11 guideline recommendations, and they give an overview of the initial workup varying from the collection of the clinical history of the patient to initial basic diagnostics by cytomorphology, flow cytometry and molecular cytogenetic analysis of peripheral blood, bone marrow, and cerebrospinal fluids. Secondly, the second category were molecular markers and MRD detection, and they were addressed by 10 of the recommendations. And these recommendations give a structural overview of the molecular and cytogenetic workup for acute lymphoblastic leukemia versus acute myeloid leukemia identifying different prognostic markers. Also, the detection of MRD is taken into account in this recommendation. There is a major difference between children and adults, and this part is given most attention in the discussion part as the developments have been major during the past few years. The third one is the context of referral to another institution with expertise in the management of acute leukemia. This is addressed by four recommendations, emphasizing the point that referral to an institution with specific expertise is of major importance for the central workup of acute leukemia. And finally, the final reporting and report keeping is reflected in three recommendations, mainly supporting conclusions from 2017 which were describing the fact that the complete report with basic diagnostics in one central report should be available within 48 to 72 hours. And this should be followed by complete, final, comprehensive report in one or two weeks. So can you tell us about those discussion points that were made and why the panel decided to include these? The discussion points include mostly issues regarding diagnostics that involve flow cytometry and molecular techniques as addressed in part one and two of the guidelines. We think that the cytomorphologic assessment is essential for initial diagnosis of acute leukemia. Multicolor flow cytometry using 8 to 10 colors has led to a better distinction between myeloids, lymphoid, and mixed lineage blast origin. Even when the number of cells are limited, for instance in CNS involvement, fine needle aspirate of extramedullary leukemic infiltration, or skin biopsy for leukemic cutis. Also, it was suggested to better assess the central nervous system involved in leukemia. The expert panel recommends the immunophenotyping studies as an additional detection technique next to the cytomorphological examination of cytospins and particularly for those with a low level involvement of acute leukemia that cannot be well addressed by a morphologic examination only. The TDT immunohistochemistry staining of cytospins has alternatively been used for detection of CNS disease in AML and evaluation of CSF by multicolor flow cytometry has been recently adopted in some centers. Flow cytometry, using at least six, but we now use in some laboratories, even 8 to 10 colors has led to a much more specific in tentative diagnosis. And this has improved the detection of CNS involvement. The use of molecular tools, for instance, polymerase change reaction, PCR, NGS for low-level CSF involvement is still under study, and therefore, we did not recommend this in our discussion. Regarding the molecular markers and MRD detection, the discussion here was mainly based upon the results of translational research supported by better molecular detection techniques. And those molecular diagnoses have been developing in the past few years with the inclusion of many more molecular markers. And they included one of the key diagnostic criteria in the revised WHO classification, which was revised in 2017. And we made substantial changes that have been made in the ASH-CAP guidelines concerning molecular diagnostics. Those newly identified targets by advanced molecular techniques give possibilities for better risk stratification. Some examples of better molecular characterization of acute lymphoblastic leukemia are, for instance, additional testing for MLL translocations. Furthermore, we can look in patients with T-ALL for NOTCH1, and FBXW7 mutations. The Ikaros family zinc finger gene, the IKZF1 gene is frequently deleted in adults as well in children with B-ALL. And it was shown to have an independent prognostic significance and was also associated with poor clinical outcome. In the current text of the current risk that the protocols IKZF1 should be regularly included in the screening panels for all ALL patients. If we look for examples for better characterization of AML, acute myeloid leukemia, we have found an increasing number of additional cytogenetic aberrations, like for instance FLT3 ITD which is associated with poor outcome. Another example is appropriate mutational analysis for kids, which can be detected both in adult patient as pediatric patients with a confirmed core binding factor acute myeloid leukemia. So this is myeloid leukemia with a translocation A21, RUNX1, or inversion 16. This recommendation is very strong in adults, whereas in children, this prognostic fact impact remains unclear. So there have been proven several publications which refer to a similar prognosis for children and others who refer to a poor prognosis in comparison to known mutated genes. So we suggest to test for this mutation in adults, especially, but also in children to learn from it. Finally, emerging evidence supports molecular studies as principle test for monitoring minimal residual disease of acute leukemia. And there are several key molecular markers that are included in the initial workup, which will be carried on for monitoring MRD, for instance, PML- RAR-alpha, RUNX1-RUNXT1, CBFB-MYH11, and NPM1, CEBP-alpha and others. Beside those aforementioned markers, it's very important to screen for other molecular markers that have predictive or prognostic value in the individual. And it is possible to use them for MRD. We have found a recent consensus from the European Leukemia Net MRD Working Group, who was proposing that for detection of molecular MRD, and they refer the RT PCR platform to NGS and digital PCR platforms. Although all those molecular techniques have been developed very quickly and it is very tempting to use them for initial diagnostics, currently, not all laboratories will have all those techniques available. So the expert panel strongly advises understanding to make distinction between diagnostic that are needed in the first phase to start treatment and subsequently, treatment stratification, in contrast to the usual dose findings in a broader research. For instance, available karyotyping, FISH, PCR techniques, if possible, NGS can be used in the initial start of treatment, whereas techniques like whole exome sequencing, whole genome sequencing, RNA sequencing, and epigenomic studies are meant for a broader research. And finally, how will these guideline recommendations affect patients? Well, in the end, the patients will receive better and especially, more personalized treatment. If we have results available within two weeks from diagnosis, it will be possible to better identify which basis will better benefit from more intensified and more personalized treatment, whereas others may need less intensive treatment with less toxicity. If you use traditional techniques to do this supported by molecular techniques like karyotyping, FISH, and PCR techniques, and in the end, following MRD to see which patients are responding to treatment, MRD detection will help to identify these patients and stratify them finally to the best treatment. Great. Thank you for your work on this important guideline, and thank you for your time today, Dr. de Haas. OK. Thanks a lot. And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

In this week's episode, Dr. Danielle Shafer, Medical Director of the Clinical Trials Office at Massey Cancer Center at Virginia Commonwealth University, explores the recent FDA approval of ivosidenib for the treatment of relapsed or refractory acute myeloid leukemia. Dr. Shafer's primary clinical focus is leukemia & lymphoma in adult patients. Her research focus is limited to the same population, with a particular interest in relapsed/refractory AML. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT [MUSIC PLAYING] Welcome to the Recent Approvals episode of the ASCO University Weekly Podcast. My name is Danielle Shafer, and I'm an assistant professor at the Massey Cancer Center at Virginia Commonwealth University. My area of specialty is leukemia and lymphoma. Today, we will discuss the approval of ivosidenib in patients with relapsed and refractory AML with a susceptible IDH1 mutation. As a background to today's discussion, somatic mutations of IDH have been identified in multiple tumor types, including AML and MDS. As a result of the mutation, there is impaired hematopoietic differentiation, as well as epigenetic alteration. IDH mutations occur in approximately 20% of adults with AML, and 5% of adults with MDS. IDH1 mutations occur in approximately 6% to 9% of adult AML patients. Enasidenib was approved by the FDA in 2017 for adult patients with relapsed and refractory AML with an IDH2 mutation. On July 20, of 2018, ivosidenib was approved by the FDA for the treatment of adult patients with relapsed and refractory AML with a susceptible IDH1 mutation, as detected by an FDA approved test. The approval of ivosidenib in the relapse to refractory setting was based on the results of a phase I dose escalation and dose expansion study published in the New England Journal of Medicine. The primary objectives of the study were to assess the safety, maximum tolerated dose, and recommended phase II dose. Of the 258 patients receiving study drug, 179 patients had relapsed and refractory disease. The median age was 67, with a range of 18 to 87 years. Patients had a median of two prior therapies, 24% had relapsed after transplant, and 59% were refractory to induction or re-induction. 59% had favorable cytogenetics. The most common co-occurring mutation was NPM1 in 26% of patients. A maximum tolerated dose was not defined, and ivosidenib 500 milligrams was selected for dose expansion. The most common adverse reactions were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, Q/T prolongation, rash, pyrexia, cough, and constipation. In the overall population, 30 day all-cause mortality was 7%. The majority of deaths were related to disease progression or complications of underlying AML. No treatment-related adverse events leading to death were seen in patients with a starting dose of 500 milligrams. IDH differentiation syndrome is of special interest, as early identification is necessary. It is similar to what has been described with ATRA and arsenic trioxide. In this study, IDH differentiation syndrome was reported in 19 patients, and was of grade 3 or higher in nine patients. Leukocytosis grade 2 or 3 accompanied differentiation syndrome in 7 of the 19 patients. Median time to onset was 29 days, with a range of 5 to 59 days. Treatment included glucocorticoids, diuretics, and hydroxyurea, if leukocytosis was present. With intervention, 17 of the 19 patients had resolution. The two remaining patients had differentiation syndrome at data cutoff. In the relapsed refractory population, the rate of complete remission or complete remission with partial hematologic recovery was 30.4%. The median duration of complete remission, or complete remission with partial hematologic recovery, was 8.2 months. The median time to response was 2.7 months. With a median follow-up of 14.8 months, the median overall survival was 8.8 months. ivosidenib is the first IDH1 inhibitor to enter the clinic for relapsed refractory AML, and clearly represents a step forward for this population. The drug is, overall, well-tolerated. Differentiation syndrome represents a unique toxicity, as early recognition is critical. Practicing physicians may encounter difficulties differentiating disease progression from differentiation syndrome in some patients. Given the success of the drug in the relapsed refractory setting, it is now being combined with other therapies and moving earlier in the treatment course. Based on the encouraging results of a phase I study, ivosidenib is currently being combined with intensive chemotherapy in a phase III study, for newly-diagnosed AML patients with IDH1 mutations. Although the drug is termed a success, the majority of patients are still dying of their disease. While some patients were bridged to transplant in the New England study, the benefit is not yet entirely clear. Additional questions emerge regarding co-mutations and IDH1 mutation clearance. Not surprisingly, in this study, there was some preliminary data to suggest that patients with IDH1 clearance had longer durations of remission and survival. We anticipate better understanding as more patients are treated with the drug. Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the treatment of AML, visit the comprehensive e-learning center at university.asco.org. [MUSIC PLAYING]

