Podcasts about asco podcast network

Dr. Manish Shah discusses the first ASCO guideline for advanced gastroesophageal cancer. He addresses biomarker testing to help guide therapy - including HER2 testing, mismatch repair testing, and assessment of PD-L1 expression. Dr. Shah then reviews the evidence-based recommendations from the ASCO Expert Panel, including first-line therapies for esophageal, gastroesophageal junction (GEJ), and gastric adenocarcinoma, along with esophageal squamous cell carcinoma, based on these biomarker results, as well as evidence in the second-line setting – and beyond – and how to provide optimal care for these patients. Read the full guideline, "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline" at www.asco.org/gastrointestinal-cancer-guidelines TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Manish Shah, from Weill Cornell Medicine, in New York, New York, lead author on 'Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline'. Thank you for being here, Dr. Shah. Dr. Manish Shah: Thank you for having me. It's great to be here, and I'm looking forward to our interview. Brittany Harvey: Great. And first, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online, with the publication of the guideline in the Journal of Clinical Oncology. Dr. Shah, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Manish Shah: Yeah. So, I've received research funding from Merck, as well as from Bristol Myers Squibb, as well as from Oncolys Pharma. These are all companies that have worked for immunotherapy and upper GI cancers. Brittany Harvey: Okay, thank you for those disclosures. Then diving into the content here, what is the scope and purpose of this first ASCO guideline for advanced gastroesophageal cancer? Dr. Manish Shah: Thank you. As you point out in the question, this is the first guideline for advanced gastroesophageal cancer, and really it is a very timely guideline because the landscape for the management of upper GI cancers has evolved and changed dramatically in the last several years. For a long time, we were really focused on chemotherapy for esophagus and gastric cancer. We, in fact, treated squamous cell cancer of the esophagus very similar to adenocarcinoma of the esophagus. And even though we knew of the different disease subtypes for gastric cancer, they didn't really play a role in differentiating management. About 10 years ago, trastuzumab was approved for the treatment of HER2-positive gastric cancer, but since then, we've had really a run of significant positive studies that have informed practice, and we felt that this was really a timely guideline to help us with regard to our patients with upper GI cancer, particularly, with metastatic disease who need first-line, and beyond therapy. Brittany Harvey: Excellent. Then you've just mentioned that the management of these upper GI cancers has evolved, so I'd like to review the key recommendations of this guideline that you just gave an overview of. So, starting with first-line therapy - is immunotherapy, or targeted therapy in combination with chemotherapy, recommended as first-line treatment for advanced gastroesophageal adenocarcinoma or squamous cell carcinoma? And what are these recommendations by the subgroups of patients by HER2 status or PD-L1 protein expression? Dr. Manish Shah: The answer to that is that, in fact, it is now recommended for most patients, but I think I might start a little bit one step behind. So, with a newly diagnosed patient with an upper GI cancer, I think the first step in the management is to test for the biomarkers that will help guide therapy. So, for esophageal adenocarcinoma gastroesophageal junction, and gastric cancer, which is almost always adenocarcinoma, we recommend that everybody undergo HER2 testing immunohistochemistry, as well as a mismatch repair testing or MSI-high; either way you get it is fine, as well as an assessment of the PD-L1 expression, which is scored according to the Combined Positive Score or CPS. So, that panel of biomarkers will help guide the management for the adenocarcinomas. And so, if you are HER2-positive, then we've known for a long time that the standard of practice would be chemotherapy with trastuzumab; typically, it's a platinum and 5-FU-based treatment with trastuzumab. Most recently, and this is in the guideline and the second part of your question, if you're HER2-positive, and you actually now are recommended to do chemotherapy with trastuzumab and pembrolizumab, which is a PD-1 inhibitor. Then that's based on the KEYNOTE-811 study, that we have the first analysis, which is a response rate analysis, and the response rate improves significantly with the addition of the immunotherapy. But for the majority of patients who are HER2-negative, we do look at the PD-L1 status by CPS, then here it's a little bit trickier. The FDA guidance is to recommend immunotherapy with chemotherapy for all patients in the first-line setting. However, we also recognize that the higher the PD-L1 expression, the more likely the benefit from immunotherapy. And several studies have demonstrated that, and we've shown that in the guideline as well. And there seems to be a very reasonable cutoff of a CPS score of five or higher, and above that, there really is clear benefit of the addition of immunotherapy, specifically, nivolumab to chemotherapy for gastroesophageal cancer, that's based on CheckMate 649. And then for esophageal adenocarcinoma, the additional recommendation is the addition of chemotherapy with pembrolizumab for a CPS of 10 or higher. And I think for CPS zero, most of us really felt pretty strongly that there was really no role for the use of immunotherapy because remember, these drugs do have some side effects, that although rare, can be really debilitating. And then, there's an intermediate category of CPS, 1-4, and here, I think you have to use a little bit of a judgment call. We didn't recommend it in general but did suggest that that would be more of an individual-use basis. And the judgment call is that if the CPS is four, if you showed the slides to another pathologist, it's very possible it could have been a five. So, that kind of heterogeneity is something that we might consider to go ahead and use the immunotherapy. But if the CPS is lower, the context is also questionable. We talked a little bit about the side effects of immunotherapy. If someone really has bad rheumatoid arthritis, we've all actually had patients given immunotherapy, they come in debilitated. So there, we really would want to be sure that the CPS is high, so that way, the patient is deriving the benefit, and we then adjust the rheumatoid arthritis medicines accordingly. So, I think the other theme through our guideline is that with more options, we are able to actually provide more personalized care to our patients, giving them the best opportunity to receive the care with minimizing toxicity and maximizing benefit. So, that was a long-winded answer to the question that we do recommend immunotherapy in the first-line setting, in the right context, and for HER2-positive tumors, we recommend trastuzumab plus immunotherapy in the first-line setting, in the right context. And then, the final thing was the mismatch repair status. So, unlike colon cancer where there's level one evidence comparing immunotherapy to first-line chemotherapy, we don't have that in upper GI cancers. So, we do recommend it, but as for the guidance, it would be in the second-line setting, or later. Brittany Harvey: Great. Those are key clinical considerations that you just reviewed, and I appreciate you talking through both the evidence, and then the discussions that the panel had on the benefits of therapy, and also the adverse effects that can affect patients. So, then, beyond first-line therapy for later-line therapies, is immunotherapy or targeted therapy recommended as second-line or third-line treatment for advanced gastroesophageal adenocarcinoma? Dr. Manish Shah: Yeah. This is a great question, and I think it can be a point of confusion. So, for a long time, immunotherapy, specifically pembrolizumab, was approved and indicated in the third-line setting for CPS 1 or higher patients. The FDA actually removed that approval, and so it's no longer indicated in that setting. And most patients will have gotten immunotherapy in the first-line setting, and as of now, there's no data that suggests that continuing immunotherapy or rechallenging with immunotherapy would be of any benefit. So, in general, the answer is that we would not use immunotherapy beyond first line. I guess the one caveat is if your CPS is low and you didn't receive immunotherapy in the first-line setting, but you happen to be MSI-high, then certainly, that would be an indication to use immunotherapy in that setting. But I think that would be a pretty rare event. So, if you use immunotherapy in the first-line setting, then there's really no role for continuing or re-challenging with immunotherapy in the second or later-line settings. But that's an active area of drug development, and we think that there will be an opportunity in the next few years for combination strategies to salvage people who had immunotherapy in the first-line setting.   So, in terms of second line and beyond, the other area that we should talk about is in squamous cell cancer. So, squamous cell cancer is a little bit unique, of the esophagus. It is more sensitive to immunotherapy than adenocarcinoma, and in fact, the guidance is to use immunotherapy, either with chemotherapy or as a doublet nivolumab and ipilimumab, in the first-line setting for most patients with squamous cell cancer. If, however, immunotherapy wasn't used in the first-line setting for squamous cell cancer, it is indicated in the second-line setting as nivolumab monotherapy. So, that would be one distinction between the squamous esophageal cancer and adenocarcinoma of the upper GI tract. Brittany Harvey: Great. I appreciate you reviewing those considerations for later-line therapies, and we'll look forward to more research in this area in the future, as you just described. Thank you for reviewing all of those recommendations. In your view, what is the importance of this guideline, and how will it impact clinical practice? Dr. Manish Shah: So, this is an important guideline, because as we've talked earlier, there are lots and lots of options for patients, and we think that the guideline will help frame the discussion on how to best manage our patients in the first line, second line, and beyond. I think it also frames where there are holes in our knowledge. These knowledge gaps are opportunities for research, for us to continue to develop therapies in gastroesophageal cancers. Brittany Harvey: So, that's excellent. And you just mentioned that there's more options for patients with advanced upper GI cancers. So, finally, Dr. Shah, how will these guideline recommendations affect patients with advanced gastroesophageal cancer? Dr. Manish Shah: Yeah. I hope that it will give patients and their physicians a strategy for how to treat patients in the first-line and beyond setting. Gastroesophageal cancer treatment has evolved significantly. Not too long ago, there was a debate of whether or not chemotherapy had a benefit in the first-line setting, or in the second-line setting, and there are randomized studies that demonstrate that for sure. Now, we're in an era where people should get chemotherapy, and then in the right context, get additional targeted agents, like immunotherapy or HER2-targeted therapy. And if we can treat patients along the continuum of their care, thinking about first line, second line, third line, much as we do for colon cancer, we think that more patients will be able to get access to more of the drugs that are available, and in the long run, that will ultimately help more patients, and give patients better outcomes. I hope this guideline will achieve that goal for our community. Brittany Harvey: Absolutely. And I appreciate you providing the details and the context for this new guideline. Thank you so much, for all of your work to develop these evidence-based recommendations. And thank you for your time today, Dr. Shah. Dr. Manish Shah: Oh, absolutely. Thanks so much for having me, and I'm happy to come back anytime. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC without driver alterations. He reviews the new evidence identified by the panel along with the updated recommendation regarding the role of bevacizumab in pemetrexed maintenance therapy. Dr. Owen also discusses exciting trials the panel is looking forward to seeing results of to drive future updates to the living guidelines. Read the update, “Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2“ and view all recommendations at www.asco.org/living-guidelines. Listen to Part 2 for recommendations for patients with stage IV NSCLC with driver alterations. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Dwight Owen, from Ohio State University in Columbus, Ohio, lead author on, 'Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, version 2022.2.' Thank you for being here, Dr. Owen. Dr. Dwight Owen: Thanks very much, Brittany, for having me. Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Owen, do you have any relevant disclosures that are directly related to the guideline topic? Dr. Dwight Owen: I have research funding to my institution to conduct clinical trials from several companies, including Merck, Pfizer, Genentech, BMS, and Palobiofarma, but no ownership, no stock, and no employment history. Brittany Harvey: Okay, Thank you for those disclosures. Then let's get into the content of this living guideline update. So, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations. What new evidence was identified by the routine literature searches to prompt an update to the guideline? Dr. Dwight Owen: Yeah, so this is a really exciting time for patients with stage IV non-small cell lung cancer. We are anxiously awaiting the results of some ongoing immunotherapy combination studies. However, for this update, we focused on a specific paper and study that evaluated a treatment that is not our first option anymore, but maybe the first option for a subset of patients. So, before the standard introduction of immunotherapy for patients with stage IV non-small cell lung cancer, we often offered platinum-based doublet chemotherapy, and for years, we studied ways to make that better. So, we might introduce maintenance therapy where we continue a treatment after the first line of induction chemotherapy. We did either continuation maintenance, which is where you continue a treatment that seemed to be effective, or switch maintenance, where you were introduced to new therapy. For many folks with non-squamous non-small cell lung cancer, the standard treatment options included carboplatin or cisplatin with pemetrexed, which is an antifolate chemotherapy, or carboplatin and paclitaxel with or without a VEGF inhibitor, such as bevacizumab. One of the big questions was whether there was a benefit for continuing maintenance therapy with something besides pemetrexed, in this case, bevacizumab, and if bevacizumab was given in combination with pemetrexed, whether continuing that as a maintenance would offer benefit. Now, it's important to point out that the current FDA approval, at least in the United States, is for bevacizumab to be given with carboplatin and paclitaxel. However, several studies looked at the combination with pemetrexed and there were several issues with those studies. So, in one study they used a different agent, so ramucirumab instead of bevacizumab, both VEGF, but slightly different. In one study, the combination that was compared of pemetrexed plus bevacizumab was only compared to bevacizumab maintenance. And so, we really had a sort of hodgepodge of different trials that never answered the question of whether bevacizumab or VEGF therapy, given as maintenance offered any benefit to our patients. What Dr. Garon and co-authors did in a study that we evaluated was conduct a meta-analysis of four of those randomized trials, focusing on the question of comparing pemetrexed maintenance therapy alone versus in combination with bevacizumab. And what they found is that there was no significant difference in overall survival with the addition of bevacizumab compared to pemetrexed by itself, and there were higher rates of toxicity in those patients, including serious and higher-grade toxicities. So, I felt that it was really important to point out that the addition of bevacizumab or other VEGF therapies does not seem to add to a survival benefit when given as maintenance. And even though this is a subset of patients who perhaps could not get immunotherapy as a first-line treatment, maybe because of a pre-existing autoimmune disorder, but for those patients, it doesn't seem that the addition of VEGF as maintenance offers what we were hoping for. Brittany Harvey: Understood, and I appreciate you laying out the landscape of the data in this area. So then, based off this new data and the meta-analysis that you just described, what is the updated recommendation from the expert panel? Dr. Dwight Owen: So, the updated recommendation is a tweak to the established recommendation, which is essentially that for patients who are not candidates for immunotherapy for any reason, that platinum doublet chemotherapy is really the mainstay, and that if maintenance is offered, that it should not include VEGF therapy in combination with pemetrexed as compared to pemetrexed by itself. Brittany Harvey: Understood. And then, what should clinicians know as they implement this updated recommendation? Dr. Dwight Owen: I think, again, this should be a relatively uncommon scenario. Most of our patients are candidates for immune therapy. Many patients are offered platinum pemetrexed by itself. But when thinking about continuing maintenance therapy, we would recommend that most clinicians avoid the addition of therapies that haven't seemed to offer a survival benefit and incur higher rates of toxicity. Brittany Harvey: Great. That's helpful to know. And then you've just mentioned that this doesn't apply to a lot of patients, but what does this change mean for patients with stage IV non-small cell lung cancer without driver alterations? Dr. Dwight Owen: I think, hopefully, for the subset of patients where we're really thinking about here that we can at least avoid additional toxicity if there isn't a trade-off in terms of benefit, in terms of survival. Brittany Harvey: Great. Definitely, that's helpful. And then finally, what ongoing research is the panel keeping an eye on for future living guideline updates? Dr. Dwight Owen: So, there are a lot of exciting trials that are ongoing, and hopefully, we'll be able to read out soon, that would offer us updates for really how to manage these patients in the frontline setting with stage IV non-small cell lung cancer. We have multiple options now. This discussion that we've had today really focuses on the pre-immunotherapy era, but of course, bevacizumab is utilized in a regimen along with carboplatin, paclitaxel, and atezolizumab, compared to monotherapy with checkpoint inhibitors compared to chemoimmunotherapy and dual checkpoint inhibitors. And we don't really have any head-to-head trials yet, or strategies on how to identify which patients need more aggressive combination therapies versus which patients could potentially do without chemotherapy, or with single-agent checkpoint inhibitor by itself. So, while we wait for those studies like the ECOG and Cigna study, we're really looking forward to having those to be able to help decide and tailor our treatment options for our patients. Brittany Harvey: Great. Well, we'll look forward to the ongoing review of the literature by the panel and any future guideline updates to recommendations in the meantime. So, thank you so much for your work on this update and thank you for your time today, Dr. Owen. Dr. Dwight Owen: Thanks for having me. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines. There's also a companion living guideline update on Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations, available there and in the JCO. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes, or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC with driver alterations. He identifies the latest trials that informed this update, and the updated evidence-based options for second- or later-line therapies for patients with advanced non-small cell lung cancer and an activating HER2 mutation or a KRAS-G12C mutation. Additionally, he provides important context on the reported toxicities associated with these therapeutics. Read the update, “Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2“ and view all recommendations at www.asco.org/living-guidelines. Listen to Part 1 for recommendations for patients with stage IV NSCLC without driver alterations. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and in our last episode, we addressed the living guideline updates for ‘Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations.' Today, Dr. Dwight Owen from Ohio State University in Columbus, Ohio, is joining us again to discuss the updates for therapy for stage IV non-small cell lung cancer with driver alterations, as the lead author on, 'Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, version 2022.2.' Thank you for being here, Dr. Owen. Dr. Dwight Owen: Thanks for having me. Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Owen, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Dwight Owen: Yeah, thanks for asking that really important question. My institution has received research funding for me to conduct clinical trials from Merck, BMS, Pfizer, and Genentech and Palobiofarma. I have no employment, stocks, stock options, or other disclosures to declare. Brittany Harvey: Thank you for those disclosures. Then getting into the content of this update, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small-cell lung cancer with driver alterations. What new studies were reviewed by the panel to prompt an update to this guideline? Dr. Dwight Owen: Thanks for that question. This is a particularly exciting update because as we were preparing for this update, reviewing two manuscripts that we think offer new options for our patients with driver alterations, there were actually updated presentations at a recent meeting that showed us even more data for these targets. So, it's really an ongoing and dynamic place. So, we really focused on two updates; one was for KRAS-G12C alterations, and then one was for HER2 alteration-positive non-small cell lung cancer. So, I'll take them one at a time; for KRAS-G12C, we included an updated recommendation based on the CodeBreak 100 study - this was a multi-center, single group, open-label, phase II study of sotorasib, which is a KRAS-G12C inhibitor, in patients with non-small cell lung cancer positive for KRAS-G12C, who had received prior systemic therapy that could either be with chemotherapy or immune therapy, and the majority of patients had received both. 124 patients were evaluable for response, and the objective response rate was 37%, with the impressive median overall survival of over 12 months, of 12.5 months, specifically. Now, there were some notable toxicities. There's GI toxicities such as diarrhea and nausea, as well as some elevations in LFTs. We also heard recently at ESMO about CodeBreak 200, which was a randomized study of sotorasib compared to docetaxel in previously treated patients with KRAS-G12C non-small cell lung cancer. And that study did meet its primary endpoint of improvement in PFS for sotorasib-treated patients compared to docetaxel, and we are very much looking forward to seeing that final publication. For HER2 alteration-positive non-small cell lung cancer, we really focused our efforts on DESTINY-Lung01. Now, this was a multi-center, multinational, open-label, phase II study evaluating trastuzumab deruxtecan in patients with previously treated HER2-positive non-small cell lung cancer. In this study, 91 patients were evaluable for response, and 50, which was 55%, had a confirmed objective response, and the median survival was presented at 17.8 months. A pretty unique toxicity was observed here. So, drug-related interstitial lung disease or pneumonitis occurred in just over a quarter of patients, and there were two deaths related to this. So, this needs to certainly be monitored for. Also at ESMO, we heard results for DESTINY-Lung02, which was a multi-center, multi cohort, randomized blinded study, which was also a dose optimization study. And this study eventually led to the accelerated approval of the 5.4 milligrams per kilogram dose that seemed to be just as effective as other doses, but perhaps with less toxicity. Again, we're currently awaiting the final publication of DESTINY-Lung02. However, these results are particularly impressive and especially leading to the FDA accelerated approval for a new treatment option for our patients with HER2 alteration positive non-small cell lung cancer. Brittany Harvey: I appreciate you reviewing that data and the new updates for both of these drugs and targets in this population. So then, I'd like to review the recommendations that the panel updated for our listeners. First, what is the new recommendation for patients with advanced non-small cell lung cancer and in activating HER2 mutation? Dr. Dwight Owen: So currently, these patients should continue to receive standard first-line treatment as we do not have head-to-head trials for HER2-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a HER2-activating mutation, trastuzumab deruxtecan certainly should be offered to these patients. Brittany Harvey: Understood. And then the second category of patients that you identified, what does the expert panel recommend for patients with advanced non-small cell lung cancer and a KRAS-G12C mutation? Dr. Dwight Owen: So, similarly, these patients should continue to receive standard first-line treatment, as we do not have head-to-head trials for KRAS-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a KRAS-G12C mutation, sotorasib can be offered as a subsequent therapy. Keep in mind that this is only approved in patients with the KRAS-G12C mutation, and not other KRAS alterations. Brittany Harvey: Thank you for reviewing those two recommendations for second or later-line therapies. What should clinicians know as they implement these updated recommendations? Dr. Dwight Owen: So, I think what we're really excited about is that both of these agents offer new treatment options for patients who historically did not have a personalized targeted treatment option. We are awaiting publication of additional studies to help interpret these data, but for now, clinicians should discuss these treatment options with their patients, and also keep in mind the pattern of toxicities that seem to be unique to each treatment. Brittany Harvey: Great. And then, you've just addressed some of this in your last response, but what does this change mean for patients with stage IV non-small lung cancer with a HER2 or KRAS-G12C mutation? Dr. Dwight Owen: I think the bottom line is that our patients for whom their cancer does not respond, or where it progresses after first-line treatment, will now have additional effective and approved treatment options that are really tailored to the unique characteristics of their tumor and cancer cells. Brittany Harvey: Absolutely. It's great to have new options for patients in this field. So then finally, are there future research developments that the panel is considering for future living guideline updates? Dr. Dwight Owen: So, we're particularly looking forward to the final publication of the studies that were recently presented, including the CodeBreak 200, and DESTINY-Lung02 trials. There are multiple ongoing studies for additional targets, including in the targets that we talked about; so, KRAS-G12C as well as HER2, as well as a number of other targeted options that may benefit subsets of our patients with metastatic non-small cell lung cancer. Brittany Harvey: Great. Well, I appreciate you reviewing all this data and the updated recommendations, and thank you for your time today, Dr. Owen. Dr. Dwight Owen: Thanks for having me. Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines.  There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer without driver alterations, available there and in the JCO. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes, or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

Dr. Emrullah Yilmaz reviews the latest evidence and recommendations for health care providers on biomarker testing and immunotherapy for head and neck cancers. He discusses the ASCO Expert Panel's recommendations for biomarkers for the selection of patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy. Additionally, he reviews recommended treatment options, including first-line treatment based on PD-L1 status, therapies for platinum-refractory disease, options for patients with nasopharyngeal cancer, the role of radiation therapy for oligometastatic head and neck cancer, and immunotherapy for rare head and neck cancers. Dr. Yilmaz also explores future areas of research for therapeutic options for patients with head and neck squamous cell carcinoma. Read the full guideline, “Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline” at www.asco.org/head-neck-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Emrullah Yilmaz, from Cleveland Clinic in Cleveland, Ohio, lead author on, 'Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline'. Thank you for being here today, Dr. Yilmaz. Dr. Emrullah Yilmaz: Thank you so much. Brittany Harvey: Then first, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Yilmaz, do you have any relevant disclosures that are directed related to this guideline topic? Dr. Emrullah Yilmaz: No, I don't have a relevant disclosure. Brittany Harvey: Thank you. Then let's dive right into this guideline. So, generally, what is the purpose and the scope of this guideline? Dr. Emrullah Yilmaz: Immunotherapy with anti-PD-1 immune checkpoint inhibitors has become one of the most important treatment options for patients with recurrent metastatic head and neck cancers. And in the last few years, there has been new studies leading to new indications such as combinations with chemotherapy, or single-agent immunotherapy in the first-line treatment. And moreover, several studies also shown the effectiveness of immunotherapy for patients with nasopharyngeal carcinoma. All these advances in this complex disease group made it necessary to have an evidence-based guideline. So, that was the basis of building this guideline. Brittany Harvey: Understood. And then this evidence-based guideline addresses six clinical questions. So, I'd like to review the key recommendations for each of those questions for our listeners. So, let's start with the first question. What did the expert panel recommend regarding biomarkers for selecting patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy? Dr. Emrullah Yilmaz: Biomarkers are key for selection of treatment for immunotherapies, especially for the first-line treatment for head and neck cancer patients. PD-L1 is measured by immunohistochemistry and reported as Combined Positive Score, CPS, or Tumor Proportion Score, TPS. CPS is slightly different than TPS, and it includes lymphocyte and macrophage PD-L1 expression, in addition to tumor cells. Head and neck cancer studies have shown that CPS is a better marker for predicting response to immune checkpoint inhibitors, and key head and neck trials started to use CPS for reporting PD-L1 status. Therefore, we recommend CPS for recurrent metastatic head and neck cancers for PD-L1 reporting. This also makes it important for the oncologists to have a communication with the pathologists to make sure the right PD-L1 scoring is reported for head and neck cancer patients. Tissue tumor mutation burden is another emerging biomarker when CPS is not available, or for rare head and neck tumors, tumor mutation burden can be used as a biomarker as well. Brittany Harvey: Great. And then based on that PD-L1 status that you just mentioned, what is the optimal first-line treatment regimen for patients with recurrent or metastatic head and neck squamous cell carcinoma? Dr. Emrullah Yilmaz: If PD-L1 is positive, which is CPS more than one, there are two different options. Both pembrolizumab, single agent or pembrolizumab plus chemotherapy with platinum and 5-Fluorouracil can be offered. KEYNOTE-048 study showed an overall survival benefit with pembrolizumab alone for patients with CPS more than one, which was greater for the patients with CPS 20 or more. However, the pembrolizumab plus chemotherapy has showed benefit for the patients regardless of the PD-L1 status. So, if an early response is needed for a patient with high disease burden, pembrolizumab with chemotherapy could be an option, even if the PD-L1 is positive. For patients with negative PD-L1, which is CPS less than one, we recommend pembrolizumab and chemotherapy. There was a recent subgroup analysis of KEYNOTE-048 for CPS-low patients. Patients with CPS less than one subgroup did not have significant survival difference with pembrolizumab plus chemotherapy when compared to cetuximab plus chemotherapy. This included a small number of patients, and this study was not powered to look at this subgroup, but cetuximab and chemotherapy can also be considered in the PD-L1 negative patient. Brittany Harvey: Understood. It's important to recognize which patients benefit from these treatments more than others in different subgroups. So, following that, what is the effect of immunotherapy compared to other systemic treatments in platinum-refractory recurrent, or metastatic head and neck squamous cell carcinoma? Dr. Emrullah Yilmaz: Platinum-refractory disease is defined as recurrence within six months of platinum-based chemotherapy. And effectiveness of immunotherapy was actually proven in this disease group first, several years ago. The effectiveness of immunotherapy as a single agent was proven in two similarly designed phase III trials in this setting. CheckMate 141 trial compared nivolumab to standard-of-care methotrexate, cetuximab, or docetaxel, and KEYNOTE-040 trial compared pembrolizumab to similar standard-of-care agents. And both studies showed overall survival benefit when compared to standard-of-care systemic agents, and the responses were independent from the PD-L1 expressions. So, nivolumab or pembrolizumab, are options as single-agent immunotherapy treatments for the patients with platinum-refractory head and neck squamous cell carcinoma, regardless of their PD-L1 expression. Brittany Harvey: Understood, and thank you for getting into those options for those patients. Getting into the specifics for nasopharyngeal carcinoma, what did the panel recommend regarding the role of immunotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma? Dr. Emrullah Yilmaz: So, the combination of immunotherapy with cisplatin and gemcitabine was shown to be effective in first-line treatment of recurrent metastatic nasopharyngeal carcinoma, in several phase III studies from Asia in the last few years. JUPITER-02 study used toripalimab, CAPTAIN-1 study used camrelizumab, and RATIONALE-309 study used tislelizumab in combination with cisplatin and gemcitabine in the first-line treatment, and all these studies showed progression-free survival benefit with addition of immunotherapy to chemotherapy. Since these agents are not available in the United States as of now, our panel members recommend that pembrolizumab or nivolumab may be offered in combination with chemotherapy for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma. But the role of immunotherapy in the platinum-refractory nasopharyngeal carcinoma without the prior immunotherapy use is not well established yet. There are phase II studies that have shown that responses to immunotherapy are comparable to chemotherapy with a better safety profile. So, single-agent immunotherapy could be considered in a platinum-refractory setting if a PD-1 inhibitor was not used before. Brittany Harvey: Those are excellent points that you just made. So, following that, the next question that the panel considered is, what is recommended regarding the use of radiation therapy in combination with immunotherapy versus immunotherapy alone, for the treatment of locoregionally recurrent or oligometastatic head and neck squamous cell carcinoma? Dr. Emrullah Yilmaz: This is a great question, and radiation therapy is used a lot in head and neck cancers for different purposes. And immunotherapy and SBRT combinations were not shown to increase efficacy for abscopal effect for the treatment of oligometastatic disease in head and neck cancers. So, radiation therapy should not be given to increase the effectiveness of immunotherapy in recurrent metastatic head and neck cancers. However, there are several ongoing studies to evaluate the efficacy of radiation such as SBRT with immunotherapy for locoregional recurrence. So, although radiation therapy is safe to give the patients with recurrent and metastatic cancers, with immunotherapy, it should be considered for palliation or local control until the results of these trials are available. Brittany Harvey: Great. And yes, we'll look forward to the results of those trials to find some more definitive results for these patients. So, then, the last clinical question that the panel addressed, what is recommended for the role of immunotherapy for rare head and neck cancers? Dr. Emrullah Yilmaz: The role of the immunotherapy for rare head and neck cancers depends on the biomarkers. KEYNOTE-158 study has shown the effectiveness of pembrolizumab in advanced cancer patients, which included different types of cancers with high tissue TMB defined as more than 10 mutations per megabase. And looking at the results from that study for the patients with advanced rare head and neck cancers with limited treatment options, such as, salivary gland cancers or sinonasal cancers, if high TMB, which is Tumor Mutational Burden, is identified, then pembrolizumab may be considered for those patients. And pembrolizumab was also shown to have activity in salivary gland cancer patients expressing more than 1% PD-L1. So, that makes it an option for these patients as well. Brittany Harvey: It sounds like understanding the biomarker status of these patients with rare head and neck cancers is essential for determining their therapy options. I want to thank you so much for reviewing all of those recommendations. So, in your view, Dr. Yilmaz, what is the importance of this guideline, and how will it impact clinicians and patients with head and neck squamous cell carcinoma? Dr. Emrullah Yilmaz: This guideline was written by panel members, experts in their field, including medical oncologists, radiation oncologists, head and neck surgeons, pathologists, and radiologists. It is really important for oncologists to communicate the treatment options to their patients clearly while planning treatment of head and neck cancers. So, this guideline can help the clinicians to provide evidence-based resource when to use the immunotherapy for their head and neck cancer patients. So, that can be really helpful to the clinicians. Brittany Harvey: Excellent. Yes, it's important to have a multidisciplinary group working on these guidelines to help clinicians in all capacities. Finally, what outstanding questions or ongoing research are you interested in for future therapeutic options in head and neck squamous cell carcinoma? Dr. Emrullah Yilmaz: Our guideline focuses on recurrent metastatic head and neck cancers since it is the only area where the immunotherapy is approved as of now. We've had a few studies in the curative intent setting, which has not shown the benefit of addition of immunotherapy to radiation therapy, or chemoradiation. There's still several studies ongoing to investigate the effectiveness of immunotherapy in the curative intent setting, and the neoadjuvant setting, or adjuvant setting, or different combinations with the radiation therapy, with the immunotherapy, with the different sequences. So, it will be interesting to see the results of those studies in the future. So, that might be another area that the field might be moving in the future. There are also studies ongoing to improve effectiveness of the immunotherapy in the recurrent and metastatic disease. Chemoimmunotherapy seems to be among the strongest systemic treatment options right now that we have, but there are several other combination strategies that are being developed combined with the PD-1 inhibitors, including combinations with EGFR inhibitors, angiogenesis inhibitors, intratumoral injections, vaccine developments, and there are a lot of different novel checkpoint inhibitors being developed. So, the field is advancing in that area as well. So, those are the areas that research are ongoing at this point. Brittany Harvey: Definitely. We'll look forward to the results of those ongoing trials to inform future updates and future guidelines in this area. So, I want to thank you so much for all of your work that you put into developing these evidence-based guidelines and thank you for your time today, Dr. Yilmaz. Dr. Emrullah Yilmaz: Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning to the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

Dr. Judith Paice and Dr. Eduardo Bruera discuss the latest evidence-based recommendations from ASCO on the use of opioids in managing cancer-related pain. They review the safe and effective use of opioids, including when clinicians should offer opioids, which opioids should be offered, how opioids should be initiated and titrated, management of opioid-related adverse events, modifying opioid use for patients with specific comorbidities, management of breakthrough pain, and how opioids should be switched. Additionally, they address barriers to care, considerations of health disparities, cost, and patient-clinician communication in achieving optimal pain management. Read the full guideline, “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline” at www.asco.org/supportive-care-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Judith Paice from Northwestern University Feinberg School of Medicine in Chicago, Illinois and Dr. Eduardo Bruera from the University of Texas MD Anderson Cancer Center in Houston, Texas, co-chairs on “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline.” Thank you for being here, Dr. Paice and Dr. Bruera. Dr. Judith Paice: Thank you. Dr. Eduardo Bruera: Thank you for having us. Brittany Harvey:  First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Paice, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Judith Paice: I have no relevant disclosures. Brittany Harvey:  Thank you. And then Dr. Bruera, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Eduardo Bruera: Regrettably, I don't. Brittany Harvey: Great. Then getting into the content of this guideline, to start us off, Dr. Paice, can you provide an overview of the purpose and the scope of this guideline? Dr. Judith Paice: The use of opioids has become so complicated, so controversial, and just so associated with so much stigma that we wanted to provide oncology clinicians some guidance about safe and effective use of opioids. We wanted to help people be aware of the current literature, and so we conducted a systematic review and identified randomized controlled clinical trials and other systematic reviews. And we found that there were 31 systematic reviews in 16 RCTs. We carefully reviewed all of these literature and all of these studies, and our expert panel met via the web and via numerous conference calls and emails, and we came to consensus regarding these recommendations related to the use of opioids for people with cancer. Brittany Harvey: Great. Sounds like there was a lot of effort that went into developing this and to tackle an important topic. So, then Dr. Bruera, I'd like to review the key recommendations of this guideline for our listeners. This guideline addresses seven different clinical questions. So, let's review these questions starting with; in what circumstances should opioids be offered? Dr. Eduardo Bruera: That's a very important point because the reality is that although opioids have been around for more than 300 years in different modalities, they continue to be the mainstay of care of patients with severe pain. So, it's very important to try to figure out in the clinical practice why the patient has a pain syndrome. But in the great majority of patients who have pain that is due to the presence of the primary cancer or metastatic disease. And also, in the vast majority of patients who develop severe complications from treatment such as mucositis from radiation and chemotherapy, an opioid will be needed. And the oncologist and the oncology clinician is in perfect conditions to safely prescribe that opioid so the patient can achieve fast relief of their pain. Brittany Harvey: Great. Thank you for that explanation. So, then the next clinical question that the panel addressed, Dr. Paice, which opioids does the panel recommend clinicians should offer? Dr. Judith Paice:  Yeah, thank you. This is a really important question, one that gets asked all of the time, and yet, the data are insufficient to really suggest that there is one preferred opioid over another. So, a patient with moderate to severe cancer-related pain is a candidate for any of the approved medications either approved by the FDA or because our audience also includes international experts, other regulatory agencies for pain treatment. We did call out a couple agents for which there is some concern or for issues where they are less than desirable in some settings. So, one of those drugs is tramadol. And our rationale for identifying tramadol as a potential agent of concern is that it's a prodrug. It has a threshold, a ceiling unlike most of the other opioids, and that threshold is pretty low for neurotoxicity, which is of particular concern in the person with cancer. And it also, has a significant amount of drug-drug interactions. So, we were concerned about tramadol, even though it is an agent that many, many people are using, in part, because it is a lower schedule on the controlled substance scheduling system, and there's a perception that it is less potent, and it is less potent. The other drug that we call out is codeine. And our rationale for identifying it as an agent that may be of difficulty in certain populations of patients, is that it is also a prodrug and it is metabolized through the cytochrome P450 system, particularly through the isoenzyme CYP2D6. And that's what allows codeine to be metabolized to morphine, which allows it to be analgesic. The challenge is there are some individuals who are poor metabolizers, and so they will not receive an analgesic effect. And then there are others who are ultra-rapid metabolizers, and they may actually experience a greater prevalence of adverse effects. So, for those reasons, we call out tramadol and codeine. Now, we don't call out methadone as an agent that we're concerned about in terms of not being desirable. It is an agent that has a role in cancer pain management. However, we do caution clinicians that it is a complex drug to use. And so, as result, people should obtain some guidance either from their palliative care program, their supportive care program, pain experts, or pharmacists, whomever can assist them in the dosing associated with this really important, but somewhat complicated drug to use. Brittany Harvey: Understood. And I appreciate you reviewing where there's a lack of evidence and where there is evidence in identifying those potential agents of concern or where clinicians need to seek other expertise in this area. So, then following those recommendations, after identifying patients who should be offered opioids, Dr. Bruera, how should opioids be initiated and titrated? Dr. Eduardo Bruera: One possible way to do this is to give the patient an immediate release opioid. That could be a combination of hydrocodone with acetaminophen, a combination of other opioids or a straight strong opioid in a low concentration. And ideally, we suggest that you use it as needed for the first few days and see if the patient needs to take it frequently. And there is a magic number around 30 milligrams of morphine equivalent per day. Once the patient needs to take that opioid on a more frequent basis and gets through that threshold of needing about five, six tablets a day of immediate release opioid, then it might be necessary to start a regular opioid that is to stay on top of the pain. And the way we do that are two ways; if the patient can afford it and insurance covers it, an extended release opioid is a wonderful option, because then, the patient can take the opioid a couple of times a day or put a patch for three days and they're going to be comfortable. But if that is not an option, taking the immediate release opioid around the clock, not anymore as needed. But now, around the clock, will maintain that blood level and allow the patient to have less episodes of breakthrough pain. An important thing to remember is that whether we decide to go with the extended release opioid or immediate release, it's nice to tell the patient that there might be moments in which the pain might break through. And so, giving that extra prescription and advice might help if there are moments in which the patient might break through. Brittany Harvey: Understood. And then the next clinical question that the guideline panel addressed, Dr. Paice, how should opioid-related adverse events be prevented or managed? Dr. Judith Paice: So, Brittany, I'm glad you asked me that question because I am called the pain and the poop nurse in the clinic, and it is so important whenever we can to prevent the adverse effects of opioids, and constipation is one where we can implement some preventive measures, and then treat unfortunately if your measures have not been totally effective. But we wanted to address the gamut of potential adverse effects. So, we included not only constipation, but delirium, endocrinopathies, sedation, nausea, vomiting, itching, and urinary retention. And we've included a table with very specific suggestions about how to prevent in some cases, and how to manage these adverse effects. Again, we wanted to make this document of the most use for all oncology clinicians who might be prescribing opioids for people with cancer. Brittany Harvey: Absolutely. And that's key to maintaining quality of life for patients. So, then Dr. Bruera, what does the panel recommend regarding modifying opioid use in patients with either renal or hepatic impairment? Dr. Eduardo Bruera: That's a great question, Brittany, and I think we have some evidence that some opioids are particularly desirable when the patient has renal dysfunction. One of the ones that comes to mind is methadone because it has almost no major renal elimination, and therefore, that might be a wonderful option. One of the challenges is that changing from one opioid to another sometimes is a little bit more complex than maintaining the opioid that is being used. And so, in absence of a major and fast deterioration, one option is to carefully titrate the dose of the opioid we're using to reduce the risk of accumulation in a given patient. There are some opioids that have traditionally been associated with a little bit more accumulation in cases of renal failure and traditionally, morphine is included, but there are other opioid agonists that also produce metabolites that are massively eliminated by urine that might be a little bit less desirable in patients with renal failure. With regards to liver failure, it's very hard to find a complete consensus about the opioids that are less desirable or potentially more desirable. And we could say that careful titration is important. But the one that was so good for renal failure might be the one you might not want to use for liver failure, and that would be methadone, because a vast majority of its metabolism happens in liver. So, I think cautious individualized titration might be a nice recommendation to our patients. And perhaps, the most important thing is that there might be a little bit of renal failure or liver failure, but it's very, very important that we maintain the opioid therapy, that we don't give up on the opioids. Brittany Harvey: Yes, those are important clinical considerations for individualized patient care. So, then Dr. Paice, Dr. Bruera touched on this a little bit earlier, but what are the recommendations regarding management of breakthrough pain? Dr. Judith Paice: So, breakthrough pain is very common in the person with cancer. We see this when the individual has bony metastases and they place pressure on that limb or joint. And the patient who's normally well-controlled with either a regularly scheduled immediate release agent or a long-acting agent, now experiences what we call breakthrough. And that's probably the most common type of breakthrough pain. There are also other breakthrough pains where the short-acting agent that's given regularly doesn't provide the relief that lasts four hours or six hours. Or similarly, if a long-acting agent is given every 12 hours, we may see that the pain breaks through prior to the next dose. But for that patient who requires breakthrough medication, unfortunately, the literature does not reveal that one agent is superior to another. So, any immediate release opioid that's appropriate for that patient can be used for breakthrough-related pain. Now, a common clinical conundrum is - which dose? What's the correct dose for the breakthrough medication? And again, the literature has a wide range of appropriate doses, and our committee established a range of 5 to 20% of the daily regular oral morphine equivalent daily dose. And our rationale for that was that you really cannot come up with one figure. Every patient is different. So, on average it's somewhere around 10%, but the range is five to 20% of the daily regular morphine equivalency. And so, what you need to do as you're examining the patient and exploring their needs is to look at the patient's frailty, the patient's pain, of course, their function when these breakthrough episodes occur. What about the comorbid kinds of organ dysfunction that Eduardo just spoke about? So, all of those other factors need to be considered when selecting the appropriate opioid for the breakthrough as well as the appropriate starting dose. Brittany Harvey: Definitely, it's important to consider all of those factors that you just mentioned. So, then the last clinical question that the panel addressed, Dr. Bruera, when and how should opioids be switched or rotated? Dr. Eduardo Bruera: Thank you, Brittany. This is a hugely important issue because for many, many years, we believe that since opioids stimulated an opioid Mu receptor, and they all had a similar effect, there will be limited rationale for changing. The answer to increasing pain was what we call opioid dose escalation. Just give more of the same. And we realized that that had serious limitations. And one of them is the development of side effects. And a lot of those side effects are neurotoxic side effects. Patients get unduly sedated, get hyperalgesia, paradoxical increase in pain due to active metabolites and changes in their receptors, and they also get sometimes myoclonus, hallucinations, confusion. And so, there are moments in which the side effects require us to say, okay, this opioid has done a good job for a while, but now, we have to change. And so, changing can be done due to side effects. But also, sometimes, since we're all different and there's a lot of interpersonal variation in response — as some patients may just not be controlled, their pain syndrome might not be controlled well-enough with one type of opioid because we know there are multiple sub-Mu receptors, and they might really benefit from another. So, the two main reasons are the development of toxicity to the opioid that so far was working reasonably well. And the second is failure, inability to control the pain, and in that case, going cautiously respecting the fact that there is limited cross-tolerance so that the dose of one opioid is not always exactly equivalent to the dose of the other opioid that you find in the actual tables that are published around is necessary to understand that that's a general guideline. But the most important thing is to go progressively and monitor your patient frequently when you change from one opioid agonist to another opioid agonist. There is limited understanding in the literature about the exact equianalgesic dosing. And because of that, a new guideline is being produced that addresses opioid rotation and deals exactly with trying to find out consensus from all the different existing tables on how to change what is the dose that is most likely to be appropriate when you move from one opioid, for example, morphine to hydromorphone or to fentanyl, or to oxycodone or vice versa. We dealt with great trepidation to give all our oncology clinicians some kind of a fixed table, but the evidence is unfortunately not there at this point. It is sad because these medications are not that new, but the evidence unfortunately, is not there. And that's why I think what we can tell you is go through your guidelines, use in a very careful monitoring of your patient to see if the dose you're giving is clearly not enough or it's a little bit too much. And you will learn that very rapidly — in a couple of days, you'll learn if you're doing okay or if you're doing too much or not enough. And stay tuned because hopefully, very soon, ASCO, together with MASCC and a couple of other organizations will provide you with a little bit more evidence around this. Brittany Harvey: Definitely, we'll look forward to that future guideline on opioid conversion tables as it is a confusing and complicated area, but it sounds like a lot of these recommendations are about providing individualized care for your patients. So, I want to thank you both for reviewing all of those recommendations that the panel came up with. So, then Dr. Paice, what does this guideline mean for both clinicians and for patients with pain from cancer or their cancer treatment? Dr. Judith Paice: Well, speaking on behalf of the panel, our wish is that this will improve the management of cancer-related pain, that people will feel more comfortable in safe and effective use of these agents, and they'll be used more effectively. There are other barriers that we've addressed, in addition to all of these recommendations. We talk about the care of people who have multiple chronic conditions. We address the disparities that we see in cancer pain management, and we talk about cost as another consideration, as one is developing a treatment plan for patients. We also address the patient-clinician communication that is so essential. This is definitely a team effort, and we guide our clinicians and offer for patients the need to have clear communication, open dialogue throughout the development of a treatment plan, and then throughout the course of treatment while we reassess whether the plan has been effective. Brittany Harvey: Absolutely. And it's really key what you just said about the safe and effective use of opioids for patients. So, then finally, Dr. Bruera, you've both mentioned this throughout our conversation today, where the literature is either inconclusive or evidence is insufficient. So, what are the outstanding questions about the use of opioids for pain from cancer or cancer therapies? Dr. Eduardo Bruera: I think there are questions that relate to the relative lack of specificity of the opioids for the different receptor pathways, and there are very likely considerable differences because they're chemically quite different, but they're considerable differences. But we have not done an awful lot of the head on comparisons that would be so wonderful to do. And I think we need more studies comparing the different existing medications, and more importantly, we need a lot of translational work to get to specific areas. Wouldn't it be fantastic if we were able to stimulate the Mu receptor all along the nociceptive pathway to reduce nociceptive input, but avoid completely the limbic system and avoid those Mu receptors in the area where reward is going to happen, an anti-reward and the possibility of developing non-medical use and eventually, opioid use disorder. That would be, to me, the corollary, the ability to dissociate those receptors along the nociceptive pathway from those receptors in the areas where we would like our opioids to not go, but we cannot avoid it because they're a bit dummy drugs. And so, hopefully, getting smarter opioids would be wonderful. Brittany Harvey: Absolutely. Well, I want to thank you both so much for your work developing this guideline, addressing these important questions for optimal pain management in patients with cancer. And thank you for your time today, Dr. Paice and Dr. Bruera. Dr.  Judith Paice: Thank you. Dr. Eduardo Bruera:Thank you so much. Brittany Harvey:And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/supportive-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. Voiceover: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

An interview with Dr. Van Morris from The University of Texas MD Anderson Cancer Center in Houston, TX and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, TN, co-chairs on "Treatment of Metastatic Colorectal Cancer: ASCO Guideline." Dr. Morris and Dr. Eng review the evidence-based recommendations from the guideline, focusing on areas of uncertainty in the treatment of metastatic colorectal cancer, and highlighting the importance of multidisciplinary collaboration and shared decision-making between patients and clinicians. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Van Morris, from The University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee - co-chairs on, 'Treatment of Metastatic Colorectal Cancer, ASCO Guideline.' Thank you for being here, Dr. Morris, and Dr. Eng. Dr. Cathy Eng: Thank you. Dr. Van Morris: Thank you. Brittany Harvey: First. I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Morris, do you have any relevant disclosures that are directly related to the guideline topic? Dr. Van Morris: Not personally, but I do have research support to my institution from Pfizer and Bristol Myers Squibb who have products that I'll be discussing on this podcast. Brittany Harvey: Thank you, Dr. Morris. And Dr. Eng, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Cathy Eng: Also, not personally associated with any honorarium specific to this topic. Brittany Harvey: Great. Thank you both. So then, let's talk about the content of this guideline. So first, Dr. Morris, can you provide an overview of the scope of this guideline? Dr. Van Morris: Sure. So colorectal cancer is the second-leading cause of cancer-related death in the United States. And especially in the time of the recent COVID-19 pandemic with people less likely to go for screening colonoscopies, there's great concern that more and more patients will be presenting at the time of their initial diagnosis with later-stage, more advanced colorectal cancer. So with that said, research is moving very quickly for the benefit of patients with colorectal cancer, and we were interested in assembling a multidisciplinary team that consisted of medical oncologists, surgical oncologists, radiation oncologists, pathologists, and radiologists as well, to help us make guidelines that really summarize the most relevant up-to-date practices, based on rigorous literature review for treatment recommendations for advanced metastatic colorectal cancer. Brittany Harvey: Great. And then as you just mentioned, this guideline provides recommendations, and a lot of those focus on areas of uncertainty in the treatment of metastatic colorectal cancer. And I'd like to review those key recommendations that you mentioned for our listeners. So, Dr. Eng, starting with - for patients with previously untreated, initially unresectable metastatic colorectal cancer, who are candidates for chemotherapy plus bevacizumab, is doublet or triplet cytotoxic chemotherapy recommended? Dr. Cathy Eng: For treatment-naive patients, bevacizumab has been approved, and we do agree that it's a very reasonable treatment option with doublet or triplet therapy for our patient population. Obviously, these are guidelines, and it's extremely important to keep in mind that as a provider, you need to discuss the potential side effects with the patient. With bevacizumab, you know, standard concerns must be discussed with the patient, especially in regards to wound healing, if they've had recent surgery or any potential risk factors for a recent cardiac event from a recent thrombosis. So, those things obviously, would preclude the patient from initiating treatment with bevacizumab. But currently, doublet therapy or triplet therapy could be a potential option for patients. Brittany Harvey: Great. And yes, as you mentioned, shared decision-making is paramount to these decisions. So then following that recommendation, Dr. Morris, which patients should be offered pembrolizumab in the first-line setting? Dr. Van Morris: Yeah. So, I think that this represents really one of the exciting advances in the treatment of metastatic colorectal cancer over the past several years. We have great data now that suggests for patients with microsatellite instability-high metastatic colorectal cancer, especially who have not had any prior treatment, we would recommend use of immune checkpoint blockade therapies, really coming from the seminal KEYNOTE-177 trial. This was a phase III international trial that looked at patients with advanced unresectable or metastatic colorectal cancer. And patients were either randomized to pembrolizumab monotherapy, or cytotoxic chemotherapy with FOLFOX, with or without bevacizumab. And this trial did meet its primary endpoint and showed an improvement in progression-free survival, with use of pembrolizumab as a single agent relative to cytotoxic chemotherapy. And based on this trial and the clear benefit that we see in patients with pembrolizumab, the FDA has approved this as an option for patients with MSI-high untreated metastatic colorectal cancer. There are other trials which have looked at use of immunotherapy; the CheckMate 142 trial looked at combination PD-1 CTLA-4 therapy as a single-arm study. And, you know, there's another trial, the CheckMate 8HW, which is looking at one versus two immunotherapy agents in this setting as well. But really, as it stands for now, patients with MSI-high untreated metastatic colorectal cancer are the ones who benefit from the use of immunotherapy. One of the questions that we often get in talking with other clinical oncologists is the FDA approval for pembrolizumab in any cancer type for a TMB, tumor mutation burden, greater than 10. And, we talked about this with our panel in this context, and we don't see that patients with microsatellite-stable metastatic colorectal cancer, who have a tumor mutation burden over 10 benefit from use of immunotherapy. There is one exception to this for patients who harbor pathogenic POLE or POLD1 mutations, these patients oftentimes do experience sustained clinical benefit with immunotherapy. But in general, patients with microsatellite-stable metastatic colorectal cancer, who don't have POLE/POLD1 mutations, we don't favor use of immunotherapy in that context at this point in time. Brittany Harvey: Great. Thank you for reviewing that recommendation and the data behind who benefits and who doesn't benefit from immunotherapy in this setting. So then following that, the next question that this guideline addressed is for treatment-naive RAS-wild type metastatic colorectal cancer. So, for these patients, Dr. Eng, is anti-EGFR therapy recommended for patients with right or left sided primary tumors? Dr. Cathy Eng: That is such an important question, and thank you for asking this. We know based upon pivotal data from CALGB/SWOG 80405, that right-sided tumors treatment-naive, even if they're RAS-wild type, these patients should not receive anti-EGFR therapy. But also, we've learned from 80405, FIRE-3, and PEAK, which was a phase two study, that there appeared to be some benefit versus anti-VEGF therapy for left-sided tumors based upon studies that have been conducted. So, at this year's ASCO, actually, the PARADIGM trial was specifically a phase III trial, more focused on left-sided tumors. It was amended twice before it decided to focus on the left-sided patient population. And it was a phase III study where patients were randomized to FOLFOX plus panitumumab versus FOLFOX and bevacizumab. And the primary endpoint was overall survival. And we added this data to our guidelines. This data just came out, hot off the presses in June, at this year's ASCO. And the primary endpoint was fulfilled. And basically, it prospectively demonstrated that the data from the other three trials, based upon a pooled analysis, suggested left-sided tumors fare better with anti-EGFR therapy. And in fact, the PARADIGM trial basically validated those findings. Obviously, the PARADIGM trial just recently presented, we have not seen the final publication, we do not know much about the maintenance setting, but specifically, when thinking about anti-EGFR therapy, it is very reasonable to consider it in a left-sided tumor, all RAS-wild type patient population. I would like to mention though, and we do highlight this also in the guidelines, which is critically important, is that there was another study, which is a phase III trial called, TRIPLETE, that was presented as well, looking at FOLFOXIRI plus panitumumab versus basically, standard treatment. And what it noted is that there is no additional benefit for FOLFOXIRI plus panitumumab in left-sided tumors in regards to response or progression-free survival, there was no additional benefit. So, FOLFOX plus panitumumab seems very reasonable, FOLFOXIRI plus panitumumab is not necessarily needed in left-sided tumors. Brittany Harvey: Great. Thank you for that explanation, and also for the work of the panel to rapidly include this new information recently presented at ASCO. So then following those recommendations, Dr. Morris, what recommendation did the panel make for patients with previously-treated metastatic colorectal cancer with a BRAF V600E mutation? Dr. Van Morris: Yeah. So, this recommendation was made essentially based on one randomized phase III clinical trial, which reported out about three years ago now, the BEACON trial. This is looking at patients with BRAF V600E mutated metastatic colorectal cancer, which we know accounts for probably eight to 10% of all patients with advanced colorectal cancer, and when found, really harbors a poor prognosis relative to BRAF-wild type counterparts. So, the BEACON trial was a trial that looked at patients with previously-treated metastatic colorectal cancer, who have BRAF mutations, either kind of standard of care cytotoxic chemotherapy, or a BRAF/EGFR combination with encorafenib and cetuximab or alternatively, a BRAF/EGFR/MEK combination. That trial showed that improvement in survival outcomes with a BRAF/EGFR-targeted approach, as well as the BRAF/MEK/EGFR. However, because there was no difference in survival with the addition of the MEK inhibitor, the FDA subsequently approved encorafenib and cetuximab as the recommended treatment for patients with BRAF V600E previously-treated metastatic colorectal cancer. Because the MEK combination with binimetinib was not recommended by the FDA, you know, we did not include that analysis in our guidelines for ASCO. But as it stands right now, we do strongly encourage all clinicians to check for their BRAF V600E mutation status in their patients with metastatic colorectal cancer, with the goal of getting them to a targeted therapy approach over their treatment course. Brittany Harvey: Great. Thank you for providing that information. So, following that, Dr. Eng, what are the recommendations for patients with colorectal peritoneal metastases? Dr. Cathy Eng: The current recommendations for colorectal cancer with peritoneal disease, really, there's no strong evidence to support the role of heated intraperitoneal chemotherapy. We now know based upon the literature from one of the largest studies to date, the PRODIGE data, demonstrating that there may be some potential benefit from cytoreductive surgery for the patients in regards to overall survival. But these patients are at high risk for bowel obstruction, potentially for perforation, and obviously, quality of life is an issue. So, these patients should always be discussed in a multidisciplinary tumor board whenever possible, and hopefully, to meet with a surgeon that is more experienced, specifically, in treating peritoneal disease, because these patients do require a lot of multidisciplinary care and discussion. So currently, based upon the existing data, we don't recommend heated intraperitoneal chemotherapy, but there may be a role for cytoreductive surgery. Brittany Harvey: Thank you, Dr. Eng for going over those recommendations. So then following that, Dr. Morris, for patients with unresectable liver-limited metastatic colorectal cancer, which liver-directed therapies are recommended? Dr. Van Morris: So, this is I think a really good question and one that just like the prior question with regards to peritoneal surgery, is one that we felt was a challenging one, but a common one that we wanted to address. And specifically, I think this is an example of where level of evidence comes into the strength of recommendation. So, for patients with unresectable liver-limited metastatic colorectal cancer, we looked at the questions of, "What is the role of SBRT - stereotactic body radiotherapy, and what is the role of SIRT, which is selective internal radiotherapy?" And for both of these, we felt that the level of evidence was weak, and I think that it's very important to make note of that in assessing the recommendations. But to start with, for SBRT, we looked at one meta-analysis for patients with oligometastatic colorectal cancer, and also analyzed 18 non-randomized control trials in this setting. Most of the patients in these studies had one to five liver metastases, with the majority having one or two liver metastases. From the meta-analysis, we saw kind of a one-year local control rate of around 67%, a two-year control rate of 59%. So, based on those and recognizing the limitations of non-randomized trials and making recommendations, the panel did feel that it was reasonable to consider use of SBRT for oligometastatic colorectal cancer. The SABR-COMET trial is one that had looked at the role of radiotherapy for treatment of oligometastatic colorectal cancer, and I just want to make the point as well, that we did not include that in our analysis or recommendations at this point in time, because this really didn't include a lot of patients with colorectal cancer that we felt warranted inclusion. Now, with regards to SIRT, we looked at kind of one meta-analysis and three randomized control trials for patients with mostly liver-limited metastatic colorectal cancer. All patients had liver disease, but there were about 40% of the patients we looked at in the meta-analysis, had extra hepatic disease as well. In the frontline setting, there really was no difference in progression-free survival or overall survival with the use of SIRT. And more recently, we've seen in a second-line trial, it was called the EPOCH trial, reported several years ago, this looked at patients with previously-treated metastatic colorectal cancer in the second-line setting. Patients were randomized to either chemotherapy with, or without transarterial radioembolization with Y90. While there was an improvement in overall response rate, there was no meaningful improvement in overall survival with the use of SIRT. But there were significant increases in grade 3 or grade 4 toxicities when SIRT was added to chemotherapy. So, kind of given this, we didn't feel at this point in time that SIRT should be recommended for patients with metastatic colorectal cancer. Although, again, I do want to highlight that really these discussions should be happening at high-volume centers, kind of with a multidisciplinary group of clinicians. Brittany Harvey: Definitely. And thank you for highlighting that multidisciplinary collaboration. And the last section of recommendations, Dr. Eng, what is recommended for patients with metastatic colorectal cancer, and potentially-curable oligometastatic liver metastases? Dr. Cathy Eng: So, another controversial topic. And once again, this is why we decided to include this as part of the guidelines, because this is a common scenario where patients are potentially curable, following liver resection for oligometastatic disease. We cannot highlight enough the importance of multidisciplinary discussion. Prior data has not been strong regarding specific guidelines following liver resection. We do recommend that based upon the existing data, there is no level one evidence to say, you should go one way or another following metastatic resection, and whether or not adjuvant therapy is warranted in that setting. But we do recommend multidisciplinary management and engagement and discussion. So, although it's not definitive, it basically suggests that there is a role for resection. It does provide improved five year survival relative to systemic chemotherapy, if the patient is potentially resectable, but does require multidisciplinary discussion. And it is a shared decision-making process. Brittany Harvey: Great. Thank you. And I appreciate you highlighting the importance of shared decision-making throughout this guideline. So then, Dr. Morris, what is the importance of this guideline in your opinion, and how will it impact clinical practice? Dr. Van Morris: Yeah. So, I think that we understand that management of metastatic colorectal cancer is extremely complex given the various molecular annotations and the multimodality therapies which are possible for our patients. So, we tried to limit the guidelines here to include what we feel are the most recent updates, but also kind of the most clinically-relevant multidisciplinary questions that get asked for treatment of metastatic colorectal cancer. We also recognize that things are changing quickly. And for example, we didn't decide to include at this point in time, management of HER2 neu amplified metastatic colorectal cancer, although we are seeing more and more data coming out, suggesting targeted therapies. So, I think it's important for clinicians to realize that these are guidelines which are ever-changing, given the updates with new therapies available for our patients. And the other thing I think that's very good about these guidelines is that, even though we may be making recommendations about controversial topics in the management of metastatic colorectal cancer - specifically, I think the use of HIPEC with cytoreductive surgery, locally-directed therapies to the liver, and the role of perioperative chemotherapy and metastasectomy - I think it's important for oncologists to realize that these recommendations come with varying strengths of level of evidence and that we as oncologists should be considering the level of evidence that's out there when making recommendations that affect our patients as well. So, we really wanted to support these guidelines and recommendations and empower clinicians to know and understand the quality of evidence that exists in the management of patients with metastatic colorectal cancer. Brittany Harvey: Excellent. And yes, those are key points on the level of evidence and the strength of recommendations throughout the guideline. And then finally, Dr. Eng, you've talked a bit about shared decision-making and the importance of this guideline for patients. So, how will these guideline recommendations affect patients with metastatic colorectal cancer? Dr. Cathy Eng: The reason that we created these guidelines is to help patients, their caregivers, and providers, learn of the most recent developments in colorectal cancer, and the best approach based upon the information that we have personally reviewed with our multidisciplinary team of faculty members that participated in this exercise. We really just want to make sure that patients do get optimal care. And we hope that these guidelines also will help provide a foundation for some of the clinical trials that may be under development, or for other clinical trials that are being considered. So, we really just want to provide the most up-to-date information to all individuals that are interested in colorectal cancer so we can help guide their care better. Brittany Harvey: So, I want to thank you both so much for your work on these guidelines, and all of the time it's spent developing these recommendations, and thank you for your time today, Dr. Morris, and Dr. Eng. Dr. Van Morris: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to: www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

An interview with Dr. William Tew from Memorial Sloan Kettering Cancer Center in New York, NY, lead author on "Poly(ADP-Ribose) Polymerase Inhibitors in the Management of Ovarian Cancer: ASCO Guideline Rapid Recommendation Update." Dr. Tew reviews changes to the recommendations for PARPi therapy for patients with epithelial ovarian cancer, and the outstanding questions in the field. For more information, visit www.asco.org/gynecologic-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today, I'm interviewing Dr. William Tew from Memorial Sloan Kettering Cancer Center in New York, New York; lead author on “PARP Inhibitors in the Management of Ovarian Cancer, ASCO Guideline Rapid Recommendation Update.” Thank you for being here, Dr. Tew.  Dr. William Tew: Thank you, Brittany. Glad to be here.  Brittany Harvey: Great. Then first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.  The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.  Dr. Tew, do you have any relevant disclosures that are directly related to this guideline topic?  Dr. William Tew: I do not.  Brittany Harvey: Thank you. Then let's get into the content of this rapid update. So, what prompted this rapid update to the ASCO Guideline on PARP inhibitor therapy in the management of ovarian cancer, which was previously published in 2020?  Dr. William Tew: Yeah, there's been rapid change in the use of PARP inhibitors over the last five years. We have seen marked improvements and patient outcomes with the use of PARP inhibitors in the maintenance setting and treatment settings.  And new data has developed specifically in the last three months that we felt it was really important to help our patients and their providers, give them the best and safest treatments with PARP inhibitors.  Brittany Harvey: Understood. So, then based off this new data that you mentioned, what are the updated recommendations from the expert panel?  Dr. William Tew: Well, there's a few. First, at ASCO 2022 in June, there was the ATHENA-MONO phase III randomized control trial that was presented and published looking at rucaparib monotherapy in patients with stage III-IV epithelial ovarian cancer who were in complete or partial response to platinum-based therapy and in remission. And then studies showed a significant improvement in progression-free survival.  And that's what first prompted the update of the guideline. We felt it was an important note that now, there are three PARP inhibitors that are approved and showing significant benefit in patients in the first remission setting. And those are olaparib, niraparib, and rucaparib.  And then as we were working on the guideline, there has been several updates provided primarily through Dear Doctor letters directed through the U.S. FDA, as well as different labeling changes that were made to different PARP inhibitors.  However, the changes that were made are in the settings outside of the first line setting. So, we are talking about patients who had recurrence of their ovarian cancer and where PARPs are being used either as treatment or as a maintenance strategy after completion of another round of platinum-based treatment.  Brittany Harvey: Understood. So, these sound like important updates to the recommendations. So, then what should clinicians know as they implement these updated recommendations?  Dr. William Tew: Well, I think first and foremost, PARP inhibitors are a really critical treatment strategy for our patients. And patients that benefit the most from PARP inhibitors are women with a germline or somatic mutation in the BRCA gene. These are the patients that are going to benefit the most.  And then I think where the confusion lies is how best to use PARP inhibitors in patients that don't have a BRCA mutation. These groups of patients kind of fall into different categories.  One, a group of patients that have what's called homologous repair deficiency, or those patients that don't have a BRCA gene or have a BRCA gene mutation, or have this HRD positive status.  The emerging data that has been presented is really focused on mostly these patients, this non-BRCA patient population. And again, I want to just be cautious here because this is all evolving data and I suspect further data is going to emerge over the coming months and years.  And we wanted to give some flexibility as far as how patients and their providers use PARP inhibitors, but we felt given that this new emerging data specifically with signals affecting survival, was important to outline to our community.  Brittany Harvey: Excellent. And then you've just touched on those who respond best to PARP inhibitor therapy, but how does this rapid update impact patients with epithelial ovarian cancer?  Dr. William Tew: Yeah, I think what we described and outlined in this updated guideline is that, one, as a general rule, PARP inhibitors are not particularly recommended in patients as a treatment.  That is, if patients have recurrence of their ovarian cancer, using PARP inhibitors as a treatment rather than a maintenance strategy does not offer significant benefit and may have some survival decrements. At least, this is the data that we are following.  And so, as a general recommendation, we're expressing caution in the use of PARP inhibitors in patients that have platinum sensitive recurrence as a treatment. And we are continuing to recommend (this was in the initial 2020 guideline) that PARP inhibitor monotherapy is not recommended for patients with platinum-resistant recurrent ovarian cancer or BRCA wild-type.  The other broad category is PARP inhibitor maintenance, and where we've made some adjustments in the guideline is as far as the strength and the overall recommendations of the use of PARP inhibitors after completion of platinum-based therapy in the recurrent setting.  And specifically, we're expressing caution and the use of PARP inhibitors, particularly for those that have BRCA wild-type, meaning they don't have a germline or somatic BRCA mutation, and expressing some caution in patients that are just homologous repair deficient score positive.  Brittany Harvey: Well, I appreciate you reviewing the updated data that the panel reviewed and what those new recommendations that you all made.  So, you just mentioned that further data may emerge over the coming days and years. So, what are the outstanding questions regarding PARPi therapy in the management of ovarian cancer?  Dr. William Tew: Well, I think a few things. One, the way PARP inhibitors have been developed was first in the recurrent setting as a treatment, then in the recurrent setting as a maintenance, and most recently, in the frontline treatment as maintenance therapy.  And what we're seeing as this data evolves is that PARP inhibitor has remain a very important treatment strategy in the first line maintenance group. And patients with BRCA mutations continue to have significant improvements and outcomes.  But what I think the data that we're following closely, is what about those patients that have recurrent ovarian cancer and where PARPs now are being used as treatment and maintenance — we're seeing that as a treatment, there may be harm, although, again, cautioned because of the data that is used. There's faults with how we look at this data.  But really, these subgroups of patients, specifically those patients without a positive HRD score or those patients without a BRCA mutation, is the benefit going to still outweigh the risk in the PARP inhibitor maintenance setting, particularly in the recurrent setting.  Brittany Harvey: Yes, those are important questions and I'm sure the panel will keep their eye on those to update the guideline further as needed.  So, I want to thank you so much for your work on this rapid update, and thank you for your time today, Dr. Tew.  Dr. William Tew: You're welcome.  Brittany: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines.   You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store.  If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.  Voiceover: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy, should not be construed as an ASCO endorsement.     

An interview with Dr. Surendra Shastri from the University of Texas MD Anderson Cancer Center in Houston, TX, and Dr. Jose Jeronimo from the National Cancer Institute in Bethesda, MD, co-chairs on "Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline Update." Dr. Shastri and Dr. Jeronimo review the updated recommendations in the guideline, covering screening, triage, management, follow-up, and considerations for special populations. Read the full guideline at www.asco.org/resource-stratified-guidelines.   TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Surendra Shastri from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. José Jerónimo from the National Cancer Institute in Bethesda, Maryland; co-chairs on ‘Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline Update'.   Thank you for being here, Dr. Shastri and Dr. Jerónimo.  Dr. José Jerónimo: My pleasure.  Dr. Surendra Shastri: Thank you very much.  Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with a publication of the guideline in the JCO Global Oncology.   Dr. Shastri, do you have any relevant disclosures that are directly related to this guideline topic?  Dr. Surendra Shastri: No, I don't have any disclosures.  Brittany Harvey: Thank you. And Dr. Jerónimo, do you have any relevant disclosures that are directly related to this guideline topic?  Dr. José Jerónimo: No, I don't have any.  Brittany Harvey: Thank you both. So, to start us off, Dr. Jerónimo, what prompted this update to ASCO's guideline on secondary prevention of cervical cancer, last published in 2016? And what is the scope of this guideline update?  Dr. José Jerónimo: That's a great question. Yes, it's natural for people to start wondering why the guidelines change or are updated so frequently. And I think there are several factors. The main one is that science on cervical cancer and other diseases is evolving very rapidly; there are new publications, there are new technologies, there is new information about different aspects of cervical cancer prevention specifically. The updates of those technologies is so fast that we need to periodically update the guidelines to accommodate these new options.  Now, I have to highlight that the ASCO guidelines in 2016 -- those guidelines were already very ahead of everyone else. What I mean is, in 2016, we were already recommending HPV testing for everyone all over the planet as a preferred option. It's something that other guidelines, other organizations were still wondering about, but we were really very upfront on that recommendation, considering that that's the best technology we have. I think the updates of the guidelines is important because we need to keep with science, and we need to keep the doctors using the guidelines also updated on what exactly is out there, and what options could be usable for the different settings.  Brittany Harvey: Great, thank you for that background on the guideline update and for describing why the guideline needs to be updated over time. So then, Dr. Shastri, as this is a resource-stratified guideline, can you describe the four-tiered framework of the guideline? Specifically, what are the Basic, Limited, Enhanced and Maximal resource levels?  Dr. Surendra Shastri: Saying one size doesn't fit all would be a cruel example in health situations where it's really unfortunate that there are large disparities across the world, between countries, within countries, and that's the reason why we need resource-stratified guidelines. We can't just sit in ivory towers and preach to people who don't have anything. So that's the reason why we have the resource-stratified guidelines, and we have followed the same resource structure that the Breast Health Global Initiative is following.  So, we basically have four different resource levels. The most Basic one, or the core resources, is where you have just very basic public health services available. It's not services which are looking for outcomes and are just part of the social welfare that the country has to provide. Many times, those are also situations where the health priorities are very different.  For example, health priorities for some countries might still be infectious diseases, as it was amply displayed in the current pandemic. So, considering those situations, the expenditure that the country does or expenditure a local governing body does on a particular disease could be very different. So, at Basic, just available screening services at the lowest level.  Then you have the Limited; the Limited is slightly better than the Basics. They have maybe some of the newer technologies like Dr. Jerónimo just explained, not all of it. Some of those may not be able to provide in the same frequency or to everybody out there. But they are at this point of time looking at outcomes, looking at cost-effectiveness and those kinds of things.   Step up a little bit, and you have Enhanced level. That's the third tier of the resource level that we are talking about. In the Enhanced level, we have much better services available, we have organized services available. And those services have probably a system of tracking and recording clients or people who undergo screening and early detection.  And the final is the Maximal level. In the Maximal level, it is what we see across North America, or what we see in Europe, where you have the latest technologies, you have established systems, and you have systems to track and follow people. Again, I will caution here, even if I say North America or Europe, it's not across North America and across Europe. There are several places in North America, there are several places in Europe, which do not have the same resources. And that's why in this guideline, we're not talking about country guidelines, we're talking about resource-limited guidelines.  Brittany Harvey: Understood. I appreciate that description of the stepwise approach and how it isn't necessarily applicable just to one country, but there are differences in resource levels across countries and within countries.   So then, the guideline panel made recommendations across these four resource levels. Next, I'd like to review the key recommendations of this guideline update across those resource levels. So, Dr. Jerónimo, what are the recommended methods for cervical cancer screening?  Dr. José Jerónimo: That's a challenging situation on what to use in the different settings. Dr. Shastri already described very clearly the different scenarios we are facing; places with extremely limited resources where basically you have only maybe an evaluation table there, and places in the other extreme with all the resources and all the technologies available.  But even though we have very different areas with very different resources, the most recommended test for a screening for cervical cancer in all of them is HPV testing; the testing for the Human papillomavirus that is directly related to cervical cancer. The question could be, "Okay, why are you recommending that test for places where maybe now they are not going to be able to do it?" I think it's important to put that technology as a target, even though the sites are not prepared right now to do it, but they have to go towards that goal of implementing HPV testing.  Meanwhile, the guidelines also highlight that there are other options that could be used in the meantime to do some screening, one is visual inspection with acetic acid that is being already implemented in many places. And the reason why we are recommending HPV testing even in those places with extremely limited resources is because there are some advantages. First, with HPV testing, it's very highly sensitive, extremely highly sensitive. That means that you have a sensitivity over 90% with good validated tests. Second, because it's highly sensitive, you have the option to have a smaller number of screenings in the lifetime. Instead of -- some people remember, some years ago, the screening for cervical cancer with Pap smear was done every year.  But now we know that it's changing. With HPV testing, we are now recommending every five years or in these guidelines, depending on the resources, could be every 10 years, or could be once or two times in the lifetime of the woman. And with that, we are going to have a huge impact.  The other great advantage of HPV testing is that it can be self-collected by women. That means that basically, a woman takes the small brush, goes to a private place and introduce that in their vagina and collect the sample herself, without the need of specula, without the need of trained personnel, without the need of having all the infrastructure that is required for a pelvic evaluation.  And that's big because in that way, we can reach populations that are hard to reach. And also, we are dealing with some issues like cultural resistance to have a pelvic evaluation. I mean, that's the biggest advantage for HPV testing. And we have now examples showing that this is very well accepted in many, many studies around the world with different populations around the world showing that self-collection is very accepted. That means that the preferred test for cervical cancer prevention is HPV testing right now. There are options displayed in the guidelines for cities where it's not possible to do it now, but that's the role.  Brittany Harvey: Understood. Thank you for explaining what testing is recommended; HPV testing, and then also the timing and collection strategies across settings. So, then following that, Dr. Shastri, what is recommended regarding triage for patients who have positive results or other abnormal results?  Dr. Surendra Shastri: So, let me briefly explain what triage is; right up following the primary screening when the woman has a positive result, a second technique or technology is used to determine whether this person needs to be treated, or this person needs to be tracked and followed up in a particular way. So, our recommendations for triage in the updated guidelines is that for the Basic settings, just like Dr. Jerónimo mentioned, if we have used HPV screening in the basic settings; that's the molecular test, and if that is positive, then we use another strategy which is known as, visual assessment for treatment. And this strategy is used to determine whether a woman should be treated with thermal ablation, or with LEEP, or she just needs to be followed. Whereas all the other three settings, HPV genotyping along with cytology, or cytology alone should be used for triage.  Brittany Harvey: Great. Thank you for explaining those triage recommendations. So then following triage, Dr. Jerónimo, what is recommended regarding management and follow-up strategies for patients with precursors of cervical cancer?  Dr. José Jerónimo: I think treatment also has evolved significantly in the last 20 or more years. And specifically, in the last five years or 10 years, there are new options that are becoming more popular because there is more evidence supporting the effectiveness of this technology, and ablation of that tissue is really one of the best options in most of the places.  I always try to compare the pre-cancer lesion like the paint on your wall, in your house. If one of the kids come with something and you start to scratch something in there, you don't need to turn the wall down in order to fix that problem. Basically, you just have to remove that area and put some new paint, and that's going to be corrected. In the same way, when you have a pre-cancer of the cervix, it's very, very superficial. It's not cancer, it's pre-cancer. You don't need to remove the whole cervix or the whole uterus to treat that. With ablation, basically what we are doing is destroying that tissue that is in the very surface, and new cells, healthy cells are going to come and are going to cover that area. That's the idea. The technologies that are more usable for areas with limited resources could be the thermal ablation or could be cryotherapy.  The other advantage of those technologies is basically there is no major complication; no bleeding, no major problems. Of course, as Dr. Shastri explained, there are more resources in other places. In other places, you have more resources, you can do a LEEP; that is, basically using an electrical device, removing part of the cervix and sending that to the pathologist. That's also one option that is acceptable and recommended in the guidelines. I think the main idea is, we need to remove that area with disease, with pre-cancer. We can remove it using ablation; just destroying the cells, or we can remove it using some excisional procedure. That all depends on the resources you have.  But how effective those technologies are, I could say there is very high cure rates using thermal ablation, for example, or LEEP. Very important to consider, doing the procedure, you can do it anywhere. Doing a LEEP, in theory, you can do it anywhere where you have electricity and you have the equipment. But remember, you have to be prepared not only for the treatment, you have to be prepared for the complication. If you have a LEEP, a very portable device and you have electricity, but if you are far from the next health facility, if you have a complication like you are bleeding in that setting, it's going to take hours, hours and hours just to evacuate that patient to the health facility. That's why you need to be very careful not only on the treatment, but also managing the complication.  Brittany Harvey: Understood. I appreciate you reviewing those technologies. So then, following those notes that Dr. Jerónimo just made, Dr. Shastri, are there any changes to the recommendations for special populations or highlights that you'd like to note that are identified in the guideline?  Dr. Surendra Shastri: This is a speciality of the ASCO guidelines really also to take a look and make recommendations for special populations. And by special populations here I mean the ones that we have looked at and recommended cervical cancer screening for are; women who are HIV positive or immunocompromised, immunosuppressed due to any other disease, or any other reasons, maybe because of medication, or cancer or other disease conditions which requires immunosuppressives.  For such women, we would say you start screening for cervical cancer as soon as the first diagnosis; the diagnosis of the disease which is causing immunosuppression is done. That's the first time. And then, through their lifetime, you screen them twice as frequently as you would do for other women who do not have an immunocompromised situation. So, you do it more frequently. As far as the management post-screening with positive results is concerned, for women with HIV as with all immunosuppressed women, it is the same. The triage is the same and the management will be the same as for all other women.  Then also pregnant women. For pregnant women, we recommend in the very Basic settings, pregnant women should be screened six weeks postpartum. And in all other settings, all other levels, we recommend that they should be screened six months postpartum. The very reason is, in many basic settings, you may not even get those women back for screening. That's the reason why we try to screen as early as possible. But on the safer side, the earliest possible is six weeks postpartum; that is, she is still probably following up for postpartum reasons of the pregnancy or immunization for the kid. That's the time we should go ahead and do it.  And finally, women who have undergone a hysterectomy but still have an intact cervix, need to get screened in the same way as other women. However, they could stop screening over a period of time, if they have more than three negative results.  A very interesting subject that we discussed in our committee, and we have put it up there as a statement to bring it up is that, we now come across several people who are transgender, who have an intact cervix. So, getting such people into screening, and screening them like all others, will be an important priority. We have put out a statement saying that, although we mentioned that this is for women, it is for all persons who have an intact cervix. So these screening guidelines apply to everyone.  Brittany Harvey: Yes, it's important that all persons with a cervix get screened for cervical cancer as it is something that can affect anyone with a cervix. And those are important considerations for clinicians that you noted across several different populations.   So then, in your view, Dr. Jerónimo, what is the importance of this guideline overall, and how does it impact clinicians?  Dr. José Jerónimo: That's, I think the core of the guidelines is how this is going to affect the practice of clinicians. I think the main message here with the guidelines is: first, clearly acknowledging that the resources are different in different settings, and we need to accommodate to those settings to provide the best service. I think for clinicians, it is presenting options that could be suitable for their setting. As Dr. Shastri mentioned at the beginning, we are not talking specifically about countries. Because in one given country, you can have areas with Maximal resources, you can have areas with Limited resources, and you can have areas with Basic resources. If you try to apply that new, most modern, expensive technologies everywhere, you're going to be just doing the screening in very few places in the country because it's not possible.  With the guidelines, we are giving the option saying, "Okay, if you don't have access to those technologies, you can get started using this. For example, visual inspection. If the technology becomes available, for example, HPV testing, you can start to use HPV testing, because that's the goal. That's what you really need to look for. If you don't have the resources or the conditions to do excision procedure like a LEEP, you can do ablation, and that's okay. And basically presenting, you have different options to accommodate to your place. But the most important part is, do it well. Do it well, reach as many women as possible with your screening, and treat as many positive women as possible." I think that's the best message here. And I think that's the way these guidelines are going to help and impact the world of clinicians.  Brittany Harvey: Yeah, that's the core message of the resource-stratified guidelines; is using the resources you need to help and treat and screen the most people possible. So then finally, Dr. Shastri, how do these guideline recommendations affect patients?  Dr. Surendra Shastri: I will just add one line to the response that Dr. Jerónimo just gave you. We already have an existing country guideline, these are meant to complement those guidelines, and meant for the policymakers in those countries to open their eyes and realize that there are people at different resource levels, who may or may not have an insurance program, who may or may not have a socialized system which provides the same level of health care for everyone. So, use what we recommend because that's the current evidence for use.  Coming to how people are going to benefit, which was your question, these guidelines are going to make cervical cancer screening available and accessible to all women across the globe. We are talking about different options. We are not saying that, "if you don't have X, don't screen." We are saying, "if you don't have X, try Y. If you don't have Y, try Z." So, this opens up doors for all women across the globe to get screening. That is the ultimate goal, because if you want to reach the WHO goal of eradication of cervical cancer, then that's possible only through two means; one, is giving cervical cancer screening, preferably HPV, through whatever means or resources that the country has, and the vaccination, which is of course, being dealt by another committee over here.  So of course, all women across the globe will get benefit of newer technologies, simpler, cost-effective technologies, technologies that don't require them to -- for example, a self-collection, the woman doesn't really have to go anywhere. She doesn't have to go and wait in a clinic for hours to get a screen. She doesn't have to make repeat visits to get a screen. She doesn't have to lose her wages. These are things which are real. She doesn't have to lose her wages for the day, she doesn't have to arrange for child support to look after her children just to go and get herself screened. Those are some of the social determinants of health, which prevent women from going and getting themselves screened. So, by a simple technique like self-collection, we removed that entirely.  Going forward, we are going to see Artificial Intelligence, we are going to have deep machine learning, we are going to change the technology and the strategies, and we will come back with another update to this, maybe very soon, sooner than what we did this time.  Brittany Harvey: Absolutely. Those are excellent points. And we'll look forward to future updates as technologies continue to advance. So, I want to thank you both so much for your work on updating these resource-stratified guidelines for the secondary prevention of cervical cancer. And thank you for your time today, Dr. Shastri and Dr. Jerónimo.  Dr. José Jerónimo: My pleasure.  Dr. Surendra Shastri: Thank you for inviting us.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO guidelines podcast series. To read the full guideline go to: www.asco.org/resource-stratified-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.   

An interview with Dr. Rohan Garje from Miami Cancer Institute in Miami, FL, lead author on "Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Rapid Recommendation." Dr. Garje reviews the new evidence and the latest recommendation update for the use of 177Lu-PSMA-617, a radioligand therapy in patients with PSMA-positive mCRPC, along with it's implications for clinicians and patients. For more information, visit www.asco.org/genitourinary-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at: asco.org/podcast. My name is Brittany Harvey, and today I'm interviewing Dr. Rohan Garje from Miami Cancer Institute in Miami, Florida, lead author on, ‘Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Rapid Recommendation'. Thank you for being here, Dr. Garje. Dr. Rohan Garje: Absolutely. Thank you so much for having me, Brittany. Brittany Harvey: Great. And first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Garje, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Rohan Garje: Yes. I have received institutional research funding from Pfizer, Amgen, Endocyte, and AAA, who have drugs for the treatment of prostate cancer. Brittany Harvey: Excellent. Thank you for those disclosures. Then getting into the content of this guideline update, what prompted this rapid update to the ‘ASCO Guideline on Systemic Therapy in Men with Metastatic Castration-Resistant Prostate Cancer', which was previously published in 2014? Dr. Rohan Garje: Since 2014, there have been several new drugs that have been approved for prostate cancer management. And most recently in March 2022, FDA has approved 177Lutetium-PSMA-617 for patients with PSMA scan-positive metastatic castration-resistant prostate cancer. This led to the team from ASCO to develop this new rapid recommendation update. Now, this approval actually has been based on the efficacy data published in Vision clinical trials. To give you a little background about Lutetium, it is a novel β-energy-emitting radioligand therapy. In this particular study, this agent was combined with best standard of care, and compared to best standard care alone, in men with metastatic castration-resistant prostate cancer, who had a positive PSMA scan. Briefly, the study was both clinically and statistically positive, and has shown improvement in both overall survival and radiographic progression-free survival. The median overall survival was about 15.3 months with the combination therapy, compared to 11.3 months with the standard care arm. Brittany Harvey: Great. And then based off this new evidence and the new approval from the FDA for 177 Lutetium-PSMA-617, what are the updated recommendations from the guideline panel? Dr. Rohan Garje: The panel recommends the use of 177 Lutetium-PSMA-617 as a treatment option in patients with PSMA PET/CT positive metastatic castration-resistant prostate cancer, who have been previously treated with at least one line of androgen receptor pathway inhibitor, and at least one line of prior axon-based chemotherapy. Brittany Harvey: Great. And then, what should clinicians know as they implement the use of this drug and this new recommendation by the guideline panel? Dr. Rohan Garje: A very good question. It is important to select patients based on a positive PSMA scan. That is, all the metastatic lesions should be positive on the PSMA scan, and there should not be any large lymph nodes or visceral organ metastatic disease that are PSMA negative. Additionally, physicians can use Gallium 68 PSMA-11, or F-18 Piflufolastat as radio tracers for PSMA scan to determine eligibility. Additionally, there are several other factors that need to be considered, such as: the patient should have baseline good blood counts, as well as renal function to be eligible for this therapy, as this treatment has a potential to cause mild suppression and impairment of renal function. The most common side effects associated with this drug are fatigue, dry mouth, dry eyes, and nausea. The treatment in general is for four to six cycles. Each cycle is for every six weeks. The fifth and sixth cycles should be considered only if patients are responding well to the therapy and have no significant toxicities. It is also important for the physicians to note that there are several additional treatment options for patients with metastatic castration-resistant prostate cancer, who had prior anti-androgen docetaxel therapy. They include; Cabazitaxel, PARP inhibitors for patients who have mutations in DNA repair, gene mutations such as BRCA1 and BRCA2, and immunotherapy with Pembrolizumab for patients with MSI-high status, or tumor mutation burden greater than 10. Brittany Harvey: Thank you for describing that nuance behind the recommendations. So then, in addition, how does this update impact patients with metastatic castration-resistant prostate cancer? Dr. Rohan Garje: 177 Lutetium-PSMA-617 is the first radioligand therapy approved for the treatment of prostate cancer. Previously, we had Radium-223 as a radiopharmaceutical, but this particular agent is unique in the sense, it is a radioligand therapy where it is chelated to PSMA. So, it is very targeted therapy which works for both bone and visceral organ metastasis. So, this is an exciting treatment option for patients, as it has been shown to have improvement in overall survival. This adds to the current treatment choices of anti-androgens, chemotherapy, as well as targeted therapies for prostate cancer patients. Brittany Harvey: Great. It's exciting to have a new treatment option for patients. So then finally, what are the outstanding questions regarding systemic therapy for metastatic castration-resistant prostate cancer? Dr. Rohan Garje: We are at an exciting stage in the management of prostate cancer. In the last decade, we have seen several new drugs; some are specific targeted agents, some are specific immunotherapy agents. Now, we are entering into this realm of radioligand therapy, which is very exciting. There are several other novel radioligand therapies such as; Actinium, Thorium, Lead, which are being evaluated in the treatment of prostate cancer. So, in the next several years, we will see several new drugs that have been developed. In addition, there are other agents called T-cell-engaging therapies, which are being evaluated to improve the outcomes. So, the last decade definitely has seen a lot of new improvements, but we are so excited that several new treatment choices are now available for patients, and several are in clinical evaluation. So, the future is bright for the patients with prostate cancer, where we have several new treatment choices to improve their outcomes. Brittany Harvey: It sounds like an exciting time for developments in prostate cancer. So, I want to thank you so much for your time today, Dr. Garje, and thank you for all of the work you did to update this guideline. Dr. Rohan Garje: Thank you so much. I really thank ASCO leadership and the team for giving me this opportunity, and thank you, Brittany, for hosting me on this podcast. Brittany Harvey: And thank you to all of our listeners for tuning into ASCO Guidelines Podcast series. To read the full guideline, go to: www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.    

An interview with Dr. Jun Mao from Memorial Sloan Kettering Cancer Center in New York, NY, lead author on "Integrative Medicine for Pain Management in Oncology: SIO-ASCO Guideline." Dr. Mao reviews the recommendations on integrative approaches, such as acupuncture, yoga, reflexology, massage, guided imagery with progressive muscle relaxation, hypnosis, and music therapy for managing pain in patients with cancer, and the evidence behind these recommendations. He also addresses the implications for clinicians and patients as well as outstanding questions about the use of integrative approaches for pain management. Read the full guideline at www.asco.org/survivorship-guidelines.   TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcast. My name is Brittany Harvey, and today I'm interviewing Dr. Jun Mao from Memorial Sloan Kettering Cancer Center in New York, New York, lead author on ‘Integrative Medicine for Pain Management in Oncology: Society for Integrative Oncology and American Society of Clinical Oncology Guideline'. Thank you for being here, Dr. Mao. Dr. Jun Mao: Thank you, Brittany. It's great to be here. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available in line with the publication of the guideline in the Journal of Clinical Oncology. Dr. Mao, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Jun Mao: No, I don't. Brittany Harvey: Great. Then I'd like to get into the content of this guideline. So what is the purpose and scope of this joint SIO-ASCO guideline? Dr. Jun Mao: So Brittany, about one in two cancer patients or survivors experience pain that often are not adequately controlled by conventional medications. So often individuals seek out complementary and alternative medicine, more recently known as integrative medicine, for the relief of pain, but there's a very little synthesized information for oncologists to help guide the patients in choosing evidence-based integrative therapy approach. Therefore, we decided to really do a systematic review and come up with a system of guidelines that can help oncologists and patients make informed decisions about choosing the right type of integrative medicine approaches to manage pain. The Society for Integrative Oncology and the American Society of Clinical Oncology joined forces that really convene a group of panelists, that represent many fields in conventional oncology in support of integrative medicine. And after reviewing over 200 articles from clinical trials to systematic review have come up with very thoughtful recommendations to help patients and physicians to provide the best evidence-based care on how to manage pain for patients with cancer. Brittany Harvey: Excellent. And yes, it's great to have SIO and ASCO join forces on this guideline. So then next, I'd like to review those key evidence-based recommendations of this guideline that you just mentioned. The recommendations are provided in the guideline by pain type. So I'd like to review each category for our listeners, starting with: what is recommended for patients experiencing aromatase inhibitor related joint pain? Dr. Jun Mao: So we recommend acupuncture should be offered to patients experiencing aromatase inhibitors related joint pain in breast cancer. And this is really evidence-based, benefits outweigh the harms. And with intermediate quality of evidence and moderate strength of recommendation. As many of our audience would know, aromatase inhibitors cause very severe types of joint pain that not only affect quality of life and functions, but make many women stop taking these life saving drugs. So the panelists want to recommend this therapy based on large randomized control trial that hope this can be part of a pain management strategy along with exercise and duloxetine so give people the options so that women can not only have better quality of life, but also hopefully they can stay on aromatase inhibitor to prevent the recurrence of breast cancer. And we also found some weak evidence for yoga to improve joint pain related to AIs. However, the evidence is weak, although the benefit outweighs the harm. So clearly, more studies are needed to make yoga as a part of therapies for cancer patients. Brittany Harvey: Understood. And thank you for reviewing the level of evidence behind those two interventions for patients experiencing aromatase inhibitor related joint pain. So following those recommendations, what is recommended for patients experiencing general cancer pain or musculoskeletal pain? Dr. Jun Mao: So in terms of general cancer pain or musculoskeletal pain, there are three therapies that we consider that may be offered to patients experiencing this type of pain: acupuncture, reflexology or acupressure, or massage. So reflexology and acupressure use the same kind of principles like acupuncture, but instead of using needles, by using hands. So that's kind of in between acupuncture and  massage. So these are evidence based recommendations with benefits outweigh harms, and the quality of evidence is intermediate with moderate level of evidence and recommendations. So clearly, for cancer patients or survivors that experience this type of general cancer pain or musculoskeletal pain, I think these approaches may be appropriately integrated along with conventional pharmacotherapy or physical therapy. Brittany Harvey: Definitely. It's great to have options to go along with conventional pharmacologic therapy. So then following those recommendations you just mentioned, what is recommended for patients with chemotherapy-induced peripheral neuropathy? Dr. Jun Mao: So chemotherapy-induced peripheral neuropathy, also known as CIPN, is a very bothersome symptom resulting from certain types of chemotherapy that can be very functional limiting, and resulting in falls and that also can cut the dosage of chemotherapy. So this is a quite bothersome to patients and also can be really challenging in the practice of oncology. So based on the current evidence, we recommend either acupuncture or reflexology or acupressure may be offered to patients who experience CIPM. So, unfortunately, the evidence base here is weaker. So although it's evidence-based, benefits outweigh harms, but the quality of evidence is low. Therefore, the level recommendation is weak. So basically, there are a number of smaller trials that really provide some good signals that this type of therapies can be beneficial. But we really need more large and definitive trials to establish the strength of the evidence Brittany Harvey: Understood. It's important to know in which patient populations we have more evidence and where we still need confirmatory results. So following those recommendations, what is recommended for patients who experience procedural or surgical pain? Dr. Jun Mao: Many surgery procedures or surgery itself can cause acute short-term pain that if not adequately treated, can then become chronic. So in this setting, there is actually a pretty reasonably robust base for hypnosis. So the evidence base really is intermediate with moderate level recommendation. We consider that hypnosis may be offered to patients experiencing procedural pain in cancer treatment or diagnostic workups. However, for other type of therapies like acupuncture or acupressure or music therapy, although there are some smaller trials to show that it could be beneficial, the current evidence base is very low and the strength of recommendation is weak. So clearly, we need more high-quality trials to establish the evidence base for those therapies for surgery or procedure-related pain Brittany Harvey: Understood, and we'll get into some of those outstanding questions or where there's insufficient evidence a little bit later in the episode. So then the last category of recommendations that the panel made: what is recommended for patients who have pain during palliative and hospice care? Dr. Jun Mao: So for patients with advanced cancer near the end of life, there is some good evidence that massage may be offered for patients experiencing pain during palliative and hospice care. So we recommend massage should be used with an intermediate level of evidence and moderate level of recommendation. And I do think the caveat is we still don't know the long-term effects for massage. Therefore, many of the trials, the follow up are reasonably short. But the evidence showing that acupuncture in the population of palliative care hospice patients can produce immediate pain relief as well as to enhance coping. Therefore, we suggest massage may be offered to patients experiencing pain during hospice or palliative care settings. Brittany Harvey: Understood. Well, thank you for reviewing all those recommendations, the level of evidence behind them and the strength of those recommendations. But you've also mentioned that in several areas, there's low evidence or insufficient evidence. So are there interventions that the panel reviewed but found insufficient or inconclusive evidence to make recommendations? Dr. Jun Mao: Brittany, I feel like the field of integrative medicines research is still in its infancy or adolescence. So there's clearly a lot of gaps, particularly in the area of mindfulness-based interventions. There are studies showing outside oncology settings, it can be very helpful for managing pain and pain coping, but that literature in oncology is very, very limited to make any reasonable recommendation. So I think research is needed. Another area is in the area of herbal medicine or supplements. A lot of cancer patients have a lot of interest in using supplements or herbs to manage symptoms, improve their sense of well-being. But the trials unfortunately in this setting are just too sparse and the quality is too poor to make any recommendation. Last but not least, is for children that experience pain. This guideline was sought out to develop recommendations for both adults and children. Unfortunately, the trials in the pediatric populations are just too few and some of the quality are just too poor. Therefore, there's inconclusive evidence in that population to recommend any specific therapy to be used to manage pain. So I do think these represent really important gaps in research that we really need to be developing and designing and conducting rigorous clinical trials to build an evidence base so we can bring integrative medicine into conventional oncology care to help patients with a variety of truths. Brittany Harvey: Yes, well, we certainly appreciate the panel reviewing this mountain of evidence across several different integrative oncology approaches, even if we ended up not making recommendations for certain interventions because of inconclusive or insufficient evidence because it still demonstrates the need for high-quality trials in those areas. In your view, Dr. Mao, what is the importance of this guideline? And how will it change clinical practice? Dr. Jun Mao: Brittany, I think this guideline is both important and timely. With the opiate epidemic experienced in the United States, managing pain for cancer patients and survivors is incredibly challenging. This is the first SIO and ASCO joint guideline for integrative medicine for pain. And for the first time, we have solid recommendations for specific integrative medicine modalities to care for patients and survivors with pain. I do think the implementation process will take time. First of all, we need to find ways to educate oncology providers as well as patients about the evidence base of this treatment so they can talk to their patients about this type of therapies. Second of all, some of the therapies are not uniformly covered by insurance. So we do need better insurance coverage for integrative therapies such as acupuncture, massage, or reflexology for managed pain for cancer patients. So people from across socioeconomic areas can access it. I think last but not least, as we know, there are disparities in healthcare infrastructures. In large hospitals like Memorial Sloan Kettering Cancer Center, Dana-Farber, or MD Anderson Cancer Center, we do have acupuncture services developed to help cancer patients. But then in smaller community hospitals, especially in those who serve predominantly black and brown populations, those services may not be in existence. So we need to partner with our community partners to develop the necessary resources to overcome those structural barriers for these therapies to be incorporated as part of standard oncology care. Brittany Harvey: Definitely. Those are key points on the implementation of this guideline and the availability and accessibility of integrative medicine modalities across different hospitals and patients. So then, this leads into my next question, how will these guideline recommendations impact patients? Dr. Jun Mao: It is my hope this will really help improve patient care, and also patients here in such  conventional oncological treatments,  whether they're chemo therapies or hormonal treatments. I do think patients in general have a lot of preferences for using therapies that are a little bit more natural or therapies are in addition to drugs to manage their pain or symptoms. So these guidelines clearly provided recommendations based on prior research. And I do think as we engage patients in shared decision making, we need to really acknowledge patients' beliefs, preferences, as well as availability of treatments in their care settings. So hopefully we can provide both evidence-based and patient-centered care to manage pain. Brittany Harvey: It's great to have more options beyond conventional treatments to offer patients to help with pain management because it occurs across cancer patients. Finally, Dr. Mao, you've already talked about some interventions where we lacked data such as mindfulness-based interventions, herbal medicines and supplements, and interventions in the pediatric population. But what are the outstanding questions for the use of integrative approaches and managing pain in patients with cancer? Dr. Jun Mao: Brittany, as a researcher, I'm always thinking about the future questions. I do think with clinical trials in the last 10 years, there's definitely larger and well done trials to demonstrate both efficacy and effectiveness of specific integrative medicine therapies for improving pain. We need to do more of that in the next 10, 20 years. In addition, I think two particular areas of research I hope to see more research as part of these guidelines being implemented, one is what I consider precision pain management. But just because acupuncture works for some patients, it doesn't work for everyone. We need to figure out what type of molecular biomarkers, so psychological attributes can help to predict who may respond to acupuncture or not so we can make sure the right person gets the right care for best pain management and at the least amount of cost to him or herself or to the society. The second issue I really think we've got to do better is I feel like there's wide acknowledgement of health disparity in pain management, particularly in cancer patients. I'd love to see more research designed for and in populations of historically underserved populations, so we can really implement this approaches to narrow the health disparity issues in cancer care. Brittany Harvey: Absolutely. Those are key points about providing equitable care for pain management in oncology. So I want to thank you for all of your work on these guidelines, Dr. Mao, and thank you for taking the time to speak with me today. Dr. Jun Mao: Brittany, it's such a pleasure. Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

"My Mother's Last Lesson," by Colt Williams: A resident learns about managing mental illness during cancer treatment.   TRANSCRIPT Narrator: My Mother's Last Lesson, by Colt Williams, MD (10.1200/JCO.21.02382)   In January 2017, my 65-year-old mother was diagnosed with treatable cancer. The problem was that she did not want to live.   Her mental health had declined precipitously after losing my father 8 years before, and her grief proved insurmountable. She had been a functional alcoholic for most of my life, and commonly smoothed over the roughness of a long day with half a bottle of whiskey. Growing up, alcohol had been ubiquitous to the point of banality, yet she was nonetheless able to lead a very successful life. But the silence of my father's absence was deafening, and her few moments of relief were only ever found at the bottom of a bottle. Her life came apart at the seams as she had stopped working, lost contact with most of her friends, and rarely left the house. Then, after years of limitless sorrow, when she was told she had advanced, but treatable squamous cell carcinoma of the tongue, she wanted to allow it to end her life.   Despite a high chance of cure, my mother saw her situation as both cause and justification to end her life. Why pursue a painful and disfiguring treatment to save a life already devoid of light, companionship, or love? She argued that she had already lived a full and rewarding life, and without my father at her side, her existence had become a shell of its former self. Her advanced directive had stated “Do Not Resuscitate” as far back as my father's initial entanglement with cancer, nearly 10 years before. Long before any of these immediate issues arose, she had made it clear that, “When it's my time, it's my time.”   Her treatment team was clear that if she received the standard treatments, her probability of survival was excellent, but that the journey would be grueling. Removing a third of her tongue would likely leave her with permanent speaking and swallowing difficulties. Radiation to her mouth and throat would cause severe inflammation and pain. A temporary feeding tube would pump tasteless, khaki colored goo directly into her stomach to bypass her swollen mouth and throat. She was assured that she would be supported by an interdisciplinary team and given any, and all, measures to ensure her comfort.   She asked what would happen if she chose not to pursue treatment. Her oncologist shifted on his stool, his arms crossing, and his speech slowing. I projected my own thoughts and discomfort onto his change of posture, “Why are you asking him that? It's treatable! Tell her, make her fight!” Her oncologist warned us that her cancer had the potential to slowly rob her of her ability to speak, eat, swallow, and eventually breathe. Even with treatment, there was still a chance she could end up in the same situation if the cancer did not respond or if it came back later. All I could think was “at least we would have tried.”   My mother found the idea of death comforting as she would be released from physical and emotional pain. After our initial visit with her oncologist, however, she became terrified of the symptoms she might experience as she was dying. I too was afraid of what would come. Nightmares of her choking while I watched on powerlessly were frequent over the next few nights. Still, she was not convinced that treatment was what she wanted. I pushed her, begged her to be treated. After a long, emotional, and arduous weighing of her options, I shared with my mother's doctors a collective sigh of relief when she reluctantly agreed to treatment.   Two weeks before her surgery, I went to visit after my medical school classes. We had talked on the phone the night before, and our conversation had left me worried. My father's death was a common topic for us, but her perseveration on the irreparable void in her soul was alarming. I found her stumbling around the house, her shoulder dragging against the wall after she had careened into it. She was a drunk, but never this sloppy—something else was going on. She slid to the floor, eyes half-lidded. “I'm going to go find your dad.” I found the empty bottle of morphine shortly after I had called 911; it was my father's from when he came home on hospice nearly a decade ago. She must have held on to it for all those years, her fire escape from a burning reality.   The morphine was too old and there was too little left in the bottle to kill her, but the message her actions sent was loud and clear. Until examined and cleared by a psychiatrist, she was unsafe to be alone. She had a long history of bipolar disorder, acknowledged but untreated. Her mood would cycle between periods of working late every night to days at a time where she would not leave bed or even shower. There had been stints in the past where she had seen a psychiatrist or tried medication, but they never lasted. She enjoyed being colorful, eccentric, and prone to strong feelings. During the week of her hospitalization, there was no argument that she was unfit to make her own decisions and that her mental health needed serious attention.   After she had returned to an acceptable level of risk to herself, she was discharged on several mood stabilizers and with a follow-up visit with a psychiatrist. She went for a few visits; I suspect more to affirm business as usual rather than out of genuine interest. She quickly stopped going, and her passive suicidality and romanticization of death were ever present. She spoke often of the simplicity and relief of simply ceasing to exist. It has been well established that the risk for suicide is twice as high in patients with cancer compared to the general population, and my mother's history of bipolar disorder and alcoholism further compounded that risk.1 I honestly do not know why there was not a psychiatrist on her care team from the very beginning; her unmanaged bipolar disorder was cause enough to justify comanagement. I deeply regret not having advocated strongly for one from the beginning of her treatment.   As her son and having recently become a new physician, I struggled to know how to help my mother. I tried to delicately toe the line between acting as my mother's advocate and protecting her from herself. In a patient as complicated as my mother, one with extensive comorbid psychiatric illness interspersed with episodes of acute delirium, the patient's history of previous preferences may be quite valuable. In my own fear of losing someone I loved, I lost track of what was truly important to her as a human being. The exigency of her attempted suicide blinded me to the otherwise valid intricacies of her longstanding values regarding her end-of-life care.   Even amid the turmoil of her attempted suicide, the specter of her cancer never strayed far. Ultimately, she resigned herself to treatment, undergoing surgery, completing radiation, and receiving two cycles of chemotherapy. She tried to quit three times, each time her radiation oncologist and I encouraged her to continue. Despite her insistence that life was not worth living, she continued onward, driven more so by the fear of a painful death than by the desire for life itself.   I was acutely aware of her existential angst. At the time, it felt like a festering wound that had been covered merely to spare the eyes of those looking on. I was starting my medicine residency at this point, and my burgeoning understanding of patient care only added to my disquiet. I found her plan of care to be hollow. If she truly did not want to be treated and only wanted to avoid suffering, did treatment have to be all or none? Couldn't her physical suffering be minimized while still respecting her autonomy in her right to choose how she should live and die? More disturbingly, if her desire to forego treatment wasn't sound, why wasn't her mental health being treated more aggressively? I could not put these worries to words, and only with the clarity afforded by time can I now explain what exactly troubled me as new physician, let alone as her son.   The hollowness I felt in her care could not be directed toward her care team, as they provided the standard of care. Her surgeon performed excellently in the operating room, her medical oncologist prescribed appropriate chemotherapy, and her radiation oncologist delivered her radiation with precision. Equally, my mother participated in her care as much as her mental health allowed her to. The health system, however, failed her. It felt as though she received her care piecemeal from each specialist, rather than visiting with members of a unified team. Where there should have been collaboration between oncology and psychiatry, there was fragmentation.   Early integration of psychiatric care would likely have had tremendous impact on the last year of her life. Cancer does not afford us the time to treat our patient's diseases sequentially; her mental health had proven to be as great of a threat to her life as her malignancy. Although distress screening and integrated psychosocial treatment are standards of care set by the Commission on Cancer, access to mental health care is still woefully inadequate in many parts of the United States.2 As oncologists, we will inevitably treat patients with mental illness, addiction, or both. Assessment of and intervention on our patient's mental well-being should be given as much priority during our visits as investigating a new anemia or peripheral neuropathy. When there is not a collaborative care model to fall back on, it is imperative that clinicians strive to ensure that patients receive the resources they need.   Despite it all, despite the arguing, the pleading, the crying, the pain, the suffering, despite completing her therapy as prescribed, her cancer continued to grow and surrounded her airway. She entered home hospice and struggled along for a few more weeks. She called me one morning after another sleepless night, gasping for air, and told me, once again, that she was ready to die.   I had learned to ignore those words, alarm fatigue blunting their emotional impact, but this time there was something different in the way she spoke. She was neither groping for consolation nor lost in the trance-like depths of her grief. Her voice was calm and determined, strength drawn from the finality of her decision. She did not need to fight anymore; the imminence of her death was now inevitable. It was the most peaceful she had ever been in my adult life. Six days later, after she stopped putting food or water into her feeding tube, she finally found the relief she had so long desired.   It has taken these 4 years to realize that my desire for what could be obscured my ability to see what was. More than anything, I wanted to spare her from what I saw as avoidable suffering, but I had also seen an opportunity. She would have needed to be sober for chemo, or risk toxicities above and beyond what was already expected. I let my emotional needs drive how I advised her. I wanted her to be treated because I was too afraid to accept her mortality, and too hopeful that this could be the start of sobriety. In the moment, I told myself that she could not truly want to forsake a future that still held so much potential, that she could not truly be willing to abandon her family. At first, I looked back upon my actions with cold acceptance, telling myself that her untreated mental illness was clouding her judgment. I felt justified in pushing her to continue with treatment in what I saw as my duty to care for her. The steadfastness of my conclusions softened into ambivalence the more I reflected. Through my supposedly benevolent interjection in her life, did I inadvertently cause her more suffering in my attempt to avoid it?   Now, I am no longer certain I would have pushed as hard or for as long as I did, or perhaps have even pushed her at all. Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one at podcast.asco.org. I'm your host, Lidia Schapira, Associate Editor for Art of Oncology and a Professor of Medicine at Stanford. My guest today is Dr. Colt Williams, a fellow in medical oncology and ethics at Mayo Clinic. He will be discussing his Art of Oncology article, ‘My Mother's Last Lesson.' Our guest has no disclosures. Colt, welcome to our podcast. Dr. Colt Williams: Dr. Shapiro, thank you so much for having me today. Dr. Lidia Schapira: It is my pleasure. I'd like to start by asking you what you are currently reading, or what you have recently read that you would recommend to our listeners. I suspect that most people who love to write are also avid readers. Am I right? Dr. Colt Williams: You are very right. I actually love science fiction. And I recently picked up Ender's Game - I had never read it despite the media attention it got a few years ago when the movie came out. And boy, it is just as good as I hoped it would be. Dr. Lidia Schapira: That's fantastic. I'm glad you enjoy it. Let's talk a little bit about your essay. It is very, very personal and very moving. The strong message I took from your essay was how important it is to support caregivers, and how important it is to recognize and attend to mental health during cancer treatment. Tell us a little bit about what led you to write and share this very personal moving story. Dr. Colt Williams: My family life growing up was very private. And both when my father initially had cancer in 2009, and then when my mother fell ill in 2017, the culture within my family was very isolating. And I found myself left without much support for myself as a caregiver to my mother. And equally for both my parents, when they were going through cancer treatment had in a way kept them from being able to experience a lot of the help that they needed for both of them. Reflecting back as I grew through my medical training, and became a resident and then a fellow. As I became my mother's primary caregiver, I saw the damage that that had played both for her and for myself. And in reflecting on this, I had always felt that there was something that wasn't quite right with how things had played out with my mother's death. And I really wanted to be able to put to words for my own healing more than anything else, a way to find closure from my experiences. Dr. Lidia Schapira: Let's talk a little bit about the process and the motivation to write as a way to express yourself to achieve some clarity, as you say, to bring closure. How did you get started? And how long did it take you to write this piece? Dr. Colt Williams: Getting started was the hardest part. I initially wrote a very early version of this in medical school when my mother was first diagnosed with cancer as a case report for how we may approach our patients with comorbid mental illness and physical illness. And that first case report changed many numbers of times in the ensuing four years that it took, or five years, actually, until its final form. I started working on it in earnest again, after shelving it about a year ago. It took a solid year of coming back to the piece a few times a month, looking at wording, looking at the way I was writing to really make sure that the message I was wanting to convey was clear because I felt there was so much that I want to explore both of myself, and so much I wanted to share about my experience. But I also knew that I needed to distill down my experience into a few key points that would, one, really resonate with myself in terms of what were the issues that kept me from feeling that I had the closure that I so desired, but two, how can I make this a digestible piece for my audience. And writing has always been something I've enjoyed. I've enjoyed writing poetry. I've enjoyed reading. And for me being able to put pen to paper to help catharsis some of my thoughts has always been very useful for me. Dr. Lidia Schapira: So, did it work? Did this piece give you what you hoped it would give you? Dr. Colt Williams: It did in a bittersweet way. It was very hard sometimes to sit down and really think about some of these harder moments that I shared with my mother and to go back and relive them but in taking the time to very thoughtfully relive what were traumatic experiences for me, I was able to examine them now with the benefit of time, in a way that I couldn't because of my emotional clouding at the time for how intense the emotions were. And so, writing did provide me with a lot of closure. Dr. Lidia Schapira: Sometimes it takes many years to be able to write about something that is emotionally resonant. It's taken me about 20 years to be able to write about a patient that I love dearly who's died, so I totally understand. But what about the other piece that is sharing these very personal thoughts with a broader audience, especially since you're sort of still in training. Dr. Colt Williams: I remember coming away after my mother had died, and we had her cremated and we had finished with our small ceremony for her thinking that the experiences I had had with her mental illness, with her alcoholism, with the attempted suicide, all of this during training were all things that seemed that, at first glance, I may not want to share. This complicates things. I don't want my residency program director to know what's going through or my potential fellowship matches to know the troubles that I've been going through. While I was doing well with things, I felt that there was a lot that not only I could learn, but that could be really helpful for others. Case in point, with how isolating things felt, I felt this need to connect with other people through my experience. And I felt like the conclusions that I had arrived at really coming to terms with the fact that I was and am ambivalent about my actions with how I pushed my mother to receive her care was something that other people could relate to, and that someone else could learn from. And I hoped that I was able to maybe shorten the period from writing, from point A to point B in that process for someone else, through reading about my own experiences. Dr. Lidia Schapira: How has this experience, Colt, informed your work? I can't help but comment on the fact that you're doing a fellowship, not only in oncology but in ethics. Dr. Colt Williams: Extraordinarily informative. I think about my mother often when I see my patients, for better or worse. I can't help but project sometimes with some of my patients, but it gives me a reason to pause and to be patient, whereas maybe some other colleagues may be less tolerant of individuals who are non-adherent with their medication regimen or decided to end their radiation treatments early because of side effects despite the clear risk to their health in doing so. I feel that I can approach patients who can be more complex and may be more nuanced in a way that I can provide them with the grace and with the space that they need to be individuals, even if that does not necessarily line up with what we as their physicians know to be best for their physical health, knowing that not everyone can abide by the restraining needs of cancer treatment. And by extension, with my interest in ethics, there were a lot of things that I saw both in the way that my mother interacted with her physicians, the ways that she was able to push them, the ways that she was able to make them uncomfortable, made me think a lot about how ought we care for patients like this? And who are we as physicians in the roles of our patients' lives? What role are we playing for them? And how should we exert the very clear power that we have and the important role that we have in a way to make sure that we're always acting in our patient's best interests? Dr. Lidia Schapira: That sounds amazing, actually. Can you give me and share with our listeners an example of how your own experience as a caregiver and as a witness to your mother's complicated history, as you talk about her romanticizing deaths, and really being prepared to die, almost from the time she was diagnosed, how that has perhaps impacted your clinical care? Dr. Colt Williams: I can think of a few patients I've seen recently who have come to me after learning that they have metastatic cancer at their time of presentation, very openly discussing forgoing treatment in its entirety, despite there being options proven to not only prolong their overall survival but their quality of life. And I feel that, even within my group, there are some providers that would really, really push strongly for those patients to consider those treatments without taking the time to consider why: why are you approaching your treatment like this? Why are you approaching your disease like this? What is it that makes you think that this is the right way? And I say think not to imply that they think it's wrong or to think that they are thinking wrong, but to truly understand where they're coming from as an individual and as human beings. We all have extraordinarily unique experiences that lead us to become the people that we are. And all those experiences are valid, and simply because my understanding of how I believe I can best take care of you doesn't line up with what your experiences are, does not mean that your goals for your own life are any less valid than what I think you ought to be doing. So, I think at the end of the day, I'm willing to have a conversation more often with my patients. I'm willing to get myself into places that might be both uncomfortable for me as the provider, and uncomfortable with the patient if they're willing to meet me there on common ground, so we can really find what is going to be for them as human beings the best treatment path moving forward - treatment or not. Dr. Lidia Schapira: It's wonderful to hear you and one of the themes that I hear in your approach is that you find medicine not only rewarding but really mission-driven. And part of the mission is to get to know the person who has the disease. I found your essay very powerful because it addressed so many different issues that make caregiving and giving of professional care so complex. One is the idea of a whole person perspective worldview, as you've just explained to us the idea that we want to listen to and help patients tell us what matters to them, and help them live their journey according to their own values and aspirations. But the other is the issue here of the sadness that emerges from your essay. The fact that your mother was ready to accept the sadness and the finality of death. The fact that it was complicated by her lifelong addiction and history of alcoholism, as you say, the deafening silence of your father's absence in her life. And perhaps what she felt she wanted to do for her children whom I am pretty sure you don't say it, but I'm sure she loved dearly. How did you manage to put all of this into the essay? It certainly impressed this reader, but how did you make that decision to include all of these different threads into your narrative? Dr. Colt Williams: It felt dis-genuine to not include them. And how I managed to do it, I think is a mystery to me as well, to be completely honest. The sadness, the pain, so many compromises with her, so many times where I worried about her, so many times where I could think to myself, if only things were a little bit different, if only she could see things and the way that I see things, that was such an integral part of my experience, and through the pain of not being able to have the person that brought you into this world see the value in their own life was really the impetus that led me to the conclusions I'm now able to draw about recognizing her own values and individual. And while I will always intrinsically see her as my mother, and for all the things that a mother means, before she was my mother, she was still her own person. And those beliefs preceded me. And while any child, I think, would want to think that they are the center of their parent's life, sometimes you're not. Dr. Lidia Schapira: In your essay, you share with the readers that you feel that she found her peace before she died. Have you made your peace with her death? Dr. Colt Williams: I think I have now. I struggled with it for a long time. I struggled with whether I did the right thing by encouraging her to seek treatment when she didn't want to. I struggled with whether I should have pushed harder. I fought with myself on both sides of the coin, which way I should have gone playing out the 'ifs'. What if I would have done this? What if I wouldn't have done this? How things could have been different. But in the end, it's the truth that when I spent my last few days with her, it truly was the most peaceful I had ever seen her in my life. That te restlessness that could be felt within her, even before she was ill, was gone. She was finally complete in a way. She, in her mind, had completed her mission. I was in medical school. I was successful. My sister's a lawyer. She's doing well. Her children were grown and taken care of. And she could finally be free of what she felt like were fetters holding her down to a horrible existence. And I think the experience of being able to be present with her and to place myself in her shoes, as best I could, was really enlightening. And I think my last week with her while she was at home dying was the most formative event of my life. Dr. Lidia Schapira: I've never seen you with patients, but I suspect that you're very sensitive to the plight and situation of caregivers. Can you tell me a little bit about that? Dr. Colt Williams: Cancer is a disease that affects not only the patient but the entire family. It takes many people to take care of our patients, from the physicians to the nurses to our pharmacists to our CNAs that are in the hospital, but equally, we see them for an hour, if we're lucky every three weeks, and our patients' family members or their caregivers are with them the other 24 hours a day and the other times, they're always there. And if it wasn't for their caregivers, our patients certainly would not be doing as well as they are. Cancer is not just a disease that affects the organs, but it's also a disease of existential angst. It's a disease that affects our understanding of what it means to be human, of what it means to have a limited time on this earth, to be mortal beings. And those are things that we often as a species avoid encountering until we absolutely have to. As I saw myself, trying to handle this in isolation does not bode well. We are a social people and we rely on our caregivers and our family extraordinarily heavily. And it's just as important to make sure that our patients' families are set up for success if we want our patients to succeed, as it is to make sure that we've dosed our chemotherapy appropriately or provided the appropriate antiemetics before infusion. Dr. Lidia Schapira: Listening to you talk convinces me that you have found your path in onc, and in ethics, and perhaps moral philosophy as well. It's wonderful to hear you reflect. I thank you very much for sending us your work and wish you much success in your career both as an oncologist and ethicist. Dr. Colt Williams: Thank you, Dr. Schapira, for having me. It's been an absolute pleasure to speak with you. Dr. Lidia Schapira: Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories: The Art of Oncology podcast. This is just one of many of ASCO's podcasts. You can find all of the shows at podcast.asco.org.   The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO the mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.    

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for first-, second-, and third-line therapy in patients with stage IV NSCLC without driver alterations. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, Michigan, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on 'Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Guideline Update'. Thank you for being here, Dr. Jaiyesimi and Dr. Robinson.  Dr. Ishmael Jaiyesimi: Thank you for inviting me.  Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.  The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.  Dr. Jaiyesimi, do you have any relevant disclosures that are directly related to this guideline topic?  Dr. Ishmael Jaiyesimi: I do not have any financial disclosures. Thank you.  Brittany Harvey: Thank you. And Dr. Robinson, do you have any relevant disclosures that are directly related to this guideline topic?  Dr: Andrew Robinson: Yes, I do. I have had funding of less than $5,000 from BMS, Merck, and AstraZeneca in the past two years.  Brittany Harvey: Okay. Thank you for those disclosures. So, then let's talk about the content of this guideline update. So, Dr. Jaiyesimi, what prompted this guideline update, and what is the scope of the update?  Dr. Ishmael Jaiyesimi: The purpose of this guideline update is to update the ASCO and Ontario Health guidelines on the systemic treatment of patients with non-driver alteration stage IV non-small cell lung cancer last published in January of 2020.  The update is the result of potentially practice-changing evidence published since the last update. ASCO published the last full clinical practice guideline updates on systemic therapy for patients with stage IV non-small cell lung cancer that included those whose cancer did not have driver alterations in January of 2020.  The scope of evidence for the update guideline is made of ongoing or completed randomized controlled trials for non-driver alterations from 2018 to 2021. These updated algorithms provide recommendations from the ASCO expert panel and emphasized rapid changes in the management of patients with advanced non-small cell lung cancer and the importance of clinical research.  Brittany Harvey: Thank you for that overview, Dr. Jaiyesimi. So, then talking about those changes you just mentioned, I'd like to review the new or changed recommendations for this guideline. So, let's start with for patients with stage IV non-small cell lung cancer without driver alterations, and with high PD-L1 expression and non-squamous cell carcinoma, what are the updated recommendations for first-line therapy?  Dr. Ishmael Jaiyesimi: In addition to 2020 options for patients with high PD-L1, 50% or more expression, non-squamous cell carcinoma, and performance status of zero to one, and absence of targetable oncogenic driver alterations, clinicians may offer a single agent atezolizumab alone, or single agent cemiplimab alone, or a combination of nivolumab and ipilimumab without chemotherapy, or a combination of nivolumab and ipilimumab with two cycles of platinum-based chemotherapy. The number of acceptable options has increased. And each of the recommendations carries a strength of recommendation and quality of evidence with it.  Brittany Harvey: I appreciate you reviewing those options. So, then Dr. Robinson, moving on to the next category of patients addressed in this guideline, for patients with stage IV non-small cell lung cancer without driver alterations and with negative or low positive PD-L1 expression and non-squamous cell carcinoma, what are the updated recommendations for first-line therapy?  Dr. Andrew Robinson: Thank you for that question. So, in addition to the 2020 options for patients with negative, 0%, and low positive PD-L1 expression, with a TPS score of 1 to 49% and I'd add, unknown PD-L1, non-squamous, non-small cell lung cancer and a good performance status, clinicians may offer combination nivolumab and ipilimumab or combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy.  These are the additional recommendations and this gives an increased number of acceptable options, particularly for patients who cannot or choose not to take cytotoxic chemotherapy.  Brittany Harvey: Understood. Thank you for reviewing those options. So. then the next category of patients this guideline addresses, for patients with stage IV non-small cell lung cancer without driver alterations and with high PD-L1 expression and squamous cell carcinoma, what are those updated recommendations for first-line therapy?  Dr. Andrew Robinson: So, similar to the patients with non-squamous cell carcinoma for patients with stage IV non-small cell lung cancer that is squamous cell and a good performance status of zero to one, clinicians may also offer single agent atezolizumab alone or single agent cemiplimab or combination nivolumab and ipilimumab or combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy followed by ongoing nivolumab and ipilimumab. So, these are additional recommendations in this group as acceptable options for treatment.  Brittany Harvey: Great thank you for reviewing those options. So, then Dr. Jaiyesimi, what is recommended for patients with stage four non-small cell lung cancer without driver alterations and with negative or low positive PD-L1 expression and squamous cell carcinoma for first-line therapy?  Dr. Ishmael Jaiyesimi: In addition to 2020 recommendations, for patients with negative, TPS 0%, and low positive, with TPS 1% to 49%, PD-L1 expression, squamous cell carcinoma, and performance status of zero to one, clinicians may offer a combination of nivolumab and ipilimumab alone or a combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy.  Brittany Harvey: Great! So, then we've just reviewed the updates and changes to the first-line therapy recommendations. So, Dr. Jaiyesimi, were there any updates to second- or third-line therapy recommendations for patients with stage IV NSCLC without driver alterations?  Dr. Ishmael Jaiyesimi: For patients with non-squamous cell carcinoma who receive an immune checkpoint inhibitor and chemotherapy as first-line therapy, the clinician may offer paclitaxel plus bevacizumab in the second-line setting.  For the majority of patients with non-squamous cell carcinoma who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, in either sequence, clinicians should offer the option of single-agent pemetrexed (non squamous cell carcinoma, non-small cell lung cancer), or docetaxel (all histologic types), or weekly paclitaxel plus bevacizumab, (non-squamous cell carcinoma, non-small cell lung cancer) in the third-line setting.  For patients in whom the initial treatment was not a chemoimmunotherapy combination should receive the treatment not given earlier that is platinum doublet chemotherapy (if the initial treatment was monotherapy with an immune checkpoint inhibitor, or dual immune checkpoint inhibitor therapy) and immunotherapy with an approved PD-1 or PD-L1 inhibitor in the second line setting (if the initial treatment was platinum doublet chemotherapy).  Brittany Harvey: Okay, thank you for reviewing those recommendations as well. So, then Dr. Robinson, what is the importance of these recommendation updates for practicing clinicians?  Dr. Andrew Robinson: These updates give an increasing menu of choices for patients and physicians, particularly in the first-line setting. The increased list of acceptable first-line options may help us physicians may run into situations where their preferred first-line option isn't available, or for other reasons shouldn't be given.  Now we recognize that given the increasing variety of options in the first line, it would be really nice if we could have guidelines, that say in this certain patient treatment with nivolumab and ipilimumab is recommended and in that certain patient chemotherapy plus pembrolizumab is recommended, and divide things up that way so that the right patient gets the right treatment.  However, the guideline committee did not feel that this was appropriate at that time as the only comparative data with these different strategies is insufficient, either population-based data or cross trial and network comparisons, that, however well done, do not have a defense against confounders and bias that a randomized study has.  So, the advances in drug development and research in non-small cell lung cancer in the past decade have made available multiple treatment options, particularly for first-line therapy for patients, and to some extent, this has also made the process of decision making in this context challenging for practicing clinicians, especially in the community and for patients and caregivers.  Clinicians need to understand patients' comorbidities as well as other variables that can potentially influence treatment decisions prior to making final therapeutic recommendations for any given patient, and also become comfortable handling a few of these regimens. Each of these are somewhat complex regimens with sometimes subtle and sometimes not-so-subtle differences that require expertise and appropriate treatment and monitoring.  So, with so many options available, it's important that clinicians get familiar with a few of them at least given that all of these regimens are now considered as appropriate standard of care regimens suitable for first-line therapy, it may also help justify physicians, researchers and ethics boards who are participating, designing and overseeing simple clinical trials that pragmatically ask the questions as to what should be used when.  So, physicians should simultaneously become familiar with these guidelines, familiar with different therapies, have expertise in a few of these therapies, and continue to stress cancer clinical trials that may improve outcomes, and also may help us determine which treatment for which patient at which time.  Brittany Harvey: Definitely, that makes sense. Thanks for reviewing these recommendations and also the limitations of the evidence around them. So, finally, Dr. Robinson, how will these guideline recommendations affect patients with stage 4 non-small cell lung cancer without driver alterations?  Dr. Andrew Robinson: Well, there are more options available which should be good but we wish what we meant when we say there are more options for patients, what we meant is that if one option doesn't work that other options are then available.  However, in this case, we mean that there are more options for patients for their initial therapy, particularly including more non-chemotherapy or reduced chemotherapy options.  It's difficult to imagine that many patients and clinicians will now discuss, say 8 options with patients with high PD-L1 lung cancer. Pembrolizumab, cemiplimab, atezolizumab, pembrolizumab with platinum doublet, nivolumab, ipilimumab, nivolumab and ipilimumab chemotherapy, and the majority of patients with high PD-L1 will likely continue to have single-agent PD-1 or PD-L1 inhibitors.  For patients with low PD-L1 lung cancer, the inclusion of nivolumab and ipilimumab without chemotherapy as a potential option may allow some patients to avoid chemotherapy toxicity and trade for other toxicities and choose a different therapy.  Patients who enroll on clinical trials where the comparator arm is any one of these therapies should be comfortable knowing that they are considered acceptable standards. The advancement in non-small cell lung cancer diagnosis and treatment would allow patients with stage IV non-small cell lung cancer without driver mutations who are eligible for immunotherapies with or without chemotherapy, a chance of living longer and the opportunity to participate in ongoing research to further move the ball down the field.  Brittany Harvey: Definitely. And, thank you for reviewing that as well. So, I want to thank you both for all of your work to review the rapid changes in evidence in this field and provide these guideline updates. I want to thank you again for your time today, Dr. Robinson and Dr. Jaiyesimi.  Dr. Ishmael Jaiyesimi: Thank you for having me.  Dr. Andrew Robinson: Thank you. It was a pleasure to be here.  Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. There's a companion guideline update on therapy for stage IV non-small cell lung cancer with driver alterations available there and on the JCO.  You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.     

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for therapeutic options for patients with stage IV NSCLC with ALK rearrangement or RET rearrangement. They also discuss new agents on the horizon. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, Michigan, and Dr. Andrew Robinson from Kingston General Hospital at Queen's University in Ontario, Canada, authors on 'Therapy for Stage IV Non-small Cell Lung Cancer with Driver Alterations: ASCO Guideline Update'. Thank you for being here, Dr. Jaiyesimi and Dr. Robinson. Dr. Ishmael Jaiyesimi: Thank you. Dr. Andrew Robinson: It's a pleasure to be here. Brittany Harvey: Great! First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Jaiyesimi, do you have any relevant disclosures that are directly related to this guideline? Dr. Ishmael Jaiyesimi: None. Brittany Harvey: Thank you. And, Dr. Robinson, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Andrew Robinson: Yes, I have received funding less than $5,000 from AstraZeneca, Merck, and BMS over the past two years. Brittany Harvey: I appreciate those disclosures. So, then Dr. Jaiyesimi, let's talk about the purpose of this guideline. So, what is the purpose of this guideline update, and what clinical scenarios does this guideline address? Dr. Ishmael Jaiyesimi: The purpose of therapy for stage IV non-small cell lung cancer with driver alterations, is to rapidly update the ASCO and Ontario Health guideline on the systemic treatment of patients with stage IV non-small cell lung cancer, last published in February of 2021. The update is a result of potentially practice-changing evidence published since the last publication in February 2021. The update is based on two clinical trials from 2020 to 2021. The clinical scenario this guideline covers are stage IV non-small cell lung cancer with driver alteration with an ALK gene rearrangement and RET gene rearrangements. Brittany Harvey: Great. So, then let's review those two clinical scenarios that you just mentioned. So, there are a few new recommendations regarding ALK rearrangement. So, what are the recommended first-line options for patients with stage 4 non-small cell lung cancer in an ALK rearrangement? Dr. Ishmael Jaiyesimi: In the previous guideline alectinib or brigatinib were recommended as first-line therapy with a strong recommendation and level of evidence in patients with ALK gene rearrangement, and a performance status of zero to two. In the current update, lorlatinib was cited as the first-line ALK inhibitor that may be offered as an alternative first-line therapy. If alectinib, brigatinib, or lorlatinib are not available, ceritinib or crizotinib should be offered. This is based on the CROWN study that showed alectinib was superior to crizotinib in the first-line setting. Unfortunately, we don't have head-to-head comparative data with alectinib or brigatinib, so we cannot conclude that any one treatment is more effective than the other, and decisions should be made on experience, toxicity, and on. Brittany Harvey: Okay, thank you for describing how a clinician should select between those treatments as well. So, then the second clinical scenario that Dr. Jaiyesimi just mentioned, Dr. Robinson, what is recommended for both first-line and second-line treatment for patients with stage IV non-small cell lung cancer and a RET rearrangement. Dr. Andrew Robinson: Thank you. So, for patients with a RET rearrangement and a good performance status of zero to two and previously untreated non-small cell lung cancer, clinicians may offer selpercatinib or pralsetinib as first-line therapy. Selpercatinib was recommended in the 2020 guidelines and pralsetinib has been added to that. As with other driver mutation recommendations for scenarios where randomized studies against standard non-driver mutation treatments have not been done or completed, these recommendations are with a lower level of evidence and somewhat weaker recommendations, an alternative approach of first-line standard non-driver mutation treatment may also be offered. As a guideline group, we listed this approach of non-driver treatment behind the targeted therapies, because there's a belief that the targeted approach may be superior upfront. But we should also continue to, of course, encourage participation in ongoing trials comparing selpercatinib or pralsetinib to standard first-line non-driver mutation treatment to determine whether our assumptions are correct. For patients with a RET rearrangement who've had previous RET targeted therapy, clinicians may offer treatment as per the non-driver mutation guidelines. And for patients with a RET rearrangement who have had previous chemotherapy, chemoimmunotherapy, clinicians may offer selpercatinib or pralsetinib for them. Brittany Harvey: Okay. And then you've just mentioned some ongoing trials as well. So, that leads to my next question of what ongoing trials and new agents is the panel monitoring for the next guideline iteration? Dr. Andrew Robinson: It's really an exciting time with new agents on trials and I think we can divide it into more driver mutations, more lines of therapy, and more certainty with what we're doing. In terms of driver mutations, there are several phase II and III trials with agents such as sotorasib and adagrasib in KRAS-G12C mutated non-small cell lung cancer, trastuzumab deruxtecan in the DESTINY trials in HER-2 mutated lung cancer, mobicertinib and amivantamab in EGFR, exon 20 insertion lung cancer or HER-2 exon 20 insertion lung cancer, etc. So, looking at more driver mutations is all of those agents plus a number of others that will be coming out over the next couple of years at ASCO. We're also interested in more lines of therapy. So, for patients who progress after standard first-line, say osimertinib with EGFR or after progression on ALK therapies such as lorlatinib. So, we're looking forward to studies such as the CHRYSALIS studies of amivantamab and lazertinib in EGFR mutation-positive patients who have progressed after osimertinib, and other studies that are looking at the increasing treatment options for second-line treatment and third-line treatment. And then we're looking at interest to phase three studies that are comparing targeted agents to docetaxel in the second-line setting such as the sotorasib studies in KRAS-G12C patients and capmatinib and MET exon 14 patients, particularly as many of these patients may do well with non-driver mutated guided first-line treatment. There are phase three trials comparing RET inhibitors to standard first-line chemoimmunotherapy which will also be keenly awaited to see if our, and when I say our, I mean, the ASCO guideline panel and also the thoracic oncology community writ large, our assumption that targeted therapy will be superior to first-line therapy is actually borne out with clinical trial evidence. So, there's plenty of evidence that we're excited to keep our eye on and update as soon as possible, which is more driver mutations, more lines of therapy for patients who have established driver mutations, and more certainty, hopefully, regarding the timing of these various interventions. Brittany Harvey: Definitely, there's a lot going on in this space. So, we'll look forward to the results from these ongoing trials and the panel's review of that evidence, and eventually updated recommendations. So, then Dr. Jaiyesimi, in your view, why is this guideline update important and how will it impact practice? Dr. Ishmael Jaiyesimi: This guideline is important because it emphasizes rapid development in the research and treatment in advanced non-small cell lung cancer and that non-small cell lung cancer are heterogeneous. Clinicians need to identify biomarkers of the molecular pathways, including targetable driver mutations, example: epidermal growth factor receptors, the BRAF, the MET, the KRAS, and etcetera, and fusion rearrangement, example: anaplastic lymphoma kinase, c-ROS oncogene 1, RET, and on that drive malignancy in patients with non-small cell lung cancer, especially in those patients with adenocarcinoma histology and a little or never smoking history regardless of histology. Because of the availability of effective targeted agent for many of these cancers, at minimum, determination of epidermal growth factor receptor mutation status and anaplastic lymphoma kinase rearrangement status before initiating therapy because rapid and sensitive tests are available. An initiation of immunotherapy could increase the toxicity of tyrosine kinase inhibitors later in the patient's course. All this, in my opinion, will impact clinical practice. Furthermore, an opportunity for patients with driver mutation to enrolled in ongoing clinical trials targeting the driver mutations. Brittany Harvey: Yes. You've just mentioned that this is not a one size fits all approach for patients. And so, in your view, Dr. Jaiyesimi, how do these guideline recommendations affect patients living with stage IV non-small cell lung cancer with driver alterations? Dr. Ishmael Jaeysimi: I believe along with my associates the improvement in the treatment of stage IV non-small cell lung cancer brings hope to the patient with driver alteration for a possibility to use targeted therapy and no chemotherapy or immunotherapy upfront to some patients and this may enhance their lives, increase longevity with some tolerable side effects, and better quality of life, and a truly wide range of opportunities for patients to participate in clinical trials. Brittany Harvey: Great! Yes, it seems like the data has come fast, and a lot of new results of recent trials have driven these updated recommendations and we're also looking forward to many of the results from upcoming clinical trials that you both mentioned. So, I want to thank you so much for your work on these guideline updates, and thank you for taking the time to speak with me today, Dr. Jaiyesimi and Dr. Robinson. Dr. Ishmael Jaiyesimi: Thank you, Brittany. Dr. Andrew Robsinson: It was a pleasure to be here and I hope that this was educational. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline go to www.asco.org/thoracic-cancer-guidelines. There's a companion guideline update on therapy for stage IV non-small cell lung cancer without driver alterations available there and on the JCO. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO the mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