Dr. Shaheenah Dawood is the Head of Medical Oncology and the Head of the Breast Cancer Program at Dubai Hospital in the United Arab Emirates. Dr. Dawood completed her M.B.B.Ch at Dubai Medical College in 1998 and a Master of Public Health degree at the Harvard School of Public Health, Boston, USA in 2008. Her postgraduate medical training programs include a Fellowship at McGill University in Canada in 2006, and the Susan Komen Breast Cancer Fellowship at the University of Texas M.D. Anderson Cancer Center in 2007. Dr. Dawood is a member of various professional organizations, including the American Society of Clinical Oncology (ASCO), the American Association of Cancer Research (AACR), the Canadian Association of Medical Oncologists, the Emirates Medical Association, and the Inflammatory Breast Cancer Research Group. She is also the co-director of the Middle East Research Network. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT [MUSIC PLAYING] Welcome to the self-evaluation episode of the ASCO University Weekly Podcast. My name is Shaheena Dawood, and I am a consulting medical oncologist and lead of the Oncology Research program at the Comprehensive Cancer Center at the Mediclinic City Hospital in Dubai, United Arab Emirates. Today, we feature a self-evaluation question looking at the predictive and prognostic role of pathological complete response attained in the treatment of breast cancer. Let us begin by reading the question stem. Here, we have a 55-year-old woman who presents with a 4 centimeter right breast mass and palpable right axillary lymph nodes. A needle biopsy of the breast mass and a lymph node are both positive for infiltrating ductal carcinoma negative for hormone receptors and negative for HER2/neu expression. The patient is interested in breast-conserving therapy, and she is referred to you for consideration of neoadjuvant chemotherapy. Which of the following do you tell her? Your choices are, A-- patients having a complete response to neoadjuvant chemotherapy have lower local and regional recurrence rates, B-- mastectomy will be required regardless of clinical response to chemotherapy, C-- chemotherapy will be administered before and after surgery, or D-- randomized trials have shown that radiotherapy is not necessary following surgery and chemotherapy if she has a complete response. At this point, please feel free to pause the recording before we discuss the correct answer. [MUSIC PLAYING] The correct answer to this question is A. Pathological complete response in the breast and lymph nodes is associated with lower local and regional recurrence rates. A combined analysis of the NSABP B18 and B27, two large trials that evaluated the role of neoadjuvant chemotherapy, revealed that the rate of local regional recurrence decreased amongst patients who initially presented with positive lymph nodes prior to neoadjuvant chemotherapy, and who become pathologically node negative after neoadjuvant chemotherapy, especially if they also achieved a pathological complete response in the breast. Briefly, the other choices presented in this question do not represent the most appropriate answer for the following reasons. The decision regarding type of surgery in the form of mastectomy versus breast-conserving surgery is dependent on multiple factors. One of the early established benefits of neoadjuvant therapy is that it increases the probability of breast-conserving surgery, making more women candidates for lumpectomy and breast radiotherapy, who otherwise would have been treated with mastectomy. Studies have shown that chemotherapy before surgery in the neoadjuvant setting versus chemotherapy after surgery in the adjuvant setting is associated with similar outcomes. And finally, attaining a pathological complete response currently does not preclude the need for adjuvant radiation therapy, the decision of which would be made on clinical stage of disease at presentation. The NSABP51 RTOG phase III trial is ongoing to evaluate the role of regional radiotherapy in women presenting with clinical N1 axillary node disease before neoadjuvant chemotherapy, and who become pathologically node negative at the time of surgery. Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the treatment of breast cancer, including opportunities for self-evaluation and board review, please visit the comprehensive e-learning center at university.asco.org. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

This week's host, Dr. Thomas Karasic, is an assistant professor at University of Pennsylvania specializing in the treatment of gastrointestinal malignancies. In this episode, Dr. Karasic discusses the recent FDA approval of lenvantinib for patients with unresectable hepatocellular carcinoma. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT [MUSIC PLAYING] Welcome to the Recent Approvals episode of the ASCO University Weekly Podcast. My name is Thomas Karasic, I'm an assistant professor at the University of Pennsylvania, specializing in the treatment of gastrointestinal malignancies. Today, we will discuss the approval of lenvatinib for the treatment of patients with un-resectable hepatocellular carcinoma. As background to our discussion today, the only FDA approved therapy prior to 2017 for hepatocellular carcinoma was sorafenib. This is based on results of the SHARP trial published in the New England Journal in 2008, which demonstrated an overall survival benefit of 10.7 months in the sorafenib arm, versus 7.9 months in the placebo arm. In the 10 years after the approval of sorafenib, a number of phase III trials attempted to establish additional drugs or combination regiments in both the first line and the second line setting for advanced hepatocellular carcinoma. But all trials failed to meet their primary endpoint, and no other treatments were approved. However, in 2017, two new drugs were approved for the second line treatment of hepatocellular carcinoma-- regorafenib, a drug similar to sorafenib, as well as the PD-1 inhibitor, nivolumab. Lenvatinib is an anti-angiogenic tyrosine kinase inhibitor that targets VEGF-1 3, FGFR 1 through 4, PDGFRA, KIT, and RET. On August 16, 2018, lenvatinib was FDA approved for the first line treatment of un-resectable hepatocellular carcinoma. Two different doses were approved-- 12 milligrams for patients with actual body weight greater than or equal to 60 kilograms, and 8 milligrams for patients with actual body weight less than 60 kilograms. The approval of lenvatinib in the first line setting was based on the results of a non-inferiority study comparing lenvatinib to sorafenib for unresectable hepatocellular carcinoma. The primary endpoint of the study was overall survival. A total of 1,492 patients were recruited, and 954 patients were randomized one-to-one between lenvatinib or sorafenib. Lenvatinib was given at a dose of 12 milligrams daily for patients of at least 60 kilograms actual body weight, or 8 milligrams for those below 60 kilograms-- while sorafenib was given at the FDA approved dose of 400 milligrams twice daily. This trial met its primary endpoint of non-inferiority for overall survival. Overall survival was 13.6 months in the lenvatinib arm, and 12.3 months in the sorafenib arm. While it met its endpoint for non-inferiority, it did not establish superiority in terms of overall survival. The hazard ratio for overall survival was 0.92. Lenvatinib did demonstrate a statistically significant increase in time to progression-- 8.9 months in the lenvatinib arm, versus 3.7 months in the sorafenib arm. It also showed a statistically significant improvement in overall response rate. Using the study endpoint of modified RECIST criteria, the objective response rate with lenvatinib was 41% versus 12% with sorafenib. Using more standard RECIST 1.1 criteria, the overall response rate of lenvatinib was 19%, versus 7% with sorafenib. Adverse events were common in both arms of the study, with 57% of those treated with lenvatinib experiencing grade 3 or greater toxicity, compared to 49% of those treated with sorafenib. Toxicities that were more common with lenvatinib included hypertension, proteinuria, hypothyroidism, weight loss, anorexia, nausea, and vomiting-- while sorafenib more commonly had hand/foot syndrome and alopecia. Toxicities, such as fatigue and diarrhea, were similar between the two arms. The approval of lenvatinib marks the first positive front line study comparing an agent to sorafenib in the first line treatment for HCC. Lenvatinib demonstrated improvements in overall response rate, as well as progression-free survival, and a modest trend towards improved overall survival, although this was not statistically significant. The toxicities of sorafenib and lenvatinib were largely comparable, although some toxicities-- such as hand/foot syndrome are more common with sorafenib-- whereas hypertension and proteinuria are more common with lenvatinib. These study results established lenvatinib as a reasonable firstline option for the treatment of HCC, and choice of sorafenib versus lenvatinib can be made based on toxicity profile, as well as the symptoms of the patient that may dictate the need for an agent with a higher response. Pending results from the CheckMate 459 study, as well as other ongoing immunotherapy front line studies, may well change the sequence of immunotherapy and anti-angiogenic therapy for HCC. But for now, lenvatinib is a reasonable front line option. Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on lenvatinib and the treatment of hepatocellular carcinoma, visit the comprehensive e-learning center at university.asco.org. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT Welcome to the Self-Evaluation episode of the ASCO University weekly podcast. My name is Dr. Karen Winkfield, and I am Associate Director for Cancer Health Equity and Director of Hematologic Radiation Oncology at the Comprehensive Cancer Center at Wake Forest Baptist Health in Winston-Salem North Carolina. Today, we feature a self-evaluation question on the treatment of multiple myeloma and other plasma cell dyscrasias, and we begin by reading the question stem. A 65-year-old woman was found to have free light-chains in her urine after she presented with proteinuria. A 24-hour urine collection contained 0.6 grams of monoclonal lambda light-chains, and the urinary sediment was normal. She had normal complete blood count, renal function, and serum lactate dehydrogenase and calcium levels. Serum protein electrophoresis was normal with no monoclonal component. Subsequent free light-chain, or FLC, studies revealed kappa at 68.5 milligram per liter and lambda at 16.7 milligram per liter with FLC ratio of 4.1 with a normal range of 0.26 to 1.65. The bone marrow aspirate revealed 6% of mature-looking plasma cells. Bone marrow biopsies failed to demonstrate any amyloid deposits. Both conventional and fluorescent in situ hybridization cytogenetic analyses were normal. Skeletal X-rays, as well as spinal access MRIs were normal. The diagnosis is light-chain monoclonal gammopathy of undetermined significance, or LC MGUS. Which of the following is an accurate description of this disease? A, around 30% of cases present with kidney disease. B, around 3/10 of 1% per year of cases progress to light-chain multiple myeloma. C, around 30% of all MGUS is comprised of this condition. D, around 3% of the general population older than 50 years has this condition. [MUSIC PLAYING] The correct answer to this question is B, around 3/10 of 1% per year of cases progress to light-chain multiple myeloma. This answer reflects the natural history of LC MGUS. Briefly, the other choices presented in this question are incorrect for the following reasons. Approximately 23% of LC MGUS cases have or will develop renal disease. Therefore, answer A slightly overstates the incidence at 30%. Similarly, LC MGUS comprises only 19% of total cases of MGUS. This is consistent with the proportion of light-chain multiple myeloma cases among newly-diagnosed multiple myeloma patients. An estimated 0.8% of the general population age 50 years and older has LC MGUS. Thank you for listening to this week's episode of the ASCO University weekly podcast. For more information on the treatment of multiple myeloma and other plasma cell dyscrasias, visit the comprehensive E-Learning Center at university.asco.org. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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

TRANSCRIPT [MUSIC PLAYING] Welcome to the ASCO Guidelines episode of the ASCO University weekly podcast. My name is Alexander Drilon, and I'm the clinical director of the early drug development service at Memorial Sloan-Kettering Cancer Center, and editorial board member for ASCO University. Today, we feature an ASCO guideline published in the Journal of Clinical Oncology. The episode you are about to hear was originally aired on the ASCO Guidelines podcast series. The ASCO Guidelines podcast series features interviews with panelists of recently published ASCO clinical practice guidelines products, highlighting recommendations and noteworthy qualifying statements made by the expert panel. [MUSIC PLAYING] Hello, and welcome to the ASCO Guidelines podcast series. My name is Shana McKernan, and today, I'm interviewing Dr. Antonio Wolff from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, an author on HER2 Testing in Breast Cancer, American Society of Clinical Oncology College of American Pathologists Clinical Practice Guideline Focus Update. Thank you for being here, Dr. Wolff. Thank you for the opportunity. It is really a privilege to be here today on behalf of all of my colleagues in the ASCO/CAP HER2 testing panel, which truly represents not just a multi-disciplinary, but a multi-society effort over many years. First, can you give us a general overview of what this guideline covers? The recommendations by the ASCO/CAP HER2 testing expert panel were first released in 2007 and updated in 2013. And this is now a 2018 focus update. The aim was to improve the analytic validity of HER2 testing and the utility of HER2 as a predictive biomarker for potential responsiveness to therapies targeting the HER2 protein. In fact, in late 2017 at the San Antonio Breast Cancer Symposium, we finally had data from the NRG trial B-47, which confirmed the lack of benefit from adjuvant trastuzumab for patients whose tumors lack gene amplification and were IHC 1+ or 2+. As a result, HER2 gene amplification assessed by In Situ Hybridization-- ISH, or I-S-H, or protein overexpression assessed by immunohistochemistry, IHC, remained the primary predictors of responsiveness to HER2-targeted therapy in breast cancer. We have seen over the years a great communication among health care providers, especially pathologists and oncologists, but also much-needed infrastructure support by administrative teams regarding specimen handling in lab facilities. And they have resulted in meaningful improvements in the analytic performance and accuracy of HER2 testing. We also have had greater clinical experience with the efficacy and safety of HER2-targeted therapies that resulted in a meaningful reduction in the high frequency of false-positive HER2 test results that were observed in the mid 2000s. And this led to the 2013 guideline update panel to provide further guidance regarding less-common clinical scenarios to allow greater discrimination between positive and negative results. Since 2013, since the 2013 update, several labs and clinical investigators have reported on the practical implications of the guideline update and the observed frequency of equivocal cases. And these results have allowed the panel recently to evaluate the observed frequency of less-common HER2 testing patterns, the apparent prognostic and predictive value when retrospectively analyzed within clinical trial data sets, and the critical need to understand the underlying distribution of HER2 immunohistochemistry test results in cases that were submitted for additional tests, specifically In Situ Hybridization by a reference lab. This all led to the ASCO/CAP HER2 testing panel to prepare and now issue this 2018 HER2 testing focus update that includes five key recommendations. What are the key recommendations of this guideline? The HER2 testing guideline panel identified five clinical questions that formed the core of the 2018 focus update. Clinical question one is, what is the most appropriate definition of IHC 2+ or IHC equivocal. And clinical question two asks whether HER2 testing must be repeated on a surgical specimen if initially negative tests on a core biopsy. And these two questions were addressed in a previous correspondence by the panel that was published in the JCO in 2015. And they referred specifically to Figure 1, the algorithm for immunohistochemistry testing, and Table 2, the histopathologic features suggestive of possible test discordance. Clinical questions three, four, and five address less-common patterns observed when performing dual-probe In Situ Hybridization testing, and are now graphically summarized in four different figures, Figures 3 to 6, that focus on the algorithm for dual-probe In Situ Hybridization testing. And these three questions help clarify the 2013 recommendations that led some labs to adopt the use of multiple alternative chromosome 17 probe testing as the sole strategy to resolve equivocal HER2 test results by In Situ Hybridization, despite limited evidence on analytical and clinical validity of such strategy. The three additional questions of the 2018 focus updates are clinical question three, should invasive cancers with HER2/CEP17 ratio of 2.0 or higher, but an average HER2 copy number of less than 4 signals per cell, be considered ISH-positive. Clinical question four, should the invasive cancers with an average HER2 copy number of 6.0 or greater signals per cell, but a HER2/CEP17 ratio of less than 2.0 be considered ISH-positive? And finally, clinical question five, what is the appropriate diagnostic workup for invasive cancers with an average HER2 copy number 4.0 or higher, but less than 6.0 signals per cell, and a HER2/CEP17 ratio less than 2.0, and initially found to have an equivocal HER2 ISH test result. The recommendations regarding dual-probe ISH testing also led to a change in figure 2 that describes the algorithm for single-probe ISH testing, and includes a new footnote with a recommendation that concomitant immunohistochemistry review should become part of the interpretation of single-probe In Situ Hybridization results. The 2018 HER2 testing focus update also includes a new Table 3 that describes the patterns of HER2 ISH testing using dual probe assays showing a clear impact of the underlying distribution of HER2 immunohistochemistry test results on the frequency of these less common patterns of In Situ Hybridization. As we expect, in total, groups 2, 3, and 4 will represent no more than 5% of all cases tested by In Situ Hybridization. And the majority, 95% of cases, tested for HER2 by dual-probe In Situ Hybridization will consist of group 1, which are clearly HER2-positive , and group 5, HER2-negative. And ultimately, the available clinical outcome data from related trials, although of limited statistical power, have allowed the panel to more carefully define this expected prognostic and predictive behavior of cases tested by dual-probe In Situ Hybridization that will fall in groups 2, 3, or 4. What are the major changes from the 2013 version of this guideline? Most important, after consideration of the available evidence and expert opinions, the ASCO/CAP HER2 testing panel revised the diagnostic approach to groups 2, 3, and 4 to include more rigorous interpretation criteria for dual-probe In Situ Hybridization testing, and to require concomitant immunohistochemistry review to arrive at the most accurate HER2 status designation, positive or negative, based on the combined interpretation of the ISH and the IHC assays. The panel therefore recommends that such concomitant review be performed in the same institution to ensure parallel interpretation and quality of the two assays. As a result, most group 2 specimens will not be confirmed as HER2-positive, as very few will be immunohistochemistry 3+, and most group 4 specimens will be confirmed HER2-negative without the need for additional testing, use alternative probes, which happen a lot since 2013. At the same time, group 3 specimens will be a mixed group of results with a small number of cases shown to be amplified, and a larger number shown not to be amplified. And so for these dual-probe ISH group 3 cases, the panel allows specimens that are IHC 2+ to be considered HER2-positive. And the rationale is described in greater detail in the manuscript. And finally, how will these guideline recommendations affect patients? While the main focus was to clarify the less common test results observed with the two-probe ISH assays, the recommendations do impact users of single-probe ISH assays. As such, the panel now recommends that concomitant immunohistochemistry review should become part of the interpretation of single-probe In Situ Hybridization results to allow a more accurate HER2 designation. And this is nicely described in Figure 2. And the panel also preferentially recommends the use of dual-probe instead of single-probe ISH assays, while it recognizes that several single-probe ISH assays have regulatory approval in many parts of the world. At the end, and to conclude, these actions, we hope, will reduce the already small number of cases that have HER2 test results that are unresolved, will reduce the frequency of alternative group testing, and will remind us all of the importance of integrating the information provided by both types of assay platforms, IHC and ISH, in difficult cases, as we expect these results to be concordant in the vast majority of cases, when expertly performed. Thank you for your insights on this guideline, and thank you for your time today, Dr. Wolff. Thank you so much. And thank you to all of our listeners for tuning in to the ASCO guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT Welcome to the Self-Evaluation episode of the ASCO University weekly podcast. My name is Apar Kishor Ganti, and I'm the Associate Director for Clinical Research and the co-leader of the Thoracic Oncology Service at the University of Nebraska Medical Center, Fred and Pamela Buffett Cancer Center. Today, we feature a self-evaluation question on locally advanced non-small cell lung cancer. I will begin by reading the question stem. A 58-year-old man with a 50-pack year history of smoking presents to your clinic with worsening cough and shortness of breath. His comorbidities include irritable bowel syndrome and coronary artery disease. A CT scan of the chest, abdomen, and pelvis reveal a two-centimeter right lower lobe mass with no evidence of lymphadenopathy in the chest. A positron emission tomography scan confirms a hypermetabolic right lower lobe mass and mildly avid mediastinal nodes. An MRI of the brain was performed and was negative. A biopsy of the right lower lobe mass was positive for squamous cell carcinoma of the lung. The patient was taken for a mediastinal lymph node evaluation by a thoracic surgeon. Additional biopsies of multiple lymph nodes were taken. Pulmonary function tests revealed that a right lower lobectomy would be feasible if warranted. Which of the following would lead you to recommend definitive chemoradiation rather than surgery as the most appropriate treatment for this patient? The answer choices are, A, metastatic squamous cell carcinoma identified in a left hilar lymph node, B, metastatic squamous cell carcinoma identified in a right hilar lymph node, C, the absence of squamous cell carcinoma in a left paratracheal lymph node, and D, the absence of squamous cell carcinoma in a right hilar lymph node? [MUSIC PLAYING] The correct answer to this question is A, metastatic squamous cell carcinoma identified in a left hilar lymph node. In the eighth edition of the AJCC TNM classification system, this tumor would be classified as T1B. The presence of cancer in a contralateral hilar lymph node represents N3 disease and thus, stage 3B. Surgery is not recommended in this setting, and definitive chemoradiation is considered standard of care. What about the other choices? Involvement of an ipsilateral hilar node would only represent N1 and stage 2B disease, for which a right lower lobectomy and mediastinal lymph node dissection are appropriate. The absence of involvement of the left paratracheal node would confirm the absence of N3 disease, while the absence of involvement of the right hilar node would confirm the absence of N1 disease. In both these scenarios, the patient would be considered resectable if other lymph node stations are not involved. Thank you for listening to this week's episode of the ASCO University weekly podcast. For more information on lung cancers, including important release for self-evaluation, visit the comprehensive E-Learning Center at university.asco.org. Thank you. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT [MUSIC PLAYING] Welcome to the ASCO Guidelines episode of the ASCO University weekly podcast. My name is Alexander Drilon, and I'm the clinical director of the early drug development service at Memorial Sloan Kettering Cancer Center and editorial board member for ASCO University. Today we feature an ASCO guideline published in the Journal of Clinical Oncology. The episode you are about to hear was originally aired on the ASCO Guidelines podcast series. The ASCO Guidelines podcast series features interviews with panelists of recently published ASCO clinical practice guidelines products, highlighting recommendations and noteworthy qualifying statements made by the expert panel. [MUSIC PLAYING] Hello, and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin, and today I'm interviewing Dr. Davendra Sohal from Cleveland Clinic, lead author on Metastatic Pancreatic Cancer American Society of Clinical Oncology Clinical Practice Guideline update. Thank you for being here today, Dr. Sohal. Thanks for having me. It's a pleasure. So this update is focused on revising the recommendations on second line treatment for metastatic pancreatic cancer. Can you tell us about the studies that informed this update? Certainly. The first study is a paper published in Science on PD-1 inhibition and solid tumors. This study included 86 patients with mismatch repair deficient tumors, also known as microsatellite instability high tumors. In this study, 53% of the patients had an objective response with a disease control rate of 71% across multiple histologies. The study also included eight patients with pancreatic cancer, two of whom had complete responses with a disease control rate of 75%. This is the study that informed our recommendation for checkpoint inhibitor therapy in the second line setting. The second study is the PANCREOX trial published in JCO, which randomized patients to 5-fluorouracil or FOLFOX. With 108 patients, the primary outcome of overall survival was 9.9 months in the control 5-fluorouracil arm, and surprisingly, only 6.1 months in the FOLFOX arm. This study informed our recommendation for chemotherapy regimens in the second line setting. And what are the new and updated recommendations for second line treatment? For second line treatment of metastatic pancreatic cancer, our first recommendation now is to consider testing for mismatch repair deficiency or microsatellite instability in patients who are candidates for checkpoint inhibitors therapy. Any standard form of testing is acceptable, whether IHC or PCR or next-gen sequencing. Patients who have mismatch repair deficient or microsatellite instability high tumors should be treated with pembrolizumab given the excellent responses noted in the study we just discussed. For patients who do not meet these criteria for checkpoint inhibitor therapy, second line therapy with gemcitabine plus nab-paclitaxel can be offered to those who received FOLFIRINOX in the first line and meet other criteria for aggressive chemotherapy as detailed in the guideline. Now, for patients who receive gemcitabine plus nab-paclitaxel in the first line, fluorouracil plus nanoliposomal irinotecan is the preferred second line therapy. Where nanoliposomal irinotecan is not accessible, fluorouracil plus regular irinotecan is an acceptable alternative. As I mentioned the combination, of 5-fluorouracil plus oxaliplatin can be considered as an option in this setting, but we have noted a qualifying statement about the PANCREOX study whose results are inconsistent with the CONCORD-3 study using the same agents as the off regimen. Given these conflicting results from different studies of 5-fluorouracil plus oxaliplatin, the recommendation for its use in the second line setting has been softened. Can you also give us an overview of the recommendations from the original 2016 version that the expert panel decided were still valid? Sure. In 2016, the expert panel made recommendations which span from initial assessment through to follow up and surveillance. For every patient with metastatic pancreatic cancer, a multi-phase CT scan should be performed and baseline performance datas and comorbidities should be evaluated. Goals of care should be discussed with a multidisciplinary team, and all patients should be offered information about clinical trials. Outside of a clinical trial, standard first line treatment options include FOLFIRINOX, gemcitabine plus nab-paclitaxel, or gemcitabine alone. And the full guideline provides details on which treatment is appropriate for which patients. The panel also recommended that every patient should be offered palliative care early in their treatment. These recommendations were endorsed in the update and are reprinted in totality in the bottom line box on the second page of the article. And finally, what are some important things to note about communicating with patients with pancreatic cancer, especially in the metastatic setting? Excellent point. It is important to communicate that participation in clinical studies is strongly encouraged. These studies could include new treatments, or supportive care measures, or collection of blood and tumor samples for further research, et cetera. While chemotherapy forms the backbone of treatment, it is only one component, and that is an important point to make. The use of supportive care or palliative care is strongly encouraged for all patients with metastatic pancreatic cancer in order to maximize not just the quantity, but also the quality of life. Great. Thank you for your work on this important guideline, and thank you for your time today, Dr. Sohal. Sure. Thank you very much. I'd like to thank our panel for diligent data review and dedicated discussions and the ASCO staff for all their support in producing the update. Thank you. And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING] Welcome to the ASCO Guidelines episode of the ASCO University Weekly Podcast. My name is Alexander Drilon, and I'm the Clinical Director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and editorial board member for ASCO University. Today, we feature an ASCO guideline published in the Journal of Clinical Oncology. The episode you are about to hear was originally aired on the ASCO Guidelines Podcast Series. The ASCO Guidelines Podcast Series features interviews with panelists of recently-published ASCO clinical practice guidelines products, highlighting recommendations and noteworthy qualifying statements made by the expert panel. [MUSIC PLAYING] Hello, and welcome to the ASCO Guidelines Podcast Series. My name is Shannon McKernin and today, I'm interviewing Dr. Supriya Mohile from University of Rochester Medical Center, lead author on "Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy-- American Society of Clinical Oncology Guideline for Geriatric Oncology." Thank you for being here today, Dr. Mohile. Thank you very much. First, what is the purpose of this guideline, and can you tell us about the research that was reviewed to inform the recommendations? Sure. So we know that our population is aging. So currently, there are an incredible number of patients who are age 65 and over with cancer. The statistics are showing that more and more older adults are developing cancer. And this was really informed by our movement in geriatric oncology that ASCO has supported over the last 10 to 15 years. When I started my fellowship, which was now close to 15 years ago, there was very little knowledge about how to treat older patients with cancer. We know that clinical trials include fewer older adults and that the older adults that are enrolled tend to be more fit than those older adults seen in community practices and being cared for by, really, community oncologists. Therefore, there is a large gap in knowledge in terms of what might be safe and effective in a phase III clinical trial that provides our evidence for cancer treatment and what might be safe and effective for an older patient-- say 75-plus-- who's being seen in community who has medical conditions such as cognitive impairment or significant comorbidities that may limit their life expectancy. So the guideline really strives to address how older patients should be evaluated and managed in oncology clinics specifically. And this guideline is geared towards older patients with cancer who are undergoing a decision or who are receiving chemotherapy because that's really where the data and the evidence for geriatric oncology practices supports at this point. There's less data for evaluating patients who are going to undergo targeted agents or immunotherapy. But we have, now, a robust level of evidence for older patients who are undergoing chemotherapy. And so this guideline could help clinicians with how to best manage and evaluate and make decisions for older patients with cancer who they're seeing in their clinic. And it can also help support other guidelines that ASCO and others put forth. For example, I sat on the ASCO Guidelines Committee, and we were looking at a guideline for bladder cancer. And some of the guidelines were related to life expectancy. So a intervention is appropriate, for example, for patients who have a 10- or more-year life expectancy. However, there's very limited information for how physicians should estimate life expectancy in our guidelines. And so this guideline includes that kind of information that could help really support other guidelines when we're talking about things like life expectancy, underlying health status, comorbidities, that might