"To the Cadaver With the Port," by Kendahl Servino: A medical student begins school in the midst of a pandemic, but also, in the middle of cancer treatment.   TRANSCRIPT Narrator: “To the Cadaver with the Port” by Kendahl Servino, B.S. (10.1200/JCO.21.01979) It was easy to spot the cadaver's port implanted in her chest. The small, triangular object stood out against the pallor of her skin, preserved in the same manner as the rest of the bodies in the anatomy laboratory. As first-year medical students, we met our very first patients here. A quiet veneration was interlaced in the air amid the formaldehyde, and it clung to us the first day we stepped into the anatomy laboratory. It was easy to spot the cadaver's port implanted in her chest. The small, triangular object stood out against the pallor of her skin, preserved in the same manner as the rest of the bodies in the anatomy laboratory. As first-year medical students, we met our very first patients here. A quiet veneration was interlaced in the air amid the formaldehyde, and it clung to us the first day we stepped in the anatomy laboratory; we recognized the privilege given to us to learn about life and death through the human body in such a personal manner. Yet amid the reverence, I mourned this cadaver in particular, because the small port was a device used to administer chemotherapy. Easily overlooked by one unfamiliar with its purpose, it was a telling sign of cancer. It was the same port that I had in my own chest. In the midst of a busy anatomy laboratory session that day, I was immediately taken back to a different day 9 months ago. During the winter break of my last year of college, I drove myself to the hospital for a seemingly innocuous visit and walked out with a cancer diagnosis, unable to fathom what had just happened. Graduating college, celebrating with friends, and starting my career in medical school had been the milestones of my foreseeable future; finishing chemotherapy, ringing the bell at the end of treatment—a monumental moment for many patients—and surviving cancer had not been among them. I never expected to grapple with my mortality at 20 years old. As I stared at the cadaver's port, I wondered: was she with anyone when she was told she had cancer, or had she been alone, like me? Had she been devastated upon learning of her diagnosis, overcome by shock as I had? What kind of care did she receive thereafter? Did she have faith in herself? Had she felt hurt, searching in vain for an explanation of why she had been dealt such desolate cards? Did she feel betrayed by her own body, as I had? Moments of my own experience flooded back as I stood by her lifeless side. Looking at her face, still as though she were asleep, I wondered if she asked herself the same questions that I could never find the answers to myself. Even if every other aspect of our life stories were different, I knew at the very least that this cadaver and I shared the burden of a shattering diagnosis. I suspected that we shared the weight of the concomitant struggles that quickly follow the words, “You have cancer.” Having spent the past year receiving chemotherapy and radiation, losing my hair, and most importantly, struggling with the overlooked, psychologic side effects of cancer, never in my life had I felt so lost. I wondered whether the cadaver with the port had felt this way too.   At times, it has been hard for me to heal while in the medical school, an environment that often reminds me, although unintentionally, of the trauma that cancer precipitated. When I observe the skillful hands of the attending physician as she instructs how to conduct a proper breast examination, I am pulled back to the memory of stumbling out of the women's health clinic in a trance, numbed by what I had just been told. During lectures taught by brilliant professors on chemotherapeutic agents, I cannot help but recall the memory of sitting in the infusion center watching those very drugs dangling from the intravenous pole drip inside me. During a charged class debate on the efficacy of self-breast examinations, I struggle to sequester the unsettling feeling that arises in my stomach as I am prompted to revisit the emotional burdens of what I endured. And soon, when my classmates and I learn how to deliver hard news to patients, such as a diagnosis of cancer, I will be reminded of what it felt like sitting in my patient's chair. As I stand at the intersection between the medical student and the patient with cancer, I am learning that studying a disease, understanding its pathophysiology and mechanisms behind the indicated treatment, is entirely different from being on the receiving end of those medications or being the recipient of the diagnosis. Because of my dual identity, I am slowly understanding what it fully means to empathize with patients' situations. As I felt connected to the cadaver, I realized so too would I see myself in my future patients' struggles. Despite the burdens that I am currently working through, my experience with cancer has provided me something to offer to others, something that has, and will continue, to connect me to others. For the first time since starting the medical school, I am beginning to see a future not clouded by trauma, but instead filled with the potential for impactful connections and beautiful moments. If nothing else, I write this as a thank you to the cadaver with the port. Thank you for teaching me about life through your death, and for reminding me that there is so much of mine left to live. Thank you for reminding me that there have been others who have shared my struggles and that our pain does not exist in a vacuum. Healing, I realize, is not linear. But the power of shared experiences can help heal wounds, including those that lie deep within us. These moments are found not in textbooks or in lectures, but instead between two individuals when all other differences are cast aside. And while my patients may thank me one day for changing their lives, I will have to thank them for changing mine. Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all of the shows, including this one at podcast.asco.org. I'm Lidia Schapira, professor of Medicine at Stanford, associate editor for JCOs Art of Oncology, and your host for this program. With me today is Kendahl Servino. Kendahl is a second-year student at the Reno School of Medicine and the author of, ‘To the Cadaver with the Port'. Our guest has no disclosures. Welcome to the program, Kendahl. Kendahl Servino: Thank you, Dr. Schapira. It's great to be here today. Dr. Lidia Schapira: So, before we start, I like to ask our authors to tell me a little bit about their process for writing, and first of all, what they enjoy reading. So, what would I find on your virtual night table today? Kendahl Servino: I've always been a writer. When I think about my childhood, it's comprised a lot about many trips to the public library. My parents encouraged my brothers and me to read from a young age and I have just a plethora of memories of going to the library after school. And on summer vacations, we would just spend our free time there. Books were just a great way to experience other lives vicariously and to really see different perspectives. My love for reading translated into my own interest for writing. As a child, I have memories as early as kindergarten of me writing. I would take those standard 8 by 10 computer pieces of paper, I would take a stack of them, I would fold it in half. And I would staple it along its spine. And I'd create essentially a little book. I think the first book that I ever wrote was in kindergarten, and it was about this talking rose on a farm. And there was this whole rivalry and it was very vivid in the imagination of a six-year-old. But writing has always just been a part of my life, and especially coping with cancer became a lot more meaningful and impactful to my life. Dr. Lidia Schapira: So, writers are usually readers as well. So, I'll go back to my initial question. Also, what books are you reading now? Or what book would you recommend to our listeners that you've read in the last year or so if you've had time to read as a medical student? Kendahl Servino: Time is definitely limited. But currently, I'm reading a book called, A Little Life, by Hanya Yanagihara. I'm not sure if I pronounced your name correctly. And I'm not sure if you've heard of this book, either. It's a pretty big book, I think it's 800 or so pages. But it's about these four men who met in college, and they are currently living in New York and they're struggling with the transition into adulthood. They're dealing with a lot of issues. It's not for the faint of heart, I would say because there are a lot of trigger warnings in this book. They deal with a lot of issues such as self-harm, eating disorders, and mental health. There's all a lot of issues that they cover, but you get really close and connected with the characters and you feel a sense of bond with them by the end of the story. I don't want to give too much away about these characters' storylines, but it's a very impactful book so far that I would recommend. Dr. Lidia Schapira: So, it's interesting to hear you talk about this book that you admire, and that touched you because your essay had the same effect on the readers and certainly on me. It starts with this amazing line. I want you to tell us a little bit about that experience that you had as a very young cancer survivor, choosing to attend med school walking into the anatomy lab, and then seeing this device that you recognize on your cadaver's chest wall as a port, and that amazing way that you phrase the fact that you immediately felt this connection to this cadaver, bring us to that day. Kendahl Servino: Yeah. So, I'll start with a little background. So, starting medical school, I was in the middle of cancer treatment. Actually, right before I started medical school, I just finished radiation therapy. And within a couple of days after finishing and leaving my radiation oncologist's clinic, I moved to Reno, I was living in Las Vegas originally. So, all of this was still pretty fresh. And, admittedly, I mean, it still is right now. It's been about a year since I finished treatment. But the height of treatment was when I started medical school. And so, everything was still really heightened emotions at the time. And upon seeing that cadaver with the port, it was really surprising to me, because even though I had finished chemotherapy myself, and I had been about three or four months out from finishing chemotherapy, my hair was finally starting to grow back at that time, I think seeing that cadaver with a port showed me that cancer is never really over. That's something that I've been learning. And so, you think about ringing the bell. For those who aren't familiar, there's this bell that's often in many cancer clinics. It's this giant bell on the wall that you get to ring when you finish treatment. It's a really impactful moment, for not only the patient who's ringing the bell, but also everyone else in the clinic who can hear and understand the struggle of what the patient went through, and it's a collective celebration and something really special for cancer patients. So, you think about that as being kind of the end all to finishing cancer treatment. But what I've been learning since finishing treatment on my own and since being in medical school is that cancer treatment or cancer itself, and any other monumental diagnosis like this does not really have a finite ending. It'll always carry and stay with you, for better or for worse. I think that reminder of seeing the port, and seeing that connection reminded me that I will always have this part of me, this has changed me even a couple of months out from chemotherapy, or even a decade into my own future practice as a physician. And this will be an experience that will always stay with me and hopefully connect me more with patients in the future as I felt connected to the cadaver. Dr. Lidia Schapira: In your essay, you reflect on the psychological side and the psychological suffering that accompanies that cancer journey and the diagnosis and you also talk a lot about connection as something that you find very important in thinking about your future as a physician. Can you tell us a little bit about the emotional process and the healing that's taking place now even? Also, if you can, can you reflect a little bit on sort of your dual identity as a cancer survivor now and medical student, and whether or not it's really problematic for you? Kendahl Servino: Some of the psychological effects were a lot more monumental, I would say a year ago from now when I started medical school. Medical school is a very challenging transition for anyone undertaking this experience. And I definitely had struggles adjusting to medical school, but I think as a cancer patient, on top of that, I faced a lot of unique challenges. I think that had a lot of impact on mental health. For example, I was wearing a wig at the time. I was bald. So, that was really hard on top of moving to medical school. And, of course, in the midst of a pandemic, on top of everything else. Things were hard for everyone at the time but being a cancer patient posed some unique challenges for me, amongst my classmates. And so, you asked about the dual identity between cancer patient and medical student, and you asked about whether it's problematic. And admittedly, at the beginning of medical school, I think I really struggled with learning about, say, the chemotherapeutic agents that we'd receive lectures on, learning about how to conduct a proper breast exam. And those were very triggering for me, having just experienced that so recently, and so sometimes I thought that the trauma that I was reminded of so frequently, but unintentionally, in medical school was a lot for me, and something that I have been working through and I'm thankful to say now that a year later, I'm no longer as triggered by these moments in school, although they still come and go. But I think seeing the flip side of what it is like from the patient's point of view and the provider's point of view is really insightful because as medical students, we're learning to become providers and our role is to offer care to our future patients. And as a cancer patient myself, I've had unique insight into what it's like sitting in the patient's chair, being a patient with more medical needs than most. So, in some ways that dual identity has proffered really great insight into what my patients might be experiencing and feeling. But on the other hand, it also precipitates a lot of emotion, sometimes strongly that I am not ready to face again, or would want to be reminded of. Dr. Lidia Schapira: As you speak, Kendahl, it occurs to me that you probably need to sort of make a decision about how much you want to share about your personal circumstances, very often with your professors, with your classmates, even with your patients. How do you manage that? Kendahl Servino: Truthfully, I'm still trying to figure out the balance too, between oversharing and wanting to share, because I think that I have a lot to offer, the way that anyone who has overcome challenges can share something with others. As far as my future practice, and you mentioned future patients, I think that's something that I would like to connect with my future patients about in a way that is understanding of their own circumstances and whatever it is that my patients are going through with the intention of letting them know that I can understand to an extent of what they're experiencing, what they're going through, and I'd hope to convey that I will do all that I can, in my own future practice to help them and to help them heal. Dr. Lidia Schapira: Back to you, has your medical school, and do your professors and classmates support you in the way that you need to be supported? Are they there for you on a bad day? Kendahl Servino: I would say so. I don't have too many bad days, thankfully, as I did before medical school. I would say that the semester before medical school, which was the semester that I was in chemotherapy, I think that was my absolute lowest. And so, being in medical school, I haven't experienced that, thankfully, but I do have my support system here. I'm really thankful for them. I have been pretty public about my experience. Also, I created a blog a couple of years ago that I started out in college to convey my experiences as a college student and going through the formative time that college brings. But during cancer treatment, I also used that as a coping mechanism. Going back to writing has been part of my roots. I blogged a lot about my experiences. And now on social media, I post about some of my experiences. I try not to post just about the accomplishments, I also like to share, to an extent, the challenges also and the hard times, because I'd like to stay true to the authentic experience that cancer was and it wasn't just ringing the bell. It wasn't just accomplishing these milestones. It was also about my lowest times and the times that I wasn't sure I'd get through it. And so, I like to share all of that, and I try to be as authentic and genuine about my experience. Dr. Lidia Schapira: Well, I hope the process of writing this essay that you sent to JCO was helpful and was therapeutic for you as well. And coming back to your writing, which is beautiful, it's crisp, it's clearly very intentional, what is the message for the readers of JCO? Kendahl Servino: Thank you! I would say that cancer was, inarguably, the most challenging thing I've ever experienced in my life, bar none. And I would never want to go through something like that again and I would never wish that upon anyone else either. But I do believe now that it will help me in becoming the best doctor that I can be one day in my future practice. I think that's the most that I can ask for from an experience like cancer and the most that I hope to bring out of it is the impact that I can give to my future patients. Dr. Lidia Schapira: Beautifully said. So, I'm just curious, do you know what path you'll follow in medicine? Do you have an idea of what kind of doctor you want to be? I know a good one and one that connects with her patients, but do you have any idea of where you're headed? Kendahl Servino: Yeah, I currently do have interests in something oncology-related. I'm not sure at the moment whether that will be the medicinal route or the surgical route. I got to know both sides of the spectrum through my oncologist, but I also got to know my plastic surgeon who was on my team as well. And I have interests on both sides of the spectrum. But I think something related to oncology would be really fulfilling and impactful to my career and hopefully be able to change the lives of patients going through something that I've experienced so personally. Dr. Lidia Schapira: Well, hold on to that feeling. Thank you so much for writing. I wish you good health. And I hope you do join the global cancer tribe in some capacity. It was lovely to get to chat with you, Kendahl, and to read and reread and reread your essay. Thank you very much! Kendahl Servino: Thank you so much. It was great being here and I appreciate you inviting me. Dr. Lidia Schapira: Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories: The Art of Oncology Podcast. This is just one of many of ASCO's podcasts. You can find all of the shows at podcast.asco.org.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.    

“My White Coat Doesn't Fit” by Narjust Florez (Duma): a medical oncologist shares her story about exclusion, depression and finding her way in oncology as a Latina in medicine and oncology.   TRANSCRIPT Narrator: My White Coat Doesn't Fit, by Narjust Duma, MD (10.1200/JCO.21.02601) There I was, crying once again all the way from the hospital's parking lot to my apartment, into the shower, and while trying to fall asleep. This had become the norm during my internal medicine residency. For years, I tried hard every day to be someone else in order to fit in. It started with off-hand comments like “Look at her red shoes,” “You are so colorful,” and “You are so Latina.” These later escalated to being interrupted during presentations with comments about my accent, being told that my medical school training in my home country was inferior to my US colleagues, and being assigned all Spanish-speaking patients because “They are your people.” Some of those comments and interactions were unintentionally harmful but led to feelings of isolation, and over time, I began to feel like an outsider. I came to the United States with the dream of becoming a physician investigator, leaving behind family, friends, and everything I knew. Over time, I felt pigeonholed into a constricting stereotype due to my ethnicity and accent. Back home, I was one of many, but in this new setting, I was one of a few, and in many instances, I was the only Latina in the room. I was raised by divorced physician parents in Venezuela; my childhood years were often spent in the clinic waiting for my mother to see that one last patient or outside the operating room waiting for my father to take me home. The hospital felt like my second home, growing up snacking on Graham crackers and drinking the infamous hospital's 1% orange juice. “She was raised in a hospital,” my mother used to say. Sadly, that feeling of being at home in the hospital changed during medical training as I felt isolated and like I did not belong, making me question my dream and the decision to come to the United States. I remember calling my family and crying as I asked “Why did I leave?” “Why didn't you stop me from coming here?” and seeking permission to return home. I felt like I was disappointing them as I was no longer the vivid, confident young woman who left her home country to pursue a bright future. I remember one colleague, Valerie (pseudonym), from Connecticut. Valerie attended medical school in the United States, did not have an accent, and was familiar with the American health care system. She understood how the senior resident-intern relationship functioned, a hierarchy that continually confused me. Over the following weeks, I took a closer look at how my colleagues and other hospital staff interacted with Valerie. I noticed that people did not comment about her clothing or personality. She was “normal” and fit in. I remember my senior resident asking me, “Narjust, why can't you be more like Valerie?” Ashamed, I mumbled that I would try and then ran to the bathroom to cry alone. That interaction was a turning point for me; I got the message. I needed to change; I needed to stop being who I was to be accepted. As the years passed, I kept key pieces of my personality hidden, hoping I could earn the respect of my colleagues. I refrained from sharing my personal stories as they were different from those around me. I grew up in a developing country with a struggling economy and an even more challenging political situation. It was clear that we simply did not share similar experiences. When I sought help from my senior residents and attending physicians, my feelings were often minimized or invalidated. I was told that “residency is tough” and that I should “man up.” A few even suggested that I mold my personality to fit the box of what a resident physician was supposed to be. I slowly realized that my clothing changed from reds and pinks to greys and blacks because it was “more professional”; my outward appearance faded, as did my once bright sense of humor and affability. All these issues led to depression and an overwhelming sense of not belonging. A few months later, I was on antidepressants, but the crying in the shower continued. Rotation by rotation, I looked for a specialty that would help me feel like I belonged, and I found that in oncology. My mentor embraced my research ideas; my ethnic background or accent did not matter; we had the same goal, improving the care of our patients with cancer. I got to travel to national and international conferences, presented my research findings, and received a few awards along the way. From the outside, it looked like I was thriving; my mentor often called me a “Rising Star,” but in reality, I was still deeply depressed and trying to fit in every day. My career successes led me to believe that not being myself was the right thing to do. I felt isolated; I was trying to be someone I was not. A year later, I matched at my top choice oncology fellowship program; the program had the balance I was looking for between clinical care and research. This meant that I needed to move to the Midwest, further away from family, and to an area of the country with less racial and ethnic diversity. After 2 years on antidepressants and the 10 extra pounds that came with it, my white coat did not fit. My white coat felt like a costume that I would put on every day to fulfill the dream of being a doctor. I would often wake up in the middle of the night exhausted and depressed. I had all the responsibilities of a hematology/ oncology trainee and the additional full-time job of trying to fit in every day; I was using all my energy trying to be someone I was not. Regardless of my fears, I felt in my element when talking to patients and interacting with my cofellows. Despite having a different skin color and accent, I felt accepted by my patients with cancer. I remember when one of my patients requested to see me while in the emergency room because “Dr Duma just gets me.” She had been evaluated by the head of the department and attending physicians, but for her, I washer doctor. Tears of happiness accompanied my bus ride to see her; at that moment, I knew I was an oncologist, and oncology was the place I belonged. The next day, I realized that it was time to be myself: Narjust from Venezuela, a Latina oncologist who was her true self. I searched the bottom of my closet for the last piece of colorful clothing I had saved, a yellow dress. I put on that brightly colored dress for the first time in 5 years and finally felt comfortable being my authentic self; the yellow dress represented freedom and embraced the culture and colors I grew up seeing in my hometown. I finally understood that I brought something special to the table: my unique understanding of the challenges faced by Latinx patients and trainees, my advocacy skills, and my persistence to endure the academic grindstone. Psychotherapy was also an essential part of my recovery; I learned that happiness lived within me as a whole person—hiding my accent, cultural background, and past experiences was also hiding the light and joy inside me. Along the way, I found colleagues who faced the same challenges and validated that my experiences resulted from an environment that excludes the difference and values homogeneity. This route to self-discovery helped me find my calling to support others in situations similar to mine.3 I learned how to incorporate and celebrate my ethnicity in the world of academic oncology by teaching others the power of cultural humility, diversity, equity, and inclusion. Together with newfound friends and colleagues, I cofounded the #LatinasinMedicine Twitter community for those who face similar burdens during their training and careers. The #LatinasinMedicine community was created to share our stories, embrace our culture, and amplify other Latinas in medicine—to create connections that alleviate the sense of isolation that many of us have experienced and serve as role models to the next generation of Latinas in medicine. To help drive systemic change, I founded the Duma Laboratory, a research group that focuses on cancer health disparities and discrimination in medical education. Through research, the Duma Laboratory has shown that my experiences are not unique but rather an everyday reality for many international medical graduates and other under-represented groups in medicine. The Duma Laboratory has become a safe environment for many trainees; we seek to change how mentorship works for under-represented groups in oncology, with the hope that the isolation I felt during my training is not something that future physicians will ever have to endure. After years of depression and self-discovery, my white coat now fits. However, this is not your regular white coat; it has touches of color to embrace my heritage and the ancestors who paved the way for me to be here today. The face of medicine and oncology is changing around the world; young women of color are standing up to demonstrate the strength of our experiences and fuel the change that medical education needs. For all minority medical students, residents, fellows, and junior faculty, we belong in medicine even during those moments when our identity is tested. Through my journey, I learned that we can and must challenge the status quo. I hope to inspire others to join me in this path of advocating for diversity, equity, and inclusion because the time for change is now. I was finally free the moment I realized I could not be anyone else but myself, a proud Latina in medicine and oncology. Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, which offers a range of educational and scientific content and enriching insight into the world of cancer care. You can find all of the shows including this one at podcast.asco.org. I'm your host, Lidia Shapira, Associate Editor for Art of Oncology and Professor of Medicine at Stanford. And with me today is Dr. Narjust Duma, Associate Director of the Cancer Care Equity Program and Medical Thoracic Oncologist at Dana Farber and an Assistant Professor at Harvard Medical School. We'll be discussing her Art of Oncology article, ‘My White Coat Doesn't Fit.' Our guest has a consulting or advisory role with AstraZeneca, Pfizer, NeoGenomics Laboratories, Janssen, Bristol Myers Squibb, Medarax, Merck, and Mirati. Our guest has also participated in a speaker's bureau for MJH Life Sciences. Narjust, welcome to our podcast. Dr. Narjust Duma: Thank you for the invitation and for letting us share our story. Dr. Lidia Schapira: It's lovely to have you. So, let's start with a bit of background. Your essay has so many powerful themes, the story of an immigrant in the US, the story of resilience, the story of aggression and bullying as a recipient of such during training, of overcoming this and finding not only meaning, but really being an advocate for a more inclusive and fair culture in the workplace. So, let's untangle all of these and start with your family. I was interested in reading that you're named after your two grandmothers, Narcisa and Justa. And this is how your parents, both physicians, Colombian and Dominican, gave you your name, and then you were raised in Venezuela. So, tell us a little bit about your family and the values that were passed on in your family. Dr. Narjust Duma: Thank you for asking. Having my two grandmothers names is something that my mother put a lot of effort into. She was a surgery resident with very limited time to decide to do that. And I don't have a middle name, which is quite unique in Latin America, most people in Latin America have one or two middle names. So, my mother did that to assure that I will use her piece of art, which is my first name. But little does she know that my grandmothers were going to be such an important part of my life, not only because they're in my name, but also because I am who I am thanks to them. So, the first part of my name, Narcisa was my grandma who raised me and she gave me the superpower of reading and disconnecting. So, I'm able to read no matter where I am and how loud it can be and disconnect with the world. So, it is often that my assistants need to knock on my door two or three times so, I don't like being scared because I'm able to travel away. That was also very unique because you will find me in the basketball games from high school or other activities with a book because I was able to block that noise. But it also makes very uncomfortable situations for my friends that find it embarrassing that I will pull a book in the basketball game. And as I grow, thanks to the influence of my grandmothers, I always have these, how can I say, mixed situation, in which they were very old school grandmothers with old school habits and values, and how I'm able to modify that. My grandma told me that you can be a feminist, but you still take care of your house. You can still, you know, cook. And that taught me that you don't have to pick a side, there is no one stereotype for one or another. Because as my mother being a single mother and a surgeon, my parents divorced early on, told me, ‘Yes, I can be the doctor but I can also be the person that has more than a career that's able to have hobbies.' I love cooking, and when I'm stressed, I cook. So, I had a grant deadline a few weeks ago and I cooked so much that there was food for days. So, having the names of my grandmothers is very important because I have their values, but I have modified them to the current times. Dr. Lidia Schapira: Let me ask a little bit about reading. I often ask the guests of this podcast who have written and therefore I know enjoy reading and writing, what their favorite books are or what is currently on their night table. But I'm going to ask you a second question and that is what languages do you read in? Dr. Narjust Duma: I prefer to read in Spanish. I found that books in Spanish, even if it's a book that originated in English, have these romantic characteristics. And I often tell my editors, ‘Just take into account that I think in Spanish, and write in English'. Because I grew up with Gabrielle Garcia Marquez, and when he describes a street, that's a page of the little things that he describes. So, that's how I write and that's how I read in a very romantic, elaborate way. The aspects of realistic imagism, which is my favorite genre in literature, and there are so many Latin American and South American writers that I don't think that I am going to run out. And when I run out, I reread the same books. I have read all of Gabrielle Garcia Marquez's books twice, and Borges, too. It's the type of stories that allows you to submerge yourself and you imagine yourself wearing those Victorian dresses in the heat of a Colombian street, as you try to understand if, you know, Love in the Time of Cholera, if they were more in love with being in love or what it was happening in the story. And that just gives me happiness on a Sunday morning. Dr. Lidia Schapira: That's beautiful. I must confess that reading Borges is not easy. So, I totally admire the fact that you have managed to read all of his work. And I think that you're absolutely right, that magical realism is a genre that is incredibly fresh, and perhaps for the work that we do in oncology, it's a wonderful antidote in a way to some of the realities, the very harsh realities that we deal with on a daily basis. So, let me ask you a little bit about growing up in Venezuela in the 80s, 90s, early aughts. That must have been difficult. Tell us a little bit about that, and your choice of attending medical school. Dr. Narjust Duma: So, growing up in Venezuela, with a Colombian mother, it was quite a unique perspective because she was very attached to her Colombian roots. So, a lot of the things that happened in the house were very Colombian, but I was in Venezuela. So, it was a unique characteristic of being from a country but your family is not from there. So, my parents are not from Venezuela, my grandparents either, and I'm Venezuelan because I was born and raised there. So, that brought a unique perspective, right? The music that I played in my house was Colombian music, not Venezuelan music. So, my family migrated from Colombia to Venezuela due to the challenges in the early 80s with violence and the Medellin, due to the drug cartels. So, we moved to Venezuela for a better future. And growing up in the first years, Venezuela was in a very good position. Oil was at the highest prices. Economically, the country was doing well. I remember, in my early years, the dollar and the bolivar had the same price. But then little by little I saw how my country deteriorated, and it was very heartbreaking. From a place where the shells were full of food to a place now when there is no food, and you go to the supermarket, and many of them are close. And now you're only limited to buying certain things. And you used to use your federal ID that has an electronic tracking on how much you can buy because of socialism. So, you're only allowed to buy two kilograms of rice per month, for example, you're only allowed to buy this number of plantains. So, every time I go home, because Venezuela is always going to be my home, it doesn't matter where I am., I see how my country has lost pieces by pieces, which is quite very hard because I had a very good childhood. I had a unique childhood because I was raised in hospitals. But I had a childhood in which I will play with my friends across the street. We were not worried about being kidnapped. We were not worried about being robbed. That's one thing that children in Venezuela cannot do right now. Children of doctors – there's a higher risk of being kidnapped as a kid right now if your father is a doctor or your mother. So, my childhood wasn't like that. When I teach my students or talk to my mentees, I'm often selling my country, and saying that's not what it used to be. That's not where I grew up. But every year I saw how it no longer is where I grew up. That place doesn't exist, and sometimes, Lidia, I feel like my imagination may have to fill it out with more good things. But I think it was a good childhood. It's just that nobody in Venezuela is experiencing what I experienced as a kid. Dr. Lidia Schapira: So, both parents were doctors and you chose to study medicine, was this just right out of high school? Dr. Narjust Duma: Even before high school, I found myself very connected to patients. So, since I turned 15, my father would give his secretary a month of vacation because that's the month that we fill in. So, I was the secretary for a month every summer since I was 15 until I was 20. That early exposure allowed me to like get to know these patients and they know I was the daughter, but I was also the secretary. So, I really cherished that. Growing up in my household, we're a house of service. So, our love language is acts of service. That's how pretty much my grandmas and my parents were. So, in order to be a physician, that's the ultimate act of service. I have wanted to be a doctor since I was 11. I think my mother face horrible gender harassment and sexual harassment as a female in the surgery in the early 80s, that she tried to push me away from medicine. Early on, when I was 11, or 12, being an oil engineer in Venezuela was the career that everybody should have, right? Like, people were going to the Emirates and moving to different parts of the world and were doing wonderful. So, my mother, based on her experience in the 80s, was pushing me away from it. She's like, ‘You can do other things.' My father always stayed in the back and said, ‘You can do what you want.' This is how our parents' experiences affect our future. If I wouldn't be this stubborn, I would probably be an oil engineer today, and I wouldn't be talking to you. Dr. Lidia Schapira: So, you went to medical school, and then after you graduated, what did you decide to do? Because when I look at what we know about the history there is I think you graduated in '09, and then the story that you write about sort of begins in '16 when you come to New Jersey to do training in the US, but what happened between '09 and '16? Dr. Narjust Duma: I started residency in 2013. '16 was my fellowship. So, going to medical school was one of the hardest decisions I made because right in 2003 and 2004 was a coup in Venezuela where part of the opposition took over the country for three days, and then the President of the time came back and the country really significantly destabilized after that coup. Most schools were closed. Entire private industries were closed for a month. And I think for some people, it's hard to understand what happened. Everything closed for a month, McDonald's was closed for a month. There was no Coke because a Coke company was not producing. Everything was closed. The country was just paralyzed. So, my mother and I, and my family, my father, took into account that we didn't know when medical school would resume in Venezuela. We didn't know if the schools would ever open again. I decided to apply for a scholarship and I left Venezuela at the age of 17 to go to the Dominican Republic for medical school. Very early on, I noticed that I was going to be a foreigner wherever I go because I left home. And since then, I think I became very resilient because I was 17 and I needed to move forward. So, that is what happened in 2004. I left everything I knew. I left for the Dominican. I do have family in the Dominican, but it was very hard because even if you speak the same language, the cultures are very different. And then I went to medical school in the Dominican and when I was in the Dominican Republic, I realized I really wanted to do science and be an advocate and focus on vulnerable populations with cancer. So, then I made the decision to come to the United States, I did a year of a research fellowship at Fred Hutchinson, and then I went to residency in 2013. Dr. Lidia Schapira: I see. And that's when you went to New Jersey, far away from home. And as you tell the story, the experience was awful, in part because of the unkindness and aggression, not only microaggression but outright bullying that you experienced. In reading the essay, my impression was that the bullying was mostly on two accounts. One was gender. The other was the fact that you were different. In this particular case, it was the ethnicity as a Latin or Hispanic woman. Tell us a little bit about that so we can understand that. Dr. Narjust Duma: I think what happened is that perfect example of intersectionality because we are now the result of one experience, we're the result of multiple identities. So many woman have faced gender inequalities in medicine, but when you are from a marginalized group, those inequalities multiply. I have an accent and clearly a different skin color. I grew up in a family in which you were encouraged to be your true self. My grandmothers and my mother said, ‘You never want to be the quiet woman in the corner because the quiet woman never generates change.' That's what they said, and I bet there are some who do. But that intersection of my identities was very challenging because I was seen as inferior just for being a woman and then you multiply being one of the few Latinas you are seen like you are less just because you are - it doesn't matter how many degrees or papers or grants you had done and all, I was the most productive research resident in my residency for two years in a row - but I would still be judged by my identity and not what I have produced, or what I do on my patients' experiences, which were great – the feedback from my patients. It's just because I was the different one. Dr. Lidia Schapira: When I hear your story about your origins, it seems to me that you came from a very capable loving family, and they basically told you to go conquer the world, and you did. And then you arrive and you're a productive successful resident, and yet, you are marginalized, as you say. People are really aggressive. Now that you've had some years that have passed, if you think back, what advice would you give that young Narjust? Dr. Narjust Duma: My number one advice, would be that, I will tell myself is that I belong, in many instances, I feel like I didn't belong. It makes me question all the decisions to that day because when you're doing a presentation, and I still remember like today, and you're interrupted by someone, just for them to make a comment about your accent, it really brings everything down to your core, like, 'Is my presentation not accurate? Is the information not all right? And why am I here? Why did I left everything I love to be treated like this?' Dr. Lidia Schapira: Of course. So, from New Jersey, you write in your essay that you really discover your passion for cancer research, and you land in a fellowship with a mentor who is encouraging, and things begin to change for you. Can you tell us a little bit about that phase of your training in your life where you slowly begin to find your voice in the state, that also where you crash, where you find yourself so vulnerable that things really fall apart? Dr. Narjust Duma: So, when I was a resident, I didn't know exactly - I was interested in oncology, but I wasn't sure if it was for me. So, Dr. Martin Gutierrez at Rutgers in Hackensack is the person who I cold emailed and said, ‘I'm interested in studying gastric cancer in Hispanic patients because I think that patients in the clinic are so young.' He, without knowing me or having any idea, he trusted me. We still meet. He still follows up with me. He encouraged me. I think him being a Latino made the experience better, too, because I didn't have to explain my experience to him. I didn't have to explain that. He understood because he went through the same things. And he's like, ‘I got you. Let's follow what you want to do.' He embraced who I was, and how I put who I was into my research. And thanks to Dr. Gutierrez, I'm at the Mayo Clinic as an international medical grad. So, finding a place in which my ideas were embraced was very important to allow me to stay in medicine because, Lidia, I can tell you several times, I decided to leave. I was very committed to finding something else to do or just being a researcher and leaving clinical medicine behind. So, when I went to Mayo, I still followed with that mentor, but I already knew what I wanted to do. I wanted to do cancer health disparities. I wanted to do inclusion and diversity. And that allowed me to develop the career I have now and is having that pathway because I, with my strong personality and everything else, faced this discrimination, and I can imagine for other trainees that may still be facing that or will face that in the future. So, I use the negative aspects to find my calling and do many things I have done after that. Dr. Lidia Schapira: Speaks to your strengths and your determination. Let's talk a little bit about the people who may also feel different but whose differences may not be so apparent. How do you now as an emerging leader, and as a mentor, make sure that you create an inclusive and safe environment for your younger colleagues and your mentees? Dr. Narjust Duma: One of the things that resulted was the founding of the Duma Lab, which is a research group that focuses on cancer, health disparities, social justice as a general, and inclusion in medical education. So, one of the things that I practice every day is cultural humility. I continue to read and remember the principles. I have them as the background on my computer at work. The number one principle in lifelong learning is that we learn from everyone and that we don't know everything and other people's cultures, and subculture, we learn their culture is rich. So, in every meeting, I remind the team of the principles of cultural humility when somebody is joining the lab. I have one-on-one meetings, and I provide information and videos about cultural humility because the lab has been created as an environment that's safe. We have a WhatsApp group that is now kind of famous - it's called The Daily Serotonin. The majority of the members of the lab are part of marginalized groups, not only by gender but race, religion, sexual and gender orientation. So, we created this group to share good and bads, and we provide support. So, a few weeks ago, a patient made reference to one of their lab member's body, the patient was being examined and that was quite inappropriate. The member debriefed with the group and we all provided insights on how she had responded, and how she should respond in the future. That's not only learning from the person that brought the scenario but anybody else feels empowered to stop those microaggressions and stop those inappropriate behaviors that woman particularly face during clinical care. So, cultural humility, and having this WhatsApp group that provides a place where, first, I remind everybody that's confidential, and a place in which anything is shared has been very successful to create inclusivity in the group. Dr. Lidia Schapira: You have such energy and I'm amazed by all of the things that you can do and how you have used social connection as a way of bringing people up. So, can you give our listeners perhaps some tips for how you view creating a flatter culture, one with fewer hierarchies that makes it safer for learners and for those who are practicing oncology? What are three quick things that all of us can do in our work starting this afternoon? Dr. Narjust Duma: The concept is that we all can be allies. And being an ally doesn't take a lot of time or money because people think that being an ally is a full-time job, it is not. So, the first one tip will be to bring people with you. Your success is not only yours. It's a success of your mentees. It's a success of your colleagues. So, don't see your success as my badge on my shoulder. It's the badge that goes on everyone. So, bring people in, leave the door open, not only bring them but leave the door open because when you do it helps the next generation. Two, little things make a difference. I'm going to give you three phrases that I use all the time. When you think somebody has been marginalized in a meeting, bring them up, it takes no time. For example, 'Chenoa, what do you think we can do next?' You're bringing that person to the table. Two, you can advocate for other women and minorities when they're easily interrupted in a meeting. This takes no time. ‘I'm sorry you interrupted Dr. Duma. Dr. Duma?' So, that helps. The third thing is very important. You can connect people. So, one of the things is that I don't have every skill, so I advocate for my mentees and I serve as a connector. I have a mentee that is into bioinformatics. Lidia, that's above my head. I don't understand any of that. So, I was able to connect that person to people that do bioinformatics. And follow up. My last thing is to follow up with your people because they need you. Dr. Lidia Schapira: Well, I'm very glad that you're not an oil engineer in the Emirates. I'm sure your family is incredibly proud. I hope that you're happy where you are. We started a little bit about where you started, I'd like to end with your idea of where you imagine yourself 10 years from now? Dr. Narjust Duma: That is a question I don't have an answer prepared for. I guess my career development plans I think I want to be in a place where I look back and I can see that the careers of my mentees being successful. And I think that we measure my success based not on myself, I would measure my success in 10 years based on where my mentees are. And medical education is a more inclusive place. That will be the two things I want to see in 10 years. In the personal aspect, I don't know if we have art, don't know if we have those grants as long as my mentees are in a better place. Dr. Lidia Schapira: It has been such a pleasure to have this conversation. Thank you so much, Narjust. Dr. Narjust Duma: Thank you. Dr. Lidia Schapira: Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories: The Art of Oncology podcast. This is just one of many of ASCO's podcasts. You can find all of the shows at podcast.asco.org. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Narrator: My White Coat Doesn't Fit, by Narjust Duma, MD (10.1200/JCO.21.02601) There I was, crying once again all the way from the hospital's parking lot to my apartment, into the shower, and while trying to fall asleep. This had become the norm during my internal medicine residency. For years, I tried hard every day to be someone else in order to fit in. It started with off-hand comments like “Look at her red shoes,” “You are so colorful,” and “You are so Latina.” These later escalated to being interrupted during presentations with comments about my accent, being told that my medical school training in my home country was inferior to my US colleagues, and being assigned all Spanish-speaking patients because “They are your people.” Some of those comments and interactions were unintentionally harmful but led to feelings of isolation, and over time, I began to feel like an outsider. I came to the United States with the dream of becoming a physician investigator, leaving behind family, friends, and everything I knew. Over time, I felt pigeonholed into a constricting stereotype due to my ethnicity and accent. Back home, I was one of many, but in this new setting, I was one of a few, and in many instances, I was the only Latina in the room. I was raised by divorced physician parents in Venezuela; my childhood years were often spent in the clinic waiting for my mother to see that one last patient or outside the operating room waiting for my father to take me home. The hospital felt like my second home, growing up snacking on Graham crackers and drinking the infamous hospital's 1% orange juice. “She was raised in a hospital,” my mother used to say. Sadly, that feeling of being at home in the hospital changed during medical training as I felt isolated and like I did not belong, making me question my dream and the decision to come to the United States. I remember calling my family and crying as I asked “Why did I leave?” “Why didn't you stop me from coming here?” and seeking permission to return home. I felt like I was disappointing them as I was no longer the vivid, confident young woman who left her home country to pursue a bright future. I remember one colleague, Valerie (pseudonym), from Connecticut. Valerie attended medical school in the United States, did not have an accent, and was familiar with the American health care system. She understood how the senior resident-intern relationship functioned, a hierarchy that continually confused me. Over the following weeks, I took a closer look at how my colleagues and other hospital staff interacted with Valerie. I noticed that people did not comment about her clothing or personality. She was “normal” and fit in. I remember my senior resident asking me, “Narjust, why can't you be more like Valerie?” Ashamed, I mumbled that I would try and then ran to the bathroom to cry alone. That interaction was a turning point for me; I got the message. I needed to change; I needed to stop being who I was to be accepted. As the years passed, I kept key pieces of my personality hidden, hoping I could earn the respect of my colleagues. I refrained from sharing my personal stories as they were different from those around me. I grew up in a developing  country with a struggling economy and an even more challenging political situation. It was clear that we simply did not share similar experiences. When I sought help from my senior residents and attending physicians, my feelings were often minimized or invalidated. I was told that “residency is tough” and that I should “man up.” A few even suggested that I mold my personality to fit the box of what a resident physician was supposed to be. I slowly realized that my clothing changed from reds and pinks to greys and blacks because it was “more professional”; my outward appearance faded, as did my once bright sense of humor and affability. All these issues led to depression and an overwhelming sense of not belonging. A few months later, I was on antidepressants, but the crying in the shower continued. Rotation by rotation, I looked for a specialty that would help me feel like I belonged, and I found that in oncology. My mentor embraced my research ideas; my ethnic background or accent did not matter; we had the same goal, improving the care of our patients with cancer. I got to travel to national and international conferences, presented my research findings, and received a few awards along the way. From the outside, it looked like I was thriving; my mentor often called me a “Rising Star,” but in reality, I was still deeply depressed and trying to fit in every day. My career successes led me to believe that not being myself was the right thing to do. I felt isolated; I was trying to be someone I was not. A year later, I matched at my top choice oncology fellowship program; the program had the balance I was looking for between clinical care and research. This meant that I needed to move to the Midwest, further away from family, and to an area of the country with less racial and ethnic diversity. After 2 years on antidepressants and the 10 extra pounds that came with it, my white coat did not fit. My white coat felt like a costume that I would put on every day to fulfill the dream of being a doctor. I would often wake up in the middle of the night exhausted and depressed. I had all the responsibilities of a hematology/ oncology trainee and the additional full-time job of trying to fit in every day; I was using all my energy trying to be someone I was not. Regardless of my fears, I felt in my element when talking to patients and interacting with my cofellows. Despite having a different skin color and accent, I felt accepted by my patients with cancer. I remember when one of my patients requested to see me while in the emergency room because “Dr Duma just gets me.” She had been evaluated by the head of the department and attending physicians, but for her, I washer doctor. Tears of happiness accompanied my bus ride to see her; at that moment, I knew I was an oncologist, and oncology was the place I belonged. The next day, I realized that it was time to be myself: Narjust from Venezuela, a Latina oncologist who was her true self. I searched the bottom of my closet for the last piece of colorful clothing I had saved, a yellow dress. I put on that brightly colored dress for the first time in 5 years and finally felt comfortable being my authentic self; the yellow dress represented freedom and embraced the culture and colors I grew up seeing in my hometown. I finally understood that I brought something special to the table: my unique understanding of the challenges faced by Latinx patients and trainees, my advocacy skills, and my persistence to endure the academic grindstone. Psychotherapy was also an essential part of my recovery; I learned that happiness lived within me as a whole person—hiding my accent, cultural background, and past experiences was also hiding the light and joy inside me. Along the way, I found colleagues who faced the same challenges and validated that my experiences resulted from an environment that excludes the difference and values homogeneity. This route to self-discovery helped me find my calling to support others in situations similar to mine.3 I learned how to incorporate and celebrate my ethnicity in the world of academic oncology by teaching others the power of cultural humility, diversity, equity, and inclusion. Together with newfound friends and colleagues, I cofounded the #LatinasinMedicine Twitter community for those who face similar burdens during their training and careers. The #LatinasinMedicine community was created to share our stories, embrace our culture, and amplify other Latinas in medicine—to create connections that alleviate the sense of isolation that many of us have experienced and serve as role models to the next generation of Latinas in medicine. To help drive systemic change, I founded the Duma Laboratory, a research group that focuses on cancer health disparities and discrimination in medical education. Through research, the Duma Laboratory has shown that my experiences are not unique but rather an everyday reality for many international medical graduates and other under-represented groups in medicine. The Duma Laboratory has become a safe environment for many trainees; we seek to change how mentorship works for under-represented groups in oncology, with the hope that the isolation I felt during my training is not something that future physicians will ever have to endure. After years of depression and self-discovery, my white coat now fits. However, this is not your regular white coat; it has touches of color to embrace my heritage and the ancestors who paved the way for me to be here today. The face of medicine and oncology is changing around the world; young women of color are standing up to demonstrate the strength of our experiences and fuel the change that medical education needs. For all minority medical students, residents, fellows, and junior faculty, we belong in medicine even during those moments when our identity is tested. Through my journey, I learned that we can and must challenge the status quo. I hope to inspire others to join me in this path of advocating for diversity, equity, and inclusion because the time for change is now. I was finally free the moment I realized I could not be anyone else but myself, a proud Latina in medicine and oncology. Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, which offers a range of educational and scientific content and enriching insight into the world of cancer care. You can find all of the shows including this one at podcast.asco.org. I'm your host, Lidia Shapira, Associate Editor for Art of Oncology and Professor of Medicine at Stanford. And with me today is Dr. Narjust Duma, Associate Director of the Cancer Care Equity Program and Medical Thoracic Oncologist at Dana Farber and an Assistant Professor at Harvard Medical School. We'll be discussing her Art of Oncology article, ‘My White Coat Doesn't Fit.' Our guest has a consulting or advisory role with AstraZeneca, Pfizer, NeoGenomics Laboratories, Janssen, Bristol Myers Squibb, Medarax, Merck, and Mirati. Our guest has also participated in a speaker's bureau for MJH Life Sciences. Narjust, welcome to our podcast. Dr. Narjust Duma: Thank you for the invitation and for letting us share our story. Dr. Lidia Schapira: It's lovely to have you. So, let's start with a bit of background. Your essay has so many powerful themes, the story of an immigrant in the US, the story of resilience, the story of aggression and bullying as a recipient of such during training, of overcoming this and finding not only meaning, but really being an advocate for a more inclusive and fair culture in the workplace. So, let's untangle all of these and start with your family. I was interested in reading that you're named after your two grandmothers, Narcisa and Justa. And this is how your parents, both physicians, Colombian and Dominican, gave you your name, and then you were raised in Venezuela. So, tell us a little bit about your family and the values that were passed on in your family. Dr. Narjust Duma: Thank you for asking. Having my two grandmothers names is something that my mother put a lot of effort into. She was a surgery resident with very limited time to decide to do that. And I don't have a middle name, which is quite unique in Latin America, most people in Latin America have one or two middle names. So, my mother did that to assure that I will use her piece of art, which is my first name. But little does she know that my grandmothers were going to be such an important part of my life, not only because they're in my name, but also because I am who I am thanks to them. So, the first part of my name, Narcisa was my grandma who raised me and she gave me the superpower of reading and disconnecting. So, I'm able to read no matter where I am and how loud it can be and disconnect with the world. So, it is often that my assistants need to knock on my door two or three times so, I don't like being scared because I'm able to travel away. That was also very unique because you will find me in the basketball games from high school or other activities with a book because I was able to block that noise. But it also makes very uncomfortable situations for my friends that find it embarrassing that I will pull a book in the basketball game. And as I grow, thanks to the influence of my grandmothers, I always have these, how can I say, mixed situation, in which they were very old school grandmothers with old school habits and values, and how I'm able to modify that. My grandma told me that you can be a feminist, but you still take care of your house. You can still, you know, cook. And that taught me that you don't have to pick a side, there is no one stereotype for one or another. Because as my mother being a single mother and a surgeon, my parents divorced early on, told me, ‘Yes, I can be the doctor but I can also be the person that has more than a career that's able to have hobbies.' I love cooking, and when I'm stressed, I cook. So, I had a grant deadline a few weeks ago and I cooked so much that there was food for days. So, having the names of my grandmothers is very important because I have their values, but I have modified them to the current times. Dr. Lidia Schapira: Let me ask a little bit about reading. I often ask the guests of this podcast who have written and therefore I know enjoy reading and writing, what their favorite books are or what is currently on their night table. But I'm going to ask you a second question and that is what languages do you read in? Dr. Narjust Duma: I prefer to read in Spanish. I found that books in Spanish, even if it's a book that originated in English, have these romantic characteristics. And I often tell my editors, ‘Just take into account that I think in Spanish, and write in English'. Because I grew up with Gabrielle Garcia Marquez, and when he describes a street, that's a page of the little things that he describes. So, that's how I write and that's how I read in a very romantic, elaborate way. The aspects of realistic imagism, which is my favorite genre in literature, and there are so many Latin American and South American writers that I don't think that I am going to run out. And when I run out, I reread the same books. I have read all of Gabrielle Garcia Marquez's books twice, and Borges, too. It's the type of stories that allows you to submerge yourself and you imagine yourself wearing those Victorian dresses in the heat of a Colombian street, as you try to understand if, you know, Love in the Time of Cholera, if they were more in love with being in love or what it was happening in the story. And that just gives me happiness on a Sunday morning. Dr. Lidia Schapira: That's beautiful. I must confess that reading Borges is not easy. So, I totally admire the fact that you have managed to read all of his work. And I think that you're absolutely right, that magical realism is a genre that is incredibly fresh, and perhaps for the work that we do in oncology, it's a wonderful antidote in a way to some of the realities, the very harsh realities that we deal with on a daily basis. So, let me ask you a little bit about growing up in Venezuela in the 80s, 90s, early aughts. That must have been difficult. Tell us a little bit about that, and your choice of attending medical school. Dr. Narjust Duma: So, growing up in Venezuela, with a Colombian mother, it was quite a unique perspective because she was very attached to her Colombian roots. So, a lot of the things that happened in the house were very Colombian, but I was in Venezuela. So, it was a unique characteristic of being from a country but your family is not from there. So, my parents are not from Venezuela, my grandparents either, and I'm Venezuelan because I was born and raised there. So, that brought a unique perspective, right? The music that I played in my house was Colombian music, not Venezuelan music. So, my family migrated from Colombia to Venezuela due to the challenges in the early 80s with violence and the Medellin, due to the drug cartels. So, we moved to Venezuela for a better future. And growing up in the first years, Venezuela was in a very good position. Oil was at the highest prices. Economically, the country was doing well. I remember, in my early years, the dollar and the bolivar had the same price. But then little by little I saw how my country deteriorated, and it was very heartbreaking. From a place where the shells were full of food to a place now when there is no food, and you go to the supermarket, and many of them are close. And now you're only limited to buying certain things. And you used to use your federal ID that has an electronic tracking on how much you can buy because of socialism. So, you're only allowed to buy two kilograms of rice per month, for example, you're only allowed to buy this number of plantains. So, every time I go home, because Venezuela is always going to be my home, it doesn't matter where I am., I see how my country has lost pieces by pieces, which is quite very hard because I had a very good childhood. I had a unique childhood because I was raised in hospitals. But I had a childhood in which I will play with my friends across the street. We were not worried about being kidnapped. We were not worried about being robbed. That's one thing that children in Venezuela cannot do right now. Children of doctors – there's a higher risk of being kidnapped as a kid right now if your father is a doctor or your mother. So, my childhood wasn't like that. When I teach my students or talk to my mentees, I'm often selling my country, and saying that's not what it used to be. That's not where I grew up. But every year I saw how it no longer is where I grew up. That place doesn't exist, and sometimes, Lidia, I feel like my imagination may have to fill it out with more good things. But I think it was a good childhood. It's just that nobody in Venezuela is experiencing what I experienced as a kid. Dr. Lidia Schapira: So, both parents were doctors and you chose to study medicine, was this just right out of high school? Dr. Narjust Duma: Even before high school, I found myself very connected to patients. So, since I turned 15, my father would give his secretary a month of vacation because that's the month that we fill in. So, I was the secretary for a month every summer since I was 15 until I was 20. That early exposure allowed me to like get to know these patients and they know I was the daughter, but I was also the secretary. So, I really cherished that. Growing up in my household, we're a house of service. So, our love language is acts of service. That's how pretty much my grandmas and my parents were. So, in order to be a physician, that's the ultimate act of service. I have wanted to be a doctor since I was 11. I think my mother face horrible gender harassment and sexual harassment as a female in the surgery in the early 80s, that she tried to push me away from medicine. Early on, when I was 11, or 12, being an oil engineer in Venezuela was the career that everybody should have, right? Like, people were going to the Emirates and moving to different parts of the world and were doing wonderful. So, my mother, based on her experience in the 80s, was pushing me away from it. She's like, ‘You can do other things.' My father always stayed in the back and said, ‘You can do what you want.' This is how our parents' experiences affect our future. If I wouldn't be this stubborn, I would probably be an oil engineer today, and I wouldn't be talking to you. Dr. Lidia Schapira: So, you went to medical school, and then after you graduated, what did you decide to do? Because when I look at what we know about the history there is I think you graduated in '09, and then the story that you write about sort of begins in '16 when you come to New Jersey to do training in the US, but what happened between '09 and '16? Dr. Narjust Duma: I started residency in 2013. '16 was my fellowship. So, going to medical school was one of the hardest decisions I made because right in 2003 and 2004 was a coup in Venezuela where part of the opposition took over the country for three days, and then the President of the time came back and the country really significantly destabilized after that coup. Most schools were closed. Entire private industries were closed for a month. And I think for some people, it's hard to understand what happened. Everything closed for a month, McDonald's was closed for a month. There was no Coke because a Coke company was not producing. Everything was closed. The country was just paralyzed. So, my mother and I, and my family, my father, took into account that we didn't know when medical school would resume in Venezuela. We didn't know if the schools would ever open again. I decided to apply for a scholarship and I left Venezuela at the age of 17 to go to the Dominican Republic for medical school. Very early on, I noticed that I was going to be a foreigner wherever I go because I left home. And since then, I think I became very resilient because I was 17 and I needed to move forward. So, that is what happened in 2004. I left everything I knew. I left for the Dominican. I do have family in the Dominican, but it was very hard because even if you speak the same language, the cultures are very different. And then I went to medical school in the Dominican and when I was in the Dominican Republic, I realized I really wanted to do science and be an advocate and focus on vulnerable populations with cancer. So, then I made the decision to come to the United States, I did a year of a research fellowship at Fred Hutchinson, and then I went to residency in 2013. Dr. Lidia Schapira: I see. And that's when you went to New Jersey, far away from home. And as you tell the story, the experience was awful, in part because of the unkindness and aggression, not only microaggression but outright bullying that you experienced. In reading the essay, my impression was that the bullying was mostly on two accounts. One was gender. The other was the fact that you were different. In this particular case, it was the ethnicity as a Latin or Hispanic woman. Tell us a little bit about that so we can understand that. Dr. Narjust Duma: I think what happened is that perfect example of intersectionality because we are now the result of one experience, we're the result of multiple identities. So many woman have faced gender inequalities in medicine, but when you are from a marginalized group, those inequalities multiply. I have an accent and clearly a different skin color. I grew up in a family in which you were encouraged to be your true self. My grandmothers and my mother said, ‘You never want to be the quiet woman in the corner because the quiet woman never generates change.' That's what they said, and I bet there are some who do. But that intersection of my identities was very challenging because I was seen as inferior just for being a woman and then you multiply being one of the few Latinas you are seen like you are less just because you are - it doesn't matter how many degrees or papers or grants you had done and all, I was the most productive research resident in my residency for two years in a row - but I would still be judged by my identity and not what I have produced, or what I do on my patients' experiences, which were great – the feedback from my patients. It's just because I was the different one. Dr. Lidia Schapira: When I hear your story about your origins, it seems to me that you came from a very capable loving family, and they basically told you to go conquer the world, and you did. And then you arrive and you're a productive successful resident, and yet, you are marginalized, as you say. People are really aggressive. Now that you've had some years that have passed, if you think back, what advice would you give that young Narjust? Dr. Narjust Duma: My number one advice, would be that, I will tell myself is that I belong, in many instances, I feel like I didn't belong. It makes me question all the decisions to that day because when you're doing a presentation, and I still remember like today, and you're interrupted by someone, just for them to make a comment about your accent, it really brings everything down to your core, like, 'Is my presentation not accurate? Is the information not all right? And why am I here? Why did I left everything I love to be treated like this?' Dr. Lidia Schapira: Of course. So, from New Jersey, you write in your essay that you really discover your passion for cancer research, and you land in a fellowship with a mentor who is encouraging, and things begin to change for you. Can you tell us a little bit about that phase of your training in your life where you slowly begin to find your voice in the state, that also where you crash, where you find yourself so vulnerable that things really fall apart? Dr. Narjust Duma: So, when I was a resident, I didn't know exactly - I was interested in oncology, but I wasn't sure if it was for me. So, Dr. Martin Gutierrez at Rutgers in Hackensack is the person who I cold emailed and said, ‘I'm interested in studying gastric cancer in Hispanic patients because I think that patients in the clinic are so young.' He, without knowing me or having any idea, he trusted me. We still meet. He still follows up with me. He encouraged me. I think him being a Latino made the experience better, too, because I didn't have to explain my experience to him. I didn't have to explain that. He understood because he went through the same things. And he's like, ‘I got you. Let's follow what you want to do.' He embraced who I was, and how I put who I was into my research. And thanks to Dr. Gutierrez, I'm at the Mayo Clinic as an international medical grad. So, finding a place in which my ideas were embraced was very important to allow me to stay in medicine because, Lidia, I can tell you several times, I decided to leave. I was very committed to finding something else to do or just being a researcher and leaving clinical medicine behind. So, when I went to Mayo, I still followed with that mentor, but I already knew what I wanted to do. I wanted to do cancer health disparities. I wanted to do inclusion and diversity. And that allowed me to develop the career I have now and is having that pathway because I, with my strong personality and everything else, faced this discrimination, and I can imagine for other trainees that may still be facing that or will face that in the future. So, I use the negative aspects to find my calling and do many things I have done after that. Dr. Lidia Schapira: Speaks to your strengths and your determination. Let's talk a little bit about the people who may also feel different but whose differences may not be so apparent. How do you now as an emerging leader, and as a mentor, make sure that you create an inclusive and safe environment for your younger colleagues and your mentees? Dr. Narjust Duma: One of the things that resulted was the founding of the Duma Lab, which is a research group that focuses on cancer, health disparities, social justice as a general, and inclusion in medical education. So, one of the things that I practice every day is cultural humility. I continue to read and remember the principles. I have them as the background on my computer at work. The number one principle in lifelong learning is that we learn from everyone and that we don't know everything and other people's cultures, and subculture, we learn their culture is rich. So, in every meeting, I remind the team of the principles of cultural humility when somebody is joining the lab. I have one-on-one meetings, and I provide information and videos about cultural humility because the lab has been created as an environment that's safe. We have a WhatsApp group that is now kind of famous - it's called The Daily Serotonin. The majority of the members of the lab are part of marginalized groups, not only by gender but race, religion, sexual and gender orientation. So, we created this group to share good and bads, and we provide support. So, a few weeks ago, a patient made reference to one of their lab member's body, the patient was being examined and that was quite inappropriate. The member debriefed with the group and we all provided insights on how she had responded, and how she should respond in the future. That's not only learning from the person that brought the scenario but anybody else feels empowered to stop those microaggressions and stop those inappropriate behaviors that woman particularly face during clinical care. So, cultural humility, and having this WhatsApp group that provides a place where, first, I remind everybody that's confidential, and a place in which anything is shared has been very successful to create inclusivity in the group. Dr. Lidia Schapira: You have such energy and I'm amazed by all of the things that you can do and how you have used social connection as a way of bringing people up. So, can you give our listeners perhaps some tips for how you view creating a flatter culture, one with fewer hierarchies that makes it safer for learners and for those who are practicing oncology? What are three quick things that all of us can do in our work starting this afternoon? Dr. Narjust Duma: The concept is that we all can be allies. And being an ally doesn't take a lot of time or money because people think that being an ally is a full-time job, it is not. So, the first one tip will be to bring people with you. Your success is not only yours. It's a success of your mentees. It's a success of your colleagues. So, don't see your success as my badge on my shoulder. It's the badge that goes on everyone. So, bring people in, leave the door open, not only bring them but leave the door open because when you do it helps the next generation. Two, little things make a difference. I'm going to give you three phrases that I use all the time. When you think somebody has been marginalized in a meeting, bring them up, it takes no time. For example, 'Chenoa, what do you think we can do next?' You're bringing that person to the table. Two, you can advocate for other women and minorities when they're easily interrupted in a meeting. This takes no time. ‘I'm sorry you interrupted Dr. Duma. Dr. Duma?' So, that helps. The third thing is very important. You can connect people. So, one of the things is that I don't have every skill, so I advocate for my mentees and I serve as a connector. I have a mentee that is into bioinformatics. Lidia, that's above my head. I don't understand any of that. So, I was able to connect that person to people that do bioinformatics. And follow up. My last thing is to follow up with your people because they need you. Dr. Lidia Schapira: Well, I'm very glad that you're not an oil engineer in the Emirates. I'm sure your family is incredibly proud. I hope that you're happy where you are. We started a little bit about where you started, I'd like to end with your idea of where you imagine yourself 10 years from now? Dr. Narjust Duma: That is a question I don't have an answer prepared for. I guess my career development plans I think I want to be in a place where I look back and I can see that the careers of my mentees being successful. And I think that we measure my success based not on myself, I would measure my success in 10 years based on where my mentees are. And medical education is a more inclusive place. That will be the two things I want to see in 10 years. In the personal aspect, I don't know if we have art, don't know if we have those grants as long as my mentees are in a better place. Dr. Lidia Schapira: It has been such a pleasure to have this conversation. Thank you so much, Narjust. Dr. Narjust Duma: Thank you. Dr. Lidia Schapira: Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget

An interview with Dr. Lynn Henry from the University of Michigan in Ann Arbor, MI, lead author on "Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update." Dr. Henry reviews new biomarkers for the purposes of making treatment decisions for triple-negative breast cancer, and hormone receptor-positive, HER2-negative breast cancer, as well as tumor agnostic tumor biomarkers. Specific biomarkers addressed in this conversation include PIK3CA, ESR1, BRCA 1/2, PALB2, HRD, PD-L1, dMMR/MSI-H, TMB, NTRK, ctDNA, and CTCs. Read the full guideline at www.asco.org/breast-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lynn Henry from the University of Michigan in Ann Arbor, Michigan, lead author on 'Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update'. Thank you for being here, Dr. Henry. Dr. Lynn Henry: Thank you very much for inviting me to participate. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Henry, do you have any relevant disclosures that are related to this guideline topic? Dr. Lynn Henry: No, I do not. Brittany Harvey: Great! Thank you. Then let's talk about the scope of this guideline. So, what prompted this update to the guideline on the use of biomarkers to guide decisions on systemic therapy for patients with metastatic breast cancer, which was last updated in 2015? And what is the scope of this guideline update? Dr. Lynn Henry: Yes, so a lot has happened in the past six or seven years that influence how we treat metastatic breast cancer. And there are many new drugs that have been approved by the FDA during that time. When we reviewed the prior guideline and the new treatment landscape, we realized that while much of what was included in the old guideline was still relevant, there were quite a number of new biomarkers related to new drugs that needed to be included. The newly recommended biomarkers are primarily applicable to making decisions about treatment of estrogen receptor, progesterone receptor, and HER2-negative breast cancer, also called triple-negative breast cancer, as well as for treatment of hormone receptor-positive HER2-negative breast cancer. And finally, there are now some tumor biomarkers that can be tested for that are tumor agnostic, and these were included as well. Brittany Harvey: Great! So, then let's discuss the updated guideline recommendations based off these new biomarkers for our listeners. The guideline reviews testing for several different biomarkers. So, I would like to review each of the biomarkers that the panel assessed. Let's start with what is the role of PIK3CA mutation testing? Dr. Lynn Henry: Yeah! So, PIK3CA activating mutations are commonly found in tumors that are hormone receptor-positive and HER2-negative. Based on the results of the SOLAR-1 trial, patients whose tumors have an activating PIK3CA mutation had improved progression-free survival when treated with the PI3 kinase inhibitor alpelisib plus fulvestrant compared to fulvestrant alone. This improvement was not seen in patients whose cancers didn't have a mutation. So, therefore, this provided the evidence for the clinical utility of evaluating tumors for the somatic PIK3CA mutations. Testing of either a tumor specimen or plasma to look for PIK3CA mutations can be performed. However, it's important that if the plasma is tested, and no PIK3CA mutations are identified in the circulating tumor DNA, then our tumor specimen should really be tested if possible, because of the possibility of a false negative finding in the plasma. Also, since these mutations can be acquired over time, a more recent specimen should be tested if possible, as opposed to testing the primary tumor. Finally, in the SOLAR-1 trial, a patient's tumor had to have one of the 11 pre-specified PIK3CA mutations in exon 7, 9, or 20. And therefore, when mutations are identified using next-generation sequencing, it is important to confirm that the identified mutation is one of those 11 activating mutations and not a different one that may not convey benefit from treatment with a PI3 kinase inhibitor. Brittany Harvey: Great! I appreciate you're reviewing that recommendation, as well as the clinical utility of it and the evidence behind it. So, then following those recommendations, what is the role of testing for ESR1 mutations? Dr. Lynn Henry: At this time, there are insufficient data to support routine testing of metastatic hormone receptor-positive HER2-negative tumors for ESR1 mutations. However, the panel did note that there's a retrospective analysis of two different phases three trials that demonstrated that fulvestrant improved progression-free survival compared to the aromatase inhibitor exemestane in patients who had previously progressed on a non-steroidal AI and whose tumors had an ESR1 mutation. Importantly, there are ongoing clinical trials addressing this issue, including the PADA-1 trial, which is evaluating the effect of the switch of fulvestrant from aromatase inhibitor therapy, versus remaining on that therapy when ESR1 mutations are detected in the blood. However, although preliminary findings were presented at a recent large breast cancer meeting, and were suggestive of a possible progression-free survival benefit from switching therapy, data have not yet been published, and therefore they were not included in this guideline. Brittany Harvey: Great! So, we'll look forward to those updated data to potentially review that recommendation in the future. So, following those recommendations, what is the role of testing for germline BRCA 1 or 2 and PALB2 pathogenic mutations? Dr. Lynn Henry: So, the answer for germline BRCA1 and BRCA2 mutations is relatively straightforward. Patients with metastatic HER2-negative breast cancer can be either hormone receptor-positive or negative, and who are candidates for treatment with a PARP inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine whether they should receive treatment with a PARP inhibitor. This recommendation is based on the results of two large randomized clinical trials comparing PARP inhibitor therapy to physician's choice chemotherapy, although notably, the chemotherapy options did not include taxanes, anthracyclines, or platinums. In contrast, there remains insufficient evidence to support a recommendation either for or against testing for germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with a PARP inhibitor. The panel did note, however, that there are small single-arm studies that show that there is high response rate to PARP inhibitors in patients with metastatic breast cancer and coding DNA repair defects, such as either germline PALB2 pathogenic variants or somatic BRCA1 or 2 mutations. It was also noted that it is likely that patients who harbored mutations in these genes will actually be identified through routine testing with panel testing for germline variants. Brittany Harvey: Okay, understood. So, then following those recommendations, what is the role of testing tumors for homologous recombination deficiency? Dr. Lynn Henry: So, although there are emerging data from other solid tumors to support the use of homologous recombination deficiency, or HRD testing to guide therapy, current data do not support the assessment of HRD in the management of metastatic breast cancer. Therefore, we did not recommend routine testing of tumors for HRD at this time. Brittany Harvey: It's important to note where we both have evidence and where we don't have evidence. So, then what is the role of testing for expression of PD-L1 in metastatic breast cancer? Dr. Lynn Henry: So, the panel recommends that patients who are candidates for treatment with immunotherapy, with either a PD1 or PD-L1 inhibitor, should undergo testing for expression of PD-L1 in the tumor and immune cells with an FDA-approved test. At present in the United States, pembrolizumab is the only approved immunotherapy for the treatment of metastatic breast cancer, and it is given in combination with chemotherapy. The FDA-approved test for this drug is the 22C3 assay which evaluates PD-L1 staining in the tumor and surrounding stroma to calculate a combined positive score or CPS, with positive considered to be a score of 10 or greater. Of note, in other countries, there are different anti PD1 and PD-L1 antibodies that are approved for treatment, and each has been approved with its own companion diagnostic. So, it is important to make sure that you're using the right biomarker test, depending on which drug you are planning to use. Brittany Harvey: Great! I appreciate you reviewing the test in addition to the role of the biomarker. So, then, following those recommendations, what is the role of testing for deficient mismatch repair microsatellite instability-high? Dr. Lynn Henry: Similar to PD-L1 testing, it is recommended that patients with metastatic breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for deficient mismatch repair or microsatellite instability-high to determine eligibility for treatment with one of the drugs that is currently FDA approved, either dostarlimab or pembrolizumab. In contrast to the PD-L1 data, however, there are no randomized studies that have been conducted specifically in patients with breast cancer addressing this question. The testing recommendation was therefore included in these guidelines because of the tumor agnostic FDA approval of these drugs. In terms of which biomarker methodology to use, it was noted that, while the original studies assessed the deficient mismatch repair and MSI high using immunochemistry, and PCR respectively. The FDA has subsequently approved the next-generation sequencing platform to use in selecting candidates for these treatments. And so, therefore, there are a number of different tests that can be used. Brittany Harvey: Thank you for reviewing those recommendations as well. So, then following, what is the role of testing for tumor mutational burden? Dr. Henry Lynn: So, tumor mutational burden describes the quantity of somatic mutations in the tumor. Similar to the biomarkers we were previously discussing, there are minimal data specifically in metastatic breast cancer to support the assessment of tumor mutational burden for making treatment decisions. However, the testing recommendation was again included in the guidelines because of the tumor agnostic FDA approval of the drug pembrolizumab in the setting of high TMB. And also there is one single arm phase two trial that looked at this specifically. Importantly, the panel noted that there are a variety of factors that influence assessment of TMB. These include sample type, pre-analytical factors so how the sample was handled, the size of the panel and mutations that are tested, depths of the sequencing, type of the mutations that are included on the panel, and cut point variables. So, in particular, assessment of TMB in cell-free DNA assays such as circulating tumor DNA is an area of evolving evidence. There are therefore very important caveats to be aware of when selecting a TMB assay and assessing the results, many of which are outlined in the guideline manuscript itself, and different assays can yield different results for the same tissue specimen. It is therefore very important to use the approved companion assay and the approved cut point when making decisions regarding a specific treatment. Brittany Harvey: Absolutely. I appreciate your reviewing those details. So, then what is the role of testing for neurotrophic tyrosine receptor kinase? Dr. Lynn Henry: So, I'm going to abbreviate that to NTRK. So, NTRK fusions are rare in metastatic breast cancer. One study said 0.39% of all breast cancers have NTRK fusions. So, as with the above biomarkers, the NTRK testing recommendation is based on the results of phase 1 and phase 2 studies that were identified by the panel evaluating the efficacy and safety of these inhibitors for the treatment of advanced solid tumors with NTRK gene fusions, noting that there are only minimal data available that are specific to metastatic breast cancer. Brittany Harvey: Understood. Some of these are very rare in metastatic breast cancer. So, then, following that recommendation, what is the role of using circulating tumor DNA? Dr. Lynn Henry: So, for circulating tumor DNA, although the ctDNA technology holds promise in metastatic disease, for its ability to potentially identify tumor-specific mutations that are shed into the blood and that may be targetable, to date, neither the measurement of changes in ctDNA as a marker of treatment responsiveness nor identification of specific mutations in the blood to direct therapy has actually been prospectively shown to improve patient outcomes compared to standard imaging-based detection of tumor progression. Therefore, at present, the guideline does not recommend routine assessment of ctDNA for monitoring response to therapy among patients with metastatic breast cancer, although many studies are underway evaluating this question. Brittany Harvey: Understood. Then the last biomarker that the panel assessed in this guideline update, what is the role of using circulating tumor cells? Dr. Lynn Henry: Similar to circulating tumor DNA, there are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among patients with metastatic breast cancer. To date, studies that have examined the clinical utility of this marker to determine the optimal time for treatment change have not led to improvements in outcomes in metastatic breast cancer. Brittany Harvey: Great! Well, thank you for reviewing all of these recommendations. The panel certainly took on a lot of biomarkers and performed a critical review of all the evidence to make recommendations in this setting. So, in your view, Dr. Henry, what is the importance of this guideline update and what should clinicians know as they implement these updated recommendations? Dr. Lynn Henry: Yeah, that's an excellent question. So, this guideline addresses the key questions that we face, as we're making decisions about how best to treat patients with metastatic breast cancer. Importantly, the guideline highlights the current state of the science, with a focus on the available published data from randomized clinical trials. It also discusses the limitations of our current knowledge, as well as key considerations for different biomarkers. Of course, we recognize that there are new data emerging on a regular basis. And the panel therefore also highlighted where data are anticipated but not yet available, as well as key questions which we hope will be able to be addressed in the more distant future. Brittany Harvey: And then finally, how will these guideline recommendations affect patients with metastatic breast cancer? Dr. Lynn Henry: Yeah, so really, that is the bottom line, isn't it? So, ideally, this guideline will enable the dissemination of best practices in terms of biomarker selection and analysis to guide clinicians as they are making treatment decisions in conjunction with patients. Treatment of metastatic breast cancer has become more complex, with regimen selection affected by both inherited germline genetics and somatic changes in the cancer that can evolve over time. The assessment of relevant biomarkers should allow patients to receive the optimal therapies that are most likely to be effective based on the individual characteristics of their cancers. Brittany Harvey: Well, I want to thank you so much for reviewing this guideline with me today, and all of the recommendations and our gaps in evidence, for our listeners. Thank you for your work on this guideline update and thank you for your time today, Dr. Henry. Dr. Lynn Henry: Thank you so much! Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

An interview with Dr. Tian Zhang from UT Southwester Medical Center in Dallas, TX, author on "Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline." Dr. Zhang reviews the guideline recommendations for the treatment and management of patients with metastatic clear cell renal cell carcinoma and it's implications for clinicians and patients. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts.  My name is Brittany Harvey and today I'm interviewing Dr. Tian Zhang from UT Southwestern Medical Center in Dallas, Texas, one of the authors on 'Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline'. Thank you for being here, Dr. Zhang.  Dr. Tian Zhang: Absolutely. Thank you so much for having me, Brittany.  Brittany Harvey: Great! First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.  Dr. Zhang, do you have any relevant disclosures that are directly related to this guideline topic?  Dr. Tian Zhang: Yes, I have received past research funding from Novartis, Merck, and Pfizer, as well as advisory board and consulting fees from Merck, Exelixis, Pfizer, BMS, Eisai, and Aveo. All of these industry partners have approved therapies in renal cancer. For the complete list, our audience can refer to the guideline's publication.  Brittany Harvey: Great, thank you for those disclosures. Then starting off on the content of this guideline, can you give us an overview of the purpose and scope of this guideline?  Dr. Tian Zhang: Sure. This is a guideline for recommendations for the treatment and management of patients with metastatic clear cell kidney cancer. ASCO gathered 14 colleagues, including myself, that were considered kidney cancer experts from around the world, and we performed a systematic literature review to guide treatment recommendations in metastatic clear cell kidney cancer.  In the series of ASCO clinical practice guidelines for genitourinary cancers, we hope this guideline will provide recommendations for kidney cancer treatment with supporting data and evidence, particularly given the therapeutic landscape changes since about 2017.  Brittany Harvey: Then I'd like to review those recommendations that you just mentioned of this guideline. So, this guideline covers six overarching clinical questions. So, I'd like to go question by question for our listeners, starting with how is metastatic clear cell renal cell carcinoma is defined and how is it diagnosed?  Dr. Tian Zhang: In this portion, we recommended a gold standard of comparing metastatic tissue outside of the primary site to the primary tumor. We discuss adding in staining for PAX8 as well as CA-IX for clarity of clear cell histology.  The timing is also pretty important in the timing of initial diagnosis and nephrectomy until the appearance of metastatic sites on scans, and radiographic diagnosis is therefore used in settings where prior diagnoses of clear cell kidney cancer has been established and when a metastatic lesion is not accessible for biopsy or when there's clear, measurable disease within a year of the initial diagnosis.  Brittany Harvey: Understood. And then in the next section of the guideline, what is the role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma?  Dr. Tian Zhang: In this section, we recommend that cytoreductive nephrectomy should be considered for select patients who present with de novo metastatic clear cell kidney cancer to palliate hematuria or pain or to remove the bulk of tumor burden.  We discuss some past trials in the settings of interferon alpha, and VEGF inhibitors and also recommend consideration of ongoing clinical trials in the era of immunotherapies. There are two such trials that are ongoing, PROBE and Cyto-KIK, that are actively accruing patients.  Brittany Harvey: Great. And then the guideline goes into options for systemic treatment. So, what are the preferred options for first-line systemic treatment?  Dr. Tian Zhang: This is probably our most extensive section, as first-line systemic treatments have changed and expanded greatly over the past five years. First, we recommend considering active surveillance for select patients with the following criteria: those who have IMDC favorable or intermediate-risk disease, those with limited or no disease-related symptoms, and also those with a long interval between nephrectomy and the development of metastasis.  Second, we recommend IMDC risk stratification to then determine treatment selection. Those with IMDC intermediate or poor risk factors should be offered combination treatment with either two immune checkpoint inhibitors or an immune checkpoint inhibitor with an anti-angiogenic VEGF tyrosine kinase inhibitor.  We provide strong level of evidence with the completed phase three trials in this first-line setting of ipilimumab and nivolumab, axitinib with pembrolizumab, axitinib with avelumab, cabozantinib with nivolumab, and lenvatinib with pembrolizumab.  For patients with IMDC favorable-risk disease, we recommend an immune checkpoint inhibitor with a VEGF tyrosine kinase inhibitor which may be offered over VEGF TKI alone for those patients who are candidates for immunotherapy.  In addition, VEGF monotherapy or an immune checkpoint inhibitor monotherapy may be offered for select patients who have certain coexisting medical conditions.  In addition, we have discussed this long history of high dose interleukin-2 treatments and that this may still be considered in first-line treatments for certain patients while discussing the significant toxicity of IL-2 relative to the newer immunotherapy regimens.  And finally, we encourage the participation and enrollment into first-line clinical trials when available. A couple of the current ongoing ones include PDIGREE and the LITESPARK-012 Trial.  Brittany Harvey: I appreciate your reviewing those options and the level of evidence along with those ongoing trials for patients. So, then following those recommendations for first- line that you just went through, what is recommended for the second or later line systemic treatment?  Dr. Tian Zhang: Subsequent treatment in later lines after initial treatment of refractory renal cell carcinoma depends largely on the initial treatment choices.  We recommend nivolumab or cabozantinib for patients who had prior progression on a VEGF TKI alone based on the large phase three trials CheckMate 025 and METEOR respectively that gain the approvals for nivolumab and cabozantinib.  For patients with disease progression on a combination immunotherapy, a VEGF TKI should be considered. Those who progress after initial combination therapy with a VEGF TKI and an immune checkpoint inhibitor should then be offered an alternative VEGF TKI as a single agent.  And finally, for those who have limited sites of disease progression, local treatment with radiation, thermal ablation, or surgical excision could be offered with continuation of the immunotherapy.  Brittany Harvey: Thank you for reviewing those second and later line treatment options. So, then following that, what did the panel recommend regarding metastasis-directed therapy?  Dr. Tian Zhang: There have been some recent studies looking at metastasis-directed treatments, especially for patients with a low volume of metastases. These can include surgical resection, ablation, or radiation therapy. And surgical resection and radiation have not actually been directly compared.  And so, for those patients, we would recommend a tailoring treatment based on sites of disease. For those patients who do have surgical resection, subsequent VEGF TKIs are not usually recommended based on a prior phase two trial.  Brittany Harvey: Understood. And then this guideline addresses a couple special subsets of patients. And so, what are those subsets, and what considerations should be applied to the treatment of these special subsets of metastatic clear cell renal cell carcinoma?  Dr. Tian Zhang: For the special subsets of patients, we considered patients with bone metastases, patients with brain metastases, and also patients with sarcomatoid features on histology.  For those patients with bone metastases, we recommend bone-directed radiation as well as a bone resorption inhibitor with either a bisphosphonate or a RANK ligand inhibitor.  We do not have a recommendation on optimal systemic treatments, although given the presence of the MET receptor on bone metastases, regimens containing cabozantinib, which targets the MET receptor in addition to other receptors, may be preferred.  For those patients who have brain metastases, no definite guidance for treatment can be made given many patients with brain metastases were excluded from the initial trials.  The overall efficacy of the systemic therapies is low for controlling metastatic kidney cancer in patients with brain metastases. We do recommend local treatment with radiation and or surgery to be undertaken based on the pattern of intracranial metastases. And we refer readers and the audience to a recent guideline from ASCO, ASTRO, and SNO on the management of brain metastases.  And finally, for patients who have sarcomatoid features on pathology, an immune checkpoint inhibitor-based combination should be chosen in the first line setting. And this is based on multiple phase three trials that have shown improvement in clinical outcomes for patients treated with immunotherapy combinations compared to sunitinib alone.  Brittany Harvey: Thank you for viewing all these recommendations. The guideline expert panel certainly covered a lot of questions on the treatment and management of metastatic clear cell renal cell carcinoma.  So, then in your opinion, Dr. Zhang, what is the importance of this guideline and how does it impact clinicians?  Dr. Tian Zhang: Sure. You know, in the past 10 years, our treatment options for metastatic kidney cancer have greatly expanded and multiple options are now available. For busy clinicians who may not treat kidney cancer, especially in the metastatic setting often or on a routine basis, this set of guidelines provides a high-level approach to the common management scenarios that clinicians are often faced with.  My fellow committee members and I hope that these guidelines will provide a comprehensive one-stop document that is relevant and updated for the busy clinician taking care of patients with metastatic kidney cancer.  Brittany Harvey: Great! And then finally, how will these guideline recommendations affect patients with metastatic clear cell renal cell carcinoma?  Dr. Tian Zhang: The fact that our treatment options for metastatic kidney cancer have improved clinical outcomes, including extending the time until progression as well as overall survival, is truly wonderful news for patients who are diagnosed with metastatic kidney cancer today.  If patients are directly reading these guidelines, they can also see whether overall recommendations align with their recommended course of treatment, with the caveat that every patient's care is tailored to them based on coexisting medical conditions and concurrent medications. But we hope these guidelines will be helpful for all of our patients.  Brittany Harvey: Yes, it's great to see improved clinical outcomes for patients. So, I want to thank you for all of your work on this guideline and for taking the time to review the guideline recommendations and its impact.  Dr. Tian Zhang: Sure. I really appreciate ASCO giving this time and opportunity, Brittany, and also the audience for their interest in the clinical guidelines for metastatic clear cell renal cell carcinoma.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series.  To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. 

"Cancer and Armed Conflict: Crossing Realities," by Tamamyan, et al: the story of a young patient with cancer from Nagorno-Karabakh Republic and his thoughts and sufferings during the war in 2020.   TRANSCRIPT Narrator: Cancer and Armed Conflict: Crossing Realities, by Alisa Kamalyan, MSc, Yeva Margaryan, MD, MPH, Jemma Arakelyan, MD, Liana Safaryan, MD, Gevorg Tamamyan, MD, MSc, DSc, and Stella Arakelyan, MD, MPH, MscIH, PhD (10.1200/JCO.22.00663) In 2007, Armen, a 6-year-old boy from a village in the mountainous Nagorno-Karabakh Republic (NKR), was diagnosed with Hodgkin lymphoma. NKR is a de facto independent state located in the South Caucasus which has historically been inhabited by Armenians and declared its independence after the collapse of Soviet Union in 1991. Armen's hometown had a small clinic offering only routine health care services. To receive treatment for lymphoma, he and his family had to travel 350 kms to the Hematology Center in Yerevan, the capital of Armenia. The journey was long and exhausting, but every visit to the Hematology Center filled him with hope, and, ultimately, he achieved a complete remission. Thirteen years later, Armen, now a young man, returned to the Hematology Center for evaluation of rapid weight loss, persistent pain, and chronic fatigue and was diagnosed with osteosarcoma. First-line chemotherapy and surgery were ineffective, as was second-line therapy with high-dose methotrexate, doxorubicin, and cisplatin. The tumor was growing and spreading rapidly, causing unbearable pain. Throughout the course of his disease, Armen kept a diary. Recently, his family shared his journal with us, hoping to give a voice to Armen and other young patients with cancer struggling with physical and emotional distress along with overwhelming existential angst. “In the hospital I had dreams which I could not understand. In one of the dreams, it was midnight, and I knew that I was going to die in 3 hours, but time was running backward, which meant that I was going to die at 8 pm … In another dream, I was undergoing a course of chemotherapy when my phone rang, the call was from Hell. I picked up the phone, and it was one of my relatives from Nagorno-Karabakh who is no longer alive. But you are dead …, I said to her, surprised. How are you, my dear? She replied. Once I hung up the phone, a man dressed in black sat down next to me, made the sign of the cross, and then disappeared …” At the time, there were no clinical trials available for patients with osteosarcoma in Armenia and his family could not afford to take Armen abroad to receive any experimental therapy, so, after exhausting all available treatment options, Armen returned home to live out his days in the village that helped raise him. We knew that his home environment would provide the support he needed as his cancer journey came to its tragic end. We hoped for his comfort, safety, and peace among those who loved him. On the morning of September 27, 2020, Armen awoke in a panic, distressed by the loud explosions of bombs dropped on his village as the war between the NKR and Azerbaijan erupted. This conflict, coinciding with the rapid spread of COVID-19 in NKR and Armenia, interrupted access to cancer care and essential palliative medications. Armen was bedridden with intolerable pain and a dwindling supply of analgesics. The encroaching sounds of high-intensity blasts further amplified his anguish and suffering. Armen's psychological trauma resulted in nightmares and chronic anxiety as evidenced by his diary entries. “My house keeps shaking with each explosion, resonating like a high-scale earthquake. Soon, the blasts will shatter all the windows in my house” (October 1, 2020). “Our electricity, heating, and water supplies are cut off. My supply of painkillers is running out” (October 9, 2020). “Don't think about death– think about the future…” Within weeks, the Nagorno-Karabakh conflict escalated, destroying homes, healthcare clinics, hospitals, and schools, resulting in massive population displacement and hundreds of civilians, including health care providers, being killed or wounded. Given these dire circumstances and Armen's worsening pain and weakness, Armen's family sought refuge in Armenia, where his battle with cancer ultimately ended. After the war ended on November 9, 2020, Armen's family took him back home to be laid to eternal rest. This had been his last wish. Armen was a fearless soul. He was a fighter who had already survived cancer once and continued his fight with a smile on his face, giving hope to many of our other patients and staff. But the day the Azeris attacked his home, the smile left his face forever. For our health care team and other colleagues, the 44 days of the Nagorno-Karabakh war caused a psychosocial and emotional crisis. We could not concentrate on our work. Hundreds of soldiers were being killed daily, and many colleagues felt compelled to leave the cancer wards to join frontline military health care workers. With increasing numbers of surgeons, anesthesiologists, and nurses traveling to the NKR or bordering regions of Armenia, we experienced acute staff shortages, undermining the provision of quality care to our patients. COVID-19, the main health care concern for the rest of the world, was no longer our priority, even as the incidence increased 8-fold during the war.1 The vicious cycle of war and pandemic was tormented as we tried to balance our own emotions and fears while continuing to care for and support our patients with cancer. Armen's story provides only a glimpse of what people with terminal cancer and the health care workforce experience in resource-limited settings affected by war. Today, around half of the world's population lives in countries affected by war, with predictions that cancer will disproportionately affect these regions in the coming decades. Because of multifactorial resource limitations, patients with cancer from these areas are usually diagnosed in advanced stages of the disease when palliation is the only viable option for care. Worldwide, an estimated 78% of adults and 98% of children in need of palliative care reside in resource-limited regions. A third of adults needing palliative care services are patients with cancer and 80% of them live with moderate or severe chronic pain. Despite these data, only 10% of the world's overall morphine consumption occurs in resource limited regions. The provision of palliative care services is even more strained by armed conflict. Recently, the World Health Organization reported that palliative care was available in less than two thirds of Syrian health care facilities and that all cancer centers surveyed in Syria lacked immediate-release oral morphine and trained palliative cancer care staff. Currently, we are witnessing an escalating war in Ukraine. The images from this and any new conflict around the world bring back our own wartime experiences with haunting clarity. The desperation we felt trying to care for the most vulnerable patients during lethal and chaotic times will never leave us. How many children are now writing tales of death in their journals? How many villages and families are being shattered, unable to provide last days of peace and comfort to their sick and dying loved ones? Despite recent initiatives to include oncologic and palliative care contingencies in humanitarian responses to crisis, they continue to remain a relatively low priority and have been minimally integrated into emergency response plans during armed conflicts. Protocols detailing how to provide basic care to patients with cancer and maintain supplies of essential medications are yet to be fully developed. We urge the international community to take action to address the existing obstacles to cancer care delivery in conflict affected regions to mitigate the adverse impact of cancer and armed conflict on our most vulnerable patients.   Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, which offers a range of educational and scientific content and enriching insights into the world of cancer care. You can find all of the shows, including this one at podcast.asco.org. I'm your host, Lidia Schapira, associate editor for Art of Oncology and Professor of Medicine at Stanford. And with me today is Dr. Gevorg Tamamyan, Chairman and Professor of the Department of Pediatric Oncology and Hematology at Yerevan State Medical University, head of the Pediatric Cancer and Blood Disorders Centers of Armenia, and Chairman of the Board of the Institute of Cancer and Crisis. We will be discussing his Art of Oncology article, ‘Cancer and Armed Conflict Crossing Realities.' Our guest has travel, accommodation, and expenses from Roche. Gevorg, welcome to our podcast. Dr. Gevorg Tamamyan: Thank you! Thank you very much, Dr. Schapira, for the invitation and for this opportunity to speak with you. Dr. Lidia Schapira: It is our pleasure. Can you tell our listeners a little bit about the origin of this narrative? How your team come together to tell the story now? Dr. Gevorg Tamamyan: So, living in a region where every day you face not only - and being an oncologist in the meantime - facing death not only from cancer but also from the war, it makes you think about cancer from a different perspective. During my not-so-long life, I experienced three wars. The second one was a little bit shorter, but the first one was quite a long one. I was a young boy at the school age and the second one, the large one, was recently in 2020. Later on, being already an oncologist, when every day you are walking in between life and death and your everyday work is dedicated to saving one more life, sometimes you realize that with one bomb people can kill hundreds and thousands. So, having this on my mind, I started exploring the field a few years ago, even not knowing that a new war is going to begin in 2020. And we wrote an editorial in Nature Cancer Reviews, I think it was 2019, if I'm not mistaken, about how the war affects cancer patients and cancer care in general. And then in 2020, when we had this sad experience, then we thought that we must express our feelings and reveal what happened, what happens with cancer patients during the war situation. And just recently, of course, there is a new war in the world and we see all this struggling every day. So, unfortunately, this topic does not lose its actuality, I would say. Dr. Lidia Schapira: You chose to tell the story of a young boy who first came to your major academic center in Armenia at age 6, and you treated and cured him of Hodgkin's lymphoma. And then he returns as a young adult, 19 years old, with an osteosarcoma that you treated. But unfortunately, treatment was not curative, and he goes back to his village and needs to receive palliative care but is suffering now in 2020 with the war in NKR. Can you tell our readers a little bit about the Nagorno-Karabakh war and how it affected your team and the care you provided to children and young adults with cancer? Dr. Gevorg Tamamyan: So, Nagorno-Karabakh Republic is located in South Caucasus. It's historically inhabited with Armenians and it has been a land for wars for many years. The first war, what I observed, started in the late 1980s. I was just born a few years ago and I cannot clearly say what happened, but I know from the history definitely. There were massacres of Armenians and the war erupted. But for many years, for three decades, the situation was unstable. And during the COVID 19 pandemic, Nagorno-Karabakh Republic was attacked by Azerbaijan, supported by Turkey. And just to kind of illustrate what the situation is, there are like 100- 150,000 people residing there. So, this is a small country. It was attacked and there were thousands of people killed and tens of thousands displaced. So, this was the sad reality, what we have seen, of course. One day I was in Stepanakert, the capital of the Nagorno-Karabakh Republic when bombs were falling on the civilian buildings. I was on the ground floor of the hospital, and I was seeing how these wounded people, civilians, were coming to the hospital. It was really, I mean, my English is very poor to describe all this situation, but back in the hospital, we had a lot of patients from Nagorno-Karabakh and we were seeing their struggles. It was not only from cancer. Some people were losing part of their families, and some of their family members were at the worst stage. And kids, I mean, there was no smile on the kids' faces. It's difficult to describe. I think it happens with every war, anywhere in the world. And we decided to describe this young boy's story and through this story, to deliver the message about the war, about cancer, and about how patients with cancer struggle during this crisis and these difficult times. Dr. Lidia Schapira: You tell in your story very movingly how difficult it was for this young man to run out of his pain medication, to also run out of all of the sources of delivery of palliative care. And also, you tell us a little bit about how this made your team feel, that you were struggling with the war, you were struggling with this idea that you couldn't relieve the symptoms and pain of your patients. Tell us a little bit about how your team struggled through this and what helped you as you went about your work every day? Dr. Gevorg Tamamyan: Our hospital is a major hospital not only for pediatric cancer. We have the only pediatric cancer center located in the hospital, but also our center, the hematology center, where our pediatric cancer center is located, is the major and the main blood bank. So, we were kind of primarily involved in saving patients' lives through the blood bank, of course, because all the people were coming to donate the blood and we were sending this blood to different hospitals. And I must confess that this pain medication and palliative care is an issue not only during the war but also during peacetime in many resource-limited settings. But during the war it becomes dramatic. And for the people living in the war area, in the region affected by conflicts, it's almost impossible for them to receive this treatment. I've seen the stories from Syria, back, let's say ten years ago, photos from the hospitals, and photos of kids who were not able to receive the treatment. Let's say a kid with lymphoma with all the chances to get cured and he or she is not receiving the medications because there is a war, because people fight, and people are dying and kids are dying in pain because they are not able to receive their opioids, their painkillers. So, for doctors, of course, realizing this is very difficult. And the second one, because the supply chains are kind of disrupted, it's difficult to get the medications on time. Then many doctors leave the hospitals and go to the war front and let's say, do surgeries there or just help the wounded people. Sometimes we're out of the staff or out of the specialists, some of our surgeons. We are a small country and there might be four narrow specialists, one or two specialists, and when your specialists are at the military hospitals, how can they operate? How can they do surgeries for the kids? And of course, everyone has a relative, everyone has a friend who is there and you are thinking about them even if you are not there. So, from all sides, you are depressed. And that's the war. That's how the war looks. In the cities which are under the bombs, of course, the situation is even more difficult than what we see in different parts of the world. Dr. Lidia Schapira: The reality of the war is always awful and I really admire your ability to bring this to our attention in such a clear way. Let me ask the question again. How do you and your colleagues get through the day? And I imagine that you're probably sort of reliving the trauma in a way when there is a new war in the world, as there is now in your general area of the world. How are you all doing? Dr. Gevorg Tamamyan: With every new war, including this new war in Ukraine, I mean, people are dying. You see these images from the cities. The worst thing is that you know these people are from both sides and you have friends from both sides, and even these fighting sides, I mean, they were brothers a day ago. And you see how kids are dying, you see how young people are dying, and you see displaced people who are leaving their houses. It's really very difficult. In the meantime, the situation here is also not calm. During the last months, several times we observed a similar situation in Karabakh, again, wherein several villages people were displaced. It's kind of a no war, no peace situation. And can you live with the thought that the war is going to begin again soon and you don't know what's going to happen? That's the reality. Dr. Lidia Schapira: So, you bring our attention, Gevorg, to the enormous disruption in care for children and adults with cancer caused by war, both the interruption of cancer-directed care, but also the interruption of palliative care. There's a general feeling, I think, among many oncologists throughout the world of wanting to help. How can people help? Dr. Gevorg Tamamyan: It's very difficult, to be frank, to single out a solution, but there are different ways. First of all, I think one kind of help would be just to write an email and say, ‘How are you doing?' Because in the world, what we are lacking the most, it's paying a little bit more attention to our friends and neighbors and people we know. And of course, with our routine daily life, we are so busy, but even a small message can help the people with the stress. At that time, maybe someone will say, “Okay, do you have ten ampoules of this or fractions of this drug?” Or something like that. “Or would you give me advice on how I might manage this child?” But of course, my suggestion would be that all the professional societies and humanitarian organizations, and major cancer institutions put their efforts into trying to find systematic solutions for how it is possible to help patients or professionals in the conflict-affected regions, and how to help displaced populations. And not only when the conflict erupts or war erupts because there are conflicts all over the world right now. For example, people in Syria, right? They experience so many struggles. I was reading in the ASCO post, there was an editorial, that tens of thousands of professionals left Syria. So, people are left without basic health care, and similarly in Iraq, Afghanistan, Ukraine, and in many parts of the world. So, I think a systematic effort is needed to help the patients and professionals. I'm sure when we get together, we'll find better solutions. But of course, the best way is to keep the peace. But sometimes it's out of our reach. Dr. Lidia Schapira: That's right. So, some things are out of our reach. But one of the things that we can all do is, as you so beautifully articulated, to show some solidarity and to start by reaching out to a colleague we know or to somebody who is in that area just by checking in, ‘How are you doing?', ‘Is there something I can do to help?' And then, of course, through the power of these stories, I think to sort of help people understand that there are ways of getting involved, as you say, to think about creating perhaps a better infrastructure to deal with both cancer care and pain and symptom management for all the people affected by and displaced by war. Dr. Gevorg Tamamyan: Yeah, I agree, definitely. Dr. Lidia Schapira: Do you have a final message perhaps for our listeners, Gevorg? Let me give you the last word. Dr. Gevorg Tamamyan: We are talking about war and we are talking about cancer. My only wish is for there to be peace in the world and there is a cancer-free world, of course. Dr. Lidia Schapira: Thank you so much for taking the time out of your busy schedule to share your thoughts. Thank you so much to you and your team for sending this beautiful essay to us. Until next time, thank you to our listeners for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review on Apple Podcasts or wherever you listen. Be sure to subscribe so you never miss an episode. JCO's Cancer Stories: The Art of Oncology is just one of ASCO's many podcasts. You can find all of the shows at podcasts.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

An interview with Dr. Pauline Funchain from Cleveland Clinic in Cleveland, OH, author on "Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update." Dr. Funchain reviews recent evidence and updated recommendations from the ASCO Expert Panel for the use of tebentafusp in patients with metastatic uveal melanoma. For more information, visit www.asco.org/melanoma-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I am interviewing Dr. Pauline Funchain from Cleveland Clinic in Cleveland, Ohio, author on Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Funchain. Dr. Pauline Funchain: It's great to be here with you, Brittany. Thank you! Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Funchain, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Pauline Funchain: I do not have relevant disclosures that relate to this guideline topic. Brittany Harvey: Great, thank you. Then getting into the rapid update, what prompted this rapid update to the Systemic Therapy for Melanoma: ASCO Guideline published in 2020? Dr. Pauline: So, earlier this year, on January 25th, the FDA approved tebentafusp for metastatic uveal melanoma. So, this is the first FDA approval for metastatic uveal melanoma. We felt it was really important to put out a rapid update to let both clinicians know about the therapy and also so that more patients can get access to it as quickly as possible. Brittany Harvey: Understood. So, then based on this new FDA approval, what are the updated recommendations for patients with uveal melanoma? Dr. Pauline Funchain: So, any patients who have a previously untreated metastatic uveal melanoma, and also who are HLA-A*02:01 positive, this group of patients should be offered tebentafusp as systemic therapy. This is the only systemic therapy that has been shown to prolong overall survival in patients with metastatic uveal melanoma. And if you look at the kind of benefit that was seen, patients who were on tebentafusp had a median overall survival of 21.7 months versus 16 months in comparison to investigator's choice. In this case, that was either single agent pembrolizumab, ipilimumab, or dacarbazine. So, it is a pretty significant overall survival benefit. Brittany Harvey: Great! Thank you for reviewing those updated recommendations and the data behind them. So, what should clinicians know as they implement this updated recommendation? Dr. Pauline Funchain: So, they should know that there was a great overall survival benefit seen, but it doesn't correlate with the objective response rate that was seen in the trial. So, for patients who were treated with tebentafusp, the objective response rate was 9%. And for those patients who were treated with the investigator's choice, again, that was single agent pembrolizumab, ipilimumab, or dacarbazine, the response rate was 5%. So, that margin was not very different in terms of objective response rate when looking at RECIST-based criteria, so radiologic criteria for response, but the survival was clearly seen. And interestingly, even in those patients that had radiologic progression, there was an improved survival for those patients who were on tebentafusp versus investigator's choice. So, there is some kind of survival benefit that may not correlate with what is seen on imaging. So, clinicians should know that they may not see a dramatic response in terms of tumor size on imaging, but patients may still benefit from the therapy. Brittany Harvey: Understood. So, then you've just talked a little bit about responses in patients. So, how does this guideline update affect patients with melanoma? Dr. Pauline Funchain: So, despite a difference in response rate, long story short, there is an overall survival difference. So, really, this is the first overall survival difference that we have seen in metastatic uveal melanoma. It is really exciting. It is finally an approved drug for metastatic uveal melanoma, which did not have any approved or standard of care, systemic drugs. So, this is a really big win for a rare disease. I think, in terms of the general melanoma field and also the cancer field in general, this is really an exciting first-in-class drug on two different fronts. It is the first approved T-cell receptor therapy. It is also the first bispecific protein and it works differently than other immunotherapies we have seen. So, hopefully, this is something we see more of in other cancers. Brittany Harvey: Definitely, it's good to see that these patients finally have an option and we'll look forward to research in other cancers as well. So, then finally, Dr. Funchain, what are the outstanding questions regarding systemic therapy for melanoma? Dr. Pauline Funchain: Well, there are multiple questions that are outstanding. I think, for metastatic uveal melanoma, I think there are a lot of questions about the dissociation between the radiologic response and survival. I think there are questions about knowing when to stop tebentafusp if it's not working because we don't really have a good sense of what we should be using to know if this is not the right therapy for that patient. I think we would love to know what the biomarkers of response are, and we may need different ways of looking for how to judge if a patient is benefiting from tebentafusp and other systemic therapies. And I think that there's still a big question in uveal melanoma about whether we start with systemic therapy or local therapy. I don't think that's been answered. Now, in terms of the entire guideline, I think for melanoma in general, there are new data that are emerging and have been recently published and we will be looking forward to the next ASCO guideline in systemic therapy for melanoma because I think that there are a lot of emerging data that need to be addressed. Brittany Harvey: Definitely. We'll look forward to that new research in uveal melanoma and to reviewing the updated data with the guideline panel for the next edition of the systemic therapy for melanoma guideline. So, I want to thank you so much for your work to rapidly updating this guideline, and thank you for your time today, Dr. Funchain. Dr. Pauline Funchain: Thank you for having me. It is really meaningful to us to be able to offer education and get the word out about therapies that can help our patients. Brittany Harvey: Agreed. And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full rapid recommendation update, go to www.asco.org/melanoma-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, TX, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, WA, co-chairs on "Systemic Therapy for Advanced HER2-Positive Breast Cancer: ASCO Guideline Update." This guideline updates recommendations on systemic therapies for advanced HER2-positive breast cancer, focusing on second-line, third-line, and greater treatment. Read the full guideline.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, Washington, co-chairs on 'Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer: ASCO Guideline Update'. Thank you for being here. Dr. Giordano and Dr. Davidson. Dr. Sharon Giordano: Thank you. Dr. Nancy Davidson: Thank you for having us. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Giordano, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Sharon Giordano: No, I do not. Brittany Harvey: Thank you. And Dr. Davidson, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Nancy Davidson: No, I do not. Brittany Harvey: Thank you. Let's talk about the content of this guideline update. So first, Dr. Giordano, what prompted an update to this guideline on the systemic therapy for advanced HER2-positive breast cancer, and what is the focus of this update? Dr. Sharon Giordano: So, we were prompted to update the guidelines for HER2-positive metastatic breast cancer because several new studies have been presented and published, which are really changing our standard of care approaches. We have new therapies and new combinations that have resulted in improvements in progression-free survival and in overall survival for this patient population. Given the clinical importance of these new studies, we felt that an update of the treatment guidelines was clearly needed. Overall, the focus of our update is really in the title, so, it's systemic therapies for advanced HER2-positive breast cancer. And specifically, what we're focusing on is updating the recommendation for second-line therapy, and then adding multiple new options for systemic therapies for third-line and greater treatment. Brittany Harvey: Great. Thank you for that overview. So, then I'd like to review the updated recommendations of this guideline for our listeners. Starting with, Dr. Davidson, what is recommended for first-line therapy for patients with advanced HER2-positive breast cancer? Dr. Nancy Davidson: So, that was the part of this guideline that really did not change. In the previous iteration and in the current iteration, we felt that the evidence suggested that a combination of trastuzumab and a taxane should be the first-line treatment for individuals with metastatic HER2-positive breast cancer unless they have some sort of contraindication to the taxanes. Now, the evidence supporting that is very strong. The trial that supported this continues to be updated and continues to show benefit. So, that's a very high level of evidence and our recommendation on this was extremely strong. Brittany Harvey: Great. And then following those first-line recommendations, Dr. Giordano, what is recommended for second-line treatment for these patients? Dr. Sharon Giordano: So, we did change our recommendation for second-line treatment for HER2-positive patients. The current new recommendation is, and I quote from our guideline, “If a patient's HER2-positive, advanced breast cancer has progressed during or after first-line HER2 targeted therapy, and the patient has not received trastuzumab deruxtecan, clinicians should recommend trastuzumab deruxtecan as a second-line treatment.” So, as I said before, this recommendation is a change from our prior second-line recommendation. Previously, we had recommended T-DM1. So, this change was really, I think, one of the most important changes to the guidelines with this update. We made the recommendation based on the initial presentation of the results of the Destiny-Breast03 trial, really given the magnitude of the benefit that was seen in the study. And the manuscript I would note was published this month in the New England Journal of Medicine. Overall, the study showed statistically significant and highly clinically meaningful reduction in progression-free survival. So, just to give you some of these numbers, to kind of give you a sense of how big the impact was, so 76% of patients who were treated with trastuzumab deruxtecan versus 34% of patients treated with trastuzumab emtansine were alive and without disease progression at a year, with a hazard ratio of 0.28. The response rates are also quite impressive with 80% versus 34% response rates. And the overall survival data are still immature but do favor treatment with trastuzumab deruxtecan and that hazard was 0.55. So, I will note though, that toxicity was a bit higher with the new drug, with trastuzumab deruxtecan. So, any grade adverse events were 98% versus 87%. And then if you look at grade three and four drug-related adverse events, it was 45% versus 40%. I think of note, rather than just kind of the overall numbers, though, one thing that clinicians need to be aware of is the risk of interstitial lung disease with this new drug. And this occurred in about 10% of treated patients in this study, although only 1%, or I think it was two patients, who had grade three or higher pulmonary toxicity. So, this is a toxicity that is specific to this drug that clinicians do need to be aware of. Dr. Nancy Davidson: I think the other thing on that, Sharon, is that the incidence was lower in the Destiny Breast03 trial than it had been in some of the really early studies of this agent, so, that should be reassuring to us. Although, of course, it doesn't mean that the side effect doesn't happen, you have to take note of it. Dr. Sharon Giordano: That's a great point. It definitely was lower than we'd seen before. So, a little bit of a relief, but still there. Brittany Harvey: Great, thank you both for reviewing that data. I appreciate the overview. So then, following those recommendations for second-line treatment, Dr. Davidson, what are the recommended options for third-line therapy for patients with HER2-positive advanced breast cancer that has progressed on second-line or greater HER2 targeted therapy? Dr. Nancy Davidson: Well, of course, this is the area where there has been considerable change as well. And that's because of the wealth of new anti-HER2 agents that Dr. Giordano talked about earlier. So, we had a variety of recommendations for clinicians and patients to make decisions about how to proceed. I think certainly one of them, is that if the patient did not receive trastuzumab emtansine (T-DM1) in the second line, as we just talked about, our new recommendation would be that they would not, that they would receive trastuzumab deruxtecan, so you put off for T-DM1 in that [third-line] setting. And that's a new recommendation for us. And the strength of the recommendation is quite high. Another agent that's come along that's very exciting is tucatinib, one of the small molecule inhibitors. And we think that that is also an alternative, that tucatinib in combination with trastuzumab and capecitabine, again, nice activity and pretty strong recommendation based on analyzed critical trials. And then finally, if for some reason the patient didn't receive the trastuzumab deruxtecan in a second-line setting and you're now in the third-line setting, that would be a very reasonable agent for them as well. Those are all pretty strong recommendations. And I think the choice of which to proceed will depend a little bit on the decision making between the patient and the doctor about the mode of administration, your side effect profile, what seems the most appropriate, and it might be more one of the order of the recommendation. As opposed to saying, 'This one, but not that one', it might be, 'Pick this one next and know that you will be able to return to some of these in the future.' Now, there are a lot of other possibilities here. We already had available to us neratinib and capecitabine, that continues to be part of the portfolio. And we also had lapatinib and capecitabine, also part of the portfolio. Other combinations of chemotherapy, trastuzumab could be considered, a new agent called margetuximab with chemotherapy, which has also come on to the market. And of course, there's the possibility of thinking about the anti-HER2 agents in the context of endocrine therapy for those patients who have estrogen receptor-positive breast cancer as well. And new information suggesting that you might, in some cases, even think about one with CDK 4/6 inhibitors in the context of trastuzumab and fulvestrant. So, lots of possibilities here that patients and doctors can weigh, and again think about order of administration as opposed to selecting for or against the other. I do think that the leading contenders at the beginning are going to be T-DM1 or trastuzumab deruxtecan, if that hasn't been used, or tucatinib in combination, those would be my personal preferences. Brittany Harvey: Great. Thank you for reviewing those options and describing where a patient might receive these during their treatment. Dr. Nancy Davidson: I'd like to hear Dr. Giordano's thoughts on that, how would you stack those up? Dr. Sharon Giordano: Yeah, well, as you said, I think it does depend on what the patient's been treated with previously. I mean, certainly, T-DM1 or trastuzumab deruxtecan, if they haven't had those agents. Otherwise, I think the data from the tucatinib trastuzumab capecitabine regimen is pretty impressive as it did show an overall survival benefit. And as you know, I think that regimen is also really interesting, because it does seem to have some efficacy for patients with brain metastases. That actually has a very nice advantage. Then the other ones, I think it just sort of depends on what they've seen previously, what side effects they may be experiencing, and kind of other quality of life issues. I don't see that there's a clear way to sequence the other ones since most of them haven't really been directly compared head-to-head against each other. Brittany Harvey: It seems like it may be an individual discussion between clinicians and patients at that level. So, then, Dr. Giordano following that, how will this guideline impact clinicians and what should they know as they implement these updated recommendations? Dr. Sharon Giordano: I think the bottom line is really the clinicians are now going to have more options for the treatment of HER2-positive advanced breast cancer which is fantastic news to have all these different choices and options for our patients. To me, I think probably the most important changes and recommendations, again, are the addition of trastuzumab deruxtecan in the second-line setting just given the very impressive clinical benefit that's seen with that drug, or, as Nancy mentioned in the third-line setting if patients, for some reason haven't received it previously. And then I also think, as we talked about, the tucatinib combination is really an exciting new combination that does seem to have significant clinical benefit. I think the clinicians will need to be aware that that might be an option for patients with CNS metastases that are progressing. And also, just to be aware, as we mentioned before, about the risk of the interstitial lung disease with trastuzumab deruxtecan but it's really encouraging to me to have such a long list of drugs and combinations that we can use to treat our patients. Brittany Harvey: Excellent. Those are great points. So, then finally, to wrap us up, Dr. Davidson, in your view, how will these guideline recommendations impact patients with advanced HER2-positive breast cancer? Dr. Nancy Davidson: Well, Brittany, I think one thing we hope, of course, is that those patients will cumulatively have a longer survival, and a better survival as a consequence of all of these new insights that we've been able to make. I can imagine it would be maybe a little confusing to patients that there are so many things that they might potentially be able to choose from, but this is one where I think that the larger the panel of agents that you have available to you, the happier it is. So, I hope that patients are going to look at this as an opportunity for partnership with their oncologists to try to figure out of all these possibilities, what's the best one for me now, and they're going to have the comfort of knowing that there'll be other things that they can fall back on in the future, and that, hopefully, these things will improve outcomes. And again, without excessive toxicity. This last thing I'm going to hope that clinicians and physicians will remember is that we've made a lot of headway here, but that our results are not perfect. And so, right now, we're able to change guidelines, these guidelines today because of clinical trials that have been put together in the last several years and successfully implemented. And I hope that we're going to continue to do that because until we get to a point where survival from HER2-positive breast cancer is 100%, we've got work to do. So, they're going to be other new clinical research strategies, and I hope that doctors and patients will take advantage of those whenever possible. Brittany Harvey: Absolutely, both hoping for longer survival and better quality of life and looking forward to more clinical trials to give clearer answers. I want to thank you both so much for your time today and for all of your work on updating these guideline recommendations, Dr. Davidson and Dr. Giordano. Dr. Nancy Davidson: Thanks, Brittany. Dr. Sharon Giordano: Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guideline Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. There's a companion guideline update on the management of advanced HER2-positive breast cancer and brain metastases also just published in the Journal of Clinical Oncology and on asco.org. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.     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 expressed their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Naren Ramakrishna from Orlando Health Cancer Institute in Orlando, FL, and Dr. Carey Anders from Duke University in Durham, NC, co-chairs on "Management of Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer and Brain Metastases: ASCO Guideline Update." This guideline reviews evidence in both the local therapy management and systemic therapy management for patients with HER2-positive breast cancer and brain metastasis, and provides updated recommendations for these patients. Read the full guideline at www.asco.org/breast-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Naren Ramakrishna from Orlando Health Cancer Institute in Orlando, Florida. And Dr. Carey Anders from Duke University in Durham, North Carolina, co-chairs on 'Management of Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer and Brain Metastases: ASCO Guideline Update'. Thank you for being here. Dr. Ramakrishna and Dr. Anders. Dr. Carey Anders: Thank you. Dr. Naren Ramakrishna: Thank you. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Ramakrishna, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Naren Ramakrishna: No. Brittany Harvey: And Dr. Anders, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Carey Anders: I do. I would just like to disclose that I receive research funding, compensated consulting roles, and royalties from several of our industry partners who are developing brain permeable compounds. Brittany Harvey: Thank you. Let's talk about the content of this guideline. So, Dr. Anders, what prompted an update to this guideline? And what is the scope of this guideline update? Dr. Carey Anders: Thank you for that question, Brittany. Our previous guideline in the management of HER2-positive breast cancer brain metastasis was published in 2018. And since that time, we've seen significant progress in both the local therapy management and systemic therapy management for our patients with HER2-positive breast cancer and brain metastasis. I think collectively, this body of work really prompted the panel to think through the changes that we could make to improve the care of our patients taking these updates into account. I'd love to hear Dr. Ramakrishna's take on the rationale for the update as he was also involved in the 2018 guideline. Dr. Naren Ramakrishna: Thank you, Carey. Well, it's really an exciting time right now for breast cancer brain metastasis treatment. And the recent data that Dr. Anders referred to has really opened up a whole new era in terms of therapeutic possibilities for breast cancer brain metastasis patients. In the past, we've relied on traditional methods of treatment like whole-brain radiotherapy, surgery, and stereotactic radiosurgery as mainstays of treatment. But this exciting data that Dr. Anders referred to, has resulted in the possibility of avoiding certain of the local therapy options in select patients, which has the potential to increase patient survival and quality of life, and is a major advancement. Brittany Harvey: Excellent. It's great to hear about those advancements. So, then next, I'd like to start by reviewing the guideline recommendations for our listeners. Dr. Ramakrishna, what are the key recommendations for local therapy for patients with HER2-positive breast cancer and brain metastases? Dr. Naren Ramakrishna: Since the 2018 updated guidelines, we've continued with our stratification of patients by prognosis by the number of metastases, size of metastases, and also whether they are symptomatic or asymptomatic. Overall, the changes include the offering of systemic therapy for patients after multidisciplinary review for asymptomatic metastases, particularly those less than two centimeters in size. In select cases, one might also offer it for patients with metastases larger than that. The other major change that we see in this update is an increasing reliance on stereotactic radiosurgery rather than whole-brain treatment as a local therapy option, both in the post-operative setting and for single or multiple metastases, for which surgery is not recommended. Finally, we see a significant change in the application of whole brain radiation, where whole-brain radiation is recommended typically for extensive disease, either with multiple, very large metastases, or many, many small metastases. We recommend whole brain treatment to always be administered with a neuroprotectant, and where possible, with what's called hippocampal sparing, which is thought to reduce the neurocognitive negative effects of whole-brain radiation treatment. Brittany Harvey: Understood, I appreciate those recommendations for local therapy and that overview that you provided. So then Dr. Anders, in addition to those recommendations, what are the key recommendations for systemic therapy for these patients? Dr. Carey Andres: Sure, Brittany, happy to review. I think some of the general principles from the 2018 guidelines remain in place. So, for instance, our patients who have progressive disease in the brain, are eligible for local therapy and have controlled extracranial disease, we still recommend continuing the current HER2-directed therapy along with the same algorithm for the treatment of patients with HER2-positive metastatic breast cancer. There are some interesting and exciting changes to the guidelines with the advent of several of the promising systemic therapies that Dr. Ramakrishna outlines such that we do have the option of leading with systemic therapy for our patients with small asymptomatic lesions in the brain predominantly based on the HER2CLIMB clinical trial which established tucatinib, capecitabine and trastuzumab in this setting. So, in concert with our local therapist, we have the consideration for moving to the HER2CLIMB regimen in the setting of active asymptomatic brain metastasis in concert with our local therapist. So, that's one key change from the 2018 guidelines. Another is the introduction of the compound trastuzumab deruxtecan, an antibody-drug conjugate, which has been shown in second line in the setting of metastatic HER2-positive breast cancer to be superior to our traditional T-DM1 therapy in this setting. In the study, the Destiny-Breast03 study that illustrated the superiority of trastuzumab deruxtecan patients with stable brain metastasis were included and illustrated in this compound, illustrated significant benefit for patients with stable brain metastasis. So, in addition to the HER2CLIMB regimen in the setting of stable brain metastasis, we also have the option of trastuzumab deruxtecan in this setting. And that was an update in our 2022 guidelines. So, we essentially have more systemic therapy tools in our toolkit to consider in concert with local therapy. And I just want to emphasize the importance of communication between the systemic therapy team and the local therapy teams, particularly when we're making the decision to move forward with the systemic therapy in the setting of progressive or stable brain metastasis. Brittany Harvey: Thank you. Yes, that multidisciplinary care is key, and I appreciate your reviewing those updates. So then, in addition to those what is recommended regarding screening for the development of brain metastases for patients with HER2-positive breast cancer? Dr. Carey Andres: So, this is a very active conversation. And in fact, I had this very conversation with two patients in the clinic just yesterday. So, should we be screening our patients with advanced HER2-positive breast cancer with brain MRIs in the absence of symptoms? I think the bottom line is we just don't have the data yet. I think we will have the data and in fact, there are ongoing prospective studies trying to determine whether or not screening brain MRIs in the absence of symptoms in this setting will improve our patient survival, and also improve our patients' quality of life. Until we have that data because we do have these new tools in the toolkit for systemic therapy treatment, the panel loosens the guidelines a bit to say that it's not that we no longer recommend screening in the asymptomatic state, but there's not enough data for or against. And I think this really will help the physician and patients as they're making decisions about their screening and restaging studies in a personalized manner. In addition to the lack of data, we also strongly recommend that clinicians and patients have a very low threshold to obtain a brain MRI in the presence of symptoms and this is really important with regards to communication about symptoms as subtle as they may be. I'd love to hear Dr. Ramakrishna's take on this challenging space where we clearly need more data. Dr. Naren Ramakrishna: Yes, Carey, I completely agree that it's quite challenging and the practice patterns are quite diverse throughout the country. It's also a source of a great deal of apprehension and anxiety for patients who automatically typically would assume that more frequent screening is better, especially when they do develop brain metastasis if that's to occur. So, we do look forward to better data for guidance. And it certainly is an area that should undergo multidisciplinary reviewing recommendations for any particular patient. Brittany Harvey: Understood, thank you both for reviewing the evidence as it states now and we'll look forward to that emerging data for perhaps a future guideline update. So then, Dr. Ramakrishna, what in your view is the importance of this guideline update and what does it mean for clinicians? Dr. Naren Ramakrishna: Well, this is a practice-changing update. I mean, I don't think that's an overstatement. Because for the first time, upfront therapy is going to include the possibility of systemic therapy. And this also means that there has to be multidisciplinary and multimodality discussions regarding local versus systemic therapy for a large proportion of HER2-positive breast cancer brain metastasis patients. So, practice patterns are going to shift as a result of the incorporation of systemic therapy into the treatment paradigm. And finally, the other very important, practice-changing local therapy change is that the use of whole-brain treatment will be reduced relative to stereotactic radiosurgery, but in some cases, also as a result of the use of systemic therapy, and when it is employed, it must be utilized with a neuroprotectant and/or hippocampal sparing. Brittany Harvey: Great and then finally, how will these guideline recommendations affect patients with HER2-positive metastatic breast cancer and brain metastases? Dr. Carey Andres: So, I would just echo Dr. Ramakrishna's comments about the advances that we've seen and the importance of multidisciplinary care. I think from a systemic therapy perspective, we have the wonderful problem of having multiple agents to consider in this space. And as we've seen, really an explosion of HER2-directed therapies that are now approved and available to patients. One of our challenges has been how to sequence these therapies. And so, we were hopeful that these guidelines will help clinicians and patients determine when to pick individual regimens that best fit the patient's scenario, whether or not their brain metastases are stable at that decision tree, or whether or not they're progressive at that decision tree. I would also point the listeners to the updated guidelines in the management of patients with HER2-positive metastatic breast cancer, as these guidelines will certainly complement the decision-making and systemic therapy, incorporating the presence or absence of brain metastasis. Brittany Harvey: Great, and yes, thank you for highlighting that companion guideline. Both are available at asco.org/breast-cancer-guidelines and in the Journal of Clinical Oncology. So, I want to thank you both so much for your work on these guidelines and for taking the time to speak with me today, Dr. Anders and Dr. Ramakrishna. Dr. Naren Ramakrishna: Thank you very much, Brittany. Dr. Carey Andres: Thank you! Thanks for the opportunity. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

"A Soft Spot," by Rebecca Snyder: A surgical oncologist discusses the hidden emotional toll experienced by patients with cancer.   TRANSCRIPT Narrator: ‘A Soft Spot', by Rebecca A. Snyder, MD, MPH. I remember a day as a child when my father, a vascular surgeon, came home and immediately retreated to his bedroom. He did not emerge for some time, and when he did, he spoke very little to anyone. When I asked my mother why, she told me softly, ‘One of your father's favorite patients died today, and he is sad.' This surprised me at the time that my father felt so deeply for his patients that it affected him for hours after coming home from work. I understand it better now. I first met Gary after his medical oncologist asked me to consider operating on him for colorectal liver metastases. During our initial visit, I observed that he was a quiet man: nervous, kind, and polite, saying little unless prompted. Over time, I came to learn that he was a solitary person who found fulfillment and purpose in his work, enjoying hunting and fishing in his spare time. He lived almost an hour and a half away in a rural part of North Carolina. Outside of his visits, we communicated mostly via his brother, because his cell phone rarely had reception. In the months before our first visit, he had been treated heavily with chemotherapy and appeared to have had a good response to treatment. Although he had disease in both sides of his liver, it looked as though his disease was resectable with a two-stage operation. The first stage to remove the left part of his liver and the second stage to remove two metastases in his right liver. He was young, in his early 50s, and otherwise healthy - a good candidate for surgery. The first-stage operation went smoothly, but when I saw him back in the office to plan for the second, his imaging revealed significant growth in the two remaining metastases in his right liver. To make matters worse, his normal liver had failed to hypertrophy enough to allow for another resection. He silently stared at the floor, visibly disappointed when I shared this with him. I told him I was disappointed too. Together with his clinical team, we then embarked on a series of treatments, beginning with microwave ablation therapy to the growing tumors. Unfortunately, in the interim, he developed a new liver metastasis with resulting biliary obstruction. We attempted unsuccessfully to drain his liver with an endoscopic stent with the goal to restart systemic chemotherapy. At our most recent visit, I expressed my concerns that the endoscopic stent had not been effective and recommended a percutaneous drain to decompress his bile duct. His gaze drifted to the floor. Sensing he was upset, I placed a hand on his shoulder, hoping to convey a steadiness and confidence that might offer some reassurance. As tears formed in his eyes, I felt his discomfort at displaying emotion in front of me, so I offered him a few minutes of privacy with his brother. Although he had been willing to undergo repeated endoscopic procedures, it seemed as though the idea of having a drain outside his body, a visible and tangible reminder of his progressive cancer, was clearly distressing to him. When I re-entered the room, we reviewed our plan for him to have an external drain placed and then begin a modified regimen of chemotherapy next week, which he and I both knew would not be curative. We did not speak this aloud, but the eye contact he made with me communicated that we shared a common understanding. I silently hoped that it would buy him some time at least. Two weeks later, I unknowingly clicked open an automated message in the electronic health record stating very matter-of-factly that Gary had been brought in by emergency medical services, dead on arrival, from a gunshot wound. I called his medical oncologist, who reluctantly confirmed the news. He told me he had hoped that I would not find out because he knew I would not take it well. Suffice it to say, he was right. Although most of the cancers I treat, pancreatic, metastatic, colorectal, and cholangiocarcinoma, are aggressive malignancies with poor long-term survival, Gary was the first patient of mine to commit suicide. When I first learned of Gary's suicide, my mind immediately returned to my last visit with him. ‘Had I been too honest and direct, not buffering the concerns we discussed with enough hopefulness? Had he expressed signs of clinical depression that I had missed, misinterpreting his responses as a normal disappointment when in fact they reflected much deeper despair? Should I have confronted him more directly?' I called his older brother while the news still freshly stung, feeling a sense of urgency to make sure his family knew how much Gary mattered to me and to his treatment team. After we exchanged platitudes, I found myself telling him that I had always had a soft spot in my heart for Gary, which was true. I tried very hard then not to cry but failed. As a private person myself, I have always felt a particular sense of community with introverts like Gary, a shared experience of a need for privacy, an appreciation for quiet and aloneness, and a discomfort with being overly expressive among anyone other than close friends or family. Nature or nurture, I inherited this trait from my mother, who preferred pursuing her solitary artistic hobbies over small talk. Like Gary, my mother also became deeply depressed when she was diagnosed with metastatic lung cancer, a depression that worsened when she experienced debilitating side effects of treatment, only to learn that these treatments had not even been effective. As her daughter and one of her caregivers, it was not her physical suffering but her emotional suffering that was most agonizing to witness. During my mother's experience with end-stage cancer, I gained an intimate awareness of cancer's emotional toll in a way never afforded by my formal training or in my clinical practice. Stepping beyond awareness toward confident intervention with my own patients, though, has remained uncomfortable for me. I listen, offering empathy and understanding, explaining treatment options when there are any, and comfort when not. For some patients and families, I morph into a punching bag, offering them an outlet for their anger when I cannot offer them anything else. With Gary, I tried to communicate to him that beneath his displays of hesitancy and reservation, I recognized the struggle he was experiencing, his hopes, and perhaps more importantly, his disappointments. Now, I do not feel like this was enough. Losing patients to cancer is something I have experienced from both a professional and personal standpoint and unfortunately, with which I have grown all too familiar. Knowing that a timid and kindhearted patient of mine felt a sense of hopelessness and despair this deep, however, is acutely and newly painful. I imagine I will always carry a soft spot for Gary with me, a tender soreness that lasts. It may go unnoticed at times, forgotten temporarily with the distraction of another patient's triumph: a curative resection, a follow-up scan with no evidence of disease, or a grandchild's high school graduation witnessed. Yet, I expect it will sting again, just as a bruise does when pressed intentionally and gently, to confirm that it is still there. I will be reminded of him, feeling a familiar ache when I witness someone's growing despair. Next time, I will pause to ask, ‘Are you losing hope?' Perhaps you will ask too. Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one at podcast.asco.org. I'm your host Lidia Schapira, Associate Editor for Art of Oncology and Professor of Medicine at Stanford. With me today is Dr. Rebecca Snyder, Assistant Professor of Surgery and Public Health at Brody School of Medicine at East Carolina University. We'll be discussing her Art of Oncology article, ‘A Soft Spot'. Our guest has no disclosures. Rebecca, welcome to our podcast. Dr. Rebecca Snyder: Thank you, Lidia. Dr. Lidia Schapira: It's a pleasure to have you with us today. I'd love to start by asking you as a gifted storyteller - I've read some of your stories published also in other publications - tell me a little bit about your writing process. Why do you write? When do you write? What brings a story to the page for you? Dr. Rebecca Snyder: I would say that I don't have a very structured process. Typically, it begins with some ideas that percolate in my mind, oftentimes prompted by one specific event. And then I think once I have time to sort of bring in some other thoughts and start to formulate them, then it really happens when I have a moment to sit down where there's quiet, and my children are not interrupting me and my pager is not interrupting me, and have a few hours to really sit down and get something on the page. And then I do quite a bit of editing over time. I reread a lot and rethink about the way I say things until I get it just right. So, it takes me days. Dr. Lidia Schapira: That's very interesting. Let's go back to something you said. Let's chase after that a little bit. You said something that sort of stays with you or percolates; is it a moment of particular emotional resonance? Is it a difficult situation? Is it something that triggers a deep memory for you? Can you tell us a little bit more about what got you to write, say this piece about Gary, you've also written about your mother, you've written about being a petite surgeon in a sexist world, what are those ideas that stay with you, that then lead you to write about them? Dr. Rebecca Snyder: They're each a little bit different. So, I don't know that I have one answer to that. I think my experience with my mother took me a long time to be ready to write about it. It was something way too emotional for me to even confront for myself for a long time. And then eventually, I felt like I was in a place where I could put something on a page and that was very therapeutic for me. With Gary, that was really an acute event. And when it happened, and I processed it emotionally, I knew that it would help me to write about that. And so, I actually did that, I believe, either the same day or the next day that I learned of that event. At that point, I wasn't necessarily writing with the intention of publishing, but just to help me get through those feelings in that experience. Dr. Lidia Schapira: So, I'd like to talk a little bit about this idea of writing and sharing with others. One thing is to write to process a difficult experience, which you've so nicely stated. The other is to take the further step of writing for publication, which means putting something that's really private out in front of your colleagues, your peers, and so on. Tell us a little bit about that. What triggers you to say, 'Alright, I've written this to process but now I want to share it'? Dr. Rebecca Snyder: I write about how I consider myself an introvert. Some people who know me well aren't surprised to hear that. Some people say, ‘Oh, I wouldn't have expected that you consider yourself an introvert.' I think that for me, there are thoughts that I don't feel comfortable communicating, necessarily in a public forum, or with people that maybe I don't know as well. But when I can do it in written form, for some reason, that's more comfortable. So, it's a way for me to share things that I feel compelled to share that I think are important and relevant to other people and may resonate with them in some way, but that I might not be comfortable broadcasting to a large audience. And so, writing allows me to share those feelings within the comfort of my introversion. Dr. Lidia Schapira: What role does narrative and narrative medicine play in your professional portfolio? Do you read other narratives? Dr. Rebecca Snyder: Honestly, it's one of the things I enjoy the most, aside from operating. I don't have formal training in it. Although I imagined I would really enjoy taking some courses. I think my writing has been informed by my own amateur reading and writing over time, I've always been a big reader. I've written about my mother's love for books. And that was something she shared with me beginning when I was a young child. I think it's become part of how I see myself professionally. Although it still feels a bit like a hobby. I think that it should play a significant role in medicine. But I don't think that we have done a great job as a medical community of incorporating that into the dialogue. Dr. Lidia Schapira: I share that sentiment. It would be lovely to see narrative medicine in the mainstream of medical education, rather than perhaps at the margins or as an optional thing for some, I think stories that are enormously powerful. And so, with that, let me ask you another question, and that is, what have you read recently that you recommend to others? Dr. Rebecca Snyder: You asked if I read another narrative medicine? I read, A Piece of My Mind at JAMA every week, and I read the Art of Oncology. One of my other favorite weekly columns is Modern Love in the New York Times, I look for that every Sunday. And then I read a variety of books. I would like to say I read more than I do because I think my clinical reading takes up quite a bit of my time as well. The last novel I read was, The House in the Cerulean Sea by TJ Klein, which was a great, very magical, lovely story. I found with the pandemic that I can't read things that are really intense or distressing. So, I chose things that are uplifting in some way or positive, and that was a lovely fantasy-type book to read. And then I read some nonfiction. I'm reading a book about the Old Testament now because I wanted to learn more about that. So, I try to have a diversity of literature that I'm reading at a given time. Dr. Lidia Schapira: Do you read books or screens? Dr. Rebecca Snyder: Books, 100%. I don't like screens to read. I print off every peer review, I do. I have to print it. I can't read. Other than editing, I don't like to read on a screen. Dr. Lidia Schapira: Let's go back to your story about this patient, Gary, whom you met and operated on. And the need you had to talk about the emotional response you had to learning that he suicided, that is something that is so very difficult for all of us. So, first of all, my deep condolences to you for your loss. Tell us a little bit about the relationship you had with Gary. Dr. Rebecca Snyder: I don't know if we're supposed to admit, as physicians, that we have favorite patients sometimes, but he was one of my favorite patients. What I appreciated about Gary early on is he was very soft-spoken, he was very bashful, and he would blush easily. I could tell he never wanted to be a burden, even in my clinic. So, he didn't want to take up too much of anybody's time. He usually brought his brother with him and allowed his brother to speak for him. And he would speak up when I would ask him directly, but often would nod or use body language and was very quiet. The first time I saw him he had been treated for a long time with chemotherapy. I believe he was sort of under the impression that he did not have any surgical options. He'd never seen a surgeon before, but his medical oncologist approached me and said, ‘I know that you're willing to be aggressive, and he's healthy and young, would you consider it?' And I had reviewed his scans ahead of time and thought it was worth an attempt. And so, I met with him and in some ways, I feel like I probably gave him some hope at that point. Maybe he had already processed that, but I reignited that. I got to know him pretty well because I cared for him for a while. Obviously, I saw him several times prior to surgery, then I operated on him, and cared for him postoperatively. And then once he recovered, and we planned for the second stage. And so, I grew attached to him because he was in no way demanding or difficult, but very unassuming, very kind, and just a gentle soul. Dr. Lidia Schapira: And you talk about having moments of sort of shared silence or shared understanding, right? So, it sounds like you, you bonded with him. Most of the communication was done through his brother because he didn't have a cell phone or his cell phone was out of reach, right? And so, you hoped with him that you would be able to really help prolong his life. And then came the bad news that his cancer was growing. Bring us a little bit into the consultation room where you share that news with him. Dr. Rebecca Snyder: When we first talked about it. He was quiet. He looks at the floor a lot. And he didn't verbalize his disappointment, but I could see it. I validated that for him and told him I was disappointed too. But I think when I really saw a shift was when I told him that I thought he needed to have an external biliary drain placed. I think he was continuing to work through all this. And that was really important to his identity, and the idea that he might have to have a drain, I think for him was incredibly distressing. I think to him it kind of marked him as different, as this is permanent, and would mean that he might not be able to work, and that was a big blow for him and I could tell that. I could tell he was starting to tear up but he was very uncomfortable doing that in my presence. So, I told him I would give him a few minutes of privacy and left the room so that he could express his emotions more comfortably. Dr. Lidia Schapira: And that was the last time you saw him, right? Dr. Rebecca Snyder: That's right. Dr. Lidia Schapira: So, then he leaves and you received the news that he suicided, but you're not told directly. You read it in the chart. And you immediately called the medical oncologist and they said that they wanted to protect you from this news. How did that feel? Dr. Rebecca Snyder: It was shocking. You know the Electronic Medical Record has some wonderful things about it. It's easy to keep up to date with your patients, you get alerts anytime a patient of yours is admitted to the hospital or discharged from the hospital. But yet, it's obviously incredibly impersonal and abrupt. And so, I had a notification that he was deceased. My initial thought was, ‘Wow! He must have had cholangitis. And he didn't complain about his symptoms and he didn't tell me by the end, so he must have gotten really sick and septic. And then that must have been what had happened. But then when I looked at the chart, and I called his medical oncologist, and I read the details, I realized that's not what had happened, and that was very hard. Dr. Lidia Schapira: I imagine it must have been absolutely awful. Again, my deep condolences to you. How did you deal with that news? How did you get on with your day after that? Dr. Rebecca Snyder: I called his brother first. I wondered, maybe I shouldn't now because it shouldn't be about my grief - I'm the physician - it should be about his family's grief. But I still wanted to connect in some way pretty immediately with someone else, in addition to his medical oncologist. He was very gracious and appreciative. We didn't speak for long, but I just wanted to make sure that he understood that we all cared that that had happened because otherwise, I would never have spoken with him. If I don't reach out. There's no follow-up visit, there's no opportunity in the system to complete that conversation. That helped me a little bit, and then I had to try to turn it off. I had to go lead our GI tumor board and have afternoon clinic and go on with the rest of the day. Dr. Lidia Schapira: Well, I'm deeply grateful to you for having written about it and decided to share it with us. I think that losing a patient is terribly hard. We do connect with our patients and feel for them. But this, learning in this way that one of your patients suicided or found living unbearable, is probably the hardest thing. Fortunately, we don't deal with it often. And many of us have or have not had those experiences. So, thank you so much, Rebecca, for reflecting and sharing that reflection with us. Are there any other thoughts that you want to share with readers of the piece that may help them understand the story or the message here? Dr. Rebecca Snyder: I can say since it's been published, I've already heard from several colleagues that they have experienced something similar. One was particularly devastating because the patient had actually completed therapy but had lost his business and committed suicide because of the financial burden of his care. If you think about it, those are the patients with the greatest extent of distress. But that's not even touching the emotional burden that so many patients are experiencing that we never see. I don't think it's possible or it's on us to alleviate that because some of that is a normal reaction to a cancer diagnosis. But I do think that being aware of the depth of despair that patients can experience is important. And having witnessed my mother being on this side of the patient, even just that recognition and empathy from one's physician can mean a lot to a patient and their family. So, I hope that we can all at least bring that awareness into our clinical encounters and try to offer that empathy when we sense those feelings. Dr. Lidia Schapira: Well, I'd like to thank you for sending us your story, and thank you very much for participating in this conversation. I deeply enjoyed it. Dr. Rebecca Snyder: Thank you, Lidia! I really appreciate being here.   Dr. Lidia Schapira: Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories: The Art of Oncology Podcast. This is just one of many of ASCO's podcasts, you can find all of the shows at podcast.asco.org.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for you in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