influence outcomes for older patients with cancer. In terms of what research was reviewed to inform the recommendations, well, we in the geriatric oncology field-- and many of the co-authors are geriatric oncologies-- worked with others in specific fields, such as cognition, physical health, and community oncologists and primary care doctors, to develop a very comprehensive yet practical way for oncologists to really assess older patients. As I mentioned, our field is small, and it started about 10 to 15 years ago, really focusing on this toolkit called geriatric assessment. Geriatric assessment is a compilation of, really, patient-reported outcomes that can assess health status for older patients. And we sort those pieces in the geriatric assessment into domains. And each domain is known to predict morbidity and mortality in older adults. So those domains include things like cognition, function, psychological status, comorbidities, polypharmacy, social support. And we know from the evidence in community-dwelling older adults without cancer that each of those domains are predictive of outcome. So it made sense to us, having been trained in both geriatrics and oncology, to think about this tool as a way to evaluate underlying health status in older patients with cancer. And the field started by looking at feasibility of geriatric assessment in oncology clinics. These efforts were led by Arti Hurria and the Cancer and Aging Research Group and others. And over time, there has been a lot of data showing that geriatric assessment is feasible in oncology clinics. They can be incorporated in both academic settings and community oncology clinics. In addition, there's been data to support that geriatric assessment is feasible in clinical trials. And so, as we started to grow that data in the field, then there have been large studies looking at prediction of outcomes and looking to see if geriatric assessment and the domains within geriatric assessment can help clinicians identify older patients who are at most risk from adverse outcomes from chemotherapy. And that data has grown significantly. So when that data grew, we paused as a community and really partnered with ASCO, who's been incredibly supportive, to think about a guideline to really summarize the literature-- and not only summarize the literature but to communicate it to clinicians as the audience to really communicate a way that geriatric assessment can be practically incorporated and integrated into routine clinical care for older adults with cancer. And so those are the studies we looked to. We worked with ASCO. ASCO, as you know, has a very rigorous methodology for looking at research. And in our field, the research is less RCT-based-- although randomized controlled trials are forthcoming-- but more based on large, robust, very well-done prospective observational studies. And we reviewed the literature for that in a systematic way and summarized that in the guidelines. And what are those key recommendations for this guideline? So the guideline breaks down into four important components. So the first component really focuses on the value added by geriatric assessment to routine oncology clinical care. And so that recommendation was based on data that shows geriatric assessment identifies factors that can be routinely missed in routine oncology care and are not captured by our routine oncology assessments like ECOG Performance Status or Karnofsky Performance Status assessments. So there is a very robust data that shows those domains that I spoke about earlier-- functional status, physical performance and falls, comorbid medical conditions, depression, social activity and support, nutritional status and cognition-- add value by identifying vulnerabilities or impairments that are not routinely captured in oncology assessments. And that's a very high level, or strong level, of evidence. The second component of the guideline really focuses on how to practically incorporate, or integrate, geriatric assessment into routine oncology care. And so we took a step back and looked at the literature, at what was feasible-- not for academic, robust groups that have a ton of support but really for community oncologists who are seeing many patients in their clinic, really getting their feedback on what might be practical and the quickest way, and the most high-priority tools to assess these domains. And so the tools that were identified were pulled out of the literature in that each of these tools captures an important domain that's predictive of outcomes. So we know that these tools can help identify older patients at high risk for adverse outcome. And they are practically able to be incorporated in the clinic and do not need to be done by a physician. They can be done by a technician, a staff member, a nurse. And so we thought about that in terms of selection of the tools. And so the second recommendation is that the evidence supports, at a minimum, assessment of function, comorbidity, falls, depression, cognition, and nutrition. And we recommended, as a panel, the Instrumental Activities of Daily Living-- which is a short, very well-validated patient-reported outcome with a few questions to assess function; a thorough history or validated tool to assess comorbidity-- so this can happen as part of a routine history and physical exam that physicians are often already doing as part of their assessment; a single question for falls-- so have you fallen in the last six months, or have you fallen since the last visit?; the Geriatric Depression Scale as a screen for depression; the Mini-Cog or Blessed Orientation-Memory-Concentration test-- they're both very short, less than two minute type assessments of cognition-- they're administered to the patient by a staff member to screen cognitive issues; and an assessment of unintentional weight loss to evaluate nutrition. And in addition to those tools, if these are being used to evaluate an older patient who's starting chemotherapy, using a validated tool that assesses the risk of chemotherapy toxicity can be informative in helping with the discussion about risk in the informed consent process. And there are two tools that do that-- the Cancer and Aging Research Group tool, and the CRASH tool out of Moffitt, which is called the Chemotherapy Risk Assessment Scale for High-Age Patients-- CRASH tool. Both of those help predict or estimate risk of chemotherapy toxicity. There are, in addition, two additional tools that are short screening tools that can help identify patients at risk for early mortality. Those are called G8 or the Vulnerable Elders Survey-13. So this can form a sort of minimal data set to a basic geriatric assessment. There are options for each of those domains in terms of the tools to be used. So these are our recommendations, but they're not set in stone. In fact, which recommendation to use doesn't have a super high level of evidence. It's a moderate level. Because we don't know, necessarily, which one tool is better than another. We do know that these domains should be captured-- so function, cognition, depression, et cetera-- but which tool to use can be more flexible. So in the guideline, there is the main tool, sort of the recommended tool, but also options for other tools so that practices and physicians can pick what works best for them. In terms of the third recommendation, the third recommendation is focused on estimation of life expectancy. As I mentioned earlier, estimating life expectancy is often part of our guidelines when we're thinking about high-risk interventions. We want to be able to identify as best as we can, with the tools that we have available, patients who are likely to live long enough to benefit from high-risk interventions like chemotherapy, like adjuvant treatment, like high-risk surgeries-- for example, cystectomy for bladder cancer. You know, those kinds of approaches deserve a thoughtful approach to life expectancy estimation. A lot of what we do in clinical practice is Gestalt, so it's sort of the eyeball test-- well, I think my patient might live five years. I think my patient might live 10 years. And we know from the literature that the eyeball test is very subjective, and every individual physician has their different perspective on how long someone might live. And we are, as a medical community, not very good at estimating prognosis. They're all tools that could help this approach and they're all available on the web. And we recommended the Schonberg Lee Index, which is part of ePrognosis, where, as part of the assessment process, there are easy-to-capture variables that can be included. And it creates a very standardized, validated approach to life expectancy estimation that can be shared with a patient. Of note, as part of that recommendation, they do ask about cancer because cancer influences life expectancy. And our recommendation is to say no to that question. Because we're looking at life expectancy from the perspective of outside of cancer-- so in other words, other medical problems that might influence life expectancy, not the cancer, in order to inform decisions for treatment of cancer. The last recommendation really focuses on management. And here's where there are randomized controlled trials in progress. There are consensus studies that are from experts in geriatric oncology that have developed algorithms to incorporate management options for each domain impairment. So for example, one finds that a patient may be falling. That's a domain impairment we assess with the question-- that's the tool-- so have you been falling? and perhaps another type of test-- an objective physical performance test, for an example. And then, we institute, or implement, geriatric-relevant management interventions such as physical therapy, an evaluation for assistive device, a safety evaluation at home, making sure that the patient is not alone at home, looking at medications to make sure their blood pressure medicines aren't too strong and they're going to become orthostatic. So there are these algorithmic approaches to each domain. And these are outlined in several papers that have looked at these Delphi consensus approaches to these algorithms. And these algorithms are now being tested in randomized controlled trials both in the United States and in Europe. And so that's the summary for the recommendations for this guideline. So you mentioned some of those assessment tools, like the CARG tool and the CRASH tool. So how do you implement those in practice? So in the guideline, we have several examples of how a practitioner can use this toolkit to really help with clinical decision-making in a very practical way. So embedded in the guideline is an older patient being considered for adjuvant chemotherapy and the approach-- all the way from the patient is sitting in the clinical setting outside and is filling out the surveys to the plan where they come into the clinic office, someone administers the cognition tool, the nurse or the physician captures the correct information, they go online, and they plug in the information, and they print out the