"Warm Companion," by Meaghann Weaver: a palliative care doctor shares her story of a gun-shy dog and a daring rescue.   TRANSCRIPT Narrator: 'Warm Companion' by Meaghann S. Weaver, MD, MPH, Ph.D. We were introduced at the front desk of a small town diner. By the time we reached the parking lot, we had committed to cohabitation. I pulled over to a small town's sole restaurant. Standing at the long counter, I waited for a carry-out dinner for the long drive home from a rural hospice visit. As a closing weekend in hunting season, I was the only one in scrubs and a mask in a diner filled with camouflage and deer antler de´ cor. The guy next to me was loudly complaining to his hunting buddy how his new puppy was gun shy and let the birds go. “Good for nothing.” I mumbled that as a pediatrician familiar with gun violence and firearm accidents, I'm also gun shy. He pointed to his truck and jokingly suggested, “Welp, maybe you'd be a better pal for that whelp.” One look at those puppy eyes from the cargo bed, and I emptied my wallet, handed him my uneaten to-go-boxed dinner, and carried his pup to my car. “No more guns,” I whispered as we hit the highway. She joined our little family at the onset of COVID-19, snuggling close to us in the midst of the pandemic's physical distancing. I had planned to name her Agape. Her first collar tag jingled with the idea of a universal, unconditional love that transcends and persists regardless of circumstances. My kindergarten-age daughter insisted on calling out “Lovey” as she followed the new pup, all paws, around the house. The name persisted until the puppy responded only to “Lovey.” Her collar tag was soon replaced with the vernacular: Lovey. Lovey represents a bonded attachment, a security and safety, and a held comfort. She is Lovey. Lovey nuzzled into our relationships and roles. My dad added milkbones to his right back pocket since his left back pocket was already filled with peppermints and lemon drops for my daughter. Lovey quickly tripled my pedometer footsteps. She motivated me back into early morning jogging. She introduced us to new parks. She taught us persistence with tennis ball retrievals and a dogged perseverance for finding frisbees. Lovey wagged her tail at kind strangers with sureness of future friendship and was on guard and protective when needed. She mastered the Labrador lean, offering my shins a counterpressure under the telehealth tabletop. She reminded us of the power of instinct and interaction. She represented goodness. One chilly morning after a night shift, I took Lovey to visit a lake further than our usual landscape. Walking through tall grass with the harsh prairie winds whipping around us, Lovey suddenly started barking an unfamiliar howl. She wouldn't let me check her paws for nettles or fur for burrows as she frantically lunged toward the lake. Far off, I then saw what she witnessed. A lone ice fisher's dog had been walking on thin ice 60 feet from the edge, crashing through, while the angler stood sturdy. The ice fisher went to rescue his dog but instead also crashed through. They both thrashed and struggled in the freezing water. They gasped and clawed at the slippery, growing ice ring around them. Without a sense of locale or direction, I pinged 911 to my cell phone and tracked their 11-minute arrival. Racing to the lake edge, I yelled out that help was coming. I prayed for a protective bradycardia, fearing a hypothermic-induced arrythmia would kill sooner. If I entered the broken ice waters to reach them, we'd all just freeze together. Helpless. I tried to throw Lovey's leash to them. Useless. Without a rope and without ability to reach out, I felt “Good for Nothing.” Except I was present. Fully present. I was bearing witness to suffering without shying away. I couldn't rescue. I could just remain. The presence of another human served as an antidote to aloneness. I instructed the fisherman to look at me. I asked him to trust me. I told him to protect his strength by stopping the struggle. Just be with me. Just hold on. I assured him that his dog knows how much he is trying to help. “Tell me about your pup.” Teeth chattering, he told me about how they met. Then, a sacred silence. I asked if he wanted to keep talking. He told me about how he named her. Silence. He told me he rescued her, but he's pretty sure she rescued him. We talked about the reciprocity of such relationships. As the minutes dragged on, his breathing changed. I suggested, as I have done time and time and time again between covering COVID-19 comfort care night calls in New York during the pandemic surge to rural home visits during relentless variants, that we breathe together. As in palliative clinical practice, I heard myself telling him to trust his strength. I suggested he curl to protect his core. I found myself instructing him to protect his heart. Then, true to medicine's focus on what matters most in life, I reminded him to remember love, forgiveness, and peace and to truly trust his body. He rallied. He lifted his dog's back legs. The dog slippery-sprinted over to join Lovey in a victory jig. Downward dogs bowed. Paws pranced. Collars jingled. We heard the sirens. Rope and rescue floaties reached him. The Sherriff turned his back while I switched his bib overalls for my sweats and fleece. Without guidance or prompting, Lovey and her new-found canine friend covered the fisherman with their bodies. They covered his core and licked his face. Our faithful companions warmed him. They remained silent and still as he started to stir. Their patient presence and warmth brought healing. After a prolonged silence filled with just gentle presence, his chattering teeth started to form words. His dog barked in recognition of a familiar, favorite voice. Companioning represents sacred stillness, not frantic fixing. Companioning means being present to another's grief, pain, or suffering. Companioning represents profound presence rather than rescuing. A primary tenet of companioning is bearing witness to the struggles of others without shying away. As I tried to add warmth to the pile of pups, I thought about how we've all been walking on thin ice in medicine, especially during the pandemic. Companioning applies to contingency or crisis phase. Companioning has meant holding up the iPad for telehealth hospice goodbyes during visitor restrictions. Companioning has meant tirelessly advocating for vaccinations and masks without judgment or unkindness. Companioning has meant pivoting to telehealth to continue to caringly check in on patients with immune system vulnerabilities while protecting them from clinic exposures. Companioning has meant wiping the brow of a colleague when they can't reach past their protective layers. We haven't been able to rescue the curve or fix the surges. Still, companioning means being present for each other and our communities to offer healing warmth in a cold world. Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network. A collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one at podcast.asco.org. I'm your host, Lidia Schapira, Associate Editor for Art of Oncology, and Professor of Medicine at Stanford University. And with me today is Dr. Meaghann Weaver, a lead regional ethicist at the National Center for Ethics in Health Care, and an adjunct associate professor at the University of Nebraska. We'll be discussing her Art of Oncology article, 'Warm Companion'. The views expressed in this podcast are those of the author and do not necessarily reflect the position or policy of the US Department of Veterans Affairs, the US government, or the National Center for Ethics in Health Care. Meaghann, welcome to our podcast. Dr. Meaghann Weaver: Thank you. It's a joy and privilege to be with you this morning. Dr. Lidia Schapira: So, tell me first a little bit about your writing process. How does a story present itself to you? When do you know that it's time to put it on paper or on screen? Dr. Meaghann Weaver: It's interesting the way that narrative medicine evolves in a really different way than research and summarizing data in written form. In many ways, I think of that as a cognitive process, where you can be planful and structured. Whereas narrative medicine, it occurs as a story that just has to be told. It's beating so profoundly in your heart, that even if you want to contain it, and hold it as personal, I think for me, it's really an uninhibited moment. So, funny enough, I tend to do research during day hours or very structured hours, whereas narrative medicine is very much waking up in the middle of the night saying, 'This has to pour out. I can't continue to contain the truths from this narrative.' Dr. Lidia Schapira: It's a lovely description. Tell me a little bit about how you decided to share with others? I totally understand the need to reflect and tell a story, but how do you decide what is private in what you want to share? Dr. Meaghann Weaver: I would say that in clinical experience, and even in ethics consults, there are so many stories that are quite profound, but are so intimate, are so personal, even if you de-identified them, they border on sacred and so those for me remain really untold. Those are held by the participants of the story. For me, it's this particular narrative in one of our staff meetings, we had a couple of extra minutes. And so, I just shared, you know, what had happened over the weekend. And my colleagues said, ‘You have to write that.' And a number of them followed up and said, ‘Have you written that? You need to write that.' So, in many ways, it's if the narrative resonates with others, in many ways, they think sharing can be selfless. It can be hard to share. But my colleagues really said, ‘You might have a duty to share this one because it resonated with our experience and COVID.' Dr. Lidia Schapira: It's a lovely story. So, tell us the story of how you met Lovey? How does the pup become your family's own? And how Lovey led you to this moment that is so amazing that you describe so beautifully in your story? Your story, unlike many other narratives in the Art of Oncology, has so much suspense to it. I mean, the reader will hold their breath, to try to see how the story ends. Dr. Meaghann Weaver: Thank you. Well, I met Lovey in really spontaneous circumstances. I, as many during the pandemic, anticipated adding a family pet to our family, was starting to prepare, but Lovey in many ways was a little bit impulsive, because I met her where she seemed particularly vulnerable. And I just experienced a time of seeing her, seeing that she might have been in an environment that wasn't actually drawing out her strength. So, she wasn't living up to the hunting dog persona. And so, in her community, she was maybe perceived as not useful or not productive, that I was encountered her at the end of a hospice visit, and we know from oncology, we know from hospice, from palliative care, presence and being and really living into your strengths, like your core identity. So, I encountered her and noted that she's really gentle, and she might not be a hunting dog, but she would have such joy and contribution to the right community in the right setting. And so, in many ways, it was an impulsive attachment. And then she so quickly nuzzled right into our family and brought so much comfort and truly brought companionship, and she helped us to re-engage and live life with a deeper level of fullness. That's Lovey. Dr. Lidia Schapira: Sounds absolutely wonderful. How old is Lovey, now? Dr. Meaghann Weaver: She just turned two. Dr. Lidia Schapira: In your essay, you talk a lot about companionship. You also mentioned the concept of bearing witness to another's suffering or crisis. And you talk about presence. Can you tell us a little bit about these three concepts and how they came to you so clearly, as you reflected on this incident, and perhaps you should tell our listeners also, what actually happened, and what the story is about? Dr. Meaghann Weaver: So, the story is about after a particularly challenging night shift, I took Lovey for a walk at a lake which is of further distance from our usual geography, and it was deep winter, there was an ice fisherman out about 60 feet from the lake edge. And it's very common in our community for ice fishers and hunters to bring their dogs with them. It's just a partnership. This particular pup fell through the ice. Lovey and I were walking quite a distance from the lake and she just had this really impulsive shrieking. I thought she was wounded. She had this really strong instinct of another animal's injury or needing rescue. So, she was really pulling and lunging me. So, I followed her, actually pretty nervous because she was acting so out of character. I followed her and she brought me to the lake's edge, and then I saw the fisherman had also fallen through in his attempt to rescue his dog. They were too far out. I tried to throw her leash, but there was no way for me to rescue, which as you can relate in our calling in medicine, we're trained to rescue, we're trained to fix, to intervene, it felt so counter natural. It felt so counter to training. And so, just calling out connecting with him, trying to let him feel that I was really close, even though I was at quite a distance. I called for help. I pinged 911 to my phone. I had no idea really where I was other than somewhere very rural area like a frozen lake. So, I pinged them to my phone. I just continued to reassure him that help was coming. And I just asked him to stay connected with me. It was clear that his dog gave him such meaning, you know, the fact that he would sacrifice his safety to rescue his animal. So, I tried to engage him in narrative. And it seems what was most helpful for him was less when I asked about him as the fisherman or as a human and more when I asked about his dog, and how he was connecting him back to what mattered to him. And so, very long story short, he was able to rally just like we see at the end of life for many of our patients, this final rally, so he rallied, and lifted his dog who came to us, and then we had a really sweet reunion with his pup. So, the sheriff arrived, it took about 11 minutes, and I was quite concerned physiologically, whether we would sustain life in that time gap. So, the sheriff arrived; he was able to throw ropes and rescue floaties, and that patient was able to then be retrieved. He was pretty obtunded when he came out of the water, but was able to hold on to the rescue equipment and to just be then pulled to safety, then warmed really with our two dogs just laying on him licking him, very instinctually, they just covered him, and it was just their warmth and being present. I think that's what we see in medicine often when disease has progressed, and we are sort of past our biomedical ability to intervene. In many ways, there is still profound healing. And for me, in this narrative, the healing was human warmth and the presence of living beings, and companioning, remaining present, bearing witness to someone who is really struggling, bearing witness without thrashing around, feeling like the only help you could offer is fixing. I think that the story would have been more exciting if it were a palliative care doctor ethicist dives into freezing water, but we wouldn't have helped him. So, it's really saying, 'I'm gonna bear witness, stay with you, companion with you as part of your healing.' I think there's a message in there for medicine, too, staying with our patients. There's actually a narrative there too, because of course, in hypothermia, you need to change the person's clothing. And so, probably the humorous part of the story is the sheriff turning around and me putting the fisherman in my fleece and my scrubs, and me putting on his bib overalls. I think that's probably quite the visual. Dr. Lidia Schapira: I must say, I saw that. I didn't know what you looked like, but I could just imagine the scene. Tell me a little bit about that moment, when you have to do this cognitive switch from, ‘I'm diving and I'm rescuing to I'm bearing witness and I'm present?' Dr. Meaghann Weaver: That's such a powerful cognitive switch because, in many ways, it's instinctual to fix and to rescue. So, I almost would say that is a practice that has to be in some ways predetermined. And so, I think it's a commitment and it takes practice outside of the clinic space to really say, ‘My role in this patient's life is to help them ask the questions they need to ask, help them explore the answers without me forcing the answers upon them', and help them in some ways you could think establish the safety net that they need. So, foster that, without forcing it, without thinking my sense of rescue would be the same that would be most beneficial to them. So, I think that is really a practice that requires contemplation and commitment because the impulse is to rescue. The impulse is to fix, and so, it really takes strategizing. Dr. Lidia Schapira: Meaghann, I'm sure you've given this some thought, how would you have felt if the story had a different ending? If the sheriff didn't arrive in time? Dr. Meaghann Weaver: I tried to protect myself from thinking in that way. I think I would have experienced immense guilt, and I perceive it would be natural to feel that I then should have gone into the water even if I couldn't have made a difference. I anticipate that there would have been a significant weight. And so, it takes thinking in a logical way because my heart would have said, ‘Well, just dive in and be with him.' And also, I think the emotive experience of guilt would have been really heavy. I thank you for asking. I think that's a courageous question and one that I've have to reflect on. Dr. Lidia Schapira: You've written about guilt before, so I know that you are certainly not shy in thinking about the emotional landscape of our work. But let me end this with a little bit more of a playful question. And that is about the pups here, the role that the dogs played because the dogs are all about instinct and impulse. We can't ask the dogs about their cognitive experience, but we can watch their behavior. And I was certainly moved, I laughed and felt this incredible energy and warmth when you describe both pups were on the body of the fisherman, warming him up. So, tell me a little bit about this bonding with dogs and using dogs both for therapy for oneself and therapy for others. Dr. Meaghann Weaver: Yes, it's amazing to me the way that our pups have a way of connecting with us and with our core self… Oops, my pup is participating. Connecting us with our core selves. I noticed even in my work, that the respite and the sense of connection that we have, with our animals, with our pups, there's something so instinctual and uninhibited about it. And I also think much of our work is so serious, but their playfulness, and then their unconditional and really uninhibited celebration, when we're sort of reunited after a long day or there's something, it's really hard to describe it just this profound feeling of warmth and of belonging, and companionship. Dr. Lidia Schapira: Well, thank you so much for the conversation today for this absolutely beautiful essay, for sending us your work, and for sharing this experience with the broader community of readers. Thank you, Meaghann! Dr. Meaghann Weaver: Thank you! I'm grateful and I do turn quickly when I receive the journal to this section. So, thank you, I find that it resonates with my head, my heart, and my spirit. So, thank you for fostering that. Dr. Lidia Schapira: You're very welcome! Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories: The Art of Oncology podcast. This is just one of many of ASCO's podcasts. You can find all of the shows at podcast.asco.org.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

"Dose-Painting," by Shivani Sud: a resident creates visual narratives within two patients' dose clouds.   TRANSCRIPT Narrator: 'Dose Painting' by Shivani Sud, MD. (10.1200/JCO.21.01524) When asked to describe radiation oncology, my first recollection is watching chart rounds as a medical student. Sitting along the conference room periphery, I observed as dosimetrists projected patients' scans, residents presented histories, and attending physicians reviewed treatment plans. Far from the usual hospital rounds with plans consisting of procedures, consults, and medication changes—here, treatment plans are scans overlaid with intricate colorful lines denoting the amount of radiation traversing internal structures to arrive at the target (ie, tumor) volume. This dose visualization is our primary method of conceptualizing and articulating radiotherapy treatments. Recent technological advances enable delivery of radiation with immense precision to the extent we dub some techniques as “dose painting.”1 Starting with our planning scan consisting of computed tomography images of the patient in the treatment position, we delineate areas of tumor and likely microscopic disease to compose our target volumes. In collaboration with dosimetrists and physicists, we adjust various parameters including multileaf collimators—movable metal leaves that sculpt the x-ray beam as it departs the linear accelerator to enter the patient—and beam angles such that we cover the intended target with radiation while avoiding delicate neighboring organs. We evaluate and iteratively optimize our radiation plans and the resultant dose distribution. Balancing the correct radiation dose, treatment field size, and shape are critical for preventing recurrence, minimizing toxicity, and improving survival. At the first glance, our peer review reduces the patient to a spectrum of grayscale pictures a few millimeters thick as we scroll through their bodies searching for tumor and ask whether our colorful delineations will adequately treat the cancer. Controversial plans elicit the most discussion as we glean insights into patients' lives and decision making. Why this shorter course of radiation? His priority is quality of life and maximizing time at home. Why no concurrent systemic therapy? She is too frail for chemotherapy—we are escalating radiation dose as an attempt for more durable local control. Why are you sparing a sliver of the scalp? She fears children will tease her for balding. Answers live within a broader narrative. These rainbow-colored three-dimensional dose clouds represent the complex convergence of patient history, goals of care, humanity, medical judgment, and cautious control of our treatment medium—radiation. As a resident, I view the dose clouds denoted by the color wash of the computationally optimized radiation distributions through the lens of the patient-physician relationship—literally and figuratively. During late nights and unrushed moments, my mind drifts back to my favorite childhood pastime—spotting shapes in the clouds. This activity is a form of pareidolia—the human tendency to perceive meaningful imagery amid a random or ambiguous pattern. As a child with a sweet tooth, I pictured popcorn and cotton candy in the sky. Now, this manifestation of my imagination was centered on my most salient thoughts—caring for an older woman (Ms V) with lung cancer and a child (Lilly) with Ewing's sarcoma. I grappled with whether our treatment plans were adequate, too little or too much. I turned to painting to articulate my angst as art is part of how I reflect on complex situations. For both Ms V and Lilly, I traced the isodose lines defining the radiation dose distributions to maintain fidelity to the original radiation plan. I then folded those dose distributions into the visual narrative of the paintings to create a reflection of their journeys amid their dose clouds. Ms V (Figures 1 and 2) had countless admissions for chronic obstructive pulmonary disease, heart failure, valve replacements, and now cancer. Ms V longed for quality time until the sun sets. Her case was complex—she had an early-stage lung cancer, but because of multiple comorbidities, she was not a surgical candidate. She projected courage and resolve in conversations about her goals of care while accepting death as inevitable. We treated her with definitive intent linear accelerator-based stereotactic body radiation therapy. Months later, she died from a heart failure exacerbation. I was heart-broken and humbled. Ms V taught me that prognostication is an elusive art for physicians—I was naively optimistic about curing her early-stage lung cancer. She was pragmatic about embracing the trajectory of her comorbidities. As I scrolled through her treatment plan, the beams enveloped the tumor in warm tones denoting high dose as it floated through a sky of trapped air. I imagined her wishes for quality time expressed as colorful, vibrant brushstrokes of light emanating from a sun setting into a calm, reflective ocean overlaid on my target volume. Lilly (Figs 3 and 4) was a bald, spunky and vivacious four-year-old girl whom I met after multiple rounds of chemotherapy for a chest wall Ewing sarcoma. As we talked about radiation therapy, Lilly flapped her arms while proclaiming herself a butterfly. Weeks later during a status check, she cried in agony from radiation esophagitis. Her mother solemnly whispered “I wish I could take the pain instead of her.” That evening as I was looking for a picture book for my niece, I came upon the story of a baby giraffe on quest to find his spots until one day while he slept, rays of sun shining through the leaves of a tree tanned his skin with perfect spots. Curiously, I searched for the evolutionary rationale for giraffe spots—they are a trait passed between mother and offspring with size and shape predicting fitness for survival. My mind wandered attempting to create meaning amid these random coincidences as I wrestled with uncertainties about how Lilly would fare after radiation. I sketched Lilly as a baby giraffe—her spots, much like the storybook, sculpted by leaves (of tungsten metal) distilling rays (of photons) to sizes and shapes reddening her skin but designed to improve her chance for survival, spots shared by a mother wishing to take her daughter's suffering upon herself. The painting's striking visual of mutually shared bold, whimsically colorful patterns inspired by the axial, coronal, and sagittal views of the radiation plan set against a stark dark matte background aimed to capture the vibrancy of the love I saw connecting Lilly to her mother and their resilience in the most trying times. Witnessing their journey underscored the permanence of the mother-child bond filled with tenderness and compassion that moved me as I was then caring for my own mother who was receiving radiation therapy. When my mother's radiation oncologist showed us her treatment plan, I was engulfed by the same questions. Is the dose and field size appropriate for tumor control? Will there be irreparable damage? Will her symptoms improve or get worse? Is this what she wants? I viewed her treatment plan through the lens of a meticulous radiation oncologist in training, but this time, I was sitting in the chair along the wall reserved for family members. Like the patients I care for every day, as we scrolled through the intricate colorful isodose lines, I trusted they were the optimal intersection between science (dose) and art of medicine (painting) we strive for as radiation oncologists. Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one at podcasts.asco.org. I'm your host Lidia Schapira, Associate Editor for Art of Oncology, and Professor of Medicine at Stanford. My guest today is Dr. Shivani Sud, a resident in radiation oncology at the University of North Carolina. We'll be discussing her Art of Oncology article, 'Dose Painting'. Our guest today has no disclosures. Shivani, welcome to our podcast. Dr. Shivani Sud: Thank you so much for having me. It's a pleasure to be here. Dr. Lidia Schapira: So, I'd like to start this by asking our authors to tell me what's on their reading list right now, or to recommend a book that has been interesting and inspiring to you that you read in the last year? Dr. Shivani Sud: That's a good question. I'll be completely honest, I've been a bit boring at the moment with copies of clinical essentials of radiation oncology, and a few of our other handbooks. Frankly, during the pandemic, and especially with current events, I think I've been more in the nonfiction realm, especially just trying to submerge myself in the news articles and the ground level journalism that's been coming out and so I would actually say that these days kind of a local newspaper and things of that nature have been a bit refreshing. Dr. Lidia Schapira: Let's turn to your essay and your art. You're very unusual in that you bring to us in your narrative, not only the beautiful narrative and written word, but also visual art. Have you always been a writer and a painter? Dr. Shivani Sud: I have enjoyed painting for a long time. It was one of those things that started by, I think I was just copying my sister, she once got an acrylic paint set, and she was painting on canvas. And there I was doodling something on paper. I was always one of those kids who couldn't help but try to fit the whole rainbow into a coloring book page, or any art assignment. And I think that as I went throughout school, and the multiple levels of training that we encounter, as physicians, that painting just became my outlet, whether it was expressing myself, decompressing, feeling like I was channeling my thoughts and my energy into something, while not necessarily kind of sitting idle with those thoughts. Dr. Lidia Schapira: Your essay helps those of us perhaps, who don't paint as a way of expressing ourselves to understand your process a little bit. And you start by saying that you've always enjoyed looking at shapes and finding connections. Can you talk to us a little bit about the way that you view shapes and find connections? And tell us how you see that in nature, and then in your work as a radiation oncologist? Dr. Shivani Sud: Certainly, I think a lot of this goes back to that word we mentioned, pareidolia, and this human tendency to want to find meaning in randomness. And so, that was that childhood memory where you're on the playground with your friends, and you're lying on a grassy hill, and you're looking up at the clouds, and somebody sees a bunny, and somebody sees popcorn. And then someone says, 'Well, it reminds me of cotton candy.' And so, I think as I then look forward to these late nights, these unrushed moments when frankly, you're maybe a little bit tired, maybe a little bit delirious, who knows, but you're looking at your work, you're seeing these shapes, you're looking at the plan, those memories of what the patient said was important, your abilities and limitations to control radiation dose, and seeing them merge together. And I think it was really that immersion of, here are these dose lines, they're not random. They reflect meaning, they reflect what I am trying to accomplish and what we as a team are trying to accomplish for this patient. And so that was really what gave rise to these visual narratives in trying to take the dose lines, take the patient's narrative, and essentially create that visual narrative within their dose clouds. Dr. Lidia Schapira: I found your essay so moving and so clear in helping somebody who is not a radiation oncologist think through all of the steps of the treatment planning and the delivery of the treatment, but what I appreciate so much about your writing is the humanity you brought into this. One of the lines I found so beautiful was when you're describing the scene of this older woman who has so many comorbidities and now is facing lung cancer, and you're trying to palliate and treat with your treatment. And you say, you imagine and I'm quoting you now, 'her wishes overlaid on my target volume'. Can you tell us a little bit about how you imagine the patient's wishes and aspirations as you are crafting a treatment plan and delivering that plan? Dr. Shivani Sud: It all starts with the consultation. I think oftentimes, even myself before I became a trainee in radiation oncology, I thought it would be a very impersonal field. I imagined just plans and computers and scans, and that it wasn't a field where you necessarily interfaced with patients as much as I learned that we do. And so, the consultation is an amazing opportunity to get to know the patient. You have reviewed their medical record, you've scrolled through their scans, and you started to think about how you want to treat things. And all of that comes into reality when you actually meet someone. You actually talk about what is important to them. Who did they come with? What does the person who was with them say about them? And what's important to them? How do they advocate for them? And so, a lot of it is that merger of this is what I've trained to know. This is what the guidelines say. This is what the studies say. And now I'm meeting you, and I have an opportunity to learn about you. So, how can I take this information? And how can we embrace it in what you want to come up with the best plan? Dr. Lidia Schapira: That's beautifully stated. You tell us in the narrative that this patient told you that she longed for a quality time until the sun sets, and then you drew or you painted this oil painting, right? It's an oil on canvas, that you titled 'Until the Sun Sets', and you said that you then use the art as a way of expressing yourself, but then also sharing it with others, perhaps gifting it to a loved one. Talk a little bit about how this art helps you to reflect, process, express, and then share? Dr. Shivani Sud: I think, for me, a lot of the expression has to do with both the patient's journey, as well as my journey here. I started out as an outsider. I didn't understand what these plans meant. How they came together. And then as a trainee, working with Ms. V, I was able to understand, how do we actually use radiation to give her a short course of treatment, so she can get back to that vibrant life that she was enjoying, that quality life that she wanted, until the sun sets? And in her case, especially, beyond just the radiation, she taught me so much about what we strive to do as providers and where our limitations are. So, I found myself very enthusiastic about treating this early-stage tumor. I had all the statistics about what the control rates were, and everything of that nature. I remember her being very pragmatic about her multiple comorbidities and whether or not she felt she would derive a lot of benefit from treatment. And indeed, in the end, she was right. You could argue there might not have been a lot of benefit from treatment, because she passed away, a few months after we treated her, from those other comorbidities. But I remember after she passed away, and I saw that chart notification, it made me rethink all of our conversations, and that was one of those moments where you pause and you say, 'What did she want? And what was I trying to achieve? And where is the overlap between the two of them?' And so, my target in the moment was that gross tumor volume. It was that nodule in the lung that I had circled, it was the hot spot in that dose cloud. And what I was trying to achieve for her was short treatment so she can get back to her day-to-day life. That meant I needed a hot dose in the center. I needed things to be cool and calm around the periphery. So, I didn't damage too much lung. And then I thought about this sunset, and there was this target volume. There was light because she was so light, so bright, so vibrant. And I had that sun setting into a calm ocean, not a turbulent one, to reflect her pragmatism, her ability to stay calm, cool, collected in the face of not only lung cancer but all of these other comorbidities. And so, really, it was meant to be 'What does she want? What is she stating? How do we accomplish it for her? And how do we put that forward in a visual narrative that someone else can understand and appreciate aside from, here are some colorful isodose lines that happened to look nice?' Dr. Lidia Schapira: I must say I find it very inspiring to hear you talk because you talk about radiation oncology, being a technical field and I hear in your voice, everything about connection and mission-driven work. So, I think it's beautiful. The idea is that you're sort of translating and applying what you hear from the human being who is bringing you this disease into your thinking and crafting your dose and your delivery. That's really very beautiful. I wonder if you can share with us a little bit about your comment about the importance of the caregiver story. And in the essay, you say that perhaps some of your response to your patients was also impacted by your experience as a caregiver for your mom when she was undergoing radiation. Can you share a little with the readers and listeners? Dr. Shivani Sud: I think this is part of the reason why Lily's situation and her journey resonated so closely with me. She and her mother were an inspirational duo, regardless, but I think there was this extra level of connection, as we took care of Lilly because my mother was about to start her radiation treatments herself. This is another one of those examples, where, as a trainee especially, it feels like you start off as an outsider, and then you're part of the system. And then here, I was, not necessarily, you know, I wasn't part of my mother's radiation treatment delivery team, but I was still a radiation oncologist in training. And here I was sitting there by her side, trusting the system that I was once an outsider to, and then was once part of, but from a different vantage point. And so that's kind of those shifts in where the chair is located. And in chart rounds, it was along the periphery for the medical students, and then you're sitting in the main seat as the radiation oncologist. And now you're sitting in the chair along the wall reserved for family members. I think the role of a caregiver is tremendously important in terms of caring for patients. First, of course, for the patient's well-being for them to have someone to speak with, at least that was the case with my mother. We would often talk about her symptoms, and what she was afraid of, what she wanted out of treatment, the parts of radiation that were scary and nerve-wracking to her. And it was interesting to now be on this cusp and, had her tumor arisen five years before, I wouldn't be able to speak both languages of daughter and radiation oncologist. But given the point in time, there were many moments where I could reassure her. And there were also many moments where, after I reassured her, I would then sit there and say, 'Oh, dear, is this actually going to work?' You have all this training, but then you kind of pause and you say, 'Well, do I believe it?' And you think about things a little bit differently, again, when you're not necessarily in the system, but you understand the system, but you're sitting in a different position. Dr. Lidia Schapira: You're clearly inside the system. Now, my final couple of questions are these, one is what motivated you to write and publish the story? Dr. Shivani Sud: The paintings themselves arose from seeing these visual narratives. And essentially the same way that a writer likes to put thoughts to paper, I wanted to put paint to canvas, because that was the way that I was going to remember this connection that I had made. And this was the best way that I would be able to share the connections that I had made with others. In terms of wanting to pen the story, part of it was giving light and continuity to these experiences of taking care of these two patients who had taught me so much and clearly struck a chord with me in terms of wanting to craft these paintings and to also share with others that there is humanity in our field, there is such a deeper connection that we make. And even though these computer-generated lines might seem so impersonal, and you see us scrolling through scans and things of that nature, there is very much a human connection, a human cause, and purpose behind all of that, and everything we do is centered around the patient. And this for me was just my way of showing a way in which I bring my mind, body, and soul to the work that I do. And take home this work and say, 'This is where it's a part of me.' Dr. Lidia Schapira: Have you shown your artwork? Dr. Shivani Sud: I have shown my artwork to a few of my co-residents. A few of my attendings have seen it as well, I haven't widely circulated it at this point in time. Dr. Lidia Schapira: Shivani, thank you so much for sending us your work, and please remember to keep your humanity about your work. It is inspiring. It is inspiring to hear you. It was really moving to read your essay and to appreciate your artwork. Thank you so much. Dr. Shivani Sud: Well, thank you so much for having me. Thank you for accepting the piece, for encouraging us to embrace our humanity in the work that we do, and for having the Art of Oncology section. It's a pleasure to be able to join. I really appreciate your taking the time to include me. Dr. Lidia Schapira: Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories: The Art of Oncology podcast. This is just one of many ASCO Podcasts. You can find all of the shows at podcast.asco.org.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Jennifer Ligibel from Dana Farber Cancer Institute in Boston, MA and Dr. Catherine Alfano from Northwell Health Cancer Institute and Feinstein Institutes for Medical Research in New York, NY, co-chairs on "Exercise, Diet and Weight Management During Cancer Treatment: ASCO Guideline." This guideline addresses recommendations for exercise, diet, and weight management for adult patients undergoing active cancer treatment, highlighting where there is evidence to recommend interventions, and where future research is needed. Read the full guideline at www.asco.org/supportive-care-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Jennifer Ligibel from Dana Farber Cancer Institute in Boston, Massachusetts, and Dr. Catherine Alfano from Northwell Health Cancer Institute, and Feinstein Institutes for Medical Research in New York, New York, co-chairs on 'Exercise, Diet and Weight Management During Cancer Treatment: ASCO Guideline'. Thank you for being here, Dr. Ligibel and Dr. Alfano. Dr. Jennifer Ligibel: Thanks for having us. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Ligibel, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Jennifer Ligibel: I have no personal conflicts with this guideline. Brittany Harvey: Thank you. Dr. Alfano, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Catherine Alfano: I have no conflicts. Brittany Harvey: Thank you. Then, getting into the content of this guideline. Dr. Ligibel, can you start us off with an overview of the scope of this guideline? Dr. Jennifer Ligibel: Sure. So, this guideline was developed to provide recommendations around exercise, diet, and weight management for patients undergoing active cancer treatment. We defined active cancer treatment as either the perioperative period or the period of time in which patients were receiving chemotherapy and/or radiation. This guideline specifically focuses on adult cancer patients and largely focuses on individuals undergoing treatment for curative intent. There were a number of reasons why we thought it was important to develop a guideline specifically for patients who were undergoing cancer treatment. There are a number of other guidelines that talk about the role of these types of lifestyle factors in preventing cancer, and also information widely available about the potential benefits of exercising more, consuming certain types of diets, or losing weight after cancer treatment is finished. But there's much less information about the feasibility and potential benefits and safety of increasing your exercise, changing your diet, or losing weight during cancer treatment. This is the time when oncology providers are primarily working with patients in a time when patients have a lot of questions about what they should be eating and what they should be doing. So, this guideline was developed to specifically try to provide guidance during treatment. Brittany Harvey: Yes, definitely an area in which guidance is very much needed. So, then Dr. Alfano, I'd like to next review the key recommendations of this guideline, starting with what are the recommendations regarding exercise during cancer treatment? Dr. Catherine Alfano: For exercise, the expert panel felt that the evidence was very strong. And so, oncology providers should recommend aerobic and resistance exercise during active treatment with curative intent because it can mitigate the side effects of cancer treatments. So, exercise has been shown during active cancer treatment to reduce fatigue, to either improve or preserve a patient's cardiorespiratory fitness, their physical functioning, their strength outcomes, and in some kinds of patients exercise has been shown to improve quality of life and reduce anxiety and depression. The evidence is not sufficient to recommend exercise specifically for improving cancer control outcomes yet. This is a source of ongoing study, but we felt that the evidence was strong enough that oncology providers should recommend aerobic and resistance exercise, and it should become the standard of care for all cancer patients. The second recommendation regarding exercise is that oncology providers may recommend pre-operative exercise for patients specifically undergoing surgery for lung cancer. So, this can be called prehab or pre-habilitation exercise. And this exercise has been shown to reduce outcomes like the length of hospital stay and postoperative complications. Brittany Harvey: Excellent. Thank you for reviewing those recommendations and the level of evidence behind them. So, then, Dr. Ligibel, what did the panel recommend regarding particular dietary patterns or foods for patients during cancer treatment? Dr. Jennifer Ligibel: One of the things that we recognized as a panel as we reviewed the evidence that shaped these guidelines was that there was much less evidence for both dietary factors and whether that was specific dietary patterns or some specific foods, as well as weight management, how those types of changes during treatment, affected outcomes, or even the feasibility of changing your diet or losing weight during cancer treatment. We, for this guideline, really relied on randomized trials to help shape our guidance, and we realized very quickly that there were few randomized trials testing dietary change or weight management during cancer treatment. So, as a panel, we debated for a long time about what we should say in this setting. We did find that there were a few randomized trials that specifically looked at neutropenic diets. We defined that as diets that omitted fresh fruits and vegetables for patients who had undergone treatment for hematologic malignancies, and in particular bone marrow transplants. Those studies were designed to look at whether those types of diets reduce the risk of infection. We did not see evidence that omitting fruits and vegetables during cancer treatment for those malignancies, reduced infection, and so the group provided a recommendation that neutropenic diets not be recommended for patients during cancer treatment, but we were unable to provide specific guidance regarding other dietary factors or the incorporation of specific foods during cancer treatment. As a group, we recognize the importance of a healthy diet for general health. But given that we were really looking at randomized trials of the effects of changing someone's diet during treatment, we ultimately did not make a recommendation for a particular diet during cancer treatment, but really called for more research with well-designed clinical trials to test the impact of things like plant-based diets, intermittent fasting, other types of diets for which there may be interesting preclinical evidence, but very little information in people about the benefits or even the safety of these types of diets during cancer treatment. Brittany Harvey: Understood, I appreciate you outlining the nuance of that recommendation, and also the areas for future research, which we can get into a little bit more in a little bit. So then, in the last category of recommendations, Dr. Alfano, what does the guideline state regarding interventions to promote intentional weight loss or avoidance of weight gain during cancer treatment? Dr. Catherine Alfano: So, when our panel reviewed the evidence for weight loss or the avoidance of weight gain during cancer treatment, unfortunately, we decided that ultimately, there's insufficient evidence right now to recommend either for or against intentional weight loss or the prevention of weight gain during active treatment to improve outcomes related to the quality of life or things like treatment toxicities, or ultimately cancer control outcomes. Brittany Harvey: Thank you, Dr. Alfano, for that recommendation, as well. So, Dr. Ligibel, in your view, what is the importance of this guideline? And how will it impact both clinicians and patients? Dr. Jennifer Ligibel: This guideline is really the first large-scale effort to pull together all of the data from randomized trials about the effects of changing your lifestyle, exercising more, in particular, changing your diet, changing your weight during cancer treatment. I think that as a panel, we found very clear and consistent evidence as Dr. Alfano outlined, that exercise has concrete benefits for patients during cancer treatment. I think that this is really an important call to action, both for providers in speaking about these topics to their patients, but also for payers. And as we think about our healthcare system, about how we're going to support patients in becoming more active in a safe way during their cancer treatment. I think that it's very important that we recognize that encouraging physical activity is not just telling people that they should go out and do it. We really need to think about how we support patients in making these types of lifestyle changes in a sustained way. So, I think that this guideline really provides clear evidence that exercise is important. It also provides clear evidence that we need more research in other areas. Patients are asking their oncology providers every day, what they should be eating, whether they should be thinking about losing weight, and we really don't have clear evidence to guide these conversations at this point. I do think it's important to recognize that as a panel, we all felt very strongly that this guideline should not be interpreted as saying that a healthy diet or maintaining a healthy weight during treatment wasn't important. But we were really struck by the dearth of high-level evidence to be able to help our patients make informed choices and I think that's something that, from this guideline, we really need to come up with a plan be better able to ask the question that comes up in the clinic every day of, 'Doctor, what should I eat?' Brittany Harvey: Those are excellent points. I appreciate the panel looking critically at the evidence that's actually out there to try and determine recommendations. So then, Dr. Ligibel just mentioned a few areas in which more research is needed. So, Dr. Alfano, what are the outstanding questions regarding optimal diet, weight management, and exercise during active cancer treatment? Dr. Catherine Alfano: Being treated for cancer makes many patients feel like they have no control over their health and that causes them enormous anxiety. Patients are really looking for things that they can do to take the reins of control back over their health to improve their long-term health and well-being during treatment. I want to underscore the importance of the oncology team in helping patients improve their exercise. Research has shown that 50% of patients undergoing cancer treatment are not getting enough exercise. Patients want to receive guidance about exercise from their oncology team. And importantly, patients whose oncology clinicians discuss exercise with them are more likely to make these healthy behavior changes. So, it really underscores the importance of the oncology team in helping patients to access these important components of their health that they're asking for. The appropriate referral for exercise in patients undergoing treatment for cancer can really depend on several factors such as comorbidities, treatment toxicities, and the patient's pre-existing physical activity level. For example, many patients can safely perform unsupervised exercise, but others may need supervised cancer-specific exercise because they've got problems that they need to deal with clinically supervised exercise or to participate in a formal cancer rehabilitation program prior to undertaking exercise on their own. I want to highlight for everyone that there are national efforts that are focusing on building referral algorithms and clinical decision support tools to help point to the most safe, feasible, and effective intervention for a given patient. Brittany Harvey: Excellent. Well, thank you both so much for outlining the recommendations here and describing the nuance that the expert panel went through. It was certainly a large effort that you've helped lead. And so, I want to thank you so much for your work on these guidelines, and for your time today, Dr. Ligibel and Dr. Alfano. Dr. Jennifer Ligibel: Thanks for having us. Dr. Catherine Alfano: Thank you. Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO guidelines podcast series. To read the full guideline go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. David Schiff from the University of Virginia Medical Center in Charlottesville, VA, Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, FL, and Dr. Vinai Gondi from Northwestern Medicine Cancer Center Warrenville and Proton Center in Warrenville, IL, authors on "Radiation Therapy for Brain Metastases: American Society of Clinical Oncology Guideline Endorsement of the American Society for Radiation Oncology Guideline." An ASCO endorsement panel endorsed the "Radiation Therapy for Brain Metastases: an ASTRO Clinical Practice Guideline," and the authors review the endorsement process and key points in this episode. Read the full guideline endorsement at www.asco.org/neurooncology-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. David Schiff, from the University of Virginia Medical Center in Charlottesville, Virginia, Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, Florida, and Dr. Vinai Gondi from Northwestern Medicine Cancer Center Warrenville and Proton Center in Warrenville, Illinois, authors on 'Radiation Therapy for Brain Metastases: American Society of Clinical Oncology Guideline Endorsement of the American Society for Radiation Oncology Guideline'. Thank you for being here, Dr. Schiff, Dr. Vogelbaum, and Dr. Gondi. Drs. Schiff, Vogelbaum, and Gondi: Our pleasure. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guideline products and ensures that the ASCO conflict of interest policy is followed for each guideline product. The full conflict of interest information for this guideline endorsement panel is available online with the publication in the Journal of Clinical Oncology. Dr. Schiff, do you have any relevant disclosures that are directly related to this topic? Dr. David Schiff: No relevant disclosures, Brittany. Brittany Harvey: Thank you. And Dr. Vogelbaum, do you have any relevant disclosures that are related to this topic? Dr. Michael Vogelbaum: I have no relevant disclosures. Brittany Harvey: Thank you. And Dr. Gondi, do you have any relevant disclosures that are related to this topic? Dr. Vinai Gondi: Brittany, my only relevant disclosure is that I served as vice-chair of the guidelines that we're discussing today, but otherwise, no relevant disclosures. Brittany Harvey: Excellent! Thank you all. So, then starting us off, Dr. Schiff, what is the scope of this guideline endorsement? And how does it intersect with the recently published 'Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline'? Dr. David Schiff: Sure. A little bit of background, from the start of the joint ASCO and SNO guideline effort, we had the participation of radiation oncologists, in addition to neurosurgeons, medical oncologists, and neuro-oncologists. As we were getting underway, ASTRO reached out asking to participate formally as well. They had been planning to update their brain metastasis guidelines but were a year or two away from getting started. And they recognized it would be redundant for them to create comprehensive guidelines that covered chemotherapy, immunotherapy, and surgery as our guidelines were poised to do. By participating with ASCO and SNO, they were able to have their task force focus specifically on key questions related to radiation oncology practices. In particular, the ASTRO project went into considerable depth on issues of radiation and radiosurgery dose, fractionation schemes, and the risk of radiation complications. These were areas that our guidelines didn't address. Several members of the ASTRO task force including their chair, Paul Brown, and co-chair Dr. Gondi were members of our committee, and we added Dr. Brown as a co-chair to our committee when ASTRO came on board. The overlap between our two groups helped ensure that our recommendations were in harmony. Brittany Harvey: So, then, Dr. Vogelbaum, can you provide us with an overview of how the ASCO guideline endorsement process works? Dr. Michael Vogelbaum: Sure, Brittany. So, as Dr. Schiff mentioned, ASCO had convened a guidelines panel to develop the new 'Treatment for Brain Metastasis: ASCO-SNO-ASTRO Guideline'. And this was a multidisciplinary panel that he and I co-chaired and was anchored by a guideline specialist from ASCO, Hans Messersmith, and the process was that we had evaluated recent literature pertaining to the treatment of the brain metastases, and so, we had a very good understanding of what was supported by high-quality evidence and what was not there yet, as a group. So, when ASTRO came to ASCO and asked whether or not we would be interested in endorsing their guidelines, we were already prepared with all the evidence. And so, the same panel got together again, to evaluate the ASTRO guidelines. And we did this, again, in a very structured manner. We reviewed the guideline questions and recommendations, compared them to the evidence, and went through the same type of review and polling process that we had when we had developed our own original guidelines. In the end, we had a conversation with the ASTRO guidelines leadership about some of the points that we raised questions about, and we were able to reach an accommodation that allowed us to fully endorse the ASTRO guidelines. Brittany Harvey: Thank you, Dr. Vogelbaum for that overview of the endorsement process. So, then, Dr. Gondi, what are the key recommendations of the ASTRO guideline? Dr. Vinai Gondi: Thank you, Brittany. As Dr. Schiff and Dr. Vogelbaum outlined, ASTRO commissioned a list of key questions that they sought to address specifically to inform the radiotherapeutic management of brain metastases. And to address these questions, ASTRO not only convened a panel of expert radiation oncologists across the country but also engaged with the Agency for Healthcare Research and Quality (AHRQ) to create a comparative effectiveness evidence review, in addition to our own high-level evidence review to address these questions. The four key questions that were addressed in the ASTRO guidelines are: Number one: What are the indications for stereotactic radiosurgery alone for patients with intact brain metastases? Number two: What are the indications for observation, preoperative radiosurgery or post-operative radiosurgery, or whole-brain radiotherapy in patients with resected brain metastases? Number three: What are the indications for whole-brain radiotherapy for patients with intact brain metastases? Number four: What are the risks of symptomatic radionecrosis with whole-brain radiotherapy and/or stereotactic radiosurgery for patients with brain metastases? The recommendations that were made are based on a high-level review of a considerable amount of literature over the past several years that addressed these specific questions. I would encourage the listeners to this podcast to read through the guidelines to understand the specific nuances of each of those recommendations. Brittany Harvey: Excellent! Thank you for that overview. Then, in addition to what Dr. Gondi just said, Dr. Vogelbaum, were there any additional points of discussion raised by the ASCO endorsement panel? Dr. Michael Vogelbaum: Brittany, yes, there was an area of discussion where we needed to interact with the ASTRO guidelines leadership, as I mentioned earlier, and it really related to that key question one that Dr. Gondi described, which is what are the indications for SRS alone for patients with intact brain metastasis. The approach that had been strongly endorsed by ASCO was that there would be a multidisciplinary approach to decision making. And really the benefit of that, the value of that radiosurgery really comes in the form of the interaction between the radiation oncologist and the neurosurgeon. The way that the original proposal had been formulated, there was a size cut-off that was higher than we thought was appropriate for really endorsing that kind of conversation between the radiation oncologist and the neurosurgeon. And so really, we proposed that we bring that cut-off down further, there actually was another subpart to the guideline that had looked at a lower cut-off, but did not specifically call out that interaction between the neurosurgeon and the radiation oncologist. And we felt it would be more appropriate to insert that at that cut-off rather than the larger lesion cut-off. And after a conversation, there was agreement, that was really the only guideline or subpart of the guidelines where there was any real debate or discussion. For the rest of it, the comments that came up from the panel were easily addressed and it really just came down to this one modification. And fortunately, ASTRO agreed, and we were able to go ahead and complete the endorsement. Brittany Harvey: Great! It's great that this was able to be a complete endorsement of that guideline. So, then, Dr. Gondi, in your view, what is the importance of this guideline endorsement? And how will it affect ASCO members? Dr. Vinai Gondi: Thank you, Brittany. A number of responses to that. Number one is, as Dr. Vogelbaum, outlined the purpose of these guidelines was meant to be patient-centric and patient-focused, that we had patient champions who had navigated, who are part of the guideline development team, but also to be multidisciplinary. And so, the type of input and feedback we received from the ASCO team was super valued and valuable, as we were formulating these guidelines and Dr. Vogelbaum outlined a good example. Number two, it had been almost a decade since the last guidelines had come out from ASTRO related to brain metastases management. And much has happened in our field over the past several years that has been practice-changing. We have several novel and innovative radiotherapy technologies and techniques, such as the emergence of radiosurgery, the use of novel radioprotectants, such as hippocampal avoidance, and memantine, but also the emergence of innovative and novel neurosurgical interventions and CNS active systemic therapies. So, the modern management of brain metastases has really undergone quite a revolution over just the past few years, and it is important that these guidelines be updated to reflect those changes, but also to inform radiation oncologists on the contemporary management of brain metastases and in evidence-based care. So, we believe that these guidelines will significantly impact ASCO members. Certainly, those who are radiation oncologists, as brain metastases are some of the most common patients that radiation oncologists manage in the community and in academic centers, but also for other members of ASCO medical oncologists, surgeons to understand sort of the nuances of radiotherapy management that is evidence-based, so they can have a patient-centered, patient-focused, multidisciplinary discussion with their radiation oncologist as well. Brittany Harvey: Those are excellent points for clinicians on the management for brain metastases. So, then finally, Dr. Schiff, Dr. Gondi just mentioned how these guidelines are patient-centric. So, how will these guideline recommendations impact patients with brain metastases? Dr. David Schiff: Yeah, well, I think what I'm about to say is really going to echo what Dr. Gondi just said. You know, 20 years ago, patients diagnosed with brain metastases were typically immediately referred to a radiation oncologist, they almost always got whole-brain radiation therapy, the median survival was about four months, and many, if not most patients, died from their brain metastases. The situation has really changed recently. With the rapid advances in management from new therapies, and well-designed clinical trials in recent years, outcomes have markedly improved, it's probably less than a quarter of patients now who succumb to their intracranial disease. But at the same time, decision-making for patients has become much more complicated. Nowadays, medical oncologists may reach out initially to neurosurgeons for consideration of radiosurgery or surgical resection, or in some circumstances utilize systemic therapy as a first step. Conversely, a patient might see a neurosurgeon first, who may or may not be aware that there's appropriate immunotherapy or targeted agent that might make sense prior to going on to radiosurgery. It's obviously a challenge for sub-specialists to keep up with all the emerging clinical trial data and new drugs. Our two sets of guidelines provide a roadmap for physicians of different expertise to help determine what types of therapies or referral should be considered when brain metastases are found. The end result of all this is improved control of intracranial disease and improved quality of life for the patients. Brittany Harvey: Absolutely. Those are key points. It's excellent to see these guidelines, and the overarching 'Treatment for Brain Metastases: ASCO-ASTRO-SNO Guideline' be published. So, I want to thank you all for your time today, Dr. Schiff, Dr. Vogelbaum, and Dr. Gondi. Thank you for all of your work on these guidelines. Dr. Michael Vogelbaum: My pleasure. Dr. Vinai Gondi: Thank you for having us. Dr. David Schiff: Thank you, Brittany. It was great to participate in this important project. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline endorsement go to www.asco.org/neurooncology-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

“A Note of Gratitude” by Austin J. Price: A senior resident honors his grandmother and expresses gratitude to a doctor who had a long lasting influence on him and his family.   TRANSCRIPT Narrator: “A Note of Gratitude” by Austin J. Price, MD-MPH (10.1200/JCO.21.01781) Mary Ann Richards-Elbrader was many things. Born in rural Kansas in 1936, she was a product of the pre-War Depression Era. That fact, I am sure, had an impact on the type of person she would become—a hard worker to a fault and a fiercely loyal family woman. She was the mother of five, the grandmother to 13 including me, and a friend to all, rarely knowing a stranger. Only a high school graduate herself, she believed wholly in the value of education, something that no other person could ever take away. Owing to that belief, all of her children earned college degrees, something that made her immensely proud. She was quick to anger and even quicker to apologize. Devoutly faithful, she taught her children to believe in something greater than themselves. On a more lighthearted note, she was known to lay back in the recliner after a hard day with a stiffly poured vodka. I recall the kindness ever present in her eyes, seen through large, clunky, 80's style frames and the lines on her face that easily divulged to the world she was someone who loved to laugh. The fact that she became a patient with cancer in 1995 is quite likely the least interesting thing about her. My grandmother's journey with cancer began, as many things did for her, in the service of others. She was a frequent blood donor. After giving blood once, she was found to be anemic and instructed to see her primary care doctor. The diagnosis came swiftly— colorectal cancer. From what I have been told, the goal initially was cure. I was very young and hardly able to grasp the nuances of her clinical course. Nonetheless, I know she had surgery and chemotherapy, and for a while after that, everything seemed fine. My mother and aunts recall a discussion when there was mention of age spots in her liver that would be monitored. That probably seemed harmless at the time, but it sounds so ominous to me now. Indeed after a 1.5-year remission, my grandmother experienced a roaring recurrence, this time in the liver. As tragic as it was, I share these details merely as a prelude to something wonderful. It was 1998, and my grandmother found herself seeking a second opinion at the University of Nebraska from a medical oncologist named Dr Tempero. As my family recalls, there was a clinical trial for patients with colorectal cancer metastatic to the liver ongoing at that time. My grandmother initially qualified but was soon disqualified for medical reasons. Despite that, our entire family quickly came to thoroughly appreciate this oncologist. What it was about her that resonated so deeply is difficult to express in words. In my mother's terms, it was her confident, no nonsense, but never cold, demeanor that provided assurance that she knew her stuff while still having her patients' best interests at heart. She was also very honest from the outset in a compassionate, preparatory way, without becoming bleak. Perhaps most striking, my mother recalls, was their last meeting in Omaha, when she explained that there was no more she could do from a medical prospective. There were tears in her eyes, but she did not cry. She exuded both empathy and resolve, which made her more human but no less professional. My grandmother succumbed to cancer on September 20, 1999. I was 8 years old. I never spoke to her specifically about Dr Tempero, but I remember hearing stories about that doctor in Omaha who was so acutely aware of the human experience. A decade later, I was about to start my freshman year of college. I had always been reasonably smart, fairly ambitious, and done well in school. However, as an 18-year-old, I shall admit that I was more preoccupied with the social aspects of college than I was with what might happen in 10 years. Slowly, I became more interested in the prospect of going on to medical school. Much of my early childhood had been fraught with my grandmother's illness and I recalled the various roles physicians had played in her life. My mother always told me, "If you are going to be a doctor, be like Dr Tempero.” I realized early on becoming such a physician would require much more than good grades and perseverance; it would require a constant commitment to being present, humble, and empathetic, without losing the confidence that allowed others to find comfort and value in my assessments. Ultimately, I decided that was a challenge I wanted and needed to pursue. With the unending support of my family and friends, I got into medical school and graduated in May 2019. I am now an internal medicine resident in San Francisco. My residency experience has been greatly different from what I anticipated. As the COVID-19 pandemic descended on our hospital, I found myself as an intern charged with facilitating end-of-life discussions through FaceTime, fully clad in personal protective equipment. Continually, I had to explain to families of the critically ill why they could not visit their loved ones. There was no instruction manual on how to have such conversations, but I know every day I channeled what I had garnered from my own family's experiences with the health care system. I am unsure if I succeeded in the ways that Dr Tempero did, but I have never stopped trying. In December 2020, I was triaging patients from the emergency department. While gathering the history on one patient, I asked “who is your oncologist?” When he replied, “Dr Tempero,” I froze. Surely it could not be the same doctor, the same one I had heard about since I was 8 years old? The one whose unique abilities I would always tried to emulate? When I left the room, it did not take much time on Google to realize it was. I shared portions of this story with my patient, who was extremely complimentary of her. That evening, when I got home, I called my mother to share this truly cathartic experience. Ultimately, it was she who implored me to personally reach out. I sat down at my desk and wrote her a note of gratitude. The following day I got an email notification while at work. I waited until I had a few minutes to read her response in privacy:   Dear Austin, Your letter is, without a doubt, the most touching letter I have ever received. I know how busy you must be right now, and I was doubly honored to know that you took the time to write this thoughtful message. Thank you from the bottom of my heart. I have had the privilege of helping so many patients over the years and each one becomes a gift. I may not be able to turn the course of their disease but I can always make the journey easier. On a Wednesday evening in early May 2021, a little over 23 years after she was my grandmother's doctor in Omaha, I met Dr Tempero for the first time. I joined her and her husband at their apartment in San Francisco for a glass of wine. We discussed medicine, our mutual love of travel, and of course the unique situation that precipitated our meeting. I could easily perceive the qualities my family had always admired about her. She was interested in my story and my goals, but yet forthcoming about her life, family, and career. Her persona was welcoming, but yet demanded respect. Two hours later, she walked me downstairs and waited until my Uber arrived at her door. As I rode across the city, I contemplated the miraculousness of these events. I wished, as I always will, that I had more memories of my grandmother that did not center upon her illness, but the reality is I do not. What I do have is the memory of this encounter that has left me with a sense of inner peace and optimism, reassured that I am exactly where I am meant to be. I write this in gratitude to a doctor, who had no way of knowing her kindnesses would have such lasting influence. Of course, I also hope to honor my grandmother's legacy. I know she would be honored to see how her own misfortune somehow managed to be the genesis of such positivity in my life. I believe she would also challenge us all, as do I, to be like that doctor in Omaha. Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of 9 programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows including this one at podcast.asco.org. I'm your host Lidia Schapira, Associate Editor for Art of Oncology and Professor of Medicine at Stanford University. With me today is Dr. Austin Price, a senior resident in internal medicine at California Pacific Medical Center, soon to be an infectious disease fellow at the University of Kansas. We'll be discussing his Art of Oncology article, “A Note of Gratitude”. Our guest has no disclosures. Austin, welcome to our podcast. Dr. Austin Price: Thank you very much. Thanks for having me. I'm happy to be here. Dr. Lidia Schapira: Let me start by asking if you are, in addition to a writer, also an avid reader? Dr. Austin Price: Yes, in the past at least I have been somewhat stymied by going into residency, but in the past, I liked to read a lot. Dr. Lidia Schapira: So, tell me a little bit about your past readings and maybe favorite authors or books, something you'd like to share with our listeners. Dr. Austin Price: I like to read about medical history. And so, one of my favorite books actually is by Dr. Paul Offit, and it talks about the early days of vaccines and how there was, I think it's called The Cutter Incident, but it's a great book. I may be misquoting the actual name, but great book. When I was in Baltimore, and doing my master's, he gave some guest lectures. And that's where I became acquainted with some of his work, I like reading that. So, those are the kinds of things that I really enjoy. And then I think, of course, I have always really enjoyed F. Scott Fitzgerald, even from high school, and Hemingway. Dr. Lidia Schapira: Very classically trained. Tell me a little bit about writing. Writing is a way of sharing an experience or perhaps processing a difficult encounter with a patient, is that something that you routinely do or have thought of? Dr. Austin Price: Yeah, it's definitely become something that's been more robust as I've gone through residency. I think part of that certainly had to do with the pandemic, and just not being able to be as close with people and have those personal relationships. And I found myself kind of cut off, maybe from a support system that I would have otherwise had, being in California with most of my friends and family in the Midwest. And so, I used writing as a way to kind of compartmentalize my feelings and my interactions with patients and to check in with myself. And I find that it's therapeutic and also enjoyable. Dr. Lidia Schapira: That's fantastic. Let's talk about the essay that you submitted and we published in Art of Oncology, which is a way of honoring the memory of your grandmother, who had cancer when you were a child, and also talks about your sense of vocation and this ideal that was held up to you by your family of aspiring to be as empathic and wise, as a doctor, who is an oncologist who helped your grandmother. Let's start a little bit with your grandmother's illness and how you remember that now that you are a physician. Dr. Austin Price: Yeah, certainly. I mean, I just remember as a child, her getting very sick, and finding out that she had cancer, and knowing that that was a bad thing, but not really knowing any of the details of it. As it turned out, she had colorectal cancer, and had surgery, for a short time she seemed okay. And then she got sick again, this time with metastatic disease to the liver. And of course, she was very sick then and ended up seeking out a second opinion from an oncologist who becomes the person in the story that I write about, in Omaha. At that time, there really wasn't anything that could be done to save her life, essentially. But the interactions that they had were very impactful to both her and the rest of our family. So much so that all through my life, my family members said, if you want to become a doctor, which I thought kind of early on, I did, that I should be like this particular person, Dr. Tempero. And so, she had just always been this kind of person on a pedestal, if you will. Dr. Lidia Schapira: Let's talk a little bit about the impact that Dr. Tempero and her consultation had on your family. Can you tell me a little bit more about how they talked about that particular meeting? Many of us who are in oncology and have been for a long time often talk about the fact that there can be a therapeutic relationship between the oncologist and the patient and the family that can actually help during difficult times and even through bereavement. But it's so interesting to me to hear you speak about it from the perspective of a family member. Tell me a little bit about how that relationship impacted the way the family understood the illness and how they went through their loss? Dr. Austin Price: I definitely think that there was a therapeutic relationship established. And I think in a way, Dr. Tempero managed to be preparatory in the sense that she knew that the outcome was likely not going to be good. I think she did that without ever being bleak or ever losing hope, in doing so she really kind of helped, in her own way, move us slowly towards accepting reality, and then learning how to move forward and enjoy the time that we had left together. I think all of my mom's siblings remember her in the same way, they really trusted her in such a robust way that her assessment that there really wasn't anything else medically that could be done, really helped them to come to terms with it and to refocus their goals, and those goals being to spend as much quality time with my grandmother that they could. Dr. Lidia Schapira: And as you've gone through your medical training, I imagine that they'll have to dangle this idea of this ideal doctor in front of you more than once. How have you interpreted or internalized this aspiration to also be wise, empathic and so kind to your patients? Dr. Austin Price: Yeah, it's definitely something that my mother in particular is always reminding me to do, because it's not always easy, as we all know. And there are times when I'm frustrated and tired and all those sorts of things. So, she and I've had many conversations where I'm maybe lamenting about feeling overworked or this or that. And she's always reminding me to be present and to realize that, although I'm tired that I'm oftentimes interfacing with people at bad points in their life. So, I always try to keep that at the forefront of my mind and try to decompress before each patient interaction, in hopes that I can be at least to some degree like Dr. Tempero was for my family. I'm sure that I don't always succeed in the ways that she did, but I hope that I do most of the time. Dr. Lidia Schapira: I assume Dr. Tempero would reassure you that even she may have a bad day or a bad hour in a day. Your essay has a moment of suspense and a twist in the plot when you find yourself now as a physician in an emergency room looking after a patient who tells you that their oncologist is none other than Dr. Tempero. Tell us a little bit about what that felt like? Dr. Austin Price: Well, I mean, it was just altogether shocking, honestly, because I had never met her and I really had never even Googled her name in the past. She was just always this person that my mother talked about so much. And then I had come to a kind of honor but I assumed for all I knew that she was still in Omaha. And so, when I heard this name, I thought, well, how many oncologists named Dr. Tempero are? Well, there's probably more than just her, but I immediately left the room and started to Google and realized, just quickly, that it was her or that I assumed that it was because she had done her training in Omaha at the University of Nebraska. It was shocking and emotional too, I will say. I immediately remember texting my mom and being like, oh my gosh, this patient just told me that Dr. Tempero was their oncologist. And I have to go back in there and finish the assessment because I kind of had to leave the room to just decompress a little. Yeah, it was a wonderful feeling and also just one of those moments where you're just like, life is so interesting in the way that you come into contact with people and in situations that are just so unique. Dr. Lidia Schapira: And then you reached out to her? Dr. Austin Price: I did. Yeah, my mom told me, she said, she may not have time to get back to you about this but you should at least reach out and explain how this made you feel. And thank her for the way that she treated our family and thanked her for the ways in which she or the idea of her has kind of impacted the type of physician that you aspire to be. Dr. Lidia Schapira: So, you wrote to her, and she wrote you back. What was that like and what happened after that? Dr. Austin Price: Well, I just remember being shocked that she wrote back so quickly. I know that she's incredibly busy. And so, I was very happy that she'd written back so quickly. Honestly, when it was written, this all happened at Christmas time. So, I wasn't able to be there because of COVID and working through the holidays. It was just the first time in 30 years that my mom hadn't seen me for the holidays. So, she was emotional about that. And so, getting to read Dr. Tempero's response to the family over FaceTime on Christmas, really was kind of like the best gift that they could have gotten. They really enjoyed it. That kind of helped to stifle the blow a little bit of me not being able to be there for the first time. Dr. Lidia Schapira: I'm just getting teary just thinking about that scene of you're reading this message to the family over FaceTime, and then talking Dr. Tempero invited you to meet her, and you had a long conversation, tell us a little bit or share with us what you feel is appropriate so that we can understand how important that reunion was for both of you? Dr. Austin Price: Yeah, sure. From the first response email, she said, 'I would like for us to get together and for us to meet in person when it's safe to do so', because when this interaction initially happened, none of us had been vaccinated yet, and so we're still in the throes of COVID and still petrified and all those things. And so, once we had been vaccinated, I reached out to her and said, I actually have started to write this essay, and I just wanted to know your thoughts on it. And she read it and she said, and this was many iterations ago when it wasn't as good as I think it is now, but she was like, 'Oh, I'm very much in support of this and I'm very honored, and by the way, we're vaccinated now and it's time for us to finally meet.' So, we did. It was great. I met her and her husband at their apartment in Mission Bay in San Francisco. We just had a lovely evening, had a glass of wine, some hors d'oeuvres, and just talked about this unique situation that had brought us together, and also talked a lot about my life and what I want to do in my career and my future. She was more interested in me than sharing so much about her life, but was very forthcoming when I would ask her questions as well, then also just had this kind of commanding aura, but welcoming at the same time, just very likable. I don't know how to explain it, other than that it was amazing and I was so thrilled to experience it. Dr. Lidia Schapira: I think you've explained it very well. It's a beautiful story for us to read, for all of us who have been in oncology for all these years, and those who are just starting, it's really inspiring. We think a lot about mentoring our students or junior faculty, but the idea that we in our clinical roles, can also have sort of in a way an indirect mentorship, relationship with or an influence with other young members of the families is really beautiful and moving. I thank you so much for having sent it to us and for sharing that experience. Is there something else, Austin, that you would like our readers and listeners to know about the essay itself, your family, or the intention that you had that brought you to not only write but share your writing so publicly? Dr. Austin Price: Yeah, I hope to honor my grandmother, because I think it's been interesting, this experience brought me a lot of joy, and I think it brought our family a lot of joy. The fact that that came from such a sad place and sad reality, I think is really great. For clinicians, it's just really important to realize how far-reaching our interactions with patients can be because we are seeing them, oftentimes, really in bad times of their lives, times that they're going to remember for a long time. And so, we can then be remembered in kind of good ways and bad. I think it's so unique in the situation that in an interaction that Dr. Tempero had with my family, nearly a quarter-century ago, it only took the mention of her name, to bring back this whole flood of memories and spawn all of this. I think that's really cool and something that we should always be cognizant of. We have very far-reaching impacts for our patients. I just think that that's cool, and a good thing to be reminded of. Dr. Lidia Schapira: I think it's very cool too and I thank you so much, Austin, for sharing your essay and for taking part in this conversation. Dr. Austin Price: Thank you for having me. Dr. Lidia Schapira: Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology Podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories: The Art of Oncology Podcast. This is just one of many ASCOs podcasts. You can find all of the shows at podcast.asco.org   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

"Questions for the Oncologist," by Barry Meisenberg: an oncologist struggles to answer a patient's “Why me?” question.   Transcript   Narrator: Questions for the Oncologist by Barry R. Meisenberg, MD (10.1200/JCO.22.00158)   Go ahead, ask me anything. Decades of meeting beseeching eyes has prepared me. Ask me anything except that one thing. That one thing that neither colleagues nor study has helped me comprehend. Ask me instead about prognosis; I will be honest, but gentle. Ask me about side effects; I will use a small spoon so as not to overfill your vessel. Unfold your notebook. Ask me anything:   “-how many cases like mine have you seen before? -what is the nectar of the bone marrow? -what (and how) should I tell the children? -is it wise to lay in the sun? -is it safe to have sex? -should I get the vaccine? -what's next if this doesn't work? -what if it were your wife?” Go ahead, ask me anything. But please, don't ask me that one thing. Don't ask, “why me?” You wouldn't like the answer. I don't. I could fill your notebook with a tale of random errors in the genes. Tiny rivulets of mutation that flow into a tumultuous river. But, I don't think of them as errors. Rather, they are Nature's engine of biodiversity. Individuals suffer, so that species survive. “Bad luck” is a second-rate explanation, I know. So please, don't ask me that one thing. Search for a better answer within, as I have. Unsuccessfully, so far.   Dr. Lidia Schapira: Welcome to JCOs Cancer Stories: The Art of Oncology brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows including this one at podcast.asco.org. I'm your host, Lidia Schapira. And with me today is Dr. Barry Meisenberg, Chair of Medicine and Director of Academic Affairs at Luminous Health. We'll be discussing his Art of Oncology article: Questions for the Oncologist. Our guest has no disclosures. Barry, welcome to our podcast. Dr. Barry Meisenberg: Good morning. Thank you very much. Dr. Lidia Schapira: It's a pleasure to have you. And before we start to talk about your poem, and the reason for your wanting to share this with a broad readership, mostly of Clinical Oncologists, let me start by asking if you are a poet and if you often write to reflect on your experiences as a physician, or for other reasons? Dr. Barry Meisenberg: Well, I will never give myself that label of poet. I have written several, what I would call reflections on what it is to be an oncologist, which this section of the JCO covers so well. Sometimes I've submitted work and said it was a poem and the editor said, 'No, this is a vignette.' Another time I thought it was a narrative and someone said, 'We liked your poem.' So, increasingly, I've entered this area reflecting a career's worth of introspective thoughts about what it is we do. Dr. Lidia Schapira: So let me ask you, given your very particular vantage and your experience, why do you think it's important for us to write and read reflections? What does narrative give us as physicians, as cancer doctors? Dr. Barry Meisenberg: Well, I think it gives us the other parts of our brain and the other parts of our personality as humans. The most humanistic of all the sciences is medicine. We can't neglect that. Mostly for our own health. But also, I think it makes us better physicians when we think about what we're doing. You know I think it was a physician author, who said that we walk around in the midst of stories. Every one of our patients has a story, sometimes multiple stories, and if we miss that, and don't really capture that, then we're just sort of functionaries. Dr. Lidia Schapira: Such an important thought. There's definitely plot. There are characters. There's the scenery. There's all of this very rich life and human content and I couldn't agree with you more. So, before I ask about this particular essay, what are you reading now or what have you read in the last year that you would recommend to your colleagues? Dr. Barry Meisenberg: Well, it's interesting you say that because, recording here in April of 2022, I've talked to many of my neighbors about their pandemic hobbies, both medical and nonmedical, and they're, you know, learning to bake, reteaching the piano, and working on developing their rhomboids. I've been doing a deep dive into the history of other pandemics. I may be little obsessive, but I've been reading about pandemics throughout history, and just appreciating the fact that human nature hasn't changed very much, nor has medical behavior. So, in Defoe's book, I think it's called Journal of a Plague Year, which by the way, is not history, is a fictional journal but based on reality. We have the same sort of medical charlatanism. We have false hopes. We have people trying to beat the quarantine for their own good. At the same time, we have just public-oriented behavior as well, feeding those who couldn't be fed or who would become orphaned by the plague. The same thing is true of the 14th-century plague. It's just remarkable how little we've changed as a species, all the behaviors on display today, both good and bad, were on display then. And so, I've been reading quite a bit about pandemics. Dr. Lidia Schapira: It's so interesting. Now, with that, let's focus on your beautiful poem, the question that you can't answer after all your scientific work and after your decades of clinical experience, “Why me?”. Tell us a little bit about what inspired this poem that I found so moving, and I'm not a great reader of poetry. But this one message was so clear that I think most of our readers will understand the sentiment. What inspired you to write it? Dr. Barry Meisenberg: Well, I woke up with this one. Sometimes that happens, you wake up with a poem that is nearly fully formed, or a narrative is nearly fully formed in your mind. Although I did get some excellent suggestions from my reviewers that I do appreciate. And I realized only after it was on paper, that seven years ago, I wrote a piece for a different oncology journal about this issue of random chance. And you may remember, in 2015, there was an article, or a science magazine published an article by Thomas Heti and Bert Vogelstein about their mathematical calculations of errors in stem cell division. They didn't do any new experiments. They accumulate what was already known, and they were able to correlate that with the incidence of cancer from the cancer databases. And their conclusions were, when stem cells make random errors, there's more likely to be cancer. Now, they didn't cover every type of cancer. They covered several. And they came up with this idea that cancer is stochastic, that is a random process. Now, stochastic is not a poetic word. And so, we didn't use it in the poem, but random, and that was covered extensively in the New York Times and other media, and a big debate about what it meant. So, I wrote an essay about that, and I realized it's been on my mind all this time, and whether it's a helpful notion or a harmful notion. Helpful in that patients can understand you didn't do anything to give yourself cancer, despite all the media noise about that, but harmful, potentially harmful, in this idea that maybe my life doesn't have meaning if this is just a random process. And so, I talk to patients about this when appropriate, because many of them have thought about it. So, it's sort of been on my mind since this article I wrote in 2015. And I must say, it disturbs me that I don't have a good way of explaining that or helping patients overcome this. Dr. Lidia Schapira: So, when a person asks you why me in some way, I mean, you, first of all, you tell us that you have answers for most of the other questions, what is my prognosis? You can answer. How do I tell the children? You can answer. Is it safe to have sex? You can answer. But the “why me” question is still with you and still troubles you. What is it, in your view, that a person is really asking you? What is the question behind the question when they say 'why me?' Dr. Barry Meisenberg: Well, that is the question. And then I think what they're saying is what does my life mean? Yeah, if the answer to Dr. Vogelstein is correct, that it's stochastic, doesn't mean my life doesn't have a meaning. I hope people wouldn't draw that conclusion. So, random things happen to people, both nice people, and mean people all the time. I remember when I was in New York doing a year of research at Sloan Kettering, there was a helicopter accident, and it didn't just kill the people in the helicopter, but a piece of the blade broke off and spun out over Manhattan, killing someone who was about to walk into a retail store, totally random. It had an impact on me in how all our lives hang by a thread, or it can, and cancer is like that. Dr. Lidia Schapira: What I hear in the “why me” question is also sort of a plea for, please reassure me and keep me safe, because this happened, and you have no explanation, I have no explanation. So, it's interesting that you talk about life's meaning. I see it more as a cry for help. If I can't deal with the uncertainty and the chaos of the universe. Dr. Barry Meisenberg: That's an excellent perspective. And you may well be right, at least for many people. It's almost like a real issue of faith and religion, or more faith and religion. When I say in the piece, 'you have to look inside for that answer, why me and what your life means?' Yeah, people ask questions for a reason. Some of it is just fact downloading, the risk of mucositis, how to treat mucositis, and so on. But other, the more important questions are these. Dr. Lidia Schapira: And that's one of the beauties, I think, of poetry and why we love to publish great poems because it's almost like a bit of a Rorschach too, right? You can read into it, you can interpret, you can use a poem as a way of exploring an important topic, and bringing perhaps to the surface some of the questions that you also deal with, as a human, instead of only your skill, as an oncologist or as a physician used to counseling people. Dr. Barry Meisenberg: I think that is one of the values of poetry. I run a program here at this health system that we call the Diastole Hour because it's important for relaxation. You can't live your whole life in systole. That's the message. And we use poetry a lot, mostly written by patients about their medical experiences, sometimes written by doctors about what it means to be a doctor or be a better doctor. And then, of course, some art that covers medical topics. And the whole goal is to train that other part of our brain to make us better at the business part of being a doctor, and I think the two are related. Dr. Lidia Schapira: Do you read poetry with your fellows or with your trainees or junior faculty? How do you incorporate this kind of thinking in their professional life? How do you use it to build a community? Dr. Barry Meisenberg: Well, that's a great point. I wish we could do more. So, I read some poetry. I am not trained in it and I tend to look for poems that one doesn't need to be an expert in the classics to understand and we use them at this event I've told you about. But also, I've been known to sneak them into Grand Rounds presentations and other venues, trying to make people pause and think a little bit about it. There's some wonderful poetry about the physician experience, for sure. And I sort of collect them. Dr. Lidia Schapira: What are some of your favorite pieces? Dr. Barry Meisenberg: There's a neurologist named Ginsburg, who has written, I remember one poem, in particular, called “Line Drive”. And it's about a man, presumably, based on a true story, who is explaining to someone their brain tumor anatomy during a hospital visit, and pointing at shadows, but recognizes that he doesn't actually do any touching. He doesn't enter their lives. He doesn't answer all their questions like the one we just talked about. And then he's driving home, and he stops at a little league Park and watches some boys play baseball. And one of the boys is struck by a line drive. And he's so moved, by the way, his teammates gather around him and offer support and touch him and help him that he drives back to the hospital to redo the consultation he had just finished doing, but this time with the touching. I thought that was a wonderful poem. Dr. Lidia Schapira: It's an amazing poem. Dr. Barry Meisenberg: I read that poem in Abu Dhabi, actually, to an audience, few of whom knew baseball, so I sort of had to explain it to an audience of oncology professionals. I might have missed my mark, I don't know, but I wanted them to understand certainly the importance of entering patients' lives. Dr. Lidia Schapira: Have you always felt this way about using narrative and poetry as a means of reflection, self-expression, and dialogue? Or is it something you came to later in your life as a more mature professional? Dr. Barry Meisenberg: Definitely the latter. I mean, I was fortunate in that I had good cultural capital growing up, but I didn't really incorporate it into my other life, my professional life until I'd say the last 10 years or 15. I've always been an admirer of Shakespeare, by the way, he wrote about the plague a little bit too, indirectly. And then one time I actually wrote an essay about this: I was given a poem by a patient, who was from Ireland and this is sort of like the national poet of Ireland. And it was his way of telling me, he didn't want any treatment. And the poem is about loss and lamentation that accumulates through life, and all his friends were in the graveyard. He wasn't interested in therapies that are designed to induce a response rate. He didn't want any treatment. The way he communicated that was through a poem. And I began to understand that really in a more realistic way that poem can do that. Dr. Lidia Schapira: Well, thank you so much for your insights. It's been a wonderful conversation. Is there something else you would like to tell our listeners and perhaps even a thought for future readers of the poem? Dr. Barry Meisenberg: By the way, I should say that the name of that poem I just referred to is called “Oft, in a Stilly Night”. It's the first line of an Irish folk song. But I would hope people take the time to indulge. Many medical journals have sections like this, they're usually short. And I will tell you, that's the first thing I read in these medical journals. I hope people will follow that pattern. Dr. Lidia Schapira: Thank you so much, Barry. It's been a lovely conversation. Thank you for your work, and thanks to the readers. And more next episode of Art of Oncology. Until next time, thank you for listening to this JCOs Cancer Stories: The Art of Oncology Podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCOs Cancer Stories: The Art of Oncology Podcast. This is just one of many ASCOs podcasts. You can find all of the shows at podcast.asco.org.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product or service organization, activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Fabrice André from Institute Gustave Roussy in Paris, France, and Dr. Komal Jhaveri from Memorial Sloan Kettering Cancer Center in New York, NY, authors on “Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update.” This updated guideline provides precise guidelines on previously endorsed genomic assays and recommendations on the use of new biomarkers to guide endocrine therapy and chemotherapy in patients with ER-positive HER2-negative tumors, and for those with HER2-positive or triple-negative breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Fabrice André from Institut Gustave Roussy in Paris, France, and Dr. Komal Jhaveri from Memorial Sloan Kettering Cancer Center in New York, NY, authors on “Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update.” Thank you for being here Dr. André and Dr. Jhaveri. Dr. Fabrice André and Dr. Komal Jhaveri: Thank you. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of guidelines and ensuring that the ASCO conflict of interest policies follow each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. André, do you have any relevant disclosures that are directly related to this guideline. Dr. Fabrice André: No. Brittany Harvey: Thank you. And Dr. Jhaveri, do you have any relevant disclosures that are related to this guideline topic? Dr. Komal Jhaveri: No. Brittany Harvey: Great, then let's talk about the content of this guideline update. So, Dr. Jhaveri, what prompted the update to the biomarkers for adjuvant endocrine therapy and chemotherapy in early-stage breast cancer, and what is the scope of this guideline update? Dr. Komal Jhaveri: So, since the biomarker guideline published in 2016, there were several new publications that came out between January 2016 and October 2021 that provided perspectives on the use of some of the genomic assays broadly, or specifically in women based on menopausal status, age or number of lymph nodes. Additionally, new biomarkers such as programmed cell death receptor ligand 1 or PD-L1, stromal TILs, circulating tumor DNA, or circulating tumor cells, or new applications, like extended endocrine therapy have also been developed. So, this updated guideline provides precise guidelines on previously endorsed genomic assays and also provides recommendations on the use of new biomarkers to guide endocrine therapy and chemotherapy in ER-positive HER2-negative, HER2-positive, and triple negative breast cancer. Brittany Harvey: Great. Thank you for setting the stage for this guideline. So, then Dr. André, I'd like to review the key recommendations of the guideline for our listeners. So, starting with, which biomarkers should be used to guide decisions on adjuvant endocrine and chemotherapy for patients with newly diagnosed ER-positive HER2-negative breast cancer? Dr. Fabrice André: Thank you. So, when we are focusing on a newly diagnosed patient with ER-positivity HER-2 negative in the context of the question about deciding on chemotherapy. First, the 21 gene recurrence score should be used in patients with node-negative and in patients with 1-3 node positive who are postmenopausal. In premenopausal, this test will be used only in patients with node-negative. The second test that is recommended is the MammaPrint 70-gene signature. And here the recommendation is to use this test if the patient is older than 50 and is node-negative or 1-3 node-positive. If the patient is 50 years or younger, the clinician should not use this test. Then also a recommendation is that the clinician could use the 12 gene risk score EndoPredict if the patient is postmenopausal and has breast cancer node negative or 1-3 positive-node. And finally, for the genomic test for the patient, the doctor could use PAM50. If the patient is postmenopausal and has breast cancer that is node-negative. Something new in this recommendation is the recommendation that the clinician could use Ki67. If the patient is postmenopausal and has stage I-II breast cancer with very specific recommendations on the cut off for positivity. Brittany Harvey: Great. Thank you for reviewing those recommendations, Dr. André, and highlighting the new Ki67. So, then, in your introduction, Dr. Jhaveri, you discuss the application of assays for extended endocrine therapy. So, which biomarkers should be used to guide decisions regarding extended endocrine therapy for patients with ER-positive HER2-negative breast cancer? Dr. Komal Jhaveri: Thank you. So, a quick word about extended endocrine therapy. I think extended adjuvant endocrine therapy, which is beyond five years of primary endocrine therapy, has certainly demonstrated improved outcomes, however, with modest absolute benefit and added toxicity and tolerability issues. Furthermore, while extended endocrine therapy is endorsed by clinical practice guidelines, clear guidance on individualized approaches to optimize patient selection for prolonged endocrine regimens, also remains limited. And this really underscores the need for prognostic and predictive information from genomic assays that can help guide this important clinical question we face. One such example that has now borne out has been the breast cancer index and really collected evidence from now five studies supports the prognostic and predictive utility of this assay, such that if a patient has node-negative or one to three positive nodes, and has been treated with five years of primary endocrine therapy, to guide decisions about extended endocrine therapy, the clinician may offer Breast Cancer Index with either tamoxifen or aromatase inhibitors or tamoxifen, followed by an aromatase inhibitor. Brittany Harvey: Great, thank you, Dr. Jhaveri. So, then, Dr. André, which biomarkers should be used to guide decisions on adjuvant therapy for early-stage HER2-positive breast cancer or triple-negative breast cancer? Dr. Fabrice André: Well, first, we have to be sure that we are good at defining HER2-positive breast cancer and triple-negative breast cancer. So, it's always good to remind colleagues to have quality control assessment in place for HER2, estrogen receptor, and progesterone receptor stainings. So far, when it's about predicting the benefit of adjuvant chemo or trastuzumab, there is no genomic test that is recommended in patients with HER2-positive or triple-negative breast cancer. Brittany Harvey: Great, thank you. So, then, Dr. Jhaveri, what recommendations did the expert panel make regarding emerging biomarkers? Dr. Komal Jhaveri: When we're talking about emerging biomarkers, we're referring to stromal TILs, we're referring to PD-L1, circulating tumor cells, and circulating tumor DNA. And while there is a lot of emerging data, currently, clinicians should not be utilizing these new biomarkers to guide decisions about adjuvant endocrine therapy or chemotherapy, as we do not have sufficient evidence to support their use. Brittany Harvey: Great and that's important for clinicians to know. So, then finally, Dr. André, in your view, how will these updated guideline recommendations impact both clinicians and patients? Dr. Fabrice André: So, we know Komal mentioned this at the beginning that now there is a very large amount of new publications, new data coming every day in the field of cancer. So, the only way for clinicians to deliver the best treatments for patients is to have the right guidelines with the right methodology, and ASCO is really putting in place a very rigorous methodology to deliver guidelines. And this is the best way to be sure that all patients will have access to the best decision by the doctor. So guidelines are also here to decrease the disparities in terms of the expert decision, and any patient in the world can have access to the best decision, thanks to guidelines delivered by ASCO and all the colleagues of the panel that worked very hard to deliver these guidelines. Brittany Harvey: Excellent! Well, thank you both so much, and the entire expert panel for your work to update these guidelines, and for taking the time to speak with me today, Dr. André and Dr. Jhaveri. Dr. Komal Jhaveri: Thank you. Dr. Fabrice André: Thank you, Brittany. Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines in interactive resources in the free ASCO guidelines app available in iTunes or Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO the mention of any product or service organization activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Lisa Carey from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, NC, panel member on “Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk, Early-stage Triple Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update.” Dr. Carey discusses the updated recommendation on the use of pembrolizumab for patients with T1cN1-2 or T2-4N0 (stage II or III), early-stage triple negative breast cancer. For more information, visit, www.asco.org/breast-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Lisa Carey from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, expert panel member on Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk Early-stage Triple-negative Breast Cancer: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Carey. Dr. Lisa Carey: It's a pleasure to be here, Brittany. Thank you! Brittany Harvey: Great! First, I like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Carey, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Lisa Carey: I do not. Brittany Harvey: Thank you. Then what prompted this rapid update to the Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline, which was last published in 2021? Dr. Lisa Carey: You know, what prompted it where there were a number of changes that had come out, particularly things like the use of immune checkpoint inhibitors, and the adoption of the neoadjuvant strategy that really made us feel that these were overdue for practice guidelines. And in particular, there were some very important changes that came out early this year, particularly with the pembrolizumab use. Dr. Brittany Harvey: Great, so, based on these changes in the pembrolizumab use, what is the updated recommendation from the guideline panel? Dr. Lisa Carey: The recommendation actually is for patients who fulfilled the KEYNOTE-522 trial criteria. KEYNOTE-522 was a seminal trial in early triple-negative breast cancer, meaning, treatment-naive of the use of pembrolizumab incorporated into a chemotherapy-based regimen given neoadjuvantly, and then with the continuation of the immune checkpoint inhibitor pembrolizumab adjuvantly. This was important because we had been using, for a couple of years now, immune checkpoint inhibitors in PD-L1 positive or immune-activated triple-negative breast cancers in the metastatic setting. But we had not had evidence of improved survival or outcomes in early triple-negative breast cancer, so that's where KEYNOTE-522 comes in. This was a trial in which patients with early untreated triple-negative breast cancer, who fulfilled at least greater than T1N0, - and I want to make that pretty clear, this is a pretty broad net for early triple-negative breast cancer; the vast majority of triple negatives will be eligible for this treatment based on the population that was studied - and they receive four chemotherapy drugs, so, a taxane plus platinum, followed by an anthracycline-based regimen, either with or without pembrolizumab throughout the entire neoadjuvant course. They then went to surgery, and then they went on to receive adjuvant for another nine cycles, adjuvant pembrolizumab. The trial had already reported an improvement in pathologic complete response with the addition of the immune checkpoint inhibitor, which has also been seen with other immune checkpoint inhibitors. But what was reported a few months ago, and then published early this year, was the impact on event-free survival. So, there was a statistically significant improvement in event-free survival with the addition of pembrolizumab, which, at that point, it's a highly clinically meaningful endpoint, there are now two highly clinically meaningful endpoints. Both of these were the primary endpoints of this study. And so, it has rapidly been adopted on that basis for use and we felt because of that it needed to be addressed in a rapid update for helping clinicians interpret the data and use them effectively. Brittany Harvey: Understood, and I appreciate your work and the panel's work to rapidly interpret this data. So then, what should clinicians know as they implement this recommendation for the use of pembrolizumab? Dr. Lisa Carey: I think the key elements are unlike the metastatic setting, there's really no role for PD-L1 testing in the early triple-negative setting because the pembrolizumab seemed to improve outcomes regardless of PD-L1 status, which is a big difference from what's true in the metastatic setting where all of these immune checkpoint inhibitors seem to only benefit patients that are PD-L1 positive. So, it's kind of regardless of PD-L1 status. It's also true that in the KEYNOTE-522 study when they did do PD-L1 testing, most early triple negatives are PD-L1 positive. There really wasn't a subset of patients in the trial. And again, this is T2 or greater in tumor size or node-positive, who didn't seem to benefit from it. So, it's a pretty broad recommendation. The 'however' is that, as we all know at this point, when you add immune-directed therapies, you have a different set of toxicities you have to be aware of, specifically what they call immune-related adverse events or irAEs, which are, of course, essentially autoimmune. The thing that you have to remember is these can be permanent. These are frequently glandular disorders. Typically things like thyroid disease, which can be handled with replacement, but you can sometimes have colitis, myositis of different kinds, pneumonitis, and things like that. And some of these can be permanent. So, they have to be monitored very carefully. And ASCO has a guideline for managing irAEs and patients treated with immune checkpoint inhibitors - because again, we use these in lots of tumor types - that gives a lot of detailed practice recommendations, that clinicians should really consult frequently, not just in triple-negative, but in other disease types that we use these drugs. Brittany Harvey: Great. Thanks for explaining that aspect of the guideline. So then, you just mentioned that this recommendation is broadly applicable to many patients with early-stage triple-negative breast cancer. So, how will these guideline recommendations impact patients with early-stage triple-negative breast cancer? Dr. Lisa Carey: Well, it means that it's a totally new game. So, as you are evaluating a patient, first off, virtually all of these are treated neoadjuvantly now, except for the T1N0s, and pembrolizumab and the addition of pembrolizumab should be considered in all of them. Again, if they have, particularly organ-threatening autoimmune disorders themselves, they are a poor choice for these drugs, but otherwise, it should at least be considered. It's also true that there's been for many years a debate about the optimal chemotherapy to give in triple-negative breast cancer in the backbone that was used to which pembro was added had four drugs in it. And I think for that reason, that is considered the standard of care now. I do think one of the challenges for us moving forward is to decide if we need all of those drugs or not. I think a challenge for us also is to figure out who actually benefits from, again, these are five drugs, you know, a lot of therapy, a fair amount of toxicity. And so, I think that's a challenge going forward. Brittany Harvey: Thank you. And then finally, you just mentioned a couple of upcoming challenges, including the debate about the optimal chemotherapy regimen. But what are the outstanding questions regarding neoadjuvant therapy for patients with breast cancer? Dr. Lisa Carey: I think the outstanding questions regarding neoadjuvant therapy are one thing. I think neoadjuvant therapy, there isn't a lot of outstanding questions that are medically related other than what's the right backbone and things like that, because I think the neoadjuvant paradigm, if you're just purely talking about whether you're giving drugs before or after surgery, the drugs themselves tend to be the same because the key endpoint for the medical oncologist and for the patient, of course, is their outcome from a relapse standpoint. But it's also true that the neoadjuvant approach allows tailoring of the medical therapy. Like, in the past before we had immune checkpoint inhibitors, patients who received chemotherapy and had residual disease would get additional chemotherapy. That wasn't allowed in the KEYNOTE study. So, I think many people, because patients with residual disease in KEYNOTE, still had pretty poor outcomes are incorporating additional chemotherapy, specifically adjuvant capecitabine with the pembrolizumab, but there's no data for that. So, I think that's a challenge that we do have to address. I think the other challenge is simply surgical management: whether we can use these improved pathologic response and clinical response outcomes to minimize some of the local therapies, in addition to tailoring the medical therapies. Brittany Harvey: Great! Well, we look forward to maybe tackling some of these challenges when we have more data in upcoming guidelines. I want to thank you so much for your time to rapidly update these guideline recommendations and for your time speaking with me today, Dr. Carey. Dr. Lisa Carey: It's my pleasure. Thank you so much, Brittany. Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product service organization activity or therapy should not be construed as an ASCO endorsement.

"Wall Street doesn't believe in this target," by Dario Altieri. A scientist shares his 12-year journey that led to the discovery of a drug now in clinic.   TRANSCRIPT Narrator: Wall Street Doesn't Believe in This Target by Dario C. Altieri, MD (10.1200/JCO.22.00180) March 2, 2009. Just published in the Journal of Clinical Investigation.1 And we even got the cover. Twists and turns of heat shock protein-90 (Hsp90), the chaperone, the evolutionary capacitor. Great name and important cancer target. People smiled when I talked about this at the Hsp90 conference. No, no, really there is a lot of it in mitochondria, and only in mitochondria of tumor cells. And, I don't know why, but Hsp90 drugs don't touch it: somehow, they don't get to mitochondria. So, I made my own. Took an old Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin and attached it to triphenylphosphonium, a carrier that basically gets anything into the mitochondria. No, of course, I didn't do the synthesis in my laboratory. What do I know about medicinal chemistry? Outsourced it. Like sneakers and sweaters. And after three months, there it was: an Hsp90 inhibitor that only goes to the mitochondria, causes aggregation of a lot of proteins, and kills tumor cells in minutes. Makes sense, right? Mitochondria must control protein folding, especially in cancer, and they do it with chaperones. Inhibit the process and tumor cells can't cope. Normal cells don't seem to mind. So, strong preclinical activity, and against a lot of different tumor types. Better than any other Hsp90 inhibitor. Good safety. Totally different mechanism of action. And even a cool name, Gamitrinib. Tired of curing mice. What if this were to work in people? Ideas are made in academia; drugs are made in companies. Okay, fine, then I'll launch a startup, spinout, whatever they are called. The (former) doctor-turned scientist now turns entrepreneur, and then captain of industry. Problem is, I am not like that. More like an (aged) boy scout. The inner soapbox says: it belongs to the American taxpayers; they funded it; it's theirs. Excellent start. What else? If doctors and scientists become businessmen (or businesswomen), who will take care of humanity and discover new things? Perfect for a campaign ad. Sold. Bring it to the patients solely from academia: no pharma, no biotech, no investors, no nothing. Soapbox meme for the day: Yes, we can. It's going to cost. So? I'll write a grant, that's what I do for a living anyway. And the fact that I know zero about drug discovery? Or drug development? Laboratory-Clinical Transition Award from the Department of Defense. Great title. Three years of funding. Perfect for me. Pass-through money, nothing for the laboratory, but it pays the bills of outsourcing. First things first. Synthesize Good Laboratory Practice (GLP) Gamitrinib. Already getting a pretty good hang on the acronyms. Hey, we made this drug lots of times before and has never taken this long. It's almost a year and counting. The Department of Defense (DoD) is on my case because I am already behind. What's going on? Yes, I understand that we don't make anything in this country anymore. New import permits that need to clear the Indian government? The what? This is just a chemical, not an international incident. Yes, I get it, nothing I can do about it. My new job is mailman. And telephone operator. Finally shipped the GLP drug for the toxicology. Two animal species, says the US Food and Drug Administration (FDA). Rats and dogs sound good to me. Should I feel sorry for the dogs? Rats not so much. But what if Gamitrinib poisons the mitochondria in the brains? Or hearts? Wait, you said it's just perfect? Animals are doing great, all of them. And no toxicity at all, like giving them…water. Wow, that's some news. Feeling quite pleased with myself. See? I said it all along: mitochondria are wired differently in cancer. That's why the drug is safe for normal tissues. Maybe I should write a review article about that. Serious boost of the citation index. I am sorry, what? Yes, of course I know that the drug is purple. Okay, you filtered it before giving it to the animals and instead of purple it turned white? And you did that to all animals. For the entire time. Oh, what do I think it means? I think it means that you filtered out the drug and we have been giving animals…water. Yes, I get it. I need a new formulation. And start over. Note to self: find a new Contract Research Organization (CRO) that doesn't give water to the animals. Formulation experts. Big pharma ex-pats who now have their own CRO. Everybody is an entrepreneur here. Is this drug oral? Nope. Is it soluble in water? Not at all. So, it's an intravenous (IV) infusion? Yes, that's what it is. Sorry, then it's not a drug. It's not? And what about things like, you know, paclitaxel or doxorubicin? Aren't they also insoluble and given IV? Last time I checked, we used them for half a century and saved millions. Oh, now we think differently? I see, Fail Fast: that's how we think now. And mine, whatever it is if it is not a drug, has already failed. Nobody likes to take risks. Soapbox meme for the day: If nobody takes risks, how do we make progress, exactly? So, maybe I am in good company: paclitaxel and doxorubicin would also Fail Fast today. It's doable. Nobody likes it but it's doable. Sterile-filter the emulsion components and then bring the particle size below 200 nm. Nice. How do I do that? With a microfluidizer. And why nobody likes it? Oh, because the microfluidizer is a dirty machine and where you make Good Manufacturing Practice is called a clean room. Impeccable logic. But a place in California may do it. For a fee, of course. Oh, and you have to buy the machine. Buy what? Or lease it, whatever. People may not like it, but the whole thing works like a charm. Except, of course, when the microfluidizer stops for no reason in the middle of the run. Media fill looks good. Drug is stable for months in the new formulation. Release testing coming together nicely. I am running out of money. Burned through not just one but two DoD grants and all my research kitty. Nothing saved for the swim back: talk about risk-taking. At least the repeat toxicology is paid for and looks good. The drug, the real thing this time, is safe. They even did ECGs on the dogs. Thank goodness I didn't have to read those, but they are normal: no QTc liability. Can't drop the ball now, but I really need money. Here is how you do it: silence the inner soapbox and enchant the big pharma suits that are coming over. Use the right words. It's not early stage anymore. Asset totally derisked. Sure it's ready for prime time. It works. I am a natural. Maybe I should have done this before. A lot of nodding around the table. The suits must be in awe with the great pharmacokinetics, long half-life, and fabulous safety. A hand goes up. I am sorry? Sales data? Sales of what? What is the unit price? No, no, no, we are not there yet. I haven't even filed an Investigational New Drug (IND) application. Something different now. Analysts who advise big-time investors. They don't wear suits. Sweaters for sure. Maybe black tees a la Steve Jobs. They like new things and totally live by risks. Sounds like my crowd. And don't forget, they can get tons of money from people who already have tons of money and want to make even more money. My crowd? Voices out of a polyphone. Yes, it is Hsp90. Yeah, the chaperone. Sure, I know, it has been around for a long time. But this is a completely new story: nobody ever tested a cancer drug that goes to a subcellular organelle: that's really where the action is. Yes, Hsp90. And mitochondria, they used to be bacteria two and a half billion years ago, but they turned out to be important in cancer. I know that too, Hsp90 drugs didn't fare well in the clinic. Lot of toxicity, basically no efficacy. Yes, very unfortunate. But this one has a completely different mechan…Sure, I would like to hear that perspective. I am sorry, did you say, Wall Street doesn't believe in this target? Triaged the first time but funded on the resubmission. Could have been worse. This one is a grant from the National Cancer Institute. And a nice award from the Gateway Foundation is coming too. Enough to pay for the clinical trial. Single site, standard phase I. Accelerated dose escalation. Up to 35 patients with advanced cancer. All comers. Drug vials ready to go. And a fantastic clinical investigator to run the trial. You really don't want me in the clinic. The only thing missing is IND approval. Right, there is that. No, not a commercial IND, investigator-initiated IND, thank you very much. The FDA people are the nicest in the world. Super-helpful, don't believe otherwise. Or maybe they just feel sorry for the clueless applicant. Thirty days to respond to the questions. Totally getting a promotion to a higher rank of telephone operator. And publisher of FDA modules. And certifier of United States Pharmacopeia (USP) . recommendations. And fixer of Chemistry, Manufacturing, and Controls deficiencies. Oh, and let's not forget the specs for polytetrafluoroethylene filters. Then the examiner mutters two words at the end of a phone call. Good luck. Then, nothing. No more questions, e-mails, or phone calls. Right on the thirty-day mark. Were you expecting this? It's a letter; it says study may proceed. What would the day look like? The first patient to be dosed. Maybe I should go to the clinic: it's in town, not far from where I am. I don't think I can pass muster as one of those confidence-inspiring docs in pharma ads. But I do well as chief executive officer. The cufflinks look good, and so do the shoes. I can impress the family. My Italian accent can pass as straight from South Philly, so I have that also going for me. And I can more than hold my own if I need to talk about Philadelphia Eagles football and worries with Jalen Hurts' arm for next season. I used to be good with my patients. Or at least I convinced myself of that. Yes, this is an experimental drug straight out of our backyard, right here in Philadelphia. No, I don't know if it will work, but I sure hope it will. And thank you, thank you so much for being part of the trial. What if I make these people even sicker than they are? I took an oath a long time ago. Anyway, I know the literature on phase I studies, chances are it just won't do anything, so nobody gets hurt and I am finally done with it. I never thought this moment would arrive. There is none of that. January 10, 2022. It's just a late-night e-mail on the anniversary of my mom passing from lung cancer. Hey, the first patient did great at the starting dose of Gamitrinib. No problem whatsoever. The next patient will now get twice the dose. I hope we get that started this month. Happy new year. And that was that. Twelve years, 10 months, and nine days from that Journal of Clinical Investigation paper.1 Affiliation: 1The Wistar Institute, Philadelphia, PA Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology. I'm Lidia Schapira, Associate Editor for Art of Oncology, and Professor of Medicine at Stanford University. And I'll be the host of this show. Cancer Stories is brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows including this one at podcast.asco.org. With me today is Dr. Dario Altieri, president, and CEO at the Wister Institute. We'll be discussing his Art of Oncology article: Wall Street Doesn't Believe in This Target. Our guest is a named inventor for patent number 2,699,794. Titled: Mitochondria Targeted Anti-Tumor Agents. Dario, welcome to our podcast. Dr. Dario Altieri: Thank you so much for having me, Lidia. It's a great privilege. Dr. Lidia Schapira: My first question to you and to our authors is this, people who enjoy writing are usually also readers, what are you reading now? Dr. Dario Altieri: Well, absolutely it has been a passion of mine since the floods. I am an absolute avid reader of novels, and history, in particular, contemporary history and modern history. Those are my favorite topics. Dr. Lidia Schapira: Do you read in English, Italian, or other languages? Dr. Dario Altieri: I typically read in English, even though some of the Italian literature is best read in the native tongue. And so, I am still attached to that. Dr. Lidia Schapira: You're clearly a very accomplished scientist. But tell me a little bit about your writing in this particular area in what I'll call creative nonfiction. How has this writing helped you perhaps process experiences or communicate with others? Dr. Dario Atieri: It has been, it's been a passion of mine for a very long time, I think. In finishing up college, of course, my major was contemporary literature and philosophy. The question was whether to continue on in a classic literature career or go to medical school, probably the wrong choice was made. But it has remained with me for a very long time, and it's a form of expression that I truly enjoy. In writing, this particular contribution was a bit transformative for me. It doesn't happen every time that you write a scientific article to express a little bit about yourself and your passions and dreams. Dr. Lidia Schapira: Let's talk a little bit about your passions and dreams in this article. You described an intensely personal journey of 12 years that led to the discovery or the availability of this drug now in the clinic. When did you think that you wanted to share this story with your colleagues? And tell me a little bit about the process of writing this article? Dr. Dario Altieri: It has certainly been a roller coaster experience. I would like to describe it as life-defining and life-changing. I've learned so much and so many things, not just about the process, but also a little bit about myself. I recognize reaching the clinic, especially in a phase one trial, is really just the beginning. But for me, as a basic scientist, somebody who has seen his last patient in the 13th century. As a basic scientist, that was a little bit of a milestone, and I wanted to share what it took, the experiences that I lived through, especially with our youngest colleagues, scientists, and doctors, starting their own careers in oncology, whether it's basic research, clinical research, translational research, I really don't think it matters. And so, issues of resilience, staying the course, passion, and not really giving up are the parameters that I had hoped to convey with this contribution. Dr. Lidia Schapira: In your article, I was so impressed by how you used humor, often self-deprecating humor, and the particular narrative style and writing style that you chose and defended as you were revising it. You know, this choppy phrasing, a staccato, and you said, this is what it feels like, how can I pack it into a small number of words and describe it all? Tell us a little bit about how you allowed your imagination to take over and how you found the proper voice and style for this particular narrative. Dr. Dario Altieri: Again, it's been a thrilling experience and it's been a thrilling experience to answer to the editors and the reviewers of the JCO, who provided incredible insightful comments. The challenge was, how do I tell a story without sounding obvious, fright, or expected, and more importantly, without sounding boring? And I think to paraphrase one of our reviewers about this journey. What the reviewer said, the author, that would be me, has encountered many of the absurdities of the path in drug development, something that we don't talk about too much because it's been the realm of a drug company for the longest time. And so, I wanted to try to capture that absurdity in a positive way. Things that the reviewer indicated, may be second nature to the pharmaceutical industry, but for academic investigators, that's been publicly funded for 30 years, is not second nature and is unusual, and is a world all in itself. And so, that was the impetus of trying to use literature advice on short sentences that are really intended to convey the impression of the moment that was what I tried to accomplish. Dr. Lidia Schapira: Well, you certainly picked a catchy title, and we have not published this sort of article in Art of Oncology before. For our listeners, tell us a little bit about why Wall Street doesn't care about your discovery? Dr. Dario Altieri: Unfortunately, I think, I mean, I don't know for sure. But I think that dealing with this particular molecule, heat shock protein 90 in the clinic has been difficult. Hsp90 has long been recognized as an important cancer target. There have been several generations of small molecule inhibitors that have been tested in the clinic. And unfortunately, I hope I'm not offending anybody, but unfortunately, the clinical results of those studies, and some of them moved all the way to really large phase two trials have been disappointing. And so, that is the idea that perhaps this was a dead target. And therefore, trying to leverage industry or biotechnology interest around it was quite a remarkable challenge. Dr. Lidia Schapira: What message do you want the young investigators to take away from your story in terms of the collaboration between academia where thoughts start, as you say, in your article, and all of the rest of the partners that you actually need it to bring this discovery and this idea to fruition? Dr. Dario Altieri: Lydia, this may sound trite, I really hope to convey one simple notion. It's not even a message, it's a very personal account. And that is don't give up. If you have run the controls. If you have done your experiments enough time. If you're convinced of the results, if you explore alternative explanations, and you keep coming back to the same conclusions, go for it. That has been a little bit of my own personal experience and if there are things that you don't know about, that's perfectly fine. Actually, that is the fun of the process, and the things that I didn't know about drug development, I can fill in the encyclopedia. I've learned some of them through people who have been doing this for a living, for a very long time. And that has been truly inspiring for me, a life lesson and professional lesson about how we can think of a drug target that has been discounted and remain true to the core value of strong basic research and try to advance that to the clinic, whether this will ever become something useful for our patients? I don't have the faintest idea. I certainly hope so. But that would be the experiment that is being done right now in the clinic. Dr. Lidia Schapira: In your article towards the end, you just give us two little glimpses into something that is personal and meaningful to you by telling us that there's an anniversary of a loss, the passing of your mother from cancer. Can you tell us a little bit more about that, and why you chose to put that sentence just where you did? Dr. Dario Altieri: I didn't know if anybody would have noticed, frankly, so I appreciate you bringing it up, Lidia. It's been a very personal journey for me as well. Both my parents died of lung cancer. They were a different generation. Both were heavy smokers. I remember those dates very well and I remember the void that they're passing is created. And so, I thought it was an interesting circumstance, that in fact, the first patient was enrolled in a clinical trial, the notion about that and of course, I am technically conflicted. So, I am not supposed to know anything about what is happening in the clinic. But it was interesting that the first notion about the first dosing came on that day, on January 10. Dr. Lidia Schapira: Well, I'm sure other readers will notice that too, the timing of that in the article and the fact that there was some emotion implied, I think, in how you chose to end your story by saying that this had happened in the clinic, but somehow, you were not there, that you had to be removed. Tell us a little bit more about that, about why you needed to be removed from the clinical site and why do you talk about yourself as a former doctor? In my mind, once you are you always are, but somehow you feel that you need to make the distinction. What does it all mean to you? Dr. Dario Altieri: Well, Lidia, let me just say you don't want me in the clinic right now. At 64years of age, like I said that the last patient was a very long time ago. I have to say, sometimes I miss those days, just as a personal account. I need to be removed because I'm technically conflicted on the trial, I was the IND holder, and then the FDA asked me to transfer the IND to the clinical investigator as proper because I'm not involved in patient care or research, in this particular case. And technically, because I am the inventor on a patent, I could potentially stand to benefit financially from the results of the trial, something that is certainly not on my mind, but that I have been reminded of. And so, I try to stay away as much as I can. Obviously, I think about this every day. But whatever information I can gain, that I can gather from my colleagues across town will be wonderful, but I'm not the one initiating those calls. Dr. Lidia Schapira: So back to the humorous side of your essay, you say that you've learned to be a telephone operator and a mailman, and a whole bunch of other things. Have those lessons been useful to the other aspects of your life? Or do you see that as a total waste of your time? Dr. Dario Altieri: Not at all. Not at all. I have been an incredible component and I think I was trying to be humorous and to take myself seriously, but not too seriously. But in fact, maintaining that level of interaction, particularly with aspects of the work that I've never encountered, for instance, regulatory aspects of an early-stage clinical trial with the Food and Drug Administration, that has been part of the life journey and I only have very good things to say about my experience. You know, it's been interesting, Lidia, being part of the experience of being a telephone operator and a mailman. I had this sense, and I could be completely wrong, but I had this sense that people out there want to see us taking small risks. They want to see testing new drugs, they want to see new targets being somehow examined, developed, if at all possible. I had the sense that there was support, you know, for the idea, and this was an entirely publicly funded program. I funded both the preclinical and now the clinical trial of Gamitrinib out of the American taxpayer's commitment and in many different study sections, in dealing with the FDA, in dealing with other regulatory consultants, I always get the sense people who wanted to help, then had perhaps the mindset, okay, we don't know whether this is going to work or not but let's give it a try. Let's give it a shot. It was wonderful, that was an absolutely awe-inspiring experience. Dr. Lidia Schapira: I'm glad they did and I'm glad you shared your experience with all of us. Is there something else that you'd like our listeners or your readers to know about you or this story? Dr. Dario Altieri: I just would like to say that I would do it again, 12 years, I would do every step of the way but I think I'm done. If I were to start over, I'll do it again, but I don't think I'm ready to do it again with another target. Dr. Lidia Schapira: And with that, I want to thank you and I want to thank our listeners. Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories: The Art of Oncology podcast. This is just one of many of ASCO's podcasts. You can find all of the shows at the podcast.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product or service organization activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Linus Chuang from Danbury Hospital and Norwalk Hospital, Nuvance Health in Connecticut and New York, co-chair on “Management and Care of Patients with Invasive Cervical Cancer: ASCO Resource-Stratified Guideline Rapid Recommendation Update.” Dr. Chuang discusses the updated recommendation on the use of pembrolizumab in patients with persistent, recurrent, or metastatic cervical carcinoma, based on the results from the KEYNOTE-826 study. For more information, visit, www.asco.org/resource-stratified-guidelines. Transcript BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Linus Chuang from Danbury Hospital in Norwalk Hospital, Nuvance Health, in Connecticut and New York, Co-Chair on "Management and Care of Patients with Invasive Cervical Cancer-- ASCO Resource-Stratified Guideline Rapid Recommendation Update." Thank you for being here, Dr. Chuang. LINUS CHUANG: Thank you for having me. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline is available online with a publication in the Journal of Clinical Oncology Global Oncology. Dr. Chuang, do you have any relevant disclosures that are directly related to this guideline topic? LINUS CHUANG: No, Brittany. BRITTANY HARVEY: Thank you. Then talking about the content of this publication, so what prompted this rapid update to the "Management and Care of Patients with Invasive Cervical Cancer-- ASCO Resource-Stratified Clinical Practice Guideline," last published in 2016? LINUS CHUANG: ASCO Rapid Recommendations Updates highlight revisions to ASCO guideline recommendations on "Management and Care of Women with Invasive Cervical Cancer, the ASCO Resource-Stratified Clinical Practice Guideline" that was published in September of 2016. We revised the guidelines to reflect new and practice-changing data on the use of pembrolizumab combination therapy in patients with metastatic, recurrent, or persistent cervical cancer in enhanced and maximal settings. BRITTANY HARVEY: Great. Then based off this new data for the pembrolizumab combination therapy, what are the updated recommendations from the guideline panel? LINUS CHUANG: Based on this recently published report about the KEYNOTE-826 study, the checkpoint inhibitor pembrolizumab alongside standard chemotherapy with or without bevacizumab as first-line therapy significantly improved the overall and progression-free survival in patients with persistent, recurrent, or metastatic PD-L1 expressing cervical cancer. BRITTANY HARVEY: Great. Thank you for providing that recommendation. So what should clinicians know as they implement these recommendations, and for which settings do these recommendations apply? LINUS CHUANG: This trial included 617 patients, pembrolizumab 200 milligrams delivered intravenously every three weeks in combination with standard chemotherapy and with or without bevacizumab for up to 35 cycles. It's worth emphasizing based on the following study results the median progression-free survival was 2.2 months longer in the pembrolizumab group that have a PD-L1 combined positive score of 1 or more. And the progression-free survival at 12 months was also longer by 20% in the pembrolizumab group when compared to the placebo group. The overall survival rate at 12 and 24 months were higher in the pembrolizumab group-- 75% and 53% respectively-- compared with the placebo cohort-- 63% and 41% respectively. According to the study, the most common adverse reactions, which occur in more than one in five patients in the pembrolizumab group, are anemia, neutropenia, alopecia, and peripheral neuropathy. Based on this data our rapid communication recommended this regimen be used in the enhanced and maximal settings where the pembrolizumab is available. BRITTANY HARVEY: Great. Thank you for reviewing that data in the context of this recommendation. So how will these guideline recommendations impact patients? LINUS CHUANG: So pembrolizumab with the standard chemotherapy with or without bevacizumab demonstrated improvement in the progression-free and overall survival much longer than those without the pembrolizumab group. And this has emerged as a front-line therapy for the group of patients that have persistent, recurrent, or metastatic cervical cancer with PD-L1 expression cervical cancer. BRITTANY HARVEY: OK, thank you. And then finally, what emerging evidence is the panel anticipating regarding treatment of invasive cervical cancer? LINUS CHUANG: This is an exciting time. Exploration of other PD-1 and PD-L1 inhibitors, monotherapy, or as part of combination therapy for cervical cancer will expand the management of patients with recurrent or metastatic cervical cancer that progressed after platinum-based chemotherapy. It is also important to explore the ability of pembrolizumab with chemoradiation with or without concurrent and maintenance pembrolizumab to improve outcomes for patients with high-risk locally advanced cervical cancer. BRITTANY HARVEY: Great. That's very exciting to see that evidence coming to fruition. So I want to thank you so much for your work to rapidly update this guideline and for your time tonight, Dr. Chuang. LINUS CHUANG: Thank you for having me today. BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/resource stratified guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. SPEAKER 3: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. 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. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, Dr. Christopher Flowers covers highlights from the 2021 American Society of Hematology Annual Meeting, held December 11 to 14 in Atlanta, Georgia. He discusses new treatments for diffuse large B-cell lymphoma, advances in immunotherapy, and a session on improving inclusivity in clinical trials. Dr. Flowers is the Chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center and was appointed Division Head ad interim of Cancer Medicine in August 2020. He is also the 2022 Cancer.Net Associate Editor for Lymphoma.   View Dr. Flowers' disclosures at Cancer.Net. Dr. Flowers: Hello. I'm Dr. Christopher Flowers, Chair of the Department of Lymphoma and Myeloma and Interim Division Head for Cancer Medicine at The University of Texas MD Anderson Cancer Center. And it's my pleasure to talk to you today about the highlights from this year's American Society of Hematology meeting. The ASH meeting this year was a very exciting meeting for lymphoma broadly across all of the lymphomas, with particular highlights around diffuse large B-cell lymphoma where there were some changes that may be changes in the standard of care in the year ahead. I was involved in one of these studies, the POLARIX study that I'll spend some time talking about, where I was the North American lead, and I've served as a consultant for Genentech-Roche in the conduct of that study and other studies related to drugs in their portfolio. The other set of studies that I will talk about are the studies around CAR T-cell therapy. And 2 of those studies, Dr. Jason Weston from my institution and MD Anderson were involved with and Dr. Weston was the senior leader on 2 of those 3 studies that I will talk about. So let's first talk about the first line in diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma, as many of you may be aware of, is the most common type of lymphoma and the most common type of aggressive lymphoma. Back in the 1970s and 80s, the standard of care for CHOP therapy was developed. And that through the 90s, through a number of comparisons of clinical trials for chemotherapy, emerged as the de facto standard of care. In early 2000, the drug rituximab, the anti-CD20 antibody therapy, so our first form of immunotherapy, was added to CHOP. And R-CHOP therapy became the standard of care around 2002. And so it's really been about 20 years that that has been the standard of care for all patients or for most patients in the front line for diffuse large B-cell lymphoma. That's not been without challenges. There have been a number of clinical trials from 2002 to the present that have challenged R-CHOP, either by adding new therapies, like new targeted therapies looking at intensifying the CD20 antibody component, adding things like stem cell transplant or intensifying the chemotherapy-- and in some cases, focusing on subsets of diffuse large B-cell lymphoma, like the activated B-cell-like subset that are at poorer outcomes in the general population. However, none of those clinical trials really emerged to change the standard of care. And R-CHOP had remained the standard of care for patients. This year, as one of the late breaking abstracts presented at the American Society of Hematology meeting and followed up by a publication in the New England Journal of Medicine, one of our top premier journals, there was a study that looked at the substitution of vincristine, one of the drugs in CHOP, for the drug polatuzumab vedotin. Polatuzumab vedotin is what we call an antibody-drug conjugate, where that antibody binds to a cell surface marker on the lymphoma cells CD79B. And with that, binding is internalized into the cell. And the conjugate is a form of chemotherapy, MMAE, that is then taken into the cell with the antibody. And that antibody-drug conjugate was substituted for vincristine in the study. In the POLARIX study, it showed that it met its primary endpoint for the study, which was an improvement in progression-free survival, where the patients who got the polatuzumab in their chemotherapy with R-CHP had an improvement in progression-free survival of approximately 26% over the group that got R-CHOP. This is the first time to show an improvement in front-line therapy for patients with diffuse large B-cell lymphoma. And regulatory bodies will be looking at this to see whether this is approved in the first line in the relatively near future. The other major trials that were presented at this year's American Society of Hematology meeting in diffuse large B-cell lymphoma were trials looking at the second line of therapy for patients with diffuse large B-cell lymphoma. And in that second line, for patients who were fit and able, stem cell transplant has formed as standard of care for patients after R-CHOP therapy. As many of you may know, diffuse large B-cell lymphoma is a disease where the goal of treatment is cure. And with that first-line therapy, the therapies that are able to produce benefits in terms of progression-free survival are expected to go on to cure for those patients if those responses are durable in 5 years. Even when patients have relapse after their first-line therapy, there's the potential of cure in the second line. And stem cell transplant has been that curative approach that we've taken for many patients in the past. In this year's ASH meeting, there were 3 trials that compared the concept of moving on, after first-line therapy, to intensive chemotherapy followed by a stem cell transplant or to performing CAR T-cell therapy as that second-line therapy. As some of you may know, CAR T-cell therapy has emerged as really an exciting form of immunotherapy, a cellular therapy, that is approved for patients who are with lymphomas and some leukemias and being explored in other diseases. CAR T-cell therapy is a form of immunotherapy where we actually re-engineer cells. So we take the cells from the patient and then genetically re-engineer those cells so they attack a marker on the cell surface. I talked about CD20 antibody therapy. All of these CAR T-cell therapies are cellular therapies against the marker on the lymphoma cells called CD19. And so in these 3 trials that compared CD19 CAR T-cell therapy versus autologous stem cell transplant, 2 of those trials, 1 presented in the plenary session—and that was one of the ones that Dr. Weston participated in—was a study that showed that there was a benefit in progression-free survival for those patients who received CAR T-cell therapy over the approach to do stem cell transplant as that second-line therapy. There was a second trial, the TRANSFORM trial, that was also presented in one of the oral abstract sessions. That one presented interim analysis of their trial. They also showed a benefit in terms of progression-free survival. And then there was a third trial that was looked at in the late breaking abstract session. That one did not show a benefit for CAR T-cell therapy in that setting, using  tisagenlecleucel as a form of CAR T-cell therapy in that study. And perhaps the reasons why that did not show a benefit or differences in the trial design between those 3 trials, not as many of the patients were able to go on to CAR T-cell therapy in that third trial. And that was really expertly described and compared by Alex Hariri in a discussion of the plenary session. So really, 4 major trials in diffuse large B-cell lymphoma that we expect will change the standard of care. Likewise, there were a number of other exciting new immunotherapies that have been presented at this year's annual meeting, namely studies looking at bispecific antibodies. And so these are antibody-based therapies in a number of different trials that both engage a portion of the lymphoma cell. And then as the other portion of the bispecific, so meaning two, that other portion engages T cells. So it brings T cells into the tumor to be able to attack the lymphoma cells. And so there are a number of exciting therapies that are on the horizon for lymphomas looking at that. And those were also presented at the ASH meeting. The last thing that I'd like to highlight from this year's annual society meeting was a joint session that looked at the role of clinical trials and ways that we can actually improve clinical trial design for patients-- 1, to increase the diversity, equity, and inclusion that we see across clinical trials to make sure that all patients who are eligible are having equal access to trials and being able to participate, but also in terms of being able to modify the eligibility criteria that we use for clinical trials. One of the things that we've explored, particularly for those challenges that I described without advances in the front line for diffuse large B-cell lymphoma in the past, have been that some of the eligibility criteria for our past trials really were not including all the patients who were most likely to benefit from trials. And so Tom Witzig at this year's annual society meeting really presented an outstanding look at the eligibility criteria that we use for lymphoma trials, and trying to be able to address those in ways that help to allow more patients to participate in trials, and those who are most likely to need a trial to be able to benefit from the activities that are engaged in a trial. So I really appreciate all of your attention to this podcast. Exciting meeting this year for the American Society of Hematology Annual Meeting. And lots of things that will come to patients in the near future. And hope to be able to create advances that will help all of you in terms of your quality of life and well-being. So thank you all for your attention. ASCO: Thank you, Dr. Flowers. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. 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. Guests statements on this podcast do not express the opinion of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor Dr. Norah Lynn Henry will discuss new research presented at the 2021 San Antonio Breast Cancer Symposium, held December 7-10. Dr. Henry is an Associate Professor in the University of Michigan's Division of Hematology/Oncology in the Department of Internal Medicine and is the Breast Oncology Disease Lead at the Rogel Cancer Center in Ann Arbor, Michigan. View Dr. Henry's disclosures at Cancer.Net. Dr. Henry: Hi, I'm Dr. Lynn Henry, a breast cancer oncologist from the University of Michigan Rogel Cancer Center. I'm here with exciting updates from the leading international breast cancer meeting, the San Antonio Breast Cancer Symposium, that was recently held in San Antonio, Texas, and online. I have no conflicts of interest for any of the trials that I will talk about. First, I'm going to give a very brief overview of the types of breast cancer, then talk about some research that was presented on both metastatic and early- stage breast cancer. Then to wrap it up, I'm going to mention an interesting study looking at lymphedema. As a reminder, there are multiple kinds of breast cancer. Some breast cancers are called hormone receptor-positive or estrogen receptor-positive, and are stimulated to grow by the hormone estrogen. We treat those cancers with antiestrogen treatments, which block estrogen or lower estrogen levels. Other breast cancers are called HER2-positive. These are often more aggressive cancers, but because they have extra copies of HER2, they often respond to treatments that block HER2. Finally, there are breast cancers that don't have hormone receptors or HER2. These are called triple-negative breast cancers and are also often aggressive cancers. So first, I'm going to talk about treatment for HER2-positive metastatic breast cancer. Many of the treatment regimens that we use for treating patients with HER2-positive breast cancer include the antibody trastuzumab, which is also called herceptin. More recently, 2 drugs have been approved that include trastuzumab linked to a chemotherapy drug. So they're sort of like smart drugs. One is called trastuzumab emtansine and the other is called trastuzumab deruxtecan. In the DESTINY-Breast03 trial, which was presented earlier this year, the deruxtecan drug was shown to be more effective than the emtansine one. At this San Antonio meeting, the investigators look specifically at how well these 2 drugs worked in patients whose breast cancer had spread to their brain. And these exciting results, the deruxtecan drug was shown to greatly lengthen the time until cancer worsens compared to the emtansine drug, from 3 months on average to 15 months. In addition, on brain MRI, almost two-thirds of the patients had shrinkage of the brain lesions when they received the deruxtecan drug, compared to only about one-third who received emtansine. These important findings give us yet another potential treatment that we can use to help patients who have HER2-positive breast cancer that has spread to their brains. So next, I'm going to switch gears and talk about treatment of metastatic hormone receptor-positive breast cancer. At this time, the initial treatments are generally with antihormone drugs, such as aromatase inhibitors or fulvestrant. Unfortunately, these drugs often stop working, and then patients have to switch to chemotherapy medication. The good news is, that there are a number of new antihormone drugs currently being developed in the EMERALD trial, which was presented at this meeting. Investigators tested a new antihormone medicine called elacestrant in postmenopausal women with metastatic breast cancer whose cancer had previously worsened during treatment with medicines called CDK4/6 inhibitors plus antihormone treatment. These findings are exciting because this new drug may work against some cancers that no longer respond to a currently available antihormone medicines. It might mean they don't yet need to switch to chemotherapy. However, the findings are still early, and this drug is not yet approved by the FDA. I'm sure we'll hear more about this drug and other similar ones in the months and years to come. There were a lot of other research findings presented related to treatment for early- stage breast cancer at the meeting. And there were quite a number of updates from studies that were previously presented. For example, in patients with stage 2 and 3 triple-negative breast cancer, adding immunotherapy to neoadjuvant chemotherapy, which is chemotherapy given before surgery, improves event-free survival. Similarly, updated results from the RxPONDER clinical trial confirm that it is okay to not to give chemotherapy to postmenopausal women with hormone receptor-positive HER2-negative breast cancer who have 1 to 3 involved lymph nodes, and a 21-gene recurrence score of 25 or less. Finally, there was a report of a large clinical trial examining whether the diabetes drug, metformin, can decrease the risk of breast cancer recurrence, especially in hormone receptor-positive breast cancer. Unfortunately, taking metformin did not lower the risk of breast cancer recurrence compared to placebo. So it is not recommended that patients take this drug specifically to try to lower their risk of breast cancer coming back. In addition to these studies reporting findings about new medications, we also learn new information about an old problem, lymphedema. A group of women were followed over 2two years after they were diagnosed with breast cancer and underwent axillary lymph node dissection or removal of a large number of lymph nodes from under their armpit. Using a specific type of lymphedema measurement that looks at swelling in the arm, they found that almost 1 in 10 patients had developed lymphedema within 1 year of surgery, and almost 1 in 4 had lymphedema within 2 years. These are similar to what other studies had previously found. But importantly, patients who were Black were much more likely to develop lymphedema compared to white or Asian patients. This association with race hadn't been carefully looked at before and suggests that additional studies need to be done to figure out how best to monitor for, prevent, and treat lymphedema in all patients with breast cancer. Importantly, at this meeting, we also got glimpses of the many new drugs on the horizon for the treatment of breast cancer. And we eagerly await the results of large randomized trials so that the drugs at work can be used to care for patients with breast cancer. But for now, that's it for this quick summary of important research from the 2021 San Antonio Breast Cancer Symposium. Overall, we continue on a fast track in breast cancer with many new and exciting therapies being actively studied, as well as research helping support our patients to do better than ever. Stay tuned to Cancer.Net for future updates from upcoming breast cancer conferences. Thank you. ASCO: Thank you, Dr. Henry. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