tools. So all of the tools will be made available on relevant ASCO websites-- so the main ASCO website, the educational ASCO websites-- and also the tools themselves, plus the guideline recommendations, and also cases. So we have one case embedded in the actual guideline, but we also, in the supplement, have several additional cases that can be reviewed to really show how to incorporate this in clinical practice. So as part of ASCO, the panel members plus the ASCO geriatric oncology task force that works out of the Health Disparities Committee are going to do our best to make the translation of these guidelines into implementation as easy as possible and have everything available. The three tools that I mentioned-- the CARG toxicity tool, the CRASH tool, and the ePrognosis tool-- are all already available online. And so those links are available in the guideline and can be used right away. The other tools will be available on the ASCO website. We will put that on so that people can download them and use them in the clinic setting. Great. And what interventions can be informed by the results of geriatric assessment? I know you mentioned physical therapy. What else can you tell us about that? So as part of those Delphi consensus process there, we developed sort of an algorithmic approach to the different interventions for each of the domains. So there is a table in the guideline that summarizes the high-priority interventions that the experts use in their clinic when they identify patients with impairments. So as I mentioned, there are things like physical therapy for people with physical performance problems or people who have functional issues, strength and balance training, assistive device evaluation, exercise programs, fall prevention. For comorbidities, thinking about communication aspects of talking to patients and caregivers about how to use multiple medications, talking to other important members of the team like the primary care doctor or pharmacist to help decrease risk from medications. For cognition, for people who have impaired cognitive status, we have very limited data about the safety of chemotherapy in this population. It's under-recognized. Even me, who have many years of working with older patients, cannot tell just by looking or talking to an older adult that they have cognitive impairment. And so screening tools are absolutely necessary. If someone has impairment on a validated cognitive screen like the Mini-Cog or Blessed that I mentioned earlier, thinking about a formal assessment of decision-making capacity and ability to consent for treatment is important. And as we start implementing practices in the clinics to really capture consent processes, even for routine chemotherapy-- off-clinical trials-- this is an important aspect to consider. Delirium risk counseling, medication review, again, are all important things to consider for somebody who has cognitive impairment. For depression, with screening for depression, there is already an ASCO guideline in place for management of patients in general who have depression. And we incorporated some of those management recommendations-- so considering cognitive behavioral therapy, if that's available, social work involvement, counseling. We do consider medications but try the other mechanisms first before medication use in an older adult because medications may have more side effects. And for nutrition, thinking about nutritional interventions, a need for extra support and availability of caregiver to provide extra support for meal preparation. So there is a table, and there's also references to other papers that have Delphi guidelines in place of how to utilize management recommendations. There is also a table that summarizes the ongoing clinical trials. And as we learn more about incorporating this as an evaluation of management plan in terms of improving outcomes for older adults with cancer, we'll be able to expand the guideline to incorporate that information, in addition. So finally, what difference does it make to patients, performing these assessments? How are they impacted by these recommendations? So we truly believe that the evidence shows that assessing older patients with a standardized validated geriatric assessment measure can improve the identification process and discussion surrounding chemotherapy risk. And that is important for this population. Because this population is less included in clinical trials and, therefore, the safety and efficacy of treatments are often uncertain for older adults who are 75-plus because just that population itself is underrepresented in clinical trials-- but also those who are older who have other medical issues. And so that discussion itself, as part of communication for informed consent, is very important. And that's outlined in the communications section of the guideline. In addition, the guideline stresses that factors that identify patients as vulnerable are captured by geriatric assessment. We have standardized tools to assess risk through toxicity tools and mortality. We have standardized tools to help assess life expectancy when one is considering an older adult for adjuvant treatment, which may be six months, a year long. If the older adult you're seeing has a life expectancy of one year based on their comorbid conditions, does it make sense to put them through a one-year program of adjuvant treatment or a big surgery? In addition, it also helps identify those older patients who are fit-- so not just identifying patients who may be at risk, but the other side of the coin is you're 80, but you're healthy. You're fit. You don't have a high risk of toxicity or higher risk than maybe those patients that were included in the clinical trial because your health status is good. And you should get treatment, right? So that conversation is also very important. And again, as I mentioned, there is an example in the guideline where we take an older adult who has some medical issues, and we take them through the process by which these tools can be used to help with the decision-making process. And also, we compare that to a patient that's 10 years older that doesn't have those same health conditions and show the comparison and the contrast between the recommendations. So the older adult, in our example, who is actually, chronologically, 10 years older is actually probably less likely to have harm from treatment than the person that was in their 70s who has other medical problems. And that just goes to show how important underlying health status is when we're making our clinical decisions for treatment. We still need to know more about direct decision-making. We know that geriatric assessment influences oncology decision-making. That data has been shown. In other words, when our oncologists get this information from geriatricians at a tumor board, or it's provided to them through a summary, they utilize that, and they change what they're going to do on average 30% to 50% of the time. Because they value that information, and that information adds value to what their plan is. But what we're still waiting for with these randomized trials is, does geriatric assessment and management approach decrease harm overall, improve survival, decrease toxicity, et cetera? There has been some data in geriatric assessment incorporated into therapeutic trials that shows that when a geriatric assessment plan is used that that might lower toxicity. But we still need more data in that area. And that was recommendation four. And so that recommendation will be more robust as the data matures from these randomized controlled trials. But just to summarize, the panel feels, and ASCO feels, based on this guideline, that there is enough data to support using the tools that we recommend to help assess and manage older adults receiving chemotherapy. Great. Thank you so much for your work on this important and very comprehensive guideline. And thank you for your time today, Dr. Mohile. Thank you very much for inviting me. And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Welcome to the self-evaluation episode of the ASCO University weekly podcast. My name is Shadia Jalal, and I am a thoracic oncologist at Indiana University. Today, we feature a self-evaluation question on the treatment of limited-stage small-cell lung cancer. And we begin by the question. A 58-year-old man with a 40-pack-year history of cigarette smoking is found to have a spiculated 2.1-centimeter left upper lobe mass on CAT scan imaging that was performed for a suspected pneumonia. His physicians decided to immediately take him to the operating room for a wedge resection of that mass. A preliminary analysis of the pathology from the wedge resection during the operation revealed small-cell lung cancer. A completion left upper lobectomy and mediastinal lymph node dissection was performed. The final pathology confirmed a T1a small-cell lung cancer with negative margins and no lymph-node involvement. Subsequent work-up included an MRI of the brain with and without gadolinium contrast and a Positron Emission Tomography, or PET scan, both of which showed no evidence of distant metastatic disease. Molecular profiling of the tumor revealed concurrent P53 and retinoblastoma mutations, as is usually seen in small-cell lung cancer. The question is, which of the following is the most appropriate next step? A, the administration of four cycles of cisplatin and etoposide in an adjuvant fashion; B, definitive radiation to the chest with concurrent cisplatin and paclitaxel; C, four cycles of carboplatin and pemetrexed; D, definitive radiation to the chest with concurrent cyclophosphamide; E, four cycles of cyclophosphamide, doxorubicin, and vincristine. The correct answer is A, four cycles of cisplatin and etoposide in an adjuvant fashion. The role of surgery in patients with limited-stage small-cell lung cancer is really limited to a very small number of those patients that might present with a peripheral small tumor. As is known, small-cell lung cancer is usually more of a central tumor with lymph node involvement. In a patient like this with limited-stage small-cell lung cancer and node-negative disease, adjuvant chemotherapy with a platinum doublet-- cisplatin or carboplatin and etoposide-- is recommended after definitive surgery, including mediastinal lymph-node dissection. Small-cell lung cancer is a cancer known for early hematogenous spread, and therefore adjuvant chemotherapy is indicated. CAV, or cyclophosphamide, doxorubicin, and vincristine, or carboplatin with pemetrexed are not appropriate treatment options in limited-stage small-cell lung cancer. In fact, pemetrexed does not have activity in small-cell lung cancer. Concurrent chemotherapy and radiation could be recommended and considered in the presence of node-positive disease, which was not the case in this situation. And if concurrent chemotherapy and radiation is to be given, cisplatin with etoposide would be the appropriate regimen administered at the time of radiation. Thank you for listening to this weekly podcast recording, "Small-Cell Lung Cancer."