An interview with Dr. Megan Daly from University of California in Davis, California and Dr. Navneet Singh from the Postgraduate Institute of Medical Education & Research in Chandigarh, India, co-chairs on “Management of Stage III Non–Small-Cell Lung Cancer: ASCO Guideline.” They summarize guideline recommendations on five subtopics – evaluation & staging, surgery, neoadjuvant therapy, adjuvant therapy, and unresectable disease. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.   TRANSCRIPT [MUSIC PLAYING]   ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at ASCO.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Megan Daley from University of California in Davis, California, and Dr. Navneet Singh from the Post-Graduate Institute of Medical Education and Research in Chandigarh, India, co-chairs on management of stage III non-small cell lung cancer ASCO guideline. Thank you for being here, Dr. Daley and Dr. Singh. MEGAN DALEY: Thank you for having us. NAVNEET SINGH: Thank you for having us, too. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Daley, do you have any relevant disclosures that are directly related to this guideline topic? MEGAN DALEY: I have research funding from EMD Serono, Merck, and Genentech. BRITTANY HARVEY: Thank you for those disclosures. Then Dr. Singh, do you have any relevant disclosures that are directly related to this guideline? NAVNEET SINGH: No, I have no financial conflicts of interest. BRITTANY HARVEY: Thank you. Getting into the content of this guideline, Dr. Singh, can you give us an overview of both the scope and the purpose of this guideline? NAVNEET SINGH: Yes, absolutely. So this guideline has been developed to assist clinicians involved in the management of patients with stage III non-small-cell lung cancer, or NSCLC, as we call it briefly. Now, stage III NSCLC represents one of the most heterogeneous subgroups of lung cancer. Consequently, it is also the subgroup in which the choice of multimodality treatment and the sequence of multimodality treatment varies significantly amongst clinicians, with variations being observed across institutes, as well as within an institute. And we sincerely hope that, with the help of this guideline, clinicians can accurately confirm the presence of stage III disease and offer the most appropriate treatment based on clinical and radiographic characteristics, as well as other medical factors that influence treatment decision-making. This evidence-based guidance also seeks to provide clarification on the common clinical dilemmas that clinicians may have while evaluating a patient with suspected or known stage III NSCLC. BRITTANY HARVEY: Thank you for that background information, Dr. Singh. Then, Dr. Daley, this guideline addresses five main sections, evaluation and staging, surgery, neoadjuvant therapy, adjuvant therapy, and unresectable disease. So starting with evaluation and staging, what are the key recommendations for workup for patients with suspected stage III non-small cell lung cancer? MEGAN DALEY: Our first recommendation for such patients is that they should undergo a history and physical exam and a CT scan of the chest and upper abdomen with contrast, unless it's contraindicated. If metastatic disease is not identified on CT, those patients should go on to a PET CT scan and MRI of the brain. If the patients are being considered for curative intent treatment, the guideline recommends pathologic mediastinal lymph node assessment. And we recommend that endoscopic techniques should be offered as the initial staging modality, if available. If not available, invasive surgical mediastinal staging should be offered. And finally, for patients who have suspected or confirmed stage III lung cancer, we recommend that multidisciplinary discussion should occur prior to any initiation of a treatment plan. BRITTANY HARVEY: Great, I appreciate your reviewing those recommendations. So following that, Dr. Singh, what does the guideline recommend regarding which patients with stage III non-small-cell lung cancer should be considered for surgical resection? NAVNEET SINGH: So in this guideline, the recommendation which has come forth is that for patients with stage IIIA, basically N2 disease, induction therapy should be followed by surgery with or without adjuvant therapy if several conditions are met. Basically, a complete resection of the primary tumor and the involved lymph nodes is deemed feasible, and three nodes or contralateral lymph nodes are deemed to be not involved, and the expected perioperative 90-day mortality is low, typically 5% or less. Another recommendation is that for selected patients with the P4N0 disease, surgical resection may be offered if medically and surgically feasible following multidisciplinary review. We would like to emphasize here that surgeons should always be involved in decisions regarding the feasibility of surgical resection. And they are an integral part of a multidisciplinary evaluation for surgical resection for stage III NSCLC patients. BRITTANY HARVEY: Great. Then Dr. Singh just reviewed who should be considered for surgical resection. So Dr. Daley, for patients with potentially resectable stage III non-small-cell lung cancer, what are the key recommendations for neoadjuvant therapy? MEGAN DALEY: Our first recommendation is that patients who are planned for a multimodality approach that will incorporate surgery should receive systemic neoadjuvant therapy. Second, that those patients with N2 disease who are planned for surgical resection should receive either neoadjuvant chemotherapy or neoadjuvant concurrent chemoradiation. And finally, for patients with a resectable superior sulcus tumor, neoadjuvant concurrent chemoradiation should be administered. BRITTANY HARVEY: Understood. Then in addition, Dr. Singh, for patients with resected stage III non-small-cell lung cancer, what are the key recommendations for adjuvant therapy? NAVNEET SINGH: So the panel came up with three recommendations for adjuvant treatment. The first is that patients with resected stage III NSCLC who did not receive neoadjuvant systemic therapy should be offered adjuvant platinum-based chemotherapy. The second recommendation which we came up was that for patients with resected stage III disease and presence of a sensitizing EGFR mutation-- classically, exon 19 deletion or the L858R exon 21 point mutation-- they may be offered adjuvant osimertinib, which is an EGFR inhibitor, after platinum-based chemotherapy. And this is based upon the ADAURA trial, which was published last year. And the third recommendation was that for patients with completely resected NSCLC and mediastinal involvement N2 disease, but without extracapsular extension, post-operative radiotherapy should not be routinely offered. BRITTANY HARVEY: OK. And then the last section of recommendations covers unresectable disease. So Dr. Daley, what does the guideline recommend regarding the management of unresectable stage III non-small-cell lung cancer? MEGAN DALEY: The guideline first recommends that these patients who have a good performance status should be offered concurrent, rather than sequential, chemoradiation, that concurrent chemotherapy delivered with radiation should include a platinum-based doublet, preferably cisplatin-etoposide, carboplatin-paclitaxel, or cisplatin-pemetrexed or cisplatin-vinorelbine. The patients who are not candidates for concurrent chemoradiation, but who are potentially candidates for chemotherapy, should be offered sequential chemoradiation, rather than radiation alone, that patients receiving concurrent chemoradiation should be treated to 60 gray. And that's based on the results of RTOG 0617. We also recommend within the guideline that doses higher than 60 gray and up to 70 gray could be considered for selected patients, with careful attention to doses to the heart, lung, and esophagus, among other organs. The guideline also recommends that patients receiving definitive radiation without chemotherapy, that hypofractionation using slightly larger doses could be considered-- over 2 gray per fraction, and up to 4 gray per fraction, and that patients without disease progression during concurrent chemoradiation should be offered consolidation durvalumab, based on the PACIFIC trial. BRITTANY HARVEY: Thank you both, then, for reviewing the key recommendations of this guideline. So, Dr. Singh, in your view, what is the importance of this guideline, and how does it impact clinicians? NAVNEET SINGH: I think this guideline will go a long way in helping clinicians who are involved in the diagnosis and treatment of lung cancer, especially stage III NSCLC. As mentioned earlier, this is a very heterogeneous disease. And there are several challenging situations, both in the context of diagnosis, as well as treatment. And using this guideline, which has an extensive evidence review, as well as the development of two very helpful algorithms, we sincerely hope that clinicians who are both in academic centers as well as in practice in the community are able to accurately diagnose stage III, appropriately stage it, and offer the best treatment, given the patient characteristics and the disease characteristics and available resources. BRITTANY HARVEY: Great. Those are important points. So then, finally, Dr. Daley, how will these guideline recommendations affect patients? MEGAN DALEY: Well, we hope very much that these guidelines will help patients consistently receive high-quality care for their stage III lung cancer. In particular, we're hoping that the recommendation from multidisciplinary assessment of patients prior to treatment is carefully followed. We're hoping that some of the recommendations surrounding the appropriate workup for patients may help ensure that all patients receive a thorough and complete workup prior to initiation of treatment. And the guideline, in particular, is highlighting some of the more recent developments in stage III lung cancer, such as the use of consolidation durvalumab based on the PACIFIC trial, the use of osimertinib in resectable disease based on the ADAURA trial. And we're hoping to make sure that these results are disseminated to practitioners everywhere so that patients can receive the latest and best care for their stage III lung cancer. BRITTANY HARVEY: Understood. Yeah, as you both mentioned, we hope that this has a positive impact for both clinicians and patients. So I want to thank you both for all of your hard work to develop this guideline and the evidence-based recommendations along with it. And thank you for taking the time to speak with me today, Dr. Daley and Dr. Singh. MEGAN DALEY: Thank you so much for having us. NAVNEET SINGH: Thank you. BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Nancy Baxter from the University of Melbourne in Melbourne, Australia, and Dr. Jeffrey Meyerhardt from Dana-Farber Cancer Institute in Boston, MA, co-chairs on “Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update.” This guideline updates recommendations for adjuvant therapy for patients with resected stage II colon cancer. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.   TRANSCRIPT [MUSIC PLAYING] ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Nancy Baxter from the University of Melbourne in Melbourne, Australia, and Dr. Jeffrey Meyerhardt from the Dana-Farber Cancer Institute in Boston, Massachusetts, co-chairs on adjuvant therapy for stage II colon cancer ASCO guideline update. Thank you for being here, Dr. Baxter and Dr. Meyerhardt. NANCY BAXTER: Thank you for having us. JEFFREY MEYERHARDT: Thanks. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Baxter, do you have any relevant disclosures that are directly related to this guideline topic? NANCY BAXTER: I don't, Brittany. BRITTANY HARVEY: Thank you. And Dr. Meyerhardt, do you have any relevant disclosures that are directly related to this guideline topic? JEFFREY MEYERHARDT: I don't, either. Thank you. BRITTANY HARVEY: Thank you, both. And getting into the content of this guideline, what prompted this guideline update, and what is the scope of this guideline? NANCY BAXTER: Well, it's been since 2004 that we've had a guideline that gives us advice about stage II colon cancer and the use of adjuvant therapy in this group of patients. And it's one where clinicians often have a lot of challenges in helping patients make decisions about what's best for them in terms of long-term survival from colon cancer. There have been changes in guidelines for stage III colon cancer. And so we thought it was timely to reevaluate our best practice recommendations for stage II colon cancer patients. JEFFREY MEYERHARDT: Yeah, I agree, Dr. Baxter. I think that this is one of the most challenging conversations that oncologists have with patients. Should they get chemotherapy? What type of chemotherapy? And as you know, there are a variety of higher risk features, of which we're able to sort of tease out a little better relatively, in terms of thinking about someone's stage II disease and trying to bring all that data together and provide some framework in the conversation for clinicians to have with patients. BRITTANY HARVEY: Great, thank you both for that background information. So then this guideline covers four clinical questions. And I'd like to review the recommendations for each question. So Dr. Baxter, starting with question 1, what does the guideline recommend for patients with resected stage II colon cancer regarding the benefit of fluoropyrimidine-based adjuvant chemotherapy versus surgery alone? NANCY BAXTER: So overall, what we did was we looked at the risk that individual patients with stage II colon cancer have. So for patients that are at low risk of recurrence-- and so those are patients with stage IIA or T3 tumors that have at least 12 sample lymph nodes in the surgical specimen and don't have any high-risk features, and I'll go over those with the later recommendations-- these patients do not need adjuvant chemotherapy. It should not be routinely offered to them because the harms may outweigh the benefits. And so the evidence of that, although the quality of the evidence was relatively low, there is quite a bit of evidence that, really, the benefits do not outweigh the risks in this particular group. That is different for patients that are at higher risk, though, within the stage II group. And so those are the patients with stage IIB or stage IIC colon cancer. So those are T4 lesions that either penetrate through the visceral peritoneum or invade surrounding organs. And in those patients, adjuvant chemotherapy may have more benefit. And so a discussion of the potential benefits and risks of harms associated with chemotherapy should be had with patients. And those are patients that should be offered adjuvant chemotherapy for their disease. Now, there's a group of patients with high-risk features-- so not the stage IIB or stage IIC-- but there's a group of patients within stage IIA. So these are patients that are T3 patients where there are high-risk features. And chemotherapy may be offered to these patients, based on their risk features. So I'll go over a little bit about what the high-risk features are that might make patients included in this group. So that is sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphatic invasion, poor or undifferentiated tumor grade, intestinal obstruction, tumor perforation, and grade BD3 tumor budding. That's more than, or equal to, 10 buds in the tumor. And so that's because these patients are at higher risk of recurrence, and the chemotherapy may be more beneficial in these patients because they have a higher baseline risk of recurrence. There were a few risk factors that it was really challenging to make any decision on. And that was specifically circulating DNA. We know that that's an area of great interest, but there really was not enough evidence of the predictive value of ctDNA when you're looking at adjuvant chemotherapy in this group to make a recommendation. We'd expect future versions of this guideline to have some recommendations about that. We do know that there is controversy around the timing of chemotherapy. So we didn't include reports on this for the guideline because we didn't have enough related to stage II colon cancer and the role of adjuvant therapy. But the trials have generally started patients on chemotherapy within six to seven weeks of surgery. And finally, all of this needs to be a part of shared decision-making. So particularly for patients at higher risk-- so stage 2A at higher risk-- it's important that this is discussed-- the risks and benefits of chemotherapy, and the possible benefits with respect to the risk of recurrence for these patients-- is discussed as part of the shared decision-making process to come to an ultimate decision about the use of chemotherapy. BRITTANY HARVEY: Understood. Thanks for detailing those recommendations stratified by risk and identifying what those high-risk features are. So then, additionally, Dr. Meyerhardt, is there a benefit of fluoropyrimidine-based adjuvant chemotherapy for patients with tumors that exhibit mismatch repair deficiency or microsatellite instability or patients with proficient mismatch repair, or microsatellite-stable, tumors? JEFFREY MEYERHARDT: Yeah, so this was a specific question that we also looked at. What we know is about 15% of stage II colon cancers have evidence of mismatch repair or microsatellite insufficiency. And data that was realized now several decades ago on several different papers-- one larger one published in The New England Journal by Dan Sargent-- showed that patients who have stage II disease who receive a fluoropyrimidine only seem to not benefit if they have microsat instability. And there was actually some evidence that they may actually have harm, or have a worse outcome. So it is not a routine recommendation to use a fluoropyrimidine-only treatment regimen in patients who have MSI-high or deficiency of mismatch repair in stage II disease. However, there are some qualifying statements that we reviewed and were important to think about in patients. So what we know is, again, some of those patients will have some high-risk features and particularly T4 tumors or some other high-risk features, except for poor differentiation, that the use of oxaliplatin may actually be a consideration in those patients. And that's basically from indirect evidence of a disease-free survival benefit with the addition of oxaliplatin in the population of patients with stage II disease that were included in the MOSAIC trial, one of the original trials that looked at the addition of oxaliplatin to a fluoropyrimidine as adjuvant therapy for colon cancer. We specifically carved out poor differentiate is not considered a high-risk prognostic feature in those patients. And so poorly differentiated tumors alone should not be a part of the decision in offering adjuvant therapy with a fluoropyrimidine or fluoropyrimidine-oxaliplatin for MSI-high or deficient mismatch repair protein tumors. And the other patients who have either proficient mismatch repair proteins or microsatellite instability are actually including the other parts of the guideline, so what Dr. Baxter just talked about and some of the other questions that we tackled that you'll be going to next. BRITTANY HARVEY: Great. Thank you for covering those recommendations for that particular patient population. So then, Dr. Baxter, if adjuvant therapy is recommended, is there a benefit to adding oxaliplatin to fluoropyrimidine-based chemotherapy? NANCY BAXTER: Well, this is obviously a question that oncologists will face when they're deciding to give adjuvant chemotherapy to high-risk stage II colon cancers or people with T4 stage IIB or C colon cancers. And you know, here's where it's challenging to make recommendations. Because we don't have a lot of evidence for this specific group. And this is why clinicians have such a challenge making recommendations for these patients. Because actually, there's insufficient evidence to routinely recommend the addition of oxaliplatin, meaning that we have to base our decisions on the best evidence that we have. And the best evidence we have, as we've talked about, is the MOSAIC trial. And so in the MOSAIC trial, a time to recurrence was longer with oxaliplatin-based adjuvant chemotherapy. And so it may be for some patients that the addition of oxaliplatin makes sense in terms of improving their overall outcome. And again, it needs to be a shared decision-making approach with the discussion of the potential benefits and risks of harms of the addition of oxaliplatin to fluoropyrimidine-based chemotherapy, so again, discussions between the oncologist and the patient. But that is with the exception of patients who are MSI-high. So those patients need oxaliplatin. If they're going to get chemotherapy, they shouldn't have 5FU-based chemotherapy alone, as we've just discussed. BRITTANY HARVEY: Great. And definitely, that shared decision-making is key. And I appreciate you reviewing the evidence behind these recommendations, as well. So then, the last clinical question addressed in this guideline, Dr. Meyerhardt, if adjuvant oxaliplatin-containing chemotherapy is considered, are outcomes affected by reducing the treatment duration from six months to three months? JEFFREY MEYERHARDT: Sure. So this was the last clinical question that the committee considered. And it is based on the IDEA collaboration. So the IDEA collaboration was the International Duration Evaluation of Adjuvant Chemotherapy. It was six trials that were done internationally-- one in the United States, one in Japan, and four in Europe-- that included patients both with stage II and stage III colon cancer. They receive three versus six months of therapy. Each of the trials had different chemotherapy choices in the sense that the United States trial, FOLFOX was the only choice that could be offered to patients, where in all the other trials, it was a physician and patient choice regarding the use of FOLFOX or capecitabine and oxaliplatin. And that, as people who know the data, is relevant to some of the discussion. And so the goal of the collaboration was to look at if we can give patients three months of therapy and not compromise outcome. And the main reason for that is we know that the peripheral neuropathy that's cumulative with oxaliplatin increases with more months of treatment. So patients who only receive three months of oxaliplatin have less likelihood of more significant cumulative neuropathy and will have less impact on function by receiving less oxaliplatin overall. Four of the trials included patients with stage II disease. And those trials, again, pooled their data and looked at the duration question in terms of for stage II patients. Those patients had high-risk disease, some high-risk feature, as discussed earlier. And what was shown is that for the patients, overall, there was not clear evidence of noninferiority with three versus six months. But when you looked at the patients who received capecitabine and oxaliplatin, the absolute five-year disease-free survival was 81.7% versus 82% for three versus six months of CAPOX, so essentially the same, with a hazard ratio of 1.02, and the confidence interval spanned across 1. And so those really didn't look like there was any compromise in outcome for patients to receive CAPOX for three months versus six months. For those patients who received FOLFOX, three months of chemotherapy led to a five-year disease-free survival of 79.2% versus 86.5% if you received six months of FOLFOX with a hazard ratio 1.41. So again, those data would suggest that if one was to choose FOLFOX, giving six months of therapy for high-risk stage II patients may be preferable to not potentially compromise some benefit in terms of disease-free survival. So again, the overall conclusion was it's a discussion with a patient regarding choice of therapy, whether receiving capecitabine, oxaliplatin or FOLFOX and then, based on that, consideration of the duration where we were most comfortable saying that three months of capecitabine, oxaliplatin is sufficient for high-risk patients when appropriate discussion between the clinician and the patient. BRITTANY HARVEY: Great. Thank you for explaining the nuance of that trial and your recommendation. So finally, to wrap us up, in your view, how does this guideline impact both clinicians and patients? JEFFREY MEYERHARDT: Yeah, so again, the last time ASCO had addressed guidelines for stage II patients was over 15 years ago. And there are more data. It was really early in the days of understanding the incorporation of oxaliplatin. There was no data versus the three versus six months. And there were less analyses trying to look at some of those particular high-risk features. So these are all important considerations in those discussions with stage II patients. And the importance of the guidelines are really to provide that framework on the various things you think about when you have a stage II patient and how to have those shared decision-making discussions with the patient. Again, it's not, probably, appropriate for all patients to receive adjuvant therapy, particularly lower risk. And even for higher risk patients, it is weighing the plus or minuses of the potential toxicities with what we know potentially are benefits. NANCY BAXTER: Yeah, I think that's very true. And I think, as anyone who treats colon cancer, or stage II colon cancer patients, is aware, this is not a homogeneous population. So in terms of the outcomes, there are people that do extremely well with surgery alone and people who, unfortunately, recur even after chemotherapy and surgery. And the future needs to focus on being able to differentiate those patients most likely to benefit from chemotherapy from those that are not likely to benefit. What we found in reviewing the evidence is we've moved forward from 2004, but we still have a long way to go. So I really hope when the next guideline is written that we're much closer to being able to identify those patients who would most benefit from chemotherapy in this group. Because we know there are patients who benefit from chemotherapy in this group. It's just we're still not perfect at identifying those people. So again, these conversations with patients are so important to talk about the limits of our knowledge, which I think is another important thing of this guideline is establishing what the limits of our knowledge are. But I think there are patients that you can confidently not give chemotherapy to. And that's very reassuring, both to clinician and to patients. And then this guideline kind of outlines the limits of our knowledge. And that's also important for clinicians and patients to understand. BRITTANY HARVEY: Definitely. I appreciate you both highlighting the importance of shared decision-making throughout this conversation that we've had. So I want to thank you so much for your work on this important guideline update and for taking the time to speak with me today, Dr. Baxter and Dr. Meyerhardt. NANCY BAXTER: Thank you very much. JEFFREY MEYERHARDT: Thank you. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/gastrointestinal cancer guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. David Schiff from the University of Virginia Medical Center in Charlottesville, VA, and Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, FL, co-chairs on “Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline.” This guideline comprehensively addresses the treatment of brain metastases from non-hematologic solid tumors, including surgery, systemic therapy, radiation therapy, and timing of therapy. Read the full guideline at www.asco.org/neurooncology-guidelines.   TRANSCRIPT [MUSIC PLAYING] SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, Florida, and Dr. David Schiff from the University of Virginia Medical Center in Charlottesville, Virginia, Co-chairs on Treatment for Brain Metastases, American Society of Clinical Oncology, Society for Neuro-Oncology, and American Society for Radiation Oncology Guideline. Thank you for being here, Dr. Vogelbaum and Dr. Schiff. MICHAEL VOGELBAUM: My pleasure. BRITTANY HARVEY: Before we begin, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in The Journal of Clinical Oncology Dr. Vogelbaum, do you have any relevant disclosures that are directly related to this guideline topic? MICHAEL VOGELBAUM: I have no disclosures relevant to this guideline. BRITTANY HARVEY: Thank you. Then, Dr. Schiff, do you have any relevant disclosures that are directly related to this guideline topic. DAVID SCHIFF: Hi, Brittany. No, I do not. BRITTANY HARVEY: Great. Then first, Dr. Schiff, can you give us an overview of the scope and the purpose of this guideline? DAVID SCHIFF: Sure. Our overall purpose was to provide guidance on the appropriate treatment of adult patients with parenchymal brain metastases from solid tumors, encompassing surgery, radiation, and systemic therapy, as well. Previous guidelines in this area were for the most part produced by neurosurgeons and radiation oncologists for their respective professional organizations, although they did incorporate multidisciplinary input. But over the last decade, treatment options for certain types of brain metastases have undergone a substantial change. The expanding armamentarium for medical oncologists in treating both extra-CNS disease as well as brain metastases highlighted the need for a new set of guidelines to evaluate the role of systemic approaches, such as targeted agents and immunotherapy, for the primary treatment of brain metastases in the context of more established treatments like surgical resection, radiosurgery, and fractionated radiotherapy. Additionally, recent studies have clarified the role of radiation techniques like whole brain radiation with hippocampal avoidance and radiosurgery to surgical resection cavities. By assembling a multidisciplinary group of experts from surgical neuro-oncologists, medical oncologists, neuro-oncologists, and radiation oncologists, we sought to provide as comprehensive and up to date a set of therapeutic guidelines as possible. In order to accomplish this, the panel performed a systematic review of randomized as well as nonrandomized evidence from 2008 through April, 2020. We focused on the roles of surgery, systemic therapy, and radiation therapy, as well as the timing and interactions among these modalities. And we included all randomized clinical trials, as well as large single arm phase II studies and institutional case series, and we also reviewed case control and cohort studies. BRITTANY HARVEY: OK, great. That's helpful background. And then you mentioned a couple focus areas, as well, of the systematic review. And so I'd like to review the key recommendations that were based off that evidence. So, starting with surgery, Dr. Vogelbaum, what are the key recommendations for surgery in adult patients with brain metastases? MICHAEL VOGELBAUM: So, the role of surgery, I think, was well established via randomized trials to some degree, and then via some of the larger single arm studies. Patients with suspected brain metastases without a primary cancer diagnosis were felt to benefit from surgery to obtain a diagnosis and undergo removal of the tumor. But more to the point, patients with larger tumors with mass effect-related symptoms are the ones most likely to benefit from surgery. What we also noted was that patients who have multiple brain metastases with extensive and uncontrolled systemic disease are unlikely to benefit from surgery unless the remaining disease is controlled via other measures, typically medical measures. We also contemplated the type of resection performed, the technique being used. There was some developing literature looking at the techniques of either an en bloc resection or a piecemeal resection. And when we critically evaluated the literature, we felt that no recommendation could be made regarding the method of resection, as there was not sufficient evidence to support one approach over another. Another technique that is being used more recently is the use of laser interstitial thermal therapy, which is a minimally invasive technique to treat tumors in general. But again, there was insufficient evidence to really be able to make a recommendation for or against the use of LITT, as it's called. BRITTANY HARVEY: OK, thank you for reviewing both those techniques and those recommendations and highlighting where there wasn't enough evidence to actually make a recommendation. So, then, following that, Dr. Schiff, what does the guideline recommend for patients with brain metastases regarding systemic therapy, including chemotherapy, immunotherapy, and targeted agents? DAVID SCHIFF: Brittany, there is a role for systemic therapy as the initial or primary modality in some cases, but I think it's really important to emphasize this only pertains to patients whose brain metastases are asymptomatic and those with particular histologies or molecular profiles. So, there are really-- there are three primary sites for which targeted or immunotherapy can be considered. The first is non-small cell lung cancer, for which osimertinib, or if you're in China, where there's access to another drug called icotinib, specifically for EGFR-mutated disease, alectinib, brigatinib, and ceritinib are appropriate approaches in ALK-rearranged asymptomatic brain metastases. And finally, pembrolizumab in combination with pemetrexed and a platinum agent in immunotherapy naive patients whose tumors express PD-L1. The second primary tumor is melanoma. And for melanoma patients who have asymptomatic BRAF V600E mutant brain metastases, dabrafenib with trametinib is an appropriate option to consider. For all melanoma patients with asymptomatic brain metastases, ipilimumab with nivolumab is also an option. And finally, for breast cancer, the combination of tucatinib, trastuzumab, and capecitabine for HER2 positive asymptomatic brain metastases in patients who have progressed on previous anti-HER2 antibody therapy. When patients treated with systemic therapy progress intracranially, local therapies such as surgery, radiation, and radiosurgery should not be deferred. BRITTANY HARVEY: OK, those are helpful notes for clinicians, and particularly around the primary tumor sites. So, then, Dr. Vogelbaum, what are the key recommendations for radiation therapy in patients with brain metastases? MICHAEL VOGELBAUM: So, Brittany, the panel started by noting which patients would not benefit from radiation therapy, in particular, those with asymptomatic brain metastases and a poor performance status, with a Karnofsky Performance Score, or KPS, of less than or equal to 50, or performance status of less than 70 and no systemic therapy options. In those cases, radiation therapy is unlikely to be of real benefit. But then when speaking to the different modalities of radiation to be used, a lot of the review focused on the two most commonly used modalities, which is Stereotactic Radiosurgery, or SRS, versus Whole Brain Radiotherapy, or WBRT. And the first recommendation was that SRS alone as opposed to either whole brain radiotherapy alone or a combination of the two should be offered to patients with one to four unresected brain metastases, except for the situation of small cell carcinoma, which has a different approach that's used often with prophylactic cranial irradiation. So, that's a separate group. But for others, SRS is the modality that should be offered. And then for patients who underwent surgical resection of their brain metastases, we know that there needs to be some form of radiation treatment to the surgical cavity. And the recommendation was that SRS alone should be offered to those patients if the surgical cavity can be safely treated, and considering the extent of remaining intracranial disease. Obviously, for patients who have a lot of disease but otherwise have a treatable systemic disease, then whole brain radiotherapy may make more sense. But for the ones that are more limited after surgery, it should be SRS. And then when the panel considered a situation where you have patients with more than four unresected metastases and the options included radiosurgery, whole brain radiotherapy, or radiosurgery plus whole brain radiotherapy-- and in general, these are reasonable options. But it was felt that SRS may be preferred for patients with better prognosis or where systemic therapy that is known to be active in the central nervous system is available. Additional recommendations revolved around both protective, radioprotective, and radiosensitizing agents. So, in terms of trying to protect memory, there are two approaches that are used. One is to give memantine during whole brain radiotherapy, or to do whole brain radiotherapy using a hippocampal avoidance technique. And it was felt that either one of those or both should be offered to patients who will receive whole brain radiotherapy and have no tumors in the hippocampus, and they're expected to live more than four months. And then finally, that radiation sensitizing agents should not be offered to patients, because they've not been shown to be effective. BRITTANY HARVEY: Understood. And it's helpful to know both what those recommendations are for specific approaches, and as you said, critical to know who will and who will not benefit from radiation therapy. So, then we've just reviewed the key surgery, systemic therapy, and radiation therapy recommendations. Dr. Schiff, did the panel recommend anything regarding the timing of surgery, radiation therapy, and systemic therapy? MICHAEL VOGELBAUM: The panel had just a couple of points in this regard. Although there are some recent data suggesting a decreased incidence of leptomeningeal metastases in patients who undergo radiosurgery before craniotomy, as compared to the reverse sequence, the panel concluded no recommendation on this point regarding the specific sequence of therapy could be made. And to reiterate, for those circumstances in which systemic therapy may be of use for brain metastases, that therapy should proceed, local therapy like surgery or radiation, only if the brain metastases are asymptomatic. BRITTANY HARVEY: Great. Thank you both for reviewing these recommendations. In your view, Dr. Vogelbaum, what is the importance of this guideline, and how will it impact clinicians? MICHAEL VOGELBAUM: I think one of the important points that David raised that at the beginning was that this really is the most comprehensive look at the evidence revolving around the treatment of patients with brain metastases and leptomeningeal disease. And in particular, this may be new information for an audience that has not been involved in that treatment for many decades, the medical oncology community. So, I think some of the impact on clinicians may be that the guidelines will help them understand the durability of surgery and radiosurgery, and those had been the only treatments available for a long time. And so now we have these new medical therapies that are showing activity in the brain, but one needs to balance that against what is known about the effective treatments in the past. Some of the new targeted immunotherapies may not provide as consistent or durable of a benefit as has been shown previously with surgery and radiotherapy. Hopefully, understanding this challenge with respect to consistency and durability will serve to support the development of phase 0 or window of opportunity clinical trials to better understand the determinants the biological determinants of response or resistance to systemic therapies we want to improve on that, for sure, and those clinical trials are going to be essential for us to be able to do that. And then ultimately, also, identify opportunities to synergistically combine radiation and medical therapies and better understand the timing of these combinations. This is a great area for clinical trial development in the future. BRITTANY HARVEY: Definitely. We'll look forward to future research in those areas. So then, finally, Dr. Schiff, to wrap us up, how will these guideline recommendations affect patients? DAVID SCHIFF: Yeah. Over the last 30 years, the management of brain metastases have involved hugely, from an area where almost everyone got whole brain radiation therapy and many patients died from their brain disease. The use of local therapies like surgical resection and radiosurgery has greatly improved local control of brain metastases. And with options like radiosurgery alone for a limited number of brain metastases, systemic therapies as the initial approach, and hippocampal avoidant whole brain radiation therapy with memantine, patients are experiencing improved long term cognitive function and quality of life, as well. So, I think the careful delineation of the role of each of these modalities that these guidelines provide will really help maximize benefit and minimize the risk for this very large number of cancer patients. BRITTANY HARVEY: Definitely, improve quality of life is always a goal. So, I want to thank you both for your work on these guidelines and thank you for taking the time to speak with me today, Dr. Vogelbaum and Dr. Schiff. DAVID SCHIFF: My pleasure. MICHAEL VOGELBAUM: Thank you, Brittany. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/neurooncology guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode. [MUSIC PLAYING]

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. 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. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, experts will discuss targeted therapy for lung cancer, including 2 new treatments that target a specific type of mutation or change in the EGFR gene in some cancer cells, called an EGFR exon 20 insertion. They will explain how targeted therapy works to treat cancer, why this specific mutation is different from other, more common EGFR mutations, and what these 2 new treatments mean for people with this type of cancer. This podcast will be led by Dr. Charu Aggarwal, Dr. Xiuning Le, Dr. Vamsidhar Velcheti, and Marcia Horn. Dr. Charu Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine in Philadelphia, Pennsylvania. She is also the Cancer.Net Associate Editor for Lung Cancer.  Dr. Xiuning Le is an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at the University of Texas MD Anderson Cancer Center in Houston, Texas.  She is also a Cancer.Net advisory panelist for lung cancer.  Dr. Vamsidhar Velcheti is the director of thoracic medical oncology at NYU Langone's Perlmutter Cancer Center in New York, New York, and is also a Cancer.Net advisory panelist for lung cancer. Marcia Horn is the President and CEO of the International Cancer Advocacy Network and the executive director of the Exon 20 Group in Phoenix, Arizona.  View full disclosures for Dr. Aggarwal, Dr. Le, Dr. Velcheti, and Ms. Horn at Cancer.Net. Dr. Charu Aggarwal: Hello and welcome to this Cancer.Net podcast on new research in lung cancer. I'm Dr. Charu Aggarwal from the University of Pennsylvania. I'm also the Cancer.Net Associate Editor for Lung Cancer. I'm here today with my colleagues from the Cancer.Net Lung Cancer Panel. First is Dr. Xiuning Le from the University of Texas MD Anderson Cancer Center. Hi, Dr. Le. Dr. Xiuning Le: Hi, everyone. This is Xiuning Le from MD Anderson. I'm happy to be here as one of the discussants. Dr. Aggarwal: Next is Dr. Vamsi Velcheti from the NYU Langone Perlmutter Cancer Center. Vamsi? Dr. Vamsidhar Velcheti: Hi, this is Vamsi Velcheti. I'm so glad to be here with you. Dr. Aggarwal: And our special guest today is Marcia Horn, the president and CEO of the International Cancer Advocacy Network and the executive director of the Exon 20 Group. Hi Marcia. Marcia Horn: Hi, everyone. Wonderful to be here. Dr. Aggarwal: So good to have you all. Before we begin, we should mention that Marcia has consulted with both Takeda Oncology and Janssen on survey research for the Exon 20 Group. You can view full disclosures for this podcast at Cancer.Net. Our podcast today is going to be about targeted therapy for non-small cell lung cancer, and specifically, 2 new treatments that target a specific type of mutation or change in the EGFR gene in some cancer cells. This mutation is called an EGFR exon 20 insertion. Dr. Velcheti, I'll start off with you. What is targeted therapy, and how does it work? Dr. Velcheti: So thank you, Charu. Lung cancer is a very complex biological disease. There are a lot of genes in the tumor cells that could be mutated, and understanding the type of genetic changes or mutations in the DNA of these tumor cells helps us really develop treatments that are very focused on that particular patient's cancer. Having a specific gene alteration could render tumors more susceptible or vulnerable to certain treatments, and these are what we call targeted therapies. And in lung cancer, these are especially important because there are a lot of drugs developed for patients with certain unique genomic aberrations, or changes in the DNA, and it's ushered in a whole wave of new treatments for patients with lung cancer, and it's really an exciting time for patients with lung cancer. Dr. Aggarwal: That's terrific. And I would like to focus on the mutation aspect a little bit more. Dr. Le, can you talk to us [about] whether all mutations found in lung cancer, can all of them be treated? Dr. Le: Like Dr. Velcheti was talking about, lung cancer is really a complex disease. And oftentimes in 1 lung cancer, we can detect more than 1, multiple mutations. Some of them function as driving the cell growth. Some of them function as a brake. We call that a tumor suppressor to release the cell from being suppressed. Clinically, we usually classify all the mutations that can be detected in the lung cancer into the 2 groups. One is called actionable. The other group is called not actionable. Actionable, meaning when we detect a mutation, we, as clinicians, can actually offer a specific targeted therapy to act on the mutation. Therefore, detection of the actionable mutation oftentimes translates to the patient potentially having the opportunity to get targeted therapy targeting that potential actionable driver oncogene. As of today, we're talking, the development of lung cancer treatment has been so advanced. We have 9 actionable genetic alterations that can be detected in non-small cell lung cancer. Even since 2 years ago, there are 4 new additions, so a total of 9 as of today, and EGFR exon 20 is one of the newest being approved in 2021, so really good news. Dr. Aggarwal: I know we've come a long way, and EGFR exon 20 insertions have been known for a long time. However, we've also known that they are not perhaps as sensitizing as the other EGFR mutations. Dr. Velcheti, could you shed some light on what is unique about these mutations in terms of testing as well as application of therapies? Dr. Velcheti: We have known about EGFR mutations in lung cancer for a very long time, and there have been quite effective treatments for EGFR activating mutation-positive lung cancer patients. However, not all mutations in the EGFR gene are the same. Depending on the location of the sequence change in the gene, they could have a different degree of response to EGFR inhibitors. So when we talk about EGFR exon 20, we're talking about a subset of these EGFR gene mutations which is in an area of the EGFR gene, a change in the sequence of the EGFR gene, that doesn't necessarily respond so well to the novel EGFR inhibitors that we have been using for a long time. So the clinical implications, and it's something to kind of think about and remember, is that the way we test for these mutations is very different. You could do comprehensive genomic profiling, or in some cases, there are some tests that actually test for a specific type of gene mutation. So it's something we call “hotspot panels.” Those are tests using certain techniques that actually only pick up certain EGFR genes, and they don't pick up all the gene mutations that happen in the EGFR gene. So it is very important to kind of keep that in mind because now we have drugs approved for exon 20 mutations. If you don't actually pick them up on a test, then obviously, we can't identify those patients for treatment with these exciting new treatments. And also, just as a quick plug, given that we have so many new drugs approved for different types of gene alterations in lung cancer, it is even more important now to focus on doing really good biomarker testing with comprehensive genomic profiling looking at a wide panel of genes, rather than focusing on certain kinds of gene mutations. So this is what we call comprehensive genomic profiling. That's absolutely critical in order to identify patients for the right treatment with targeted therapy. So it's extremely important to do that upfront so that we have patients kind of matched up to the right treatment. Dr. Le: I do also want to add with Dr. Velcheti in that I fully agree that exon 20 is oftentimes not on the hotspot PCR-based testing, so please use a comprehensive, what we call, next-generation sequencing base. I also want to say that also, exon 20 can be detected in liquid biopsy. So it's not you have to do the tissue biopsy if the patient has the opportunity to get liquid biopsy. As long as it's a good, comprehensive panel, it should also be able to detect that. Dr. Aggarwal: Absolutely, can never underemphasize the benefits and importance of comprehensive testing. Marcia, I'll turn to you. You lead a large group called the Exon 20 Group. How common is the EGFR exon 20 insertion-- how common is this mutation in people with lung cancer? Marcia Horn: It's not at all common. In fact, EGFR exon 20 insertion mutations in non-small cell lung cancer are exceedingly rare, a total of about 2% of all NSCLC and about 9 to 10% of all EGFR mutations. And it's an insertion mutation that hits, for the most part, never-smokers and members of Asian populations, although we at the Exon 20 Group have seen diagnoses in virtually every racial and ethnic group imaginable. The Exon 20 Group was established in 2017 as a special project of ICAN. It was founded by an EGFR exon 20 insertion patient, Kevin Hamlin, and his brother, Bob Hamlin, who's a senior lecturer at MIT. What we all wanted to do was get an international working group put together, and before we knew it, we had this huge global coalition of not only many hundreds of patients for EGFR exon 20 insertion and HER2 exon 20 insertion representing about 54 countries, but we had care partners, family members, several hundred leading thoracic oncologists, medical oncologists, and members of the community oncology setting as well, plus biotechs, pharmas with drugs in the exon 20 pipeline, and members from molecular profiling labs and the basic sciences in exon 20 bench science. So altogether, we're working to turn this into a chronic and manageable disease, and for the last 4 and a half years, we've been connecting our patients to promising clinical trials, especially the 2 newly approved drugs, and our angel buddy program provides our patients with peer-to-peer counseling to help them through side effects. So we're all united in blasting this disease off the planet and making the patient journey far more manageable. Dr. Aggarwal: Incredible. I'm just so proud of what all you've achieved, and you serve such an important mission in terms of patient advocacy and, more importantly, support. Dr. Velcheti, there have been 2 new recently approved targeted therapies to treat non-small cell lung cancer that harbors an EGFR exon 20 insertion mutation, and really, these drugs have come to us within the last few months. How does the first drug, mobocertinib, work to treat this cancer? Dr. Velcheti: Yeah, definitely. I think this is a really exciting time for thoracic oncology as we have more to offer our patients, especially for exon 20 and EGFR exon 20 specifically. We have 2 drugs now, FDA-approved, and mobocertinib is a small-molecule inhibitor. It's an oral drug, and this has been approved for patients who have EGFR exon 20 mutation. This is for patients who have already had platinum-based chemotherapy, and they have progressed, and these patients could now be treated with mobocertinib. Certainly, the activity, it seems like a very active drug. It's very promising. It's kind of similar to the other small-molecule targeted therapies that we have, but it does have side effects. Patients could potentially have diarrhea, which is kind of similar to other EGFR small-molecule inhibitors or drugs in the class, so it's something to kind of know when patients are being treated with this drug. Certainly, it's really nice to have more treatment options for these patients. So I think now we haven't had any EGFR small-molecule inhibitors show significant efficacy in this patient population, so this is a really welcome approval for patients. And there's also a new drug, which I'm sure Dr. Le is going to be talking about, amivantamab, which could also be an option for these patients. Dr. Aggarwal: Speaking of, let's turn to Dr. Le about amivantamab. Can you tell us a little bit more? Dr. Le: Yeah, amivantamab, again, represents a very exciting approval. I think, like Dr. Velcheti was talking about, the small-molecule inhibitor, but amivantamab represents a brand-new class of potential agents for exon 20 and many other oncogene targets in lung cancer. So amivantamab, as the name signifies, is an antibody drug. It's not an oral drug. It's an IV drug. The antibody has 2 heads, basically. One is targeting EGFR. The other is targeting another oncogene called MET. So it's a bispecific antibody. The mechanism of action is also different than the small-molecule inhibitor such as mobocertinib in that it's not disabling the ATP-binding kinase activity of EGFR, rather than its antibodies to go after the EGFR on the cell surface and disable or internalize the receptor a different way. So I say that we're excited because it represents a really brand-new group of targeted therapy that we're probably going to see coming in the next decade, not just limited to the small-molecule inhibitor, of course, from the research, and also opens opportunity for future combinations. In terms of usage, so again, this medication is approved in patients who have EGFR exon 20 insertion, who had prior treatment. It's an IV treatment, and then the IV is rather frequent, every 2 weeks. The drug showed really great safety and then induced response in about 40% of the patients, a nice addition to the tools we have that we can battle the disease. Dr. Aggarwal: It's amazing that we have 2 drugs in this space. Can you talk, in your personal experience, pros and cons of each approach and if there is any data to guide using 1 drug versus another or in sequence? We'll start with you, Dr. Le, and then we'll go to Dr. Velcheti. Dr. Le: Yeah. So that's a very good question. I don't think we have the 1 perfect answer because we haven't conducted either head-to-head trials or sequential trials. When I'm in my clinic, I tell my patients that both of them are valid options. And most likely, 1 patient will be receiving 1 and the other because I think each of the medications also have a limit of after a certain time, the disease will continue to progress. So we shouldn't be ruling out either of them rather than thinking of them as being the sequential treatment. One thing I do also discuss with the patient is the drug administration - one is IV; one is oral - and then toxicity profile. The amivantamab, the most common issue is the infusion reaction in the first time that the patient's receiving it. However, after that's properly managed, the drug is really easy to tolerate down the line. So usually, I present both options to patients. I would have to say that numerically speaking, the response rate of amivantamab is higher than the reported of mobocertinib. So sometimes, together with the patients and family, we decide to go for amivantamab first and then save oral TKI as the next option, but really, there's no right or wrong. And then I tell the patient most likely, they will be receiving both in the end. Dr. Aggarwal: Your thoughts, Dr. Velcheti, on that approach? Anything different that you do? Dr. Velcheti: No, I completely agree with Dr. Le. Both of them are very different drugs. So Dr. Le mentioned they work in very different ways. They have, most importantly, very different adverse event profile. So we don't know about what the right sequencing should be. We don't have those studies to really inform us. But I do the same thing that Dr. Le just mentioned. Given slightly higher response rates, we tend to use amivantamab first, but again, it's really patient preference. I've had patients who said they don't want to have IV infusions. They prefer oral treatment. They don't want to come into the hospital that often. And there are some patients who are really concerned about the diarrhea. So it's really hard to kind of know what would be the perfect sequence, and especially, it's a rare population, so it's going to be really hard to do a trial, to kind of do a cross-trial comparison. That's all we have here in terms of making decisions. The other thing to also consider is, do we use these 2 drugs, one after the other, if they progress? I think given that they work in a very different way mechanistically, I do think if you progress on mobocertinib that doesn't necessarily mean you will not respond to amivantamab and vice versa. So I would encourage trying sequential approach. And also the other thing to also keep in mind is there are a lot of clinical trials with exciting drugs which are in the pipeline, and, of course, some of the data has already been presented and those look really promising. So I highly encourage patients to kind of consider participating in clinical trials. Dr. Aggarwal: That's such a fantastic summary. And Marcia, I will turn to you. What do these new drugs mean for patients with this rare subset of an actionable mutation? Marcia Horn: I totally agree with Dr. Le and Dr. Velcheti and their comments based on their deep, deep experience with EGFR exon 20 insertion patients. No question that, from the point of view of the Exon 20 Group, we were totally thrilled at the FDA approvals of both amivantamab and mobocertinib. And we, like everyone else, affectionately call both drugs as ami and mobo. These drugs are providing a concrete lifeline of hope, for the first time, that patients' lives can be extended and patient journeys can be manageable in terms of side effects. So what we're really excited about in the Exon 20 Group is not only the continuing clinical development of ami and mobo and other promising drugs in the pipeline, as Dr. Velcheti said, but we're looking forward to seeing ami and mobo in combination with second drugs. We're awaiting data down the road, obviously, from the ongoing amivantamab plus lazertinib trial that is recruiting, in part, EGFR exon 20 insertion patients, and we're really excited about drugs that can be combined with mobocertinib as well. We want a robust pipeline of numerous choices and good compounds. Dr. Aggarwal: And Marcia, given the amount of information in this subgroup, what questions should patients ask their doctors about these new treatments? Marcia Horn: We really think it's important for patients on diagnosis to ask their clinicians what the method of communication is going to be between patient and physician. This is not only important on diagnosis of EGFR exon 20 insertion mutated cancer, but it's really, really important when the patient is accessing either ami or mobo or a drug in clinical trials. So patients need answers on who is going to be answering their questions about side effects when they write those questions into a patient portal, and they have to have the sense that somebody is going to be listening to them in the event that the collateral medications that an oncologist may be giving them in conjunction with a clinical trial drug or in tandem with either ami or mobo-- if those collateral medications are not tamping down on side effects to the extent that we all want to see, we, for sure, want that patient to be talking to the treatment team, the study team, or whoever, and getting some quick answers because frankly, nothing is more tragic than a patient withdrawing from a drug for failure to manage toxicities, and we never want to see that happen. We do everything possible at the Exon 20 Group to make sure patients are outfitted with angel buddies who have lived, battle-hardened experience with that particular drug, and these drugs are manageable. Dr. Aggarwal: So much excitement going on in this space, and we are thrilled to be able to offer these approaches. But I will just summarize that we wouldn't be able to extend these benefits if we don't test, and comprehensive testing remains critical in diagnosing and delivering appropriate therapy. Thank you so much, Dr. Le, Dr. Vamsi Velcheti, as well as Marcia, for joining us today for this Cancer.Net podcast. You can learn more about lung cancer and how it's treated by visiting Cancer.Net. Thank you, everyone. Dr. Le: Thank you. Marcia Horn: Thank you. ASCO: Thank you, Dr. Aggarwal, Dr. Le, Dr. Velcheti, and Ms. Horn. Learn more about lung cancer at www.cancer.net/lung. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

An interview with Dr. Jaishri Blakeley from Johns Hopkins University School of Medicine in Baltimore, MD, and Dr. Nimish Mohile from the University of Rochester Medical Center in Rochester, NY, co-chairs on “Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline”. This guideline addresses evidence-based therapies for patients with newly diagnosed and recurrent gliomas. Read the full guideline at www.asco.org/neurooncology-guidelines.   TRANSCRIPT [MUSIC PLAYING]   SPEAKER 1: 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. SPEAKER 2: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Jaishri Blakeley from Johns Hopkins University School of Medicine in Baltimore, Maryland, and Dr. Nimish Mohile from the University of Rochester Medical Center in Rochester, New York, co-chairs on therapy for diffuse astrocytic and oligodendroglial tumors in adults American Society of Clinical Oncology and Society for Neuro-Oncology guideline. Thank you for being here, Dr. Blakeley and Dr. Mohile. SPEAKER 3: Thank you. SPEAKER 4: Thank you. SPEAKER 2: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with a publication of the guideline in the Journal of Clinical Oncology. Dr. Blakeley, do you have any relevant disclosures that are directly related to this guideline topic? SPEAKER 3: No, I do not. SPEAKER 2: Thank you. And Dr. Mohile, do you have any relevant disclosures that are related to this guideline topic? SPEAKER 4: No, I don't have any relevant disclosures. SPEAKER 2: Great. Thank you. Then let's get into the content of this guideline. So Dr. Mohile, can you start by giving us a general overview of the scope and purpose of this guideline? SPEAKER 4: Yeah, so over the past 10 years, there have been several positive clinical trials in various glioma subtypes, and several of them have demonstrated a benefit for chemotherapy. The primary purpose of this guideline is to help practicing clinicians understand how these trials might impact treatment for patients with gliomas. During this period, there's also been two updates to the World Health Organization classification of gliomas, and the terminology of gliomas has changed. So what we call tumors today is different from what we might have called them 10 years ago. And so a second purpose of our guideline is essentially to provide a key or a translator so a clinician can look at a pathology report today in 2021 with a current terminology and know what to do with that patient and what treatment best fits for that patient today based on what they would have been called in a trial several years ago. SPEAKER 2: Great. That makes a lot of sense. So then Dr. Blakeley, looking at this guideline, it addresses four clinical questions, which are after maximal safe surgical resection, what are the evidence-based therapies for adults with newly diagnosed glioma including optimal regimens, settings, and timing of therapy? Then also, what are the appropriate therapies for adults with recurrent glioma, including optimal regimens, settings, and timing of therapy, followed by what should the effect of MGMT promoter methylation status be on choice of therapy and if there are subpopulations that should affect the choice of therapy. I'd like to review the key recommendations for those clinical questions. In reading through the guideline, the expert panel provided recommendations based on the IDH mutation status and the diagnostic categories in the WHO 2016 and 2021 classification systems for tumors of the central nervous system. So it seems appropriate to review the recommendations in this manner as well. Starting with IDH mutant astrocytic and oligodendroglial tumors, what is recommended for patients with oligodendroglioma, IDH mutant, 1p19q deleted CNS WHO grade 2 or 3? SPEAKER 3: Absolutely, and I'll just summarize for our listeners to help simplify that as you said, essentially, all of the guidelines are divided along molecular markers. And the first cohort are 1p19q co-deleted gliomas. Something that is a 1p19q deleted gliomas also an oligodendroglioma. Those are interchangeable. If you are 1p19q co-deleted, you have oligodendroglioma and vise versa. In general, 1p19q co-deleted tumors also are IDH mutant. So you can consider that one bundle. And oligodendroglioma is something that is 1p19q co-deleted and IDH mutant. And for that whole classification, whether it's WHO grade 2 or WHO grade 3, the recommendation is for radiation followed by the combination of procarbazine, CCNU, and vincristine, based on two prospective studies that showed similar results at different time points. There are a couple of modifications to that guideline. There is a statement that if people feel that the combination of Procarbazine, CCNU, and Vincristine, also called PCV, is too toxic, they can consider temozolomide as an alternative for this subclass of tumors 1p19q co-deleted IDH mutant. And also, importantly, the 1p19q co-deleted grade 2 gliomas are some of the best performing tumors in terms of prognosis of all glial tumors and maybe all CNS tumors. And so there is a statement in the recommendations that say-- it says it is reasonable to defer therapy under appropriate circumstances. And the text goes into what those appropriate circumstances might be, including how much of a resection could be achieved, what the functional status of the person is, how old they are, et cetera. But big picture-- 1p19q co-deleted tumor equals an oligodendroglioma, and those are almost all IDH mutant. And the bottom line recommendation is radiation followed by PCV with the parentheses saying temozolomide might be a reasonable alternative to PCV, and if you have a particularly benign presentation with a grade 2 tumor, you can consider deferring that therapy start for a time. The next big bundle is astrocytic tumors that are not 1p19q co-deleted. So in the guidelines, those are termed as 1p19q non-co-deleted. And those tumors do come in two flavors-- IDH mutant or IDH wild type. And I'm going to focus on the IDH mutant because they track closer to the oligodendroglioma, but they are kind of a bridge between the very good prognosis associated with oligodendrogliomas and the more aggressive prognosis associated with malignant gliomas. And for this cohort, the 1p19q non-co-deleted IDH mutant cohort, the recommendation is for radiation therapy with adjuvant chemotherapy, and there is data that supports that adjuvant chemotherapy being either PCV or temozolomide. We don't prioritize between those two regimens. And why I'm highlighting the word adjuvant is in some centers, there is a tendency to use temozolomide concurrent with radiation therapy. And the recommendation for these 1p19q non-co-deleted IDH mutant WHO grade 2 tumors is not to use it concurrent but to use it in the adjuvant setting. And then I will round out with talking about IDH wild type. So now we're, again, 1p19q non-co-deleted but IDH wild type. Those tumors may act closer to the glioblastoma. And in that setting, we would say-- the recommendations say to treat with radiation and consider concurrent temozolomide as you would with glioblastoma or only adjuvant temozolomide as you would with the lower grade astrocytoma. SPEAKER 2: Great. Thank you for going through that and providing such clarity to those recommendations. Then following that, Dr. Mohile, moving on to glioblastoma and other IDH wild type diffuse glioma, what are the key recommendations for people with newly diagnosed glioblastoma IDH wild type CNS WHO grade 4? SPEAKER 4: So in the current classification, IDH wild type CNS World Health Organization grade 4 is what we've known of classically as glioblastoma. And for patients with glioblastoma who are fit and can tolerate therapy, we recommend treatment with radiation, concurrent temozolomide, and a six month course of adjuvant temozolomide. We also recommend that they can receive alternating electric field therapy along with the adjuvant temozolomide. Now the recommendations become a little bit more complicated for patients who might not be as fit-- so patients who might be older, have poor performance status, have other measures of frailty. And the way we wrote this is we said that if a patient who is undergoing a six week course of radiation, if that course of radiation, if the benefits did not outweigh the harm, then you could consider alternate regimens. And these include shorter courses or hypofractionated courses of radiation with or without chemotherapy and also includes courses that are chemotherapy alone. So in people who have tumors that have MGMT promoter methylation, we can consider the option of temozolomide alone. So this would be specifically for patients who either are older, more frail, who we feel are going to have difficulty going through a radiation course. There is some data to support this temozolomide alone approach. SPEAKER 2: Thank you. I appreciate you going through those recommendations very clearly as well. You clearly put a lot of effort into these recommendations. So then, Dr. Blakeley, what is recommended for patients with astrocytomas IDH wild type CNS WHO grade 2 or 3? SPEAKER 3: Yes, thank you. So as Dr. Mohile was just saying, for glioblastoma, you can really think about the recommendations for WHO grade 4 very similarly for IDH wild type independent of grade. And that is a new shift in the management of gliomas in adults. Previously, the histologic grading had a lot of weight on whether or not we would offer radiation and chemotherapy. But with the new prognostic and predictive value known associated with the IDH1 mutation or lack of mutation being IDH wild type, the recommendation is if somebody is IDH wild type CNS WHO grade 2 astrocytoma or grade 2 or grade 3, they would be offered treatment similar to a glioblastoma, which would be concurrent radiation and temozolomide followed by adjuvant temozolomide as long as performance status and all other factors support doing so. SPEAKER 2: Understood. I appreciate you providing that information as well. So were there additional areas where the expert panel found evidence either insufficient or was unable to make a recommendation? SPEAKER 4: Yeah, so there's two tumor types where we didn't have enough data to make a specific therapeutic recommendation. The first, unfortunately, is in recurrent glioblastoma. And there were no randomized controlled trials that demonstrated a benefit of one therapy over another. And so our recommendation is that when available, patients should be referred for a clinical trial. The other area is in a tumor type called diffuse midline glioma. This is a tumor characterized by the h3k27 mutation more commonly seen in children. But we do see this in adults. And here as well, there were no randomized trials that could clearly give us guidance on what the best therapy was even in the newly diagnosed setting. And our recommendation here also was, if available, to be considering a clinical trial. SPEAKER 2: Understood. It's important to recognize where there are areas where we're lacking evidence as well. So then, Dr. Blakeley, in your view, why is this guideline important and how will it change practice? SPEAKER 3: Thank you. Well, as Dr. Mohile said at the start, it is quite challenging to review the literature for gliomas in adults because we've had different nomenclature applied across clinical trials and diagnostic studies over the last 10 to 15 years. And this document and these guidelines really seek to be the clearinghouse to help clinicians match up what they see on the pathology report for their patient to the data that is published on phase III studies that has influenced our current standards of care. So I think the most important way it will change practice is bringing clarity to the data that already exists but has not been accessible to providers trying to help patients make the best decisions for them. It also importantly highlighted how much more work is needed. We desperately need new clinical trials for patients with glioblastoma and patients with astrocytoma IDH wild type 1p19q non-co-deleted WHO grade 2 and 3 and the other areas that Dr. Mohile highlighted. But we're hopeful that this will help provide clarity on both what we do know to help us identify patients who have the best chance of truly meaningful benefit from chemotherapy and where we need to invest more resources. SPEAKER 2: Absolutely. It seems like this will be a helpful resource for how to treat now and a guide as to what areas of research should be investigated in the future. So in addition to that, Dr. Mohile, finally, how do you view that these guideline recommendations will impact patients? SPEAKER 4: Yeah, my hope is that this will help standardize our approach to patients with gliomas. In the United States, patients with gliomas get care in all kinds of different settings. And when they're seeing an oncologist, particularly in the community, this might be a very small percentage of the types of cancers that they might be seeing, and it's hard to keep up with all of these trials and hard to keep up with the changes in classification. So our hope is that this guideline helps that oncologist in providing them the clarity, as Dr. Blakeley said, on how to approach treatment here so that all of our patients are getting the best standard of care based on the best available evidence and that they're being considered in those areas where there is not good evidence or referral for clinical trials so that in 10 years, when we put together the next guideline, that we're able to make some progress on some of these questions. SPEAKER 2: Great. Well, thank you both for all of your work that you did to review the literature and produce these evidence-based recommendations and, as you said, provide a real clear and helpful resource to both clinicians and to improve the quality of care for patients. And thank you for taking the time to speak with me today, Dr. Mohile and Dr. Blakeley. Finally, thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/neurooncology guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Leslie Fecher from the University of Michigan Health System, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews considerations for the use of steroids to manage immune-related adverse events in patients treated with immune checkpoint inhibitor therapy in the final episode of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today we're continuing our series on the management of immune related adverse events. I am joined by Dr. Leslie Fecher from the University of Michigan Health System in Ann Arbor, Michigan, author on "Management of Immune Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy. ASCO Guideline Update" and "Management of Immune Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T Cell Therapy, ASCO Guideline." And today we're focusing on considerations for the use of steroids to manage immune related adverse events in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Fecher. LESLIE FECHER: Thank you, Brittany, for this invitation. BRITTANY HARVEY: Great. Then I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with a publication of the guidelines in the Journal of Clinical Oncology. Dr. Fecher, do you have any relevant disclosures that are related to these guidelines? LESLIE FECHER: The details of my disclosures are included in the manuscript, but I'd just like to note that I have received research funding, specifically in the form of clinical trial funding, from companies that do manufacture these immunotherapies. BRITTANY HARVEY: Thank you. Then getting into the content, so steroids are valuable agents in the management of immunotherapy related adverse events. So first, what should clinicians consider pretreatment with steroids? LESLIE FECHER: So I think one of the first things is obviously going back to the traditional history and physical exam, and making sure you understand any preexisting comorbid conditions, such as diabetes, high blood pressure, preexisting cataracts or glaucoma, infections, osteopenia or osteoporosis. It's always good to try and optimize things before getting started on steroids. Additionally, it's typically considered very reasonable to check hepatitis B and C serologies prior to starting immunotherapy treatment. And also consideration of assessment for tuberculosis, if there are specific risk factors, understanding if somebody already carries a diagnosis of HIV, and Understanding the status of that in advanced would be relevant. BRITTANY HARVEY: Those are important considerations. Then in addition to that, how should opportunistic infections be prevented? LESLIE FECHER: So one of the most common infections that we tend to try and prevent is pneumocystis jirovecii pneumonia, or PJP, previously known as PCP pneumonia. And this is one of the more common things that we recommend prevention for. So in patients who have received the equivalent of prednisone dosing of 20 milligrams per day for four or more weeks, or greater than 30 milligrams per day for three weeks or more, that's when it would reasonably be indicated. There are obviously specific institutional guidelines for the preferred regimen, but I think that's important to consider. The role of viral prophylaxis as well as antifungal prophylaxis is a bit less clear, but is something to be considered, especially depending on the duration of the steroid course. And whether or not in the setting of herpes zoster, for example, if the patient has had issues with zoster in the past. BRITTANY HARVEY: OK. and then the use of these steroids is to treat immunotherapy related adverse events. But what are the key recommendations for monitoring both the short term and long term adverse effects from steroids? LESLIE FECHER: So I think being aware of the side effects as well as making sure that the patients and the family members or loved ones that are helping them are aware of them as well. From a short term standpoint, typically we recommend things such as GI prophylaxis, with either a proton pump inhibitor or a histamine 2 antagonist, to reduce or prevent gastric ulcers or duodenal ulcers or gastritis. Given some of the long term effects, such as bone loss as well as steroid myopathies, we encourage exercise as well as physical therapy in some circumstances. But really one of the most important things is to make sure that you're constantly both assessing and eliciting from the patient and family members for any other side effects. So often, common acute short term side effects can be increased risk of infection. So making sure you're asking about it. They may not have the typical manifestations of infection, such as fevers or chills. Insomnia or difficulty with anxiety, irritability, skin changes for sure, or high blood pressure. And then obviously being aware that laboratory evaluation for glucose intolerance is important as well. BRITTANY HARVEY: Definitely. Those are important points for clinicians, patients, and caregivers. So then we've had some of the other authors on this guideline talk about tapering steroids. So what are those recommendations on how clinicians should taper steroids? LESLIE FECHER: So tapering is an art in and of itself in my opinion, and there's lots of different ways to do it. Some general concepts are you want to really try and understand what the side effect is that you are managing, because that will require frequent reassessment. And so when we talk about reassessing patients during the treatment of their toxicities, the management of the toxicities, in my opinion, is almost as important as the management of the immunotherapy itself. And so patients still need to be seen, still need to be assessed, still need blood work done. And so reassessment for the toxicity that you're managing, given that we can see rebounding of symptoms. So for example, if they were getting treated for diarrhea or colitis, having a really good understanding of what their baseline bowel movements were, how bad they got, and then a constant reassessment and making sure that the patient, as well as the family, knows that this should not come back again, if you will, in the midst of the taper. I think the other things to be aware of is that I tend to always reassess before giving the next decrease in dose of the steroids rather than having an automatic decrease. Because again, patients sometimes will follow those, even if their symptoms recur. So ensuring that there's that, again, reassessment. When we're on oral steroids, some of the general concepts we say is that the course should be at least usually about four weeks total, sometimes as long as six weeks or even longer, depending on the toxicity. And we think about, on average, decreasing from a prednisone or prednisolone amount roughly 10 milligrams every three to seven days, depending on the side effect that you're managing. The longer the taper, the slower you might need to go, depending at the end. And also being aware of the risk of adrenal insufficiency towards the end of a long steroid course is also an important thing to assess for. BRITTANY HARVEY: Great. I appreciate you reviewing those considerations. So then in your view, Dr. Fecher, how will these recommendations for the use of steroids in the management of immune related adverse effects impact both clinicians and patients? LESLIE FECHER: I think it will bring ongoing awareness to the physician and their team, as well as the patient and their team. I think that this is obviously really important that everybody is involved and aware. And I use the term engagement from a patient and family member standpoint. It's really critical to have an understanding of the side effects, have an understanding of the prednisone management. And explaining that not only to the physician team and nurses and other people involved in their care, but when patients call in, that they know to look out for rebounding of their symptoms and to report them immediately, as that can impact steroid tapering. I think, again, the awareness and engagement is going to ensure that patients get the best care and best results. BRITTANY HARVEY: Absolutely, and thanks for highlighting both that awareness and engagement. So thank you so much for your work on these guidelines, and for taking the time to speak with me today, Dr. Fecher. LESLIE FECHER: Thank you so much, Brittany. I appreciate your time. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

An interview with Dr. Marc Ernstoff from the National Cancer Institute, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” He reviews identification, evaluation & management of ocular toxicities in patients receiving ICPis, including uveitis, iritis, and episcleritis in Part 12 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today we're continuing our series on the management of immune related adverse events. I am joined by Dr. Marc Ernstoff from the National Cancer Institute in Bethesda, Maryland, author on "Management of Immune Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy, ASCO Guideline Update" and "Management of Immune Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T Cell Therapy, ASCO Guideline." And today we're focusing on ocular toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Ernstoff. MARC ERNSTOFF: Thank you, Brittany. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Ernstoff, do you have any relevant disclosures that are directly related to this guideline? MARC ERNSTOFF: I have no further disclosures at this time. SPEAKER 1: Great. Thank you. Then let's get into these ocular toxicities. So first, what are the immune related ocular toxicities addressed in this guideline? MARC ERNSTOFF: So the ocular toxicity is addressed in the guidelines represent a relatively uncommon side effect of immune checkpoint inhibition, and represents inflammation of all components of the eye from the superficial component to the internal uveal component. So there is iritis. There's episcleritis and uveitis, are the ones that are usually identified by physical examination and by complaints. BRITTANY HARVEY: Understood. Then so let's start with what are the key recommendations for identification, evaluation, and management of uveitis and iritis. MARC ERNSTOFF: So those are excellent questions. I think that it's important for clinicians to recognize that while most of the eye toxicities are relatively minor, low grade, and can be managed effectively, there are some that are very important to identify, particularly as they may lead to blindness, particularly uveitis or pan uveitis. So identification of these symptoms and signs are important. So evaluation of the patient by asking whether there are any eye symptoms-- dryness or irritation-- is important in your evaluation of the patient's side effects. In addition, looking at the eye, both with a penlight, looking for any inflammatory signs, and doing a ophthalmologic examination to make sure there's no cloudiness or anything identified in the retina is important. BRITTANY HARVEY: Great. And then furthermore, what are the key recommendations for identification, evaluation, and management of episcleritis? MARC ERNSTOFF: So episcleritis can usually be seen by irritation in the superficial areas of the eye. Usually if it's low grade, it can be managed with topical steroids and continuation of the immune checkpoint inhibitor. On the other hand, if it's more bothersome and not responding to topical therapy, evaluation by an ophthalmologist, potentially interruption of immune checkpoint inhibitor, is important. And if it's severe, systemic steroids might be required at that time. BRITTANY HARVEY: Great. Thank you for reviewing how to best identify and manage that particular toxicity. So then in your view, how will these recommendations for the management of ocular toxicities impact both clinicians and patients? MARC ERNSTOFF: So again, I think it's important that both from symptom management, that these, many times, can be managed with topical steroids and tears effectively, and that a patient's therapy can continue, which I believe is important. On the other hand, identifying areas that may be beyond the expertise of an oncologist, would require evaluation by an ophthalmologist, including a slit light examination. It is important to recognize that uveitis can have minimal symptoms and yet be more severe in its condition, requiring intervention and holding of immune checkpoint. And if really severe-- grade 3 or 4-- the interruption and discontinuation of immune checkpoint inhibition is probably going to be required to manage the side effect. Again, if undiagnosed and untreated, it can lead to blindness. So while not quote life-threatening, clearly a major impact in quality of life of a patient that is preventable, if identified. BRITTANY HARVEY: Great. Thank you so much for viewing these recommendations for the management of ocular toxicities, to ensure both the quality of life of patients and the best practices for management of these toxicities. So I want to thank you for your work on these guidelines and for taking the time to speak to you today, Dr. Ernstoff. MARC ERNSTOFF: Thank, you very much, Brittany. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

An interview with Dr. Pauline Funchain from Cleveland Clinic, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews the recommendations for cardiovascular toxicities in patients receiving ICPis, including overall cardiac toxicities (i.e., myocarditis, pericarditis & arrhythmias), and VTE in Part 11 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today we're continuing our series on the management of immune related adverse events. I am joined by Dr. Pauline Fontaine from the Cleveland Clinic in Cleveland, Ohio, author on "Management of Immune Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy, ASCO Guideline Update," and Management of Immune Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T Cell Therapy, ASCO Guideline." And today we're focusing on the cardiovascular toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Fontaine. PAULINE FONTAINE: Thank you, Brittany, for the invitation. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Fontaine, do you have any relevant disclosures that are directly related to these guidelines? PAULINE FONTAINE: So I do. My institution receives research funding from Pfizer and Bristol Myers Squibb for clinical trials where I'm a primary investigator. And I have done some consultation work with Eisai. BRITTANY HARVEY: OK. thank you for those disclosures. Then talking about the content of this guideline, what are the immune related cardiovascular toxicities addressed in this guideline? PAULINE FONTAINE: So there are two major categories. One is an overall cardiovascular category. That includes myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis. That's overall. And there's a second category of venous thromboembolism. BRITTANY HARVEY: Great. Then starting with that overall category, what are the key recommendations for identification, evaluation, and management of myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis? PAULINE FONTAINE: So in that overall category, I think it's important to recognize that there are symptoms that are a little bit more general. They may be cardiovascular. They may be pulmonary. But we have to be aware that some of these can be cardiovascular. So that would include worsening fatigue, progressive or acute dyspnea. I think they're generally going to be other things, but you really have to recognize a potential cardiac IRE, as those can have major medical consequences. I mean there are other things that are more obviously cardiac, like chest pain, arrhythmia, palpitations, acute onset peripheral edema. And it is important to note that they can, like every other IRE, happen at any time. In the literature, the median time to onset is 6 weeks, but the range is somewhere between 1.4 to 54, and we know that it can be all over the place with IREs in terms of presentation. Then next would be evaluation. So with evaluation, whenever you see this type of side effect, fatigue, dyspnea, chest pain, it's natural to want to get an EKG troponin. I think that's a great place to start. And I think if there's more concern for cardiac type of IRE, then an echocardiogram, a chest X-ray, I think, are probably the next easiest evaluations to assess for cardiac IRE. One of the important things to note is that cardiac IREs, especially myocarditis, tend to happen along with concurrent myocytis, so it's important to check a CPK to rule that in or rule that out. And typically, then if people need more evaluation, the cardiac MRI is the next step, but things like cardiac catheterization may be involved. And so that's where I think it's really important with management to have cardiology involved early. I mentioned this briefly before, but it's really important to know that myocarditis has a very high fatality rate, up to about 50% in published series. I think as we get better at recognizing myocarditis, that fatality rate will likely go down, but catching a cardiac IRE late can have some very serious implications for our patients. So immediately recognizing that a cardiac workup is necessary, and referring early to cardiology is really important, no matter what grade of cardiac IRE we see. And I do think that with cardiac IREs, it's really, is it an inpatient workup? Does it require immediate cardiac consultation and workup? If there are elevated troponins that are going up, or conduction abnormalities, does that patient need to be in a cardiac unit? I think those are the major things to keep in mind with management. Another thing, I think, that is really important because of the high fatality rate: starting corticosteroids early. So like our other IREs, you can start corticosteroids that 1 to 2 mgs per kg per day. And doing that early has the potential to quickly improve cardiac inflammation, keep people from the very serious and potentially fatal side effects for cardiac IREs. And it really doesn't have that much of a consequence in the short term. So I think in discussions about this guideline, we all felt that if a patient has a Grade 2 or higher IRE-- so that's anything that has a cardiac biomarker that's abnormal plus symptoms of any kind-- it's important to keep in mind early steroids and early cardiac consultation. For very, very severe cases where management with corticosteroids is not improving the patient's status, then we highly recommend considering cardiac transplant rejection doses, which would be methyl pred at 1 gram daily, or adding other immunosuppressants. So there are not as many studies as we would like, but mycophenolate, infliximab, antithymocyte globulin have all been reported. There have also been case reports on abatacept or alemtuzumab, with good outcomes. So those are things to consider, of course, with cardiology input for severe cases. BRITTANY HARVEY: Thank you. Those are important notes for clinicians to keep in mind for management and evaluation. So then, the second category that you mentioned, what are the key recommendations for identification, evaluation, and management of venous thromboembolism? PAULINE FONTAINE: So for identification, most everyone listening to this podcast knows what a venous thromboembolism looks like. That's extremity swelling, extremity pain, sometimes accompanied by fever, pleuritic pain, cough, dyspnea. And the evaluation is the same as what you would see in clinic. That would be venous ultrasounds for any suspected deep vein thromboembolisms. And CT, PE for any suspected pulmonary embolism. And of course, a VQ scan if you can't do that type of CT. And the management is the same as what you would normally do in clinic. So if it's a superficial thrombosis, that would be a grade 1. You would do a warm compress, do supportive care. But importantly, you can continue the immune checkpoint inhibitor per our recommendations. For grade 2, so a symptomatic thrombosis, a deep vein thrombosis, that would require anticoagulation. But again, once anticoagulation has been started, the recommendation is that it is safe to continue the immune checkpoint inhibitor therapy, because at this point, you're protected. Should be, in theory, protected from future embolic events. And then, I think the major thing is that for management in general once there is anticoagulation on board, then there isn't necessarily a reason to hold immune checkpoint inhibitor therapy. I think that the major reasons we would recommend to hold it are life threatening consequences, organ damage. So grade 4 embolic event, where you would have to admit the patient. And then it becomes a risk benefit discussion after an admission. In general, I think the recognition and treatment are the same in terms of venous thromboemboli that are identified in the context of immune checkpoint inhibitor therapy. The major thing is just to know that it exists as a potential side effect, that the incidences appear to be higher, and that there is something about immune checkpoint inhibitor therapy that may put our patients at higher risk for these embolic events. BRITTANY HARVEY: Definitely. That's key to know, and particularly also when to hold or continue ICPI therapy. So then in your view, Dr. Fontaine, how will these recommendations for management of cardiovascular toxicities impact both clinicians and patients? PAULINE FONTAINE: I think the major thing is to know that these exist. The overall cardiac toxicities are less common, so if we're talking about myocarditis, that is a pretty rare event. But it's important to know that this is an event that is potentially fatal, that that fatality happens often, and that myocarditis can occur along with a myositis, and in some cases with myasthenia gravis. So these are three different rare side effects that can happen together, sometimes in pairs, sometimes in triplets, sometimes just one of them. But any one of these three has a higher risk for fatality. So I think just to know that it's out there. So that that is just hanging around in the differential for someone who is tired or out of breath. It may be pulmonary, but also keep in mind that it could be cardiac, and that is serious, and that should be worked up early and treated early. I think that's the major thing that I hope these guidelines do, is put these important but rare side effects out there and potentially save lives. I will say for VTEs, for venous thromboemboli, again, so PE can happen, and it can be fatal. I think this is not as rare, but of course, it's not rare in our patient population either. So these are things that we already look out for. Just, I think, if this podcast and the guidelines can add to the education that immune checkpoint inhibitors will increase the risk of thromboembolism, I think that those are the important takeaways. BRITTANY HARVEY: Absolutely. Recognition of these IREs is a common theme across the affected organ sites that we've heard in many of these podcast episodes. So I want to thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Fontaine. PAULINE FONTAINE: Thank you for having me. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