Victoria Lai is a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center with a clinical and research focus on small cell lung cancer and other pulmonary neuroendocrine tumors.  She conducts clinical trials that aim to elucidate the underlying biology of small cell lung cancer in order to develop new biomarkers and treatments options to improve patient outcomes.   TRANSCRIPT [MUSIC PLAYING] Welcome to the recent approvals episode of the ASCO University weekly podcast. My name is Victoria Lai. I am an assistant attending physician in a thoracic oncology service at Memorial Sloan Kettering Cancer Center. Today, we will discuss the approval of nivolumab for the treatment of patients with metastatic small cell lung cancer in the third-line setting. As a background to today's discussion, we know that FDA approved therapies for small cell lung cancer are extremely limited and remain a large, unmet need. Immune checkpoint inhibitors, including nivolumab, are active therapies in several different tumor types. Nivolumab is a monoclonal antibody against PD-1 and has previously been shown to be effective in non-small cell lung cancer. More recently, the role of immune checkpoint inhibitors in the treatment of small cell lung cancer has been explored in an effort to develop more effective treatment options for these patients. On August 16 2018, nivolumab was granted an accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression after prior platinum-based chemotherapy and at least one other line of treatment regardless of PD-L1 expression of the tumor. This approval of nivolumab in the third-line setting in small cell lung cancer was based on results from the CheckMate 032 study that was initially published in The Lancet in 2016 and has since reported updated results. CheckMate 032 was a multi-center open-label trial in patients with metastatic solid tumors. The study included a subgroup of 109 patients with metastatic small cell lung cancer who experienced disease progression after platinum-based therapy and at least one other line of therapy regardless of tumor PD-L1 status. All patients received nivolumab 3 milligrams per kilogram by intravenous infusion over 60 minutes every two weeks. The primary endpoint of this study was the objective response rate. The overall response rate was 12% with a 95% confidence interval between 6.5 to 19.5% with responses seen in 13 out of 109 patients. Responses were durable for six months or longer in 77% of patients, 12 months or longer in 62% of patients, and 18 months or longer in 39% of patients. PD-L1 tumor status did not appear to be predictive of response. Of all the patients who received at least one dose of nivolumab, the most common side effects were fatigue, decreased appetite, musculoskeletal pain, dyspnea, nausea, diarrhea, constipation, and cough. Serious adverse reactions occurred in 45% of patients and included pneumonia, dyspnea, pneumonitis, pleural effusion, and dehydration. The recommended dosing schedule of nivolumab for this approved indication is 240 milligrams every two weeks over 30 minutes. The approval of nivolumab as subsequent line therapy marks a significant advancement in the treatment of patients with metastatic small cell lung cancer. Prior to this, topotecan was the only other agent approved by the FDA for treatment in this setting, which did not yield durable responses. Although the response to nivolumab was modest, the majority of patients responded to treatment were able to achieve durable responses of greater than 12 months with over 1/3 of patients achieving a durable response of greater than 18 months. Further more, responses to nivolumab were seen regardless of the patient's prior response to chemotherapy. Given that topotecan yields a response rate in the single digits as subsequent line therapy for chemo-resistant disease, nivolumab adds an especially valuable treatment option for these patients whose disease did not previously respond to chemotherapy. Nivolumab adds an especially valuable treatment option for these patients whose disease did not previously respond to chemotherapy. Responses to nivolumab were also seen in patients who had exceeded three prior lines of therapy indicating that nivolumab can still be effective in heavily pre-treated patients. With 45% of patients in this study having developed a serious adverse reaction, patients undergoing treatment with nivolumab should be monitored closely. Finally, this study did not show any correlation or responses to nivolumab with PD-L1 expression, suggesting that the role of PD-L1 as a predictive biomarker in small cell lung cancer remains unclear. Thank you for listening to this week's episode of the ASCO University weekly podcast. For more information on immunotherapy and the treatment of small cell lung cancer, please visit the comprehensive eLearning center at university.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Shadia Jalal, MD, Assistant Professor of Clinical Medicine in the Department of Medicine, Division of Hematology/Oncology at Indiana University School of Medicine discusses updated guideline for palliative care in the global setting. TRANSCRIPT Welcome to the ASCO Guidelines episode of the ASCO University weekly podcast. My name is Alexander Drilon, and I am the clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and editorial board member for ASCO University. Today, we feature an ASCO Guideline published in the Journal of Clinical Oncology. The episode you are about to hear was originally aired on the ASCO Guidelines podcast series. The ASCO Guidelines podcast series features interviews with panelists of recently-published ASCO clinical practice guidelines products, highlighting recommendations and noteworthy qualifying statements made by the expert panel. [MUSIC PLAYING] Hello, and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernan, and today, I'm interviewing Dr. Nahla Gaffer, from the Radiation S Isotope Center in Sudan, an author on palliative care in the global setting, American Society of Clinical Oncology resource-stratified practice guideline. Thank you for being here today Dr. Gaffer. Good morning. Thank you, so much, Mrs. Shannon for this opportunity. First, can you give us a general overview of what this guideline covers, and what it means to be a resource-stratified practice guideline? Yes. These guidelines outline and they cover the recommended set of palliative care integration concerning personnel needed, training needed for this staff, structure, and availability of medicines at different resource levels. And by a resource-stratified guideline, we mean that it's suitable for different levels of development. Yes. For example, if you are speaking about a community level, you are speaking of primary care centers, or if we are speaking about in a different setting, like a regional hospital and also, the highest level might be the oncology center. And at every level, there should be a better structure and better training and availability of palliative care. But at all of these levels, we should have palliative care. What are the key recommendations of this guideline? Yes. The key recommendations, as I mentioned, is that we should have a coordinated system, where the patient's palliative care needs are identified and met at every level and from the moment of diagnosis. So we are speaking about, at the basic level, we should have at least a volunteer or community worker or better even, a nurse trained in palliative care. And these people have got the job to facilitate identification of patients who need palliative care at the community level. Another level is the limited level, and here, we should have at least one doctor and a nurse trained in basic palliative care, and they work with the people working in the community. And they address minor issues, prescribing basic medicines, referring patients, and they also have the ability to support the patient and the family in [INAUDIBLE]. At another enhanced level, and we are speaking here about setting like a regional hospital, there should be a team, at least of three personnel-- doctor, nurse, pharmacist. Of course, if there is a psychologist or religious chaplain, it's OK, but at least these three personnel should be trained about palliative care, so a minimum of six weeks training. And they can provide palliative care, and they can offer as outpatient service in this regional hospital. The best setting or the maximum setting is when we are speaking about a bigger hospital or an oncology center. And we are speaking that no oncology center or any facility for palliative care patients, like hospices, should exist without a well-developed palliative care team. And having personnel and all personnel working in that center should receive basic training in palliative care. The main treating doctors, for example, the oncologists, should have secondary training in palliative care, so it's a higher level of training in palliative care. And we need for palliative care physicians to supervise and develop the service. At such a setting, we should have psychologists, we should have chaplains all integrated in the service. Another recommendation is that palliative care should be given and provided at all levels ideally, at the moment of diagnosis of the patient, but especially for patients who are coming with overwhelming symptoms, whether physical, psychological, or spiritual or patients who have metastasis or patients who cannot receive active treatment for curative intent, for example, for comorbidities or age or patients with a disease with a known short life expectancy. All these patients should receive palliative care from the moment of diagnosis. Why is this guideline so important, and how will it change practice? Yes, it is very important because palliative care is important to be given to all patients at every setting. It is not expensive. It doesn't require special equipment. It can be given. It not only should be given, but it can also be given. It's not difficult to change. And this guideline is very important, because sometimes people don't hear other colleagues or junior doctors. They hear high recommendations, like from the ASCO guidelines. And finally, how will these guideline recommendations affect patients? Yes. We hope the directors of hospitals, people or personnel at administerial levels, our fellow colleagues, they embrace these recommendations more and more. As I mentioned, sometimes it needs to come from higher up, and for that, we thank the American Society of Clinical Oncology for taking this task. Once we are caring for our patients holistically, which includes social, spiritual, psychological dimensions, in addition to physical, it leads to a better quality of life, affecting not only the patient and the family in all dimensions but even leading to a better survival, and here, I mean both in time and quality. Great. Thank you for your time today, Dr. Gaffer. Thanks. Thanks a lot. And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Rachel Freedman, MD, MPH- Assistant Professor, Medicine, Harvard Medical School, Dana-Farber Cancer Institute presents a self-assessment question from an ASCO University course focusing on the treatment breast cancer.  AUDIO TRANSCRIPT Welcome to the self-evaluation episode of the ASCO University weekly podcast. My name is Rachel Friedman, and I'm a medical oncologist and clinical researcher in the Breast Oncology Center at Dana-Farber Cancer Institute. Today, we feature a self-evaluation question on the treatment of early stage breast cancer. We begin by reading the question stem. A 75-year-old woman with a past medical history of coronary artery disease and diabetes, with an ECOG performance status of 2, has been seen in the medical oncology office following a partial mastectomy for a 1 centimeter invasive breast cancer. The margins were clear and hormone receptors are reported as positive. The HER2/neu status is reported as negative. An Oncotype recurrence score is reported as 5. Which of the following is the best adjuvant therapy for this patient? Choice A, doxorubicin, cyclophosphamide, and weekly paclitaxel, followed by an aromatase inhibitor. B, docetaxel and cyclophosphamide for four cycles, followed by an aromatase inhibitor for five years with radiation therapy to the breast. C, radiation therapy to the breast and axilla, followed by an aromatase inhibitor. D, aromatase inhibitor. E, tamoxifen. The correct answer to this question is D, aromatase inhibitor. This patient has a poor performance status and high co-morbidity burden, with a higher likelihood of non-breast cancer deaths over breast cancer death, over time. The cancer is low risk, with a low likelihood for local and distant recurrence. Radiation and chemotherapy are unlikely to improve her outcome and will increase her toxicity risk. Further, we have multiple randomized trials to support safe omission of radiation and the setting of older age and stage 1 hormone receptor positive disease. Briefly, the benefit of adjuvant chemotherapy is anticipated to be negligible, and even harmful, in the setting of her low risk disease, advanced co-morbidity, poor functional status, and Oncotype score of 5. Chemotherapy should be avoided in this setting, making answers A and B incorrect. Although radiation should be considered and administered in most patients with invasive breast cancer, undergoing breast conservation, as mentioned earlier, we have prospective randomized controlled trial data, supporting omission of radiation in this clinical scenario, making option C also incorrect for this reason. Further, there is no indication for radiation to the axilla in a low risk breast cancer, such as the one described here, making option C incorrect for that reason as well. Option E, tamoxifen, is also a treatment option here, but may be less appealing in an older patient who lives a more sedentary lifestyle who may be at more risk for adverse events on tamoxifen, such as thrombosis, and where the use of aromatase inhibitors may be of a small incremental benefit over tamoxifen, with regard to risk for recurrences over time. Thank you for listening to this week's episode of the ASCO University weekly podcast. For more information on the treatment of breast cancer, including opportunities for self-evaluation and for a review, please visit the comprehensive eLearning center at university.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Rachel Freedman, MD, MPH- Assistant Professor, Medicine, Harvard Medical School, Dana-Farber Cancer Institute, presents a self-assessment question from an ASCO University course focusing on the treatment breast cancer.   

Self-Evaluation: Karen M. Winkfield, MD, PhD, Associate Professor of Radiation Oncology, Comprehensive Cancer Center at Wake Forest Baptist Health, presents a self-assessment question from an ASCO University course focusing on, the appropriate first line therapy for newly diagnosed primary CNS lymphoma.

Self-Evaluation: Apar Kishor Ganti, MD, Professor in the Department of Internal Medicine, Division of Oncology/Hematology, and Associate Director of Clinical Research at the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, presents a self-evaluation question from an ASCO University course focusing on the treatment of an EGFR Mutation.  

Shadia Jalal, MD, Assistant Professor of Clinical Medicine Department of Medicine Division of Hematology/Oncology Indiana University School of Medicine, presents a self-evaluation question from an ASCO University course focusing on the treatment of non-small cell lung cancers.

Welcome to the ASCO University Weekly Podcast! Dr. Alexander Drilon from Memorial Sloan Kettering Cancer Center provides a brief overview of what you can expect from the series. Be sure to subscribe for automatic updates on new episodes and visit university.asco.org for more from our comprehensive eLearning catalog.

This presentation, part of the Literature Reviews Series on ASCO University (http://university.asco.org), reviews the leading journals to compile the most relevant, practice-changing science. Reviews focus on the following areas: translational science, clinical trials, reviews, guidelines, and editorials.

This presentation, part of the Literature Reviews Series on ASCO University (http://university.asco.org), reviews the leading journals to compile the most relevant, practice-changing science. Reviews focus on the following areas: translational science, clinical trials, reviews, guidelines, and editorials.

This presentation, part of the Literature Reviews Series on ASCO University (http://university.asco.org), reviews the leading journals to compile the most relevant, practice-changing science. Reviews focus on the following areas: translational science, clinical trials, reviews, guidelines, and editorials.

This presentation, part of the Literature Reviews Series on ASCO University (http://university.asco.org), reviews the leading journals to compile the most relevant, practice-changing science. Reviews focus on the following areas: translational science, clinical trials, reviews, guidelines, and editorials.

This presentation, part of the Melanoma in Adolescents and Young Adults (AYAs) course on ASCO University (http://university.asco.org), covers recurrence of disease in the patient from the previous vodcast. New emerging therapies for stage 3+ disease are discussed, as is palliative treatment for end-stage disease.

This presentation, part of the Melanoma in Adolescents and Young Adults (AYAs) course on ASCO University (http://university.asco.org), introduces a case of newly diagnosed, early stage, curable disease. Issues of prevention, detection (recognizing new disease), and early management are addressed, as well as potential therapeutics and related toxicities of these therapies.

This presentation, part of the Fertility Preservation Issues (AYA Males) course on ASCO University (http://university.asco.org), includes the case of a 19-year-old diagnosed with acute myeloid leukemia who wishes to undergo sperm banking to preserve his options for conceiving a child in the future. Issues related to communicating with the patient and health concerns prior to banking are discussed.

This presentation, part of the Fertility Preservation Issues (AYA Males) course on ASCO University (http://university.asco.org), includes the case of a 28-year-old with testicular cancer who wishes to undergo sperm retrieval during radical orchiectomy. Factors related to advanced fertility preservation techniques are discussed, including timing, cost, and psychosocial concerns.

This presentation, part of the Diagnosis and Treatment course on ASCO University (http://university.asco.org), discusses the unique issues related to diagnosis and treatment of an AYA patient with colorectal cancer. It covers topics such as choosing the correct diagnostic tests and selecting the most appropriate treatment options and follow-up care plans.

This presentation, part of the Diagnosis and Treatment course on ASCO University (http://university.asco.org), discusses the unique issues related to diagnosis and treatment of an AYA patient with acute lymphoblastic leukemia. It covers topics such as choosing the correct diagnostic tests and selecting the most appropriate treatment options and follow-up care plans.

This presentation, part of the Fertility Preservation Issues (AYA Females) course on ASCO University (http://university.asco.org), includes the case of a 34-year-old woman with breast cancer who wants to get pregnant following treatment for her disease. Management options for preserving her fertility are discussed.

This presentation, part of the Fertility Preservation Issues (AYA Females) course on ASCO University (http://university.asco.org), includes the case of a 20-year-old student with Ewing Sarcoma who wishes to conceive naturally in the future. Issues related to oocyte and ovarian tissue banking are discussed.

This presentation, part of the Clinical Trials for Adolescents and Young Adults (AYA) course on ASCO University (http://university.asco.org), covers the need and relevance of including AYAs on clinical trials, especially as it relates to current care and outcomes.

This presentation, part of the Clinical Trials for Adolescents and Young Adults (AYA) course on ASCO University (http://university.asco.org), discusses options for clinical trials for AYAs, and will aim to raise awareness about including clinical trials as an option for therapy for these patients.

This presentation, part of the Clinical Trials for Adolescents and Young Adults (AYA) course on ASCO University (http://university.asco.org), covers the processes involved in trial participation, and uses a case scenario to depict issues arising during consent. It will also discuss the communications, time required, and shared care involved with these particular AYA patients.

Dr. Patricia Ganz, MD discusses and overviews the Breast Cancer as a Second Malignancy course on ASCO University.

Dr. William Wood Jr., MD, MPH discusses and overviews the Hodgkin Lymphoma: Treatment and Late Effects course on ASCO University.

This presentation, part of the Literature Reviews Series on ASCO University (http://university.asco.org), reviews the leading journals to compile the most relevant, practice-changing science. Reviews focus on the following areas: translational science, clinical trials, reviews, guidelines, and editorials.

This multidisciplinary presentation, part of the Tumor Board Series on ASCO University (http://university.asco.org) presents a case study of a patient with a history of coronary artery disease who is diagnosed with renal cell carcinoma and treated with a tyrosine kinase inhibitor.

This presentation, part of the Literature Reviews Series on ASCO University (http://university.asco.org), reviews the leading journals to compile the most relevant, practice-changing science. Reviews focus on the following areas: translational science, clinical trials, reviews, guidelines, and editorials.