An interview with Dr. Loretta Nastoupil from MD Anderson Cancer Center, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She discusses the identification, evaluation, and management of hematologic toxicities in patients receiving ICPis, including hemolytic anemia among others in Part 10 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at ASCO.org/podcasts. My name is Brittany Harvey. And today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Loretta Nastoupil from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy, ASCO Guideline Update, and Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy ASCO Guideline. And today, we're focusing on hematologic toxicities in patients treated with immune-checkpoint inhibitor therapy. Thank you for being here, Dr. Nastoupil. LORETTA NASTOUPIL: Thanks, Brittany. I'm happy to be here. BRITTANY HARVEY: Great. Then first I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Nastoupil, do you have any relevant disclosures that are related to these guidelines? LORETTA NASTOUPIL: Yes, Brittany. So I have received honorarium for participation in advisory boards from the following companies, including BMS/Celgene, Genentech, Janssen, Novartis, Merck, MorphoSys TG Therapeutics, and Takeda. And I've also received research funding support from BMS/Celgene, Gilead Kite, Genentech, Janssen, Novartis and Takeda. BRITTANY HARVEY: I thank you for those disclosures. Then let's get into what we're here today to talk about. So what are the immune-related hematologic toxicities addressed in this guideline? LORETTA NASTOUPIL: So it's important to recognize that hematologic toxicities that are immune-related as a result of immune therapy are infrequent occurrences. So it's important to recognize when they do occur and some of the unique workups given that they are so infrequent. So probably one of the most common is hemolytic anemia. It's important to recognize that these are cancer patients. And they may have multiple reasons for the development of acute or new onset anemia, but recognizing if they're on either checkpoint inhibitors or immune therapies, it's important to recognize that it might be spurred on as a result of immune-mediated anemia. We advise in terms of history and workup to consider whether or not they've been exposed to new drugs, whether or not they've had a recent insect or snakebite exposure. The recommended workup includes a CBC with also a peripheral blood smear to look for evidence of hemolysis or macroketosis. In addition, other hemolytic anemia workup includes evaluation for LDH, haptoglobin, reticulocyte count, bilirubin, and free hemoglobin. Other potential diagnoses on the differential include DIC, so a panel, including coags, PT, INR, and PTT, exploring autoimmune serologies, PNH screening, evaluation for infection such as viral or bacterial causes of hemolysis, and also consideration for bone marrow failure syndrome, including evaluation for potentially reversible causes, such as B12, folate, copper, parvovirus, iron, thyroid, infection, et cetera. G6PD level is helpful in the evaluation, as well as exploration as I mentioned of potentially new drugs that might be linked, including ribavirin, rifampin, dapsone, interferon, some of the antibiotics, such as cephalosporins, penicillins, NSAIDs, ciprofloxacin, for instance, et cetera. So as part of the workup, if we have excluded alternative causes and we think that the immune-checkpoint inhibitor might be the underlying cause of the autoimmune hemolytic anemia, then generally we will continue unless they have grade 2 or higher toxicity, which is generally a hemoglobin less than 10. In which case, we would recommend to hold the immune-checkpoint inhibitor, again, with significant anemia. So those with grade 2 or higher, you might consider initiating corticosteroids, including 1.5 to 1 milligram per kilogram per day until improvement. For grade 3 or higher-- so this is more severe anemia So hemoglobin is less than 8. Generally, we're recommending permanent discontinuation of the checkpoint inhibitor and potentially higher doses, including up to 2 milligrams per kilogram per day of prednisone or corticosteroid equivalent to speed up the recovery. In regards to transfusion requirements or consideration, we are suggesting you evaluate or consider your local or regional guidelines. We generally do not transfuse for a target hemoglobin greater than seven to eight. And we also recommend supplementation with folic acid. BRITTANY HARVEY: Great. And then beyond those recommendations for hemolytic anemia, what are the key recommendations for identification, evaluation, and management of acquired thrombotic thrombocytopenia purpura? LORETTA NASTOUPIL: Sure. So fortunately, TTP is quite rare, but, again, something that is worth exploring. Some of the challenges are in the clinical syndrome. And that it can mimic some of the other toxicities that are covered in other sections, particularly the neurotoxicity section. But essentially, for patients who have pretty dramatic change in platelet count, again, they may have additional clinical sequelae such as neurologic toxicity or adverse events. It's important to recognize that TTP might be an underlying cause, again, for patients who are on immune-checkpoint inhibitors. This is where a hematology consult early in the clinical course would be particularly of importance to recognize it and potentially to minimize offending agents. Drug exposure is always important, because many of these patients might have other drugs, in addition to their immune-checkpoint inhibitors, such as chemotherapy, sirolimus, tacrolimus, antibiotics et cetera. And so exploring offending agents is important. An ADAMTS13 level, an inhibitor titer, would be important to send if you're considering TTP, in addition to evaluating the peripheral smear, and the hemolytic anemia workup, as I just mentioned, including LDH, haptoglobin and reticulocyte count. Exploring infectious etiology, including CMV titers or serology, would be particularly helpful, an additional clinical evaluation, such as brain imaging with CT or MRI, echocardiogram, and EKG would be of help. For all grades of TTP, again, even with a clinical suspicion for the diagnosis, in addition to hematology consult, we recommend stabilizing the patient. That might require care in an acute care setting, making sure that they have adequate organ function and that this is stabilized. For grade 1 or higher, we recommend holding the immune-checkpoint inhibitor. And you might consider, again, initiation of corticosteroids with 0.5 to 1 milligram per kilogram per day of prednisone or an equivalent. For grade 3 or higher, we would, again, in addition to holding the checkpoint inhibitor and in conjunction with your hematology colleagues, you might initiate a therapeutic plasma exchange. Again, in accordance with existing guidelines, you may consider higher doses of steroids, including methylprednisolone 1 gram IV daily for three days. You could consider some additional supportive agents, such as rituximab or pembrolizumab if the ADAMTS13 level is less than 10 or less than 10% of normal and an inhibitor or elevated ADAMTS13 IgG has been detected. BRITTANY HARVEY: I appreciate you going through the details for TTP. So then, additionally, this guideline addresses aplastic anemia. So what are the key recommendations for identification, evaluation, and management of aplastic anemia? LORETTA NASTOUPIL: Yeah. So fortunately, again, these are quite rare situations. So with aplastic anemia, similar to what we've discussed in terms of workup of anemia, globally, it's important to explore potentially causes of, again, bone marrow failure syndrome. And aplastic anemia is one of those such causes. Exploration of a bone marrow biopsy in conjunction, again, with your hematology consult would be critically important, and exploring potentially reversible causes, again, such as deficiencies and important nutrients, viral etiologies, in addition to parvovirus, CMV, HHV-6 is important to consider and rule out. But I think the end of the day, a bone marrow biopsy and aspirate is going to be the most helpful assessment to ensure that aplastic anemia has been considered and worked up. In regards to management of aplastic anemia, we're going to hold the immune-checkpoint inhibitor. You may need to provide additional support such as growth factors. And close follow-up, I think is the most critical aspect of this. Sometimes we initiate patients on corticosteroids. We hold the checkpoint inhibitor. And then we may monitor them less frequently. Oftentimes, these patients with high malignancies are going to need to be followed very closely, sometimes weekly or multiple times a week. So in regards to management of aplastic anemia that might be immune mediated as a result of immune-checkpoint inhibitors and in conjunction with your hematology and colleagues, consideration of management might include administration of horse ATG and cyclosporine, but again transfusion support, growth factor support, even consideration for HLA typing and evaluation first. Stem cell transplantation might be appropriate, particularly for a young patient with minimal comorbidities. For grade 3 or higher, in addition to these considerations, we're going to hold the checkpoint inhibitor and monitor weekly for improvement. If no response, you might consider repeating immune suppression with Rabbit ATG plus cyclosporine or cyclophosphamide. And for refractory patients, consider eltrombopag plus best supportive care. BRITTANY HARVEY: Great. Thank you. Those are important notes on the management of aplastic anemia. So then, additionally, what are the key recommendations for the identification, evaluation, and management of lymphopenia? LORETTA NASTOUPIL: Yeah. I think one of the challenges with lymphopenia, it's common for patients who've had cancer-directed therapy, particularly things like chemotherapy. And so understanding whether or not this is a new onset after exposure to checkpoint inhibitors is one of the critical aspects, in addition to considering alternative causes. But for patients in which we do think the lymphopenia is a result of the immune-checkpoint inhibitor, we're not generally advising discontinuation or holding of the immune-checkpoint inhibitor, but it is important to consider best supportive measures, including whether or not patients might benefit from monitoring for reactivation of certain viral etiologies, including CMV and HHV-6, for instance, in addition to potential consideration for prophylactic strategies, such as PJP prophylaxis. Also, zoster reactivation might be something that these patients might indeed be at risk for. So as opposed to holding your checkpoint inhibitor and initiating things like corticosteroids, if we have excluded alternative causes and think lymphopenia is a result of the immune-checkpoint inhibitor or as immune mediated, ensuring that they are receiving best supportive care to mitigate some of their toxicity that may result as the result of the lymphopenia. BRITTANY HARVEY: Understood. And it's important to note for clinicians that management is different from a lot of the management of the other hematologic toxicities. So then the last hematologic toxicity that was addressed in this guideline was acquired hemophilia A. So what are those key recommendations? LORETTA NASTOUPIL: Acquired hemophilia A, again, fortunately is very rare and uncommon, but this is one situation where engagement of a hematologist, who is an expert in management of hemophilia, will be critical. So that would potentially be step one. In terms of laboratory assessment, that would be helpful, in addition to your CBC, where you're assessing things like platelet count, coagulation workup, including fibrinogen, PT, PTT, INR, that would be informative. Patients with acquired hemophilia A will likely have a prolonged activated PTT with a normal PT. So that might be one of the clues. Imaging would be helpful to ensure the patients don't have any signs of spontaneous bleeding or hematoma basis, such as MRI, CT, or ultrasound, if particularly they have any localizing symptoms. Medication review to look for alternative causes would always be helpful. And determination of the Bethesda unit level of inhibitor would be critical. In regards to management, we would hold the checkpoint inhibitor, initiate corticosteroids, transfusion support as indicated, and you want to treat the underlying acquired hemophilia with conjunction of a hematologist. For grade 2 or higher, this may require factor replacement. And the choice is usually based on the Bethesda unit of the titer. Administration of prednisone, in addition to rituximab 375 milligrams per meter squared weekly for four weeks or cyclophosphamide dosed at 1 to 2 milligrams per kilogram per day may be patient specific. And, again, that decision should be made in conjunction with your hematology consult. Prednisone, rituximab, and cyclophosphamide should be given for a minimum of five weeks. And factors should be prescribed to increase the level, particularly during bleeding episodes. And, again, the choice of the factor is based on the presence or absence of an inhibitor. For grade 3 or higher, we advise to permanently discontinue the immune-checkpoint inhibitor. These patients generally will be admitted for stabilization. They do require factor replacement. Bypassing agents may also be required, including factor VII. Caution should be taken in elderly patients and those with coronary artery disease. Corticosteroids, rituximab, and cyclophosphamide should also be considered, transfusion support, if they're having active bleeding. And if worsening or no improvement, you could consider adding cyclosporine or immune suppression to try and stabilize these patients. Again, acquired hemophilia A requires special clinical and laboratory expertise. This would require consult and potentially even transfer to a specialized center, and consultation with a hemophilia center should be initiated as soon as this is considered or confirmed. BRITTANY HARVEY: That's a great summary of these recommendations. The expert panel and you clearly put in a lot of work into these recommendations. So then in your view, how will these recommendations for the management of hematologic toxicities impact both clinicians and patients? LORETTA NASTOUPIL: I think the most important thing are disseminating this information. I think ASCO plays a critical role in helping clinicians first recognize some of the toxicities that are different from what we have traditionally seen with chemotherapy and may have different management strategies. So guidelines, such as this, are critically helpful. Podcasts, such as this, are incredibly helpful to get the information out, recognizing that all of us authors are more than willing to provide additional guidance and are willing to be contacted in this situation where someone's facing one of these unique and rare toxicities and would like some additional guidance in terms of further management. Hematologic toxicities are sometimes hard to distinguish or maybe potentially hard to recognize, given many of these patients may have been on prior chemotherapy agents, and anemia or thrombocytopenia may not be unusual, but recognizing if it's new or more severe than what has been seen previously and that, at least, consideration of an immune-mediated hematologic toxicity, be considered, because the management might be unique. And so I hope that we've outlined today some of the hematologic toxicities that are rare that may be seen with immune therapy and some of the strategies to work up alternative diagnoses and management if it is indeed immune-mediated toxicity. BRITTANY HARVEY: Definitely. And I really appreciate you going through these rare but very important toxicities. So thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Nastoupil. LORETTA NASTOUPIL: Thanks, Brittany. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.ASCO.org/supportive care guidlines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews neurologic toxicities in patients receiving ICPis, such as myasthenia gravis, Guillain-Barre Syndrome, peripheral neuropathy, aseptic meningitis & encephalitis in Part 9 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey. And today, we're continuing our series on the management of immune related adverse events. I am joined by Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center in New York, New York, author on Management of Immune Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy ASCO Guideline Update and Management of Immune Related Adverse Events in patients Treated with Chimeric Antigen Receptor T Cell Therapy ASCO Guideline. And today, we're focusing on nervous system toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Santomasso. BIANCA SANTOMASSO: Thank you for having me. BRITTANY HARVEY: Then I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Santomasso, do you have any relevant disclosures that are directly related to these guidelines? BIANCA SANTOMASSO: Yes, I'd like to disclose that I've served as a paid consultant for Celgene, Janssen Pharmaceutical, and Legend Biotech for advising them on the topics of T cell therapy side effects. BRITTANY HARVEY: Thank you. Then getting into the content of this guideline, what are the immune related nervous system toxicities addressed in this guideline? And what are the overarching recommendations for evaluation of these neurologic immune related adverse events? BIANCA SANTOMASSO: So neurologic immune related adverse events actually encompass a very diverse spectrum of neurologic syndromes that can occur as a complication of treatment with checkpoint inhibitors. So the spectrum that is covered by this guideline includes myasthenia gravis, Guillain-Barre syndrome, polyneuropathy, aseptic meningitis, and encephalitis. And although these are rarer than many of the other immune related adverse event types affecting other organ systems, they're increasingly being encountered due to more patients being treated with novel combinations of immunotherapies. And they're important to recognize, because along with myocarditis, they have generally more morbidity and even more mortality than irAEs affecting other organ systems. So it's important for clinical care providers to have a high index of suspicion for these events. Studies have suggested that these tend to occur in about 3% to 12% of patients, probably between 1% and 2% of patients developing severe events. So they're rare. But again, the events are probably more commonly seen in patients treated with combination checkpoint blockade. And we're increasingly seeing more combinations. So we should be on the lookout for these. Neurologic immune related adverse events can be divided into syndromes that affect the peripheral nervous system, so meaning the peripheral nerves, the neuromuscular junction, and muscle. So that would be Guillain-Barre syndrome, myasthenia gravis, and myositis. And those that affect the central nervous system, such as the brain, spinal cord, or leptomeninges. So those would be aseptic meningitis and encephalitis. The peripheral nervous system irAE appear to be more common than those affecting the central nervous system. And patients can present with a number of different symptoms that kind of relate to these syndromes. That can be as diverse as a headache to numbness, tingling, or focal weakness, such as a foot drop or facial weakness. You may see patients with severe altered mental status or personality changes or gait difficulty, walking difficulty, which could actually mean any number of syndromes. It's generally important to be aware that the timing of onset is generally early, a median of four weeks after the start of treatment, but can range anywhere from one week after the start of treatment to greater than a year. And because we know that cancer can spread to many parts of the nervous system, neurologic toxicity should be considered a diagnosis of exclusion. So that means that as part of the workup for neurologic immune related adverse events, it's imperative to rule out nervous system metastasis, stroke, and infection, which we know can occur at higher rates in patients with cancer. So for most neurologic immune related adverse events, diagnostic workup is similar. It should include MRI brain and/or of the spine, with and without contrast, and often a lumbar puncture for cerebrospinal fluid analysis, including cytology to rule out leptomeningeal metastasis. BRITTANY HARVEY: Thank you for that overview. In addition to those points for evaluation for all nervous system toxicities, what are the key recommendations for identification, evaluation, and management of myasthenia gravis? BIANCA SANTOMASSO: So for myasthenia gravis, presenting symptoms usually include fatiguable or fluctuating muscle weakness. It's generally more proximal than distal. And there's frequently ocular and/or bulbar involvement. So that means either ptosis, like a droopy eyelid, diplopia, or double vision, difficulty swallowing, dysarthria, facial muscle weakness, and/or head drop or neck weakness. Again, for any patient with new neurologic symptoms, an MRI of the brain or spine should be performed depending upon the symptoms to rule out central nervous system involvement by disease or some alternative diagnosis. And similar to idiopathic myasthenia gravis, acetylcholine receptor antibodies can be positive. So these should be checked. This is a blood test. But it's important to note that while these antibodies may be confirmatory, their absence does not rule out the syndrome. The rate of acetylcholine receptor antibody positivity in immune related myasthenia gravis has not been definitively established. So depending on the presentation, one might also consider sending a paraneoplastic panel for Lambert-Eaton myasthenic syndrome. The single most important point I'd like to make regarding suspected immune related myasthenia gravis is that orbital myositis and generalized myositis from immune checkpoint inhibitors can present similarly. For this reason, early neurology consultation and electrodiagnostic testing with repetitive stimulation or single fiber EMG becomes important and helpful to distinguish the two. And to make matters even more complicated, we've learned that there's an overlap syndrome, where patients may develop not only myasthenia gravis, but also myositis and/or myocarditis at the same time. So basically, the neuromuscular junction is affected. But the local muscle and myocardium, which is heart muscle that's kind of related, may be affected all at once. And this overlap of syndromes may increase disease severity and mortality. So they're important to recognize. So what this means is that when you encounter a patient with suspected myasthenia gravis, you should also be checking CPK, muscle enzymes, aldolase to evaluate for myositis, and troponin and electrocardiogram to evaluate for myocarditis. And this should be done even if there are no obvious symptoms. So onto the treatment of myasthenia gravis, this is similar to the management of the idiopathic form. Therefore, it's helpful to have the involvement of a neurologist. The immune checkpoint inhibitor therapy should be held. And patients with mild symptoms are often started on pyridostigmine and corticosteroids. And patients with more severe symptoms should initiate IVIG or plasmapheresis. And patients with more severe symptoms may need to be admitted to the hospital. So that their neurologic and pulmonary status can be monitored closely for improvement. Some patients may require ICU level of monitoring. And considering adding rituximab if symptoms are refractory, and often, as symptoms improve, the steroids can be de-escalated. BRITTANY HARVEY: Understood. Those are all very important points for clinicians to consider. So then following that, what are the key recommendations for identification, evaluation, and management of Guillain-Barre syndrome? BIANCA SANTOMASSO: So Guillain-Barre syndrome, like myasthenia gravis, also presents with weakness. Most often, patients present with a progressive ascending muscle weakness. The syndrome can start with sensory symptoms or neuropathic pain that can be localized to the lower back and thighs. In addition to the classic ascending weakness, there may be facial weakness, double vision, numbness or tingling in the hands or feet, loss of balance, and coordination. And shortness of breath may occur due to respiratory muscle weakness. The autonomic nerves can also be affected and can present as new severe constipation or nausea, urinary problems, or orthostatic hypotension. The reflexes are often reduced or absent, deep tendon reflexes. So again, as for all of the syndromes, early involvement by a neurologist is recommended, if possible. Usually, MRI imaging of the spine is important to rule out spinal cord compression. And it also may show cauda nerve thickening or enhancement, which can occur with this syndrome. And the second aspect is cerebrospinal fluid analysis is important for diagnosis. This is important really for ruling out leptomeningeal metastasis, since that could present similarly. And often, what can be seen in GBS is an elevated protein level in the cerebrospinal fluid. In addition, unlike idiopathic GBS, there can be an elevated white blood cell count in the cerebrospinal fluid. Electrode diagnostic testing can also be helpful for confirmation, and serum tests for antiganglioside antibodies, and a paraneoplastic antibody workup may also be considered. Bedside pulmonary function test and swallowing evaluation should be performed if there's a concern for respiratory or swallowing dysfunction. And some patients do need to have inpatient admission and monitoring if symptoms are severe or if they appear to be progressing from mild. For management, the checkpoint inhibitor therapy should be held. And patients are most often treated with IVIG or plasmapheresis. Corticosteroids can be added to the IVIG or plasmapheresis. These are not usually recommended for idiopathic Guillain-Barre syndrome. However, in immune checkpoint inhibitor related forms, a trial is reasonable. And steroids are usually given at a higher dose for five days and then tapered over several weeks. BRITTANY HARVEY: Understood. I appreciate that overview. So then what are the key recommendations for identification, evaluation, and management of peripheral neuropathy? BIANCA SANTOMASSO: So peripheral neuropathy, or polyneuropathy, is a rare but likely underreported complication of immune checkpoint inhibitor therapy. So in the large databases and meta-analyses, those have really focused on Guillain-Barre syndrome for reporting. But other types of neuropathies, such as painful length dependent sensory and motor axonal neuropathies, or polyradiculopathies or sensory neuropathies do occur after immune checkpoint inhibitors and are probably under-recognized. So evaluation of immune related neuropathy should include neurology consultation to guide the neurology phenotype determination and also the workup. The evaluation primarily relies on a combination of electrodiagnostic studies, serologic tests, and MRI neuroimaging. Because peripheral nervous syndromes can overlap, screening for neuromuscular junction dysfunction with electrodiagnostic testing and myopathy is recommended for any patient who presents with at least motor symptoms that are thought to be peripheral. Serum testing can be helpful for ruling out reversible causes of neuropathy. Spinal imaging is recommended to exclude metastatic disease. And for management, it usually involves holding the checkpoint inhibitor in mild cases, using neuropathic pain medication or steroids in more severe cases. And very severe cases that kind of resembled GBS would be managed as per the GBS algorithm with IVIG or plasmapheresis. BRITTANY HARVEY: Understood. And it's key to look out for those overlapping adverse events. So then following that, what are the key recommendations for aseptic meningitis? BIANCA SANTOMASSO: Right, so now we're getting into the central nervous system toxicity. So aseptic meningitis is an inflammation of the meninges. And it can present with headache, photophobia, neck stiffness. Patients can have nausea, and vomiting, and occasionally fever. The mental status is usually normal. And in patients presenting with headache, which in isolation, could suggest an aseptic meningitis, it's important to evaluate if they have any confusion or altered behavior, which might suggest an encephalitis. And this distinction is important, because suspected encephalitis triggers a different workup, which we'll be discussing later, and also even different management. So the workup for aseptic meningitis includes neuroimaging, usually an MRI of the brain. And on that imaging, we sometimes see abnormal leptomeningeal enhancement. It's important not to assume that this is cancer and to do a lumbar puncture to evaluate cerebrospinal fluid both for inflammation and to exclude other causes of meningeal disease, particularly neoplastic and infectious causes. So cytology, Gram stain, and culture, and other infectious studies should be negative. And it's recommended that empiric antibiotics or antiviral therapy be considered to cover for infectious meningitis until the cerebrospinal fluid results return negative. What's seen in the cerebrospinal fluid in aseptic meningitis is typically reactive lymphocytes, but also neutrophils or histiocytes may be prominent on the cytology. And while the symptoms can be severe, sometimes requiring hospitalization, the management of this entity, these are usually quite treatable. Aseptic meningitis generally responds very well to corticosteroids. So management involves holding the checkpoint inhibitor. And you can often get away with starting a fairly modest dose of corticosteroids, such as oral prednisone, 0.5 to 1 milligram per kilogram or the equivalent. And steroids can usually be tapered over two to four weeks. BRITTANY HARVEY: Great, thank you for reviewing those recommendations. So then you just mentioned the distinction of aseptic meningitis and encephalitis. So what are those key recommendations for identification, evaluation, and management of encephalitis? BIANCA SANTOMASSO: So in encephalitis, the mental status is not normal. It's characterized by, really, an acute or subacute confusion, altered mental status, altered behavior, memory deficits, including working memory and short-term memory. There can be, as associated symptoms, headaches, new onset seizures, psychiatric symptoms, which can include delusions or hallucinations. There could be weakness, sensory changes, imbalance, or gait instability, along with the mental status changes. And so similar to aseptic meningitis, the other central nervous system toxicity, it's important to distinguish encephalitis from other causes of altered mental status, such as CNS metastases, stroke, or infection. And as for the other syndromes, it's very helpful to have neurologic consultation early, if possible. An MRI of the brain is critical. And in addition, MRI of the spine may be obtained to evaluate for inflammatory demyelinating ischemic or metastatic lesions. In immune related encephalitis, MRI brain imaging may reveal T2 flare changes, typical of what can be seen in idiopathic autoimmune or limbic encephalitis. But most often, the MRI imaging is normal. So in this situation, a lumbar puncture for CSF studies to evaluate for evidence of inflammation can be very helpful. You can expect to see either a lymphocytic pleocytosis or an elevated protein, or CSF restricted oligoclonal bands. CSF analysis is also helpful for excluding other causes of encephalitis, particularly viral encephalitis. So HSV, Herpes Simplex Virus, or varicella zoster virus encephalitis should be ruled out and treated with antivirals while the tests are pending. So typically, these entities can be excluded by PCR testing for HSV and VZV. Electroencephalogram, or EEG, can also be helpful for revealing subclinical seizures or status epilepticus, which can occur as a complication of encephalitis or as a cause of persistently depressed sensorium. But these are not specific to encephalitis. Other testing that's done includes screening metabolic tests to look for alternative etiologies. And for this entity, serum and CSF autoimmune antibody evaluation should be sent to assess for malignancy associated neurologic syndromes. And your neurologist can help you with the workup and management, in particular which tests to send. There have been reported cases of antibody positive checkpoint inhibitor related encephalitis. For management, in contrast to aseptic meningitis, these are generally not as steroid sensitive. So you often have to treat with either higher steroid doses, even pulsed steroid doses, along with IVIG or plasmapheresis. If no improvement, escalation to rituximab and cyclophosphamide can be considered, with the assistance of neurology. This management guidance is taken from how to treat autoimmune encephalitities that are not related to checkpoint inhibitors. Unfortunately, these can be difficult to treat. The response may only be partial. So this is one area in need of better understanding of best therapeutics. BRITTANY HARVEY: OK, thank you for reviewing that and pointing out where there's future research needed as well. And I appreciate your reviewing the recommendations for each of these neurologic immune related adverse events. So then to wrap us up, in your view, how will these recommendations for the management of nervous system toxicities impact both clinicians and patients? BIANCA SANTOMASSO: Yeah, so I think this is a daunting list of toxicities. But I'll say that in most situations, the immune checkpoint inhibitor side effects are often manageable and reversible with proper supportive care. They can be serious, and they require close vigilance and prompt treatment and identification. But by knowing what to look for in early identification, that allows early intervention, which is really the key to reversibility and the best outcomes. So having these toxicities on your differential diagnosis is critical. And I think these guidelines really help inform both clinicians, and care providers, and patients on what the possible manifestations are. So we believe this guideline and its recommendations will help members of clinical teams with the recognition and the management of these unique toxicities. And again, it's timely recognition and early intervention that helps patients, really, by increasing their safety with early management. BRITTANY HARVEY: Great, well, thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Santomasso. BIANCA SANTOMASSO: My pleasure. Thank you so much. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. Stay tuned for additional episodes on the management of immune related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe. So you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Umang Swami from the Huntsman Cancer Institute, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” He discusses the identification, evaluation, and management of renal toxicities in patients receiving ICPis, focusing on nephritis/acute kidney injury in Part 8 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT [MUSIC PLAYING] SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING]   BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, we're continuing our series on the management of immune related adverse events. I am joined by Dr. Umang Swami from the Huntsman Cancer Institute at the University of Utah in Salt Lake City, Utah, author on Management of Immune Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy ASCO guideline update, and Management of Immune Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T Cell Therapy ASCO guideline. And today, we're focusing on renal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Swami. UMANG SWAMI: Thank you, Brittany. And I appreciate the invitation to be here today. BRITTANY HARVEY: Great. Then first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Swami, do you have any relevant disclosures that are directly related to these guidelines? UMANG SWAMI: No, I do not have any relevant disclosures that are directly related to these guidelines. BRITTANY HARVEY: Thank you. Then let's dive into what we're here today to talk about. So what are these immune related renal toxicities that are addressed in this guideline? UMANG SWAMI: So this guideline focuses on nephritis, or acute kidney injury, as an adverse event due to immunotherapy. Acute kidney injury, or AKI, an uncommon complication of immune checkpoint inhibitor therapy. Just to give a little context before we start, the incidence of any grade AKI around 1% to 2% in patients treated with a single agent immune checkpoint inhibitor, such as ipilimumab, nivolumab or pembrolizumab, and 4.5% in those treated with anti-CTLA-4 for and anti-PD-1 combination of nivolumab plus ipilimumab therapy. The incidence of grade 3 or grade 4 AKI is very low. I will say less than 1% with single agents, and around 1.6% with the combination of nivolumab plus ipilimumab. While initial studies had quoted a small incidence of AKI with immune checkpoint inhibitor use, emerging data now suggests that a higher incidence might be present, which might range between 9.9% to around 29% of AKI with the immune checkpoint inhibitors. However, most of this extra toxicity is grade 1. The median time to onset of renal toxicity with these agents is around 14 weeks, but can range from 6.5 to 21 weeks. BRITTANY HARVEY: Thank you for that background information. I think it's helpful for clinicians to understand how rare or common these adverse events are. So then, what are the key recommendations for identification, evaluation, and management of nephritis or acute kidney injury? UMANG SWAMI: That's a great question. Presenting symptoms related to immune therapy induced renal toxicities may include urinary frequency, dark, cloudy urine, fluid retention, or edema of face, abdomen, extremities. There might be sudden weight gain. There might be associated abdominal or pelvic pain. Patients might have nausea, vomiting, high blood pressure, or they may have a change in mental status such as drowsiness. However, we should remember that a vast majority of them will be asymptomatic at presentation. Therefore, patients should have their renal function, that is, serum creatinine, checked prior to administration of each dose of checkpoint inhibitor therapy. For patients with new elevations in creatinine, one should consider holding checkpoint inhibitor therapy while other potential causes are evaluated. These other causes may include recent IV radiographic contrast administration, dehydration, urinary tract infection, other natural toxic medications, including concurrent chemotherapy, herbals, or other supplements. Patients without their obvious causes or who don't respond to alternative treatment measures should be presumed to have immune related renal toxicity and treated empirically depending on the grade of AKI. Safe treatment of autoimmune component is important. So with regards to the grading of AKI, grade 1 means a creatinine level increase of more than 0.3 milligrams per deciliter, or creatinine 1.5 to two times above baseline. And in this situation, physicians should consider temporarily holding checkpoint inhibitor therapy and evaluating other potential contributing agents in combination regimes, pending consideration of potential alternative pathologies. A change that is still less than 1.5 times of upper limit of normal could be meaningful and should be remembered. For grade 2 AKI, which is creatinine two to three times above baseline, apart from holding immune checkpoint inhibitor and evaluating for alternative causes, nephrology should be consulted. If other ideologies are ruled out, administer 0.5 to 1 milligram per kg per day prednisone or its equivalent. If kidney function worsens or does not improve after one week, increase the dose of prednisone to 1 to 2 milligrams per kg per day or its equivalent, and permanently discontinue immune checkpoint inhibitor. If the AKI improves to grade 1 or less, taper steroids over at least four weeks, otherwise we might see recurrence. If there is no recurrence, a physician might discuss resumption of immune checkpoint inhibitor with patient after taking into account what are the risks and what are the benefits. Resumption of immune checkpoint inhibitor can be considered once steroids have been successfully tapered to 10 milligrams per day or less, or discontinued. However, if elevation persists for more than seven days or worsens, and no cause is found, then the grade 2 AKI needs to be treated as grade 3. Now grade 3 and grade 4 AKI are managed similarly. Grade 3 AKI is defined as creatinine more than three times the baseline, or more than 4 milligrams per deciliter, or when hospitalization is indicated. And grade 4 AKI defined as an AKI associated with life-threatening consequences, when dialysis is indicated, or creatinine six times above baseline. Management includes nephrology consult, evaluation for alternative causes, and permanent discontinuation of immune checkpoint inhibitor. If they are directly implicated in renal toxicity, the administration of corticosteroids in grade 3 or grade 4 AKI is at an initial dose of 1 to 2 milligrams per kg per day of prednisone or its equivalent. If and when the AKI improves to grade 1, corticosteroids can be tapered over at least four weeks. However, if elevation persists for more than three to five days for grade 3 or more than two to three days for grade 4 or worsens, we should consider additional immunosuppression, such as infliximab as a time frame, cyclophosphamide, cyclosporine, or mycophenolate. Usually, reflex renal biopsy is typically not necessary or recommended unless the AKI is refractory to steroids or other immunosuppressive agents. BRITTANY HARVEY: I appreciate your reviewing those details for immune related renal toxicity. So then, in your view, Dr. Swami, how will these recommendations for the management of renal toxicities impact both clinicians and patients? UMANG SWAMI: This guideline presents a concise, up to date, and a stepwise approach to diagnose, grade, and treat this rare, but serious side effect of immunotherapy. In my view, this would be immensely helpful to clinicians in busy practices. Prompt identification and treatment is also expected to help our patients experiencing immune related kidney injury. For patients, it will provide a readily available document to refer to for information regarding side effects of immune checkpoint inhibitor therapy. I applaud the efforts by the ASCO and the authorship team in developing the patient focused version of this guideline. This may allow patients, especially when between clinic visits, to identify this unusual condition and seek medical help in a timely fashion. BRITTANY HARVEY: Great. Thank you for highlighting the importance of this guideline, for all your work you did on this guideline, and for your time today, Dr. Swami. UMANG SWAMI: Thanks so much, Brittany. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can find many of our guidelines and interactive resources in the free ASCO guidelines app, available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Maria Suarez-Almazor from MD Anderson Cancer Center, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews identification, evaluation & management of musculoskeletal toxicities in patients receiving ICPis, including inflammatory arthritis, myositis & polymyalgia-like syndrome in Part 7 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at ASCO.org/podcasts. My name is Brittany Harvey, and today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Maria Suarez-Almazor from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on musculoskeletal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Suarez-Almazor. MARIA SUAREZ-ALMAZOR: Thank you. BRITTANY HARVEY: First I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for the guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Suarez-Almazor, do you have any relevant disclosures that are directly related to these guidelines? MARIA SUAREZ-ALMAZOR: Thank you, Brittany. I don't have any disclosures directly related to the guidelines. BRITTANY HARVEY: Thanks very much. Then getting into the content of this, what are the immune-related musculoskeletal toxicities addressed in this guideline? MARIA SUAREZ-ALMAZOR: There are three major musculoskeletal syndromes covered in this guideline-- inflammatory arthritis, myositis, and polymyalgia rheumatica. BRITTANY HARVEY: Great. Then let's start with that first one that you mentioned. So what are the key recommendations for identification, evaluation, and management of inflammatory arthritis? MARIA SUAREZ-ALMAZOR: The diagnosis of inflammatory arthritis is primarily based on a thorough joint exam to detect the presence of synovitis and how many joints and what joints are actually involved. For this reason, we recommend early referral to a rheumatologist. From a diagnostic perspective, we recommend testing for antinuclear antibodies or ANA, rheumatoid factor, and cyclic citrullinated peptide antibodies or anti-CCP. These are only positive in 10% to 20% of patients but may be indicative of a more persistent disease. As inflammatory arthritis does not have any specific biochemical parameters for follow up, we use inflammatory markers such as sed rate and CRP in conjunction with the clinical exam as indicators of disease activity. For grades 1 and 2, we recommend treatment with nonsteroidal anti-inflammatory drugs or NSAIDs, or low-dose steroids up to 20 milligrams of oral prednisone or equivalent. If there is involvement of only one or two joints, local treatment with steroid injections can be indicated. For grade 3 and higher, the dose of steroids can be increased up to 0.5 to 1 milligram per kilogram of body weight. And if there is no improvement within two weeks or if the steroids cannot be satisfactorily tapered, we recommend early initiation of a disease-modifying antirheumatic drug or a DMARD, such as methotrexate, hydroxychloroquine, or sulfasalazine. We need to understand though that these may take up to two or three months to be effective. Alternatively, we can use biologic agents which have a faster onset of action. Recommended agents include tumor necrosis factor or interleukin 6 receptor inhibitors. In severe cases, immune checkpoint inhibitors may need to be permanently discontinued. But the overall goal is to try to continue therapy while we treat the adverse event. BRITTANY HARVEY: Understood. Appreciate your reviewing that information for inflammatory arthritis. Following that, what are the key recommendations for identification, evaluation, and management of myositis? MARIA SUAREZ-ALMAZOR: Well, myositis is really the most serious of the musculoskeletal toxicities. And it can be life threatening, especially when it's associated with myocarditis and with myasthenia gravis features. It usually presents with proximal weakness of the upper and lower extremities and sometimes with myalgia and even rhabdomyolysis. It usually is very acute in its presentation. Specific testing includes muscle enzymes, creatine kinase and aldolase, and electromyography and muscle biopsy if the diagnosis is uncertain. MRI can be useful as it can show muscle inflammation. And it can also assist in identifying a location for a biopsy if needed. Consultation with rheumatology and neurology should be requested early on. We also recommend that all patients undergo testing of cardiac enzymes such as troponin. And if elevated, a cardiology consultation should be placed right away and further testing performed. For grades 1 and 2, if patient has symptoms, treatment with corticosteroids are 0.5 to 1 milligram per kilogram should be initiated. For patients with grade 3 or 4, checkpoint inhibitors should be discontinued and the patient should be hospitalized. Corticosteroids should be initiated at a dose of 1 milligram per kilogram of prednisone or equivalent. And patients with severe compromise may need intravenous corticosteroid doses at higher doses of 1 or 2 milligrams per kilogram or even higher. For severe disease or if there is myocarditis or concomitant myasthenia gravis, we can consider plasmapheresis. IVIG can also be used, but it has a slower onset of action. And it is important to remember that plasmapheresis can remove immunoglobulins. So if it is to be used, the IVIG should be administered after the plasmapheresis is completed. There are other immunosuppressant therapies such as biologic agents that can also be considered. And sometimes for maintenance, oral immunosuppressants such as azathioprine, methotrexate, or mycophenolate mofetil can also be considered. Patients with severe disease may need to permanently discontinue the checkpoint therapy. BRITTANY HARVEY: OK, those details are helpful for clinicians. So then, for the last category, addressed in this guideline that you mentioned, what are the key recommendations for identification, evaluation, and management of polymyalgia-like syndrome. MARIA SUAREZ-ALMAZOR: Polymyalgia rheumatica syndromes present with marked pain and stiffness of the muscles in the shoulder and hip girdles. But some patients can also present with concomitant inflammatory arthritis. The workup is very similar to that of arthritis. In these patients, it is very important though to obtain a creatine kinase so that the muscle enzyme to be certain that the myalgia is not from myositis, as a treatment would be very different. Although very rare, polymyalgia, in some instances can be associated with giant cell arteritis which, if present, would require more aggressive treatment. For this reason, it is important to ask the patient about symptoms such as headache, visual disturbances, or jaw claudication. The management of polymyalgia-like immune adverse events alone, without any associated vasculitis, is very similar to that of arthritis. So we would use NSAIDs and low-dose steroids for grade 1 and 2. Higher doses of steroids and disease modifying agents, including biologics, might be needed for grades 3 and 4. But overall, very similar management as that of inflammatory arthritis. BRITTANY HARVEY: Great. Thanks for reviewing all of those recommendations for those three different categories. So then, in your view, Dr. Suarez-Almazor, how will these recommendations for the management of musculoskeletal toxicities impact both clinicians and patients? MARIA SUAREZ-ALMAZOR: Thank you, Brittany. For the most common rheumatologic adverse events, such as arthralgia, inflammatory arthritis, or polymyalgia-like syndromes, because they are not life threatening, we may not be as worried. But we need to recognize that they can greatly impair quality of life. So we really hope that these recommendations can assist patients and clinicians in the early recognition of symptoms and also in initiating prompt treatment so our goal to be able to continue checkpoint inhibitor therapy can be achieved by controlling the symptoms that really impair quality of life. Myositis is a much more serious adverse event that can lead to death. Patients may not be able to restart immune checkpoint inhibitor therapy again after they develop myositis. So we hope that these recommendations do highlight the need for very prompt diagnosis, consultation with specialists, and very aggressive treatment early on to control and manage these devastating, life-threatening adverse event. BRITTANY HARVEY: Definitely. Early recognition, treatment, and improved quality of life are key. So I want to thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Suarez-Almazor. MARIA SUAREZ-ALMAZOR: Thank you, Brittany. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.ASCO.org/supportive-care-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

A physician attempts to ease a patient's pain, a painful moment somewhat eased by the joy of music.   TRANSCRIPT SPEAKER 1: 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]   RICHARD LEITER: Ode to Joy. "Is now an OK time?" I asked as I quietly entered the dimly lit room on a Saturday afternoon. "Yes, we've been waiting for you," my patient's wife Julie responded in the same calm, composed voice she had maintained all week. "Before we start, what questions do you have?" "I think you answered all of them this morning. I'm ready. Tom is ready. We just don't want him to suffer anymore." "OK, we'll get started." When I was in training, I had seen my preceptors initiate palliative sedation, but this was my first experience doing so as an attending physician. After being dormant for so long, my impostor syndrome returned. Though I was confident that I was taking the clinically-appropriate next step, I was nervous. I asked Tanya, our charge nurse and the nurse who was primarily caring for him over the last few days, to draw up the syringe. She did so with practiced confidence and handed it to me. I held it between my fingers, wondering how slowly I would need to push it to ensure the 2 milliliters of midazolam went in over a full five minutes. Tanya cleaned off the side port of his IV. I twisted the syringe into place. I looked up at Julie. She squeezed Tom's hand. I had first heard about Tom nearly a week earlier, when my colleague was handing off the service to me. "He's in his 50s, metastatic cancer. He was home on hospice and came in yesterday with uncontrolled pain. We started him on ketamine and he looks much better. The plan is to wean his ketamine, increase his methadone, and get him back home, hopefully in the next day or two." Stoic from years of pain from cancer eating away at his bones, Tom lay in bed with his eyes closed, his furrowed brow the only sign of his ongoing agony. When the nurses tried to move him, he screamed. After we weaned his ketamine, his pain quickly worsened. We increased methadone and hydromorphone. Neither gave him adequate relief. We restarted ketamine, but it proved to be no match for his pain. On rounds one morning, Julie asked if Tom could make it home. I told her I didn't think so and explained how worried I was about his pain. If we sent him home, I was concerned the pain would force him to come right back. Julie told me her kids would be disappointed, but that they'd understand, as she did. Easing Tom's suffering was more important. The hospital bed his family had set up in the living room would remain empty, a physical manifestation of cancer's unending cruelty. The hospital bed his family had set up in the living room would remain empty, a physical manifestation of cancer's unending cruelty. We talked about what would come next. If further titrating his medications proved ineffective, which I worried it would be, we would need to consider palliative sedation. "Whatever you need to do," Julie responded, her voice barely betraying the exhaustion I imagine she was feeling. Palliative sedation is a procedure used to relieve refractory suffering in a terminally-ill patient. Clinicians carefully sedate the patient, often to the point of unconsciousness, to relieve symptoms such as pain, nausea, shortness of breath, or agitated delirium. It is a procedure of last resort, and in our hospital, requires the approval of two attending physicians and the unit's nursing director. Though palliative sedation may shorten a patient's life, ethicists and clinicians have long regarded it as acceptable because its goal is not to hasten death but rather to relieve suffering. This is known as the doctrine of double effect, by which an action with at least one possible good effect and at least one possible bad effect can be morally permissible. Back in his room on that Saturday afternoon, I looked over at Tanya, the nurse, then at Harry, my fellow, who had been caring for Tom all week. I took in a breath under my mask, then slowly began to inject the contents of the syringe into his IV. In the quiet, I could hear the music coming from Julie's phone, which she had placed on the pillow beside his head. A pianist played a slow, mournful rendition of the final movement of Beethoven's Ninth Symphony, the Ode to Joy. In my head, I sang along. (SINGING) Joyful, joyful, we adore thee. I went to a traditionally Anglican school. 600 boys of all faiths and backgrounds, we'd rise each morning in assembly and sing hymns together. We cheered, yelled, and thumped on our pews-- a few minutes of raucous togetherness before we devolved into the usual bullies and cliques for the rest of the day. Tom's room couldn't have been more different. He remained completely still. Though Julie held his hand, he was alone, as we all felt in that room. (SINGING) Hearts unfold like flowers before thee, opening to the sun above. I felt the soft resistance of the syringe's plunger hitting the barrel. I looked back up at Tom. His chest fell, but didn't rise. I waited. He didn't breathe. The music slowed down. I felt Harry's eyes pivoting back and forth between my face and Tom's chest. I fixed my eyes on Julie's hands wrapped around her husband's. Despite the tension of the last week, she was calm, gentle. I matched my breath to hers. If she could exude such peace, so could I, I thought. I noticed Tom's hands. He had a piano player's fingers, long and slender. I pictured him sitting at the piano in their living room. I wondered who would take his place on the bench. I wondered if he could hear the song playing beside him. Had he and Julie chosen it for this moment? Did it bring back joyful memories, as it did for me? (SINGING) Melt the clouds of sin and sadness, drive the dark of doubt away. He didn't breathe. Did my first attempt at palliative sedation become euthanasia? Even if so, was this OK? I rehashed our conversations from the last few days. We talked about the risks. I went over the dose. Double effect, I reassured myself. Even so, as bedside nurses have told me, it's easier to talk about philosophy when you're not holding the syringe. I thought about how I would explain Tom's death to Julie. I wondered if she would be angry, upset, relieved? With the help of my outpatient colleagues, they had spent years preparing for his death. His financial affairs were in order, and he had done legacy work with his kids. More than nearly anyone I had cared for, they were ready. Were we? Was I? (SINGING) Mortals join the happy chorus which the morning stars began. He breathed in. Not a grand gasp, a slow, soft inhalation. Tom's hand flexed ever so slightly around Julie's. In my head, I thumped a pew. [MUSIC PLAYING]   SPEAKER 2: Welcome to "JCO's Cancer Stories-- The Art of Oncology," brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. SPEAKER 3: The guest on this podcast episode has no disclosures to declare. [MUSIC PLAYING] LIDIA SCHAPIRA: Welcome to "Cancer Stories-- The Art of Oncology" podcast series. I'm your host Lidia Schapira. And with me today is Dr. Richard Leiter, physician and member of the Psychosocial Oncology and Palliative Care team at Dana-Farber Cancer Institute in Boston and the Brigham and Women's Hospital. Welcome to our podcast. RICHARD LEITER: Thank you so much for having me. LIDIA SCHAPIRA: It's a real pleasure. You submitted a beautiful narrative piece called "Ode to Joy." And I'd like to start today, Richard, by just focusing first on the case that you present to us. Let me tell you how I understand Tom's history, and then you can correct me if this is not the way that you'd like him to be understood. And remember, Tom is a man in his 50s who's lived with metastatic cancer to bones for years. In your narrative, you're very careful and document the fact that you've worked with many members of your palliative medicine team for a long time, that there had been many efforts to control his pain, his suffering, and he had to be hospitalized for pain management. He was already receiving home hospice care. There was a bed in the living room in the center of the family home. And he had a very supportive family and a wife that we'll call Julie at bedside. Is that the proper framing for the story? RICHARD LEITER: Exactly. Yep. Yeah. I think what I would add is that the goal was really to control his pain and get him back home. LIDIA SCHAPIRA: So now you're there as the fresh attending in palliative medicine, and you're called in, and it becomes quite clear to you after a few days of changing his medications that the pain is refractory. And that it-- you note here that he screams when he is moved, that the level of pain reaches what you have called agony. So tell us a little bit more about how a palliative medicine consultant or physician approaches this kind of situation in hospital today. RICHARD LEITER: Yeah, no. Great. Thanks so much. So we were, I would say, lucky enough to have him on our intensive palliative care unit, where we're caring for patients with difficult and sometimes refractory symptoms at any stage of the disease. So not only for end of life. But we do see a number of cases like his every year, every few months, where someone is getting closer to the end of life. The goal is to really focus on intensive symptom management. And their symptoms are challenging to control. So I think the first step, always, is a good history, right? Where is this pain coming from? What treatments have they tried already? What's worked? What hasn't? We're going to titrate medications, but select medications based on that and titrate them. I think someone who has been involved with my outpatient colleagues and has been receiving hospice services at home has often gone through many treatment modalities. So it's really taking what they've been on before and starting to add to it. So for Tom, I had inherited him from one of my colleagues, who had admitted him a couple of days earlier. And at that point, he was already on a hydromorphone infusion and ketamine, as I talk about in the piece. Ketamine had been started, hopefully, as a bridge to get him back home. And he had been on methadone, which is one of our most potent agents for, not only nociceptive pain, so our basic kind of bony pain or visceral organ pain, but also if there's pain with a neuropathic component. Methadone is an opioid that can be particularly effective there. So I think it's saying, OK, well, have we hit all of our receptors in managing their pain? Are we managing the anxiety on top of that? Are we doing everything we can? Are there procedures that we could do to help with their pain? Sometimes we're talking about intrathecal pumps for instance. And obviously, that's a more involved discussion. How much time does someone have left? Are the goals really to put them through a procedure in order to get their pain under control? But we frequently work with our interventional pain colleagues to tease out whether a procedure would be helpful for a particular patient. So those are the thoughts that always go through my mind when I'm approaching someone with severe cancer-related pain. LIDIA SCHAPIRA: So this is a very thoughtful approach. And I think one of the messages is that it seems palliative medicine and pain management are integrated into the care of patients with advanced cancer, which is a very important message for our listeners and our readers. And here you are, you have all of this, you have good communication, it seems, with your team members, with the patient's family, and there's nothing more that you can think of doing. And you're now starting to think about interventions that we normally don't think of, except as a last resort. Bring this to the bedside. Tell us a little bit about the recommendation for palliative sedation and when that's indicated in care. RICHARD LEITER: Yeah. So palliative sedation, as I write in the piece, it's a measure of last resort. And certainly, in our hospital's protocol, it explicitly states it's when all other options have been tried. As we start to integrate more options, it's always a conversation we're having among our team-- is when is palliative sedation truly indicated. How many boxes do we need to check before going down the palliative sedation route? And I think-- so we started to think about-- we had him on ketamine. We tried to wean him off, it didn't go well. We restarted ketamine. We started dexmedetomidine, which can be useful. Precedex, the brand name, they oftentimes use it in the ICU for sedation, but we find that it can be helpful in cases of refractory pain as well. And my practice has been-- and though I haven't gotten to palliative sedation until this case-- when I'm thinking about Precedex, I'm also starting conversations with the patient or their family, and certainly our team, about palliative sedation to say if this doesn't work, this is where we're headed. LIDIA SCHAPIRA: And why is this situation so difficult, so personally anxiety-provoking for you? You do use words that convey that you are feeling nervous, or perhaps even anxious. Tell us why. RICHARD LEITER: I think it's-- relieving our patient's suffering, relieving their families suffering is certainly the core of much of medicine and very much the core of what we do in palliative care. And I think to have someone in just such a terrible situation-- putting aside the pain, right? This is a man who's dying of his cancer, has a relatively young family. That alone is an awful situation. And my job is to make that situation a little bit less bad, is to ease the suffering. LIDIA SCHAPIRA: And there's something about this particular procedure, however, that adds a level of intensity and nervousness for you, and that is that perhaps-- you can describe this better than I-- but the fact that in some cases, this could have the unintended effect of actually causing respiratory depression or even hastening death and something that you have explained in your piece, if I understood you correctly, as the double effect. Did I get that right? RICHARD LEITER: Yeah, that's right. So the worry or one of the considerations with palliative sedation is that it could hasten someone's death. Oftentimes, the doses of the medications that we're using, if we're titrating them slowly, there are studies that show that it doesn't necessarily. I do think, though, when we tie it into withholding artificial nutrition and hydration, in that case, had the person been awake enough to eat and drink before, we do know that it would probably hasten their death, right, from that part of it, but not necessarily the sedation aspect. So double effect is basically saying this is ethically OK-- and there are a number of criteria. But if we are intending the good effect and not the bad effect and that it's proportional to the gravity of the situation so that not every patient who comes in with bad pain undergoes palliative sedation. LIDIA SCHAPIRA: My favorite line, Richard, in the piece-- and one that I now have read probably dozens of times-- is this-- "the double effect, I reassured myself. Even so, as bedside nurses have told me, it's easier to talk about philosophy when you're not holding the syringe." And that just gives me goosebumps thinking about it. What did you feel when you were holding the syringe? RICHARD LEITER: Exactly as I wrote about. There's all of the cognitive processes going on. And I ran it by another attending, I ran it by the nursing director, I ran-- everyone was on the same page, that this was medically indicated in this situation. And yet, when I'm standing there in the room-- patient, his wife, my fellow, and the nurse-- and I'm the one holding the syringe, watching the medication go in, it felt completely different to me. And there's a power that comes with it. In one sense, I felt like I was there for my patient. Here I am, standing here doing this to ease his suffering. And then the other, the unintended consequences of the sedation are real, and that feels different when you're the one physically doing it. LIDIA SCHAPIRA: I think one of the incredible gifts you've given us as readers is to share this with us and really adds a different dimension to the discussion of the complexity of what it is to be present, not just as a witness, in this case, but as somebody, as you say, with a power to really control so many things in the situation. And I thank you for sharing that with us. And question to you is, did writing about it in any way help you process this emotional, very powerful experience? RICHARD LEITER: Absolutely. I write to process. I write when I feel like I have something to say. And oftentimes, I write when a particular moment struck me. And I think that that moment, sitting there, pushing the medication, waiting for that breath while the music was playing was so poignant for me that I walked out of the room and I remember thinking to myself that night as I was decompressing on my walk home from work, I think I need to write about this. LIDIA SCHAPIRA: So thank you for writing about it, and then, of course, for submitting for review and to share it with people. Let me bring the music in. Music is such an important part of our sensory experience. So as you were holding the syringe, Julie, Tom's wife, puts the phone on the pillow and she plays the piano version of Ode to Joy from Beethoven's Ninth Symphony, which I want to play for our listeners now. [MUSIC PLAYING]   So Ode to Joy meant something, clearly, to Tom and Julie. And you said that you watched-- perhaps you were watching for his reactions. But tell me a little bit about what it meant to you. You sprinkled your essay with the lines for the choral for Ode to Joy, which has a religious significance as well. So tell us a little bit about that. RICHARD LEITER: Yeah. So I grew up in Toronto. I went to an all-boys school there that had a traditionally Anglican background, though I'm not-- I'm Jewish. We would sing hymns. And over the course of my time there, the hymns became less denominational and more multicultural and inclusive. And it was a moment-- it was a nice moment where everyone got into it. It's 600 boys singing, and so I still remember the words to Ode to Joy vividly. Anytime I hear it, I can replay the words in my head. And I found myself, in those moments in the room, really thinking about it. And the words were still-- as I was processing and watching Tom and Julie and making sure I was pushing the medication at the right speed, there was this soundtrack. It's a strange moment too, because they're good memories for me, and yet I'm in this incredibly solemn, intimate moment in my patient's room. LIDIA SCHAPIRA: And so as we're getting to the end of the piece and there's all of this tension that you've built up in the writing and the narrative-- and here you are, you're waiting and you hear the music and so on-- and then you finally let the tension out and he breathes. It's not a huge breath, but it's a soft, slow inhalation. And you see that the hand is flexed slightly around his wife, so he's still breathing. And you finish with this line that you say, "In my head, I thumped a pew." And I have to ask you about that. What does that mean to you? RICHARD LEITER: Yeah. So in that moment, it was relief, is what it was. Just the sense of, OK, this went-- it's my first time doing this, and this went OK. He appears more comfortable. He is still breathing. This is OK. And it just brought me back when we would thump the pews as we were singing the hymns. Our principal did not like it, but-- [LAUGHTER] But I think it was just that it was relief. I hesitate to say it was joy because I don't think there's joy in a situation like that, in the room. But there was a sense of satisfaction maybe, or professional satisfaction, the, OK, this is what we can do. And as bad as the situation is, there was something that we could do to make him somewhat more comfortable. LIDIA SCHAPIRA: Well, I certainly learned a lot. I wonder if now that some time has passed since this event, if you have any additional reflections on how this story has impacted your professional delivery of care, or perhaps the way you teach others, and if there are any parting comments that you'd like to leave us with. So I haven't had another case where I've needed to do palliative sedation, though we've thought about it in a couple of cases. I do think it's helped me, when I talk about palliative sedation with our trainees, to add the emotional valence. I think I was pretty good at talking about the importance of making sure everyone's on the same page and talking to the patient and the family and nursing staff. But to really talk about the significance of that moment for us as clinicians and how it does feel different-- at least it did for me-- and I think drawing on my personal experience is helpful in teaching it to the fellows that it's OK to feel like that when you're doing this. LIDIA SCHAPIRA: There are moments in medicine-- certainly in what you do-- that are really difficult. And this, probably, I would imagine, ranks as one of the top things. And it should never be easy. It will never be easy. The day that you think it's easy, you need to find something else, right? RICHARD LEITER: I think that's right. I think that's right. LIDIA SCHAPIRA: Well, thank you so much, Richard. You made me laugh, you made me cry reading this, and I thank you very much. My last question is, have you had a chance to talk with Tom's widow Julie about what that moment felt like to her? RICHARD LEITER: I have not, although I hope to in the near future. LIDIA SCHAPIRA: And that will be your next piece for us. [CHUCKLES] All right. Well, thank you very much and until the next time. Hope you all enjoy reading Ode to Joy. RICHARD LEITER: Thank you so much. SPEAKER 1: Until next time, thank you for listening to this "JCO's Cancer Stories-- The Art of Oncology" podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. "JCO's Cancer Stories-- The Art of Oncology" podcast is just one of ASCO's many podcasts. You can find all of the shows at podcast.asco.org. [MUSIC PLAYING]

An interview with Dr. Jennifer Mammen from Johns Hopkins University, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She discusses the identification, evaluation, and management of endocrine toxicities in patients receiving ICPis, including thyroid-related irAEs, primary AI, hypophysitis, and diabetes in Part 6 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Jennifer Mammen from Johns Hopkins University in Baltimore, Maryland, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on endocrine toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Mammen. JENNIFER MAMMEN: My pleasure, Brittany. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Mammen, do you have any relevant disclosures that are related to these guidelines? JENNIFER MAMMEN: I do not. BRITTANY HARVEY: OK. Thank you. Then, to start us off, what are the immune-related endocrine toxicities addressed in this guideline? JENNIFER MAMMEN: Yeah. So irAEs affect the thyroid and the pituitary most commonly. But we also addressed the possibility of primary adrenal toxicity and also the emerging toxicity of insulin-dependent type 1 diabetes, which, while rare, can present with grade 4 toxicity in the form of diabetic ketoacidosis. BRITTANY HARVEY: Understood. Then, starting with adverse events affecting the thyroid, what are the key recommendations for identification, evaluation, and management of thyrotoxicosis? JENNIFER MAMMEN: So thyrotoxicosis after ICI exposure is almost entirely due to subacute thyroiditis. That's a transient inflammation of the thyroid gland that causes a few weeks of high levels of thyroid hormone, followed by at least several weeks of hypothyroidism as the stores of thyroid hormone are replenished. In the irAE context, many patients do not ever actually recover adequate thyroid function and will remain hypothyroid, requiring thyroid hormone long term. Because the thyrotoxicosis is transient and results from the release of preformed thyroid hormone, anti-thyroid drugs do not help and actually can even make the hypothyroidism phase worse. Therefore, the treatment is really supportive care with beta blockers in particular to control symptoms of the hypothyroidism, such as tachycardia, tremor, or anxiety. BRITTANY HARVEY: In addition to those points for thyrotoxicosis, what are the key recommendations for primary hypothyroidism? JENNIFER MAMMEN: Yeah. So primary hypothyroidism is very common both in the general population and now in this population as a result of thyroiditis. Many patients might actually already be on thyroid hormone when starting immunotherapy. When the pituitary is working, the pituitary hormone thyrotropin or TSH is a reliable indicator of the adequacy of thyroid hormone replacement. And the goal is to use a dose of thyroid hormone that maintains the TSH in the mid reference range, generally between 1 and 3 million international units per liter. When a patient is first presenting or diagnosed with hypothyroidism, for example, in that second phase of thyroiditis, a weight-based dose can be used to estimate the needed replacement dose. For those with higher BMI, generally, an ideal body weight rather than an actual body weight gives a better estimate. And those specific recommendations are in the guidelines. Proton pump inhibitors, calcium/iron supplementation, or GI inflammation can all decrease the absorption of thyroid hormone. And so even the thyroid hormone is really common, and many oncologists are used to managing it, it can be tricky in these patients if there's issues with malabsorption. And so, therefore, an endocrinology consultation can be helpful to titrate and ensure that the dosing is adequate. Once that adequate dose, that stable dose is found, if other factors don't change, dose requirements are generally quite stable and can be monitored annually either by a primary care physician or an oncologist. BRITTANY HARVEY: Great. Those are important points. Then, addressing the immune-related adverse event that impacts the pituitary, what are the key recommendations for identification, evaluation, and management of hypophysitis? JENNIFER MAMMEN: So hypophysitis is inflammation of the pituitary, as you said. And although there are five hormone systems at risk, it's actually most common that the thyroid and the adrenal gland axes are what are affected. The diagnosis is made by a combination of assessing the pituitary hormone and the primary hormone, in this case, the thyroid hormone and cortisol along with the TSH and ACTH, which is the pituitary hormone that regulates the adrenal gland. With primary gland failure, as we said, the pituitary hormones will be elevated. But in hypophysitis, the problem actually comes from the pituitary. And so TSH and ACTH will be low or inappropriately normal for the low primary thyroid hormone level. There are several key points for oncologists who might need to initiate therapy before the patient can see endocrinology. First, thyroid hormone increases the metabolism of cortisol. And so if you've diagnosed central hypothyroidism due to hypophysitis, it's really important to replace cortisol, if needed, before replacing thyroid hormone, because in someone with both deficits, thyroid hormone alone can precipitate an adrenal crisis. Thus, the ASCO Guidelines really emphasize the need to assess both before starting thyroid hormone and also give the option to use steroids empirically, if needed, since the diagnosis can be sorted out later by an endocrinologist. A second important point is that headaches, visual changes, and diabetes insipidus, which is loss of fluid and generally marked by hypernatremia, those are much more common with metastatic disease in the pituitary rather than hypophysitis. And so such symptoms should really prompt a pituitary MRI when they're found in the setting of hormonal losses. The management of central hypothyroidism is similar to that of primary hypothyroidism. But as I said, the TSH is no longer a reliable marker for adequate replacement. So the goal, then, shifts from a TSH in the reference range to a free T4 at the upper half of the reference range. Adrenal insufficiency, as with thyroid hormone insufficiency, is managed by physiologic hormone replacement, and that's best done using hydrocortisone. This is a short-acting steroid that can be given in a way to imitate the natural diurnal rhythm. We use 2/3 of the dose in the morning and 1/3 in the early afternoon, allowing levels to fall as they naturally would overnight. Dose-titration is based on symptoms. And usually, 15 to 25 milligrams of a total daily dose is adequate to control symptoms from adrenal insufficiency. I do think all patients should see endocrinology at some point if they have been diagnosed with hypophysitis because they do need education on sick day rules, otherwise known as stress dosing, and also to be instructed on wearing an emergency alert bracelet or necklace or something. Long-acting steroids can be used for patients who have adherence problems. And of course, those long-acting steroids are more appropriate for the treatment of any other irAE that a patient may develop. While on higher doses of prednisone, patients can discontinue hydrocortisone and then restart it when the prednisone dose is weaned down below 5 milligrams daily. If there's a question about whether the central adrenal insufficiency is from hypophysitis or due to suppression after weaning off high-dose exposure, use of hydrocortisone because of the diurnal rhythm actually allows the adrenal axis to recover normally. And so after weeks, you can test for adrenal recovery using a morning endogenous level 24 hours after the last dose is given, which is another advantage to using the hydrocortisone mode of hormone replacement. BRITTANY HARVEY: Understood. And I appreciate you highlighting those key points for oncologists. Then, following that, what are the key recommendations for primary adrenal insufficiency? JENNIFER MAMMEN: Yeah. So primary adrenal insufficiency, you'll see the ACTH elevated just like in primary thyroid disease, and the cortisol will be low. Again, this situation is actually much more common with metastatic disease, and therefore, imaging is called for if you find that pattern of hormonal changes. It's been case-reported to happen with irAEs, but in general, this is incredibly rare. The management of hydrocortisone replacement for people with primary adrenal insufficiency is really the same as for hypophysitis. We're using hydrocortisone with that diurnal physiologic replacement pattern. Primary adrenal insufficiency, however, also generally results in the loss of mineralocorticoid function. And so most patients also need at least a low dose of fludrocortisone replacement. BRITTANY HARVEY: OK. And then the last adverse event addressed in the endocrine toxicity section of this guideline, what are the key recommendations for identification, evaluation, and management of diabetes? JENNIFER MAMMEN: Yeah. So diabetes in this patient population is very tricky because so many of these patients are getting high-dose steroids as part of their chemotherapy regimens, and this can cause a lot of hyperglycemia. And I think it's actually easy to become complacent about seeing blood glucoses in the 200s. And in fact, most of the hyperglycemia will be just that, secondary to steroid exposure and worsening type 2 diabetes. It can be managed with a titration of routine medications. But they are now increasingly less rare but still rare events of acute loss of pancreatic function, presumably autoimmune, that can be accompanied by life-threatening diabetic ketoacidosis. And the challenge for oncologists, I think, is to have a low enough threshold to investigate a suspicious pattern of hyperglycemia, for example, hyperglycemia with complaints of polyurea or, on physical exam, a more rapid respiratory rate that could indicate compensation for metabolic acidosis. So it's really a question of being a good clinician and taking the diabetes in context and not just assuming that it's due to steroid exposure. This is, I think, important because, like I said, diabetic ketoacidosis can be a grade 4 emergency, and patients can end up in the intensive care unit, needing a lot of intervention, which if we have a higher suspicion in clinic, we might be able to avert by getting rapid communication with endocrinology, starting people on insulin and that kind of an approach. BRITTANY HARVEY: Definitely. A common theme with these toxicities seems to be early identification is key. So thank you for reviewing the high-level recommendations for each of these toxicities. In your view, how will these recommendations for the management of endocrine toxicities impact both clinicians and patients? JENNIFER MAMMEN: Yeah. So I think making diagnoses in the hormonal systems can be complex and does require attention to the interactions, like we were talking about, between the pituitary and the primary gland. It's not something that oncologists necessarily have front of mind. And yet hormone replacement is actually quite straightforward. Once the need for it is recognized, since there's no side effects from replacing a hormone at an appropriate dose, it's just a replacement. And so, therefore, rapid diagnosis and initiation of hormone replacement can really allow patients to continue immunotherapy with a very minimal disruption, even in the face of an endocrine irAE. Although at our institution the close coordination between treating oncologists and endocrinologists is available, that's certainly not true everywhere. And I think that the ASCO Guidelines are designed to try and help oncologists make these diagnoses and initiate therapy to stabilize patients and even allow them to continue treatment while awaiting any necessary consultations, even in the case of thyroiditis, perhaps, managing what's a self-limited event and then moving on, which reduces the burden on patients with other priorities to focus on. BRITTANY HARVEY: Great. Those are very important points. So I really want to thank you for all of your work on these guidelines. And I appreciate you taking the time to speak with me today, Dr. Mammen. JENNIFER MAMMEN: It's my pleasure. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

Dr. Pennell and Dr. James Hammock discuss the provision of oncologic services by Project Access safety net care coordination programs.   NATHAN PENNELL: Hello, and welcome to the latest JCO Oncology Practice podcast, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all recordings, including this one, at podcast.asco.org. My name is Dr. Nate Pennell, medical oncologist at the Cleveland Clinic and consulting editor for the JCO OP. I have no conflicts of interest related to this podcast. And a complete list of disclosures is available at the end of the podcast. Today, I'd like to talk a little bit about the complexities of providing cancer care for patients who are uninsured or underinsured, which is a relatively large percentage of patients in the US. How do patients without insurance receive cancer care? One way is through community programs, including a program called Project Access, a care coordination program connecting patients to specialty medical care at no or reduced cost, including, in some instances, oncology care. But how does it work? Who does it help? And how impactful are this and other programs designed to obtain cancer care for low-income, uninsured, and underserved patients? With me today to discuss this topic is Dr. Jamey Hammock, a resident in internal medicine at the University of Alabama Birmingham. We'll be discussing the paper from he and his colleagues titled, Oncologic Services Through Project Access and Other Safety Net Care Coordination Programs, which was published online July 31, 2020 in the JCO OP. Welcome, Jamey, and thank you for joining me on the podcast. JAMEY HAMMOCK: Hey. Thank you, very excited to be here. I did want to say too that I do not have any conflicts of interest or disclosures for this particular study. NATHAN PENNELL: Why don't we start out by talking a little bit about how big a problem it is for providing cancer care in uninsured and underinsured patients in the US. JAMEY HAMMOCK: It's an enormous problem. If you look at previous studies, they've looked at patients who are underserved, underinsured, or even uninsured with cancer. And these patients actually typically present with later stage disease, they experience delays in treatment, and ultimately have worse overall survival compared to well-insured patients. So just that alone tells you how big of a problem that this is. I think that when you look at cancer care for underinsured and uninsured, you have to break those things up. And you can't really talk about it without talking about the Affordable Care Act. So let's take uninsured patients, for example. If you look at pre-Affordable Care Act and post-Affordable Care Act, there's a great study in 2017 that really broke down these two groups, pre and post. And what they found is with the Affordable Care Act, if you are uninsured across any income level and you lived in a Medicaid expansion state, the percentage of patients who were uninsured decreased from about 5% to 2 and 1/2%. So it really cut that percentage in half, which is pretty impressive. And then if you look at low-income uninsured patients, because they broke that down in the study, the percentage actually dropped from around 10% to 3 and 1/2%. So It just shows you when you talk about absolute numbers and then those percentages, how many individuals are really affected that have a diagnosis of cancer and are uninsured. And it gives you a little bit of insight of what Medicaid expansion has done for that group. And then I want to touch really quickly too on underinsured. So basically underinsured patients, they don't have the means to get the care that they need, even if they have insurance. That's important. And patients with Medicaid, for example, they have insurance, but they have their own challenges. For example, there's been studies showing that they have longer wait times to see some specialists. It's harder to find a physician that takes patients with Medicaid. Lastly, these providers are so few and far between that sometimes these patients are asked to drive very long distances to get the care they need. And you're already talking about a disadvantaged patient population who may not have the means to drive an hour away to get to their visit. NATHAN PENNELL: That sounds very challenging situation, even for people who technically have health insurance, and still don't necessarily have what they need to access care the way it should be given. Can you tell us a little bit about Project Access? I have to admit, I had never heard of that before I read this paper. And it was a fascinating program that something like this exists. Can you tell us a little bit about it? JAMEY HAMMOCK: Absolutely. So Project Access, first off, they do great work. It's a nonprofit organization that really, really works hard to try to get patients who are underinsured and uninsured subspecialty care. So I want to talk real briefly about the history first because I think it helps you understand why Project Access came to be. I think we need primary care pretty well in the US for patients who are underinsured and uninsured. We have things called community health centers, which are federal qualified health centers funded by the government. And they really do a good job providing primary care for patients who cannot get it elsewhere. The problem is that a lot of these patients ultimately will end up meaning a subspecialist. And there does not exist a community health center for subspecialty care that's funded by the government the way that community health centers are. One thing to address this was Medicaid expansion. Medicaid expansion was supposed to increase the amount of patients who got insurance and thus wouldn't be able to obtain the subspecialty care that they need. But we've already talked about some of the shortcomings of Medicaid expansion, including not all states have done that, decided to expand unfortunately. And if you're an undocumented immigrant, unfortunately, you don't have access many times to government programs. So it doesn't do anything for those populations. There's been some other strategies, Dr. Pennell, to try to address subspecialty care in these populations, things like telehealth, and which you would need the technology, things like subspecialists actually coming to community health centers, let's say, every other Friday to see a patient who needs a cardiologist or an oncologist. But the problem with that is it's a little sporadic, it's inconsistent. And sometimes these patients can't be that flexible and come in the only day that the specialist is going to be there. And so really, here enters Project Access to say, you know what, let us negotiate-- pre-negotiate with subspecialists in the community that surround these community health centers and find subspecialists that agree to see x amount of patients a year. And when it comes time to refer a patient to a specialist, you contact us, and the work has been done. And so they sort of broker, if you will, or negotiate between some specialists in primary care. And they do a lot of the groundwork that it takes to get these patients the subspecialty care they need to get the results of the subspecialty visit back to the primary care. They do all of that legwork. And so they really are an incredible, incredible service. I do want to mention, they're more of a local solution. So Project Access Birmingham, for example, it serves the residents of Jefferson County. It's not meant to be a statewide solution. They're very good at serving the patients who are near, who are in the county. And in fact, a lot of them have requirements that you be a resident of the county that they operate in. But they do a wonderful job getting these patients the subspecialty care that they need. NATHAN PENNELL: Well, I have more questions about Project Access. But I think you're going to answer some of them when we start to talk about your paper. So why don't you just start off by talking us a little bit about, what was the purpose of the project that you did and how did you design your quality project. JAMEY HAMMOCK: This project started out as a genuine question I had working as an intern in internal medicine. I would see patients come into our hospital who were uninsured who had a malignancy or cancer. And I would just ask, where do these patients get their care. How are they suppose to get outpatient clinic follow-up? So that's when I learned about Project Access locally here in Birmingham. And as you just mentioned, I had a ton of questions. So I actually went and met with Project Access and just asked them all of these questions. How do you work? How is your funding? Who do you see? What specialties do you provide, et cetera, et cetera. And I decided I wanted to really take an in-depth study and look at our Project Access here in Birmingham. When I began doing the literature review for that, I realized that there was not much out there in terms of this Project Access model. I was told that many other ones exist across the country, but there had not been a lot done in the medical literature describing these places and the wonderful work that they do. And so at that point, I began to zoom out a little bit and look at all of the Project Access centers that exist in the country. NATHAN PENNELL: What did you find out when you started calling and checking in with all of the different Project Access programs? JAMEY HAMMOCK: To kind of bring things back to home, I really was particularly interested in how these Project Access centers offer oncology care because oncology care is a little bit different than other subspecialties in terms of the resources needed to provide such care. And my interest was, how do programs who are nonprofit who are trying to work with underinsured/uninsured patients provide care that require so much resources. So that was really one of my objectives is to tailor my approach to oncology care, specifically, while also describing the programs in general. And so what I found was that out of about 30 programs that I found, roughly 2/3 offered care medical oncologists. And then out of those 2/3, about 1/2 of those programs actually offered chemotherapy. Fortunately, everyone offered radiographic studies, such as MRI, CT, PET scan. So they could at least assist in diagnosing or helping to diagnose suspicion for a malignancy. Obviously, that doesn't include a biopsy, but could at least sort get the ball rolling, if you will. And then the other thing I discovered is, as I mentioned previously in the podcast, there was a lot of heterogeneity between the programs. So some programs offer transportation, some programs offered interpreter services, while others did not. Some programs required small co-pays. It seemed that everything was really tailored to their respective local community and what worked best for that community. In terms of Medicaid expansion, which was sort of another thing we were looking at with this study, what we found is about 2/3 of the states that have not expanded Medicaid have a Project Access center. And if you compare that to states that have expanded, only about one third of those have Project Access centers. And so our study suggests that the need for pro bono care is a little higher in Medicaid non-expansion states. And I think that that's intuitive. The percentage of uninsured patients with cancer in a non-expansion state is as high as 13%, depending on what their income is. And that's compared to about 2% to 3% in a state that's expanded Medicaid. So those are drastically different numbers and drastically different needs for patients, depending on if they reside in a state that has expanded Medicaid. NATHAN PENNELL: But it seems as though the difference between areas that had programs that offered cancer care and those that didn't probably revolve around whether they're able to find practitioners who are willing to provide those services. And it looks like you did some investigating of programs that did and did not offer cancer care. So what were the differences between those? JAMEY HAMMOCK: The next step of my project was to interview those program coordinators of the centers who were not able to offer medical oncology care. And three common themes emerged as I talked to these program directors. The first of those themes was cost. And I think that that's intuitive. And it did not surprise me. Medical care is expensive. Oncology care is expensive. And these programs, they're mostly nonprofit and rely on donations and such. And so the first barrier to offering this is cost. The patient see the medical oncologist, and they prescribe chemotherapy, someone has to pay for that chemotherapy. And a lot of Project Access centers were not prepared to do that. One in particular I spoke with, they had actually considered it. And when they ran the numbers, it would account for over half of their annual budget. So it just was not feasible. The second barrier that emerged while I was talking to these program directors was the concept of continuity and a longitudinal commitment. So for example, if I'm a medical oncologist and I decide that I want to take part in this and donate some of my services, and I see a patient that has a new diagnosis of cancer, and we treat the cancer, what happens if they relapse or what happens in five years that they need a medical oncologist again? And I don't think many oncologists were comfortable committing to a situation that had no clear end date. That's in contrast to a patient that has COPD and the primary care physician is referring them to a pulmonologist to get recommendations on maintenance inhalers and what might work best for this patient. That's more of a one and done visit. The third area barrier emerged as I talked to these patients was the concept of multiple physician buy-in. And so, as you're aware, many patients that have a cancer may require care from multiple subspecialties, whether that be surgical oncology, medical oncology, radiology, diagnostic radiology, and even palliative care. And so it really is a disservice to a patient if you can offer them not the full scope of oncological care that they need. A lot of Project Access centers were not comfortable providing some of the care without providing all of the care, if that makes sense. NATHAN PENNELL: I mean, all of those make perfect sense. I mean, although in some ways they relate partly back to the first issue, which is that things cost more if they take a long time and have to continue indefinitely over time. So I'm curious, for the places that did offer chemotherapy, and actually even though it was a relatively small percentage, it was not trivial, chemotherapy is extremely expensive. As you mentioned, some of them looked at it and decided it was going to be something like half of their revenue for the year would be taken and providing this. How did those that covered chemo actually cover the cost of that? JAMEY HAMMOCK: That's a great question. I had the same question. And so what we found is that most of the programs who were able to offer medical oncology and then services, and then taking the next step to offer chemotherapy, they were affiliated with very large hospital systems in the area. So I'll give you an example. Here in Birmingham, our Project Access center works with UAB. And they're able to offer these services because UAB takes the baton, if you will, and carries the care forward, offers that chemotherapy that is needed. So it's done through large affiliated hospital systems. If that does not exist, or if that relationship is not there, then what my study has shown is that it's not feasible. NATHAN PENNELL: Right. That makes sense. I mean, individual oncology offices that order their own chemotherapy could probably never afford to just donate that, whereas large systems have other ways to do that. And of course, the large nonprofits also have to give back to the community and may just consider that part of their community service. What's the next step to extend this? I guess, the larger question is, it'd be great if perhaps everyone had health insurance. But until that happens, what steps can be taken to provide something like this more broadly? JAMEY HAMMOCK: Yeah, so that is exactly what I was thinking. Medicare for all is the answer. And ultimately I think we need a centralized universal health insurance policy. But that's not the topic of this podcast. So until then, Project Access is stepping into the gap and doing this great work. And I really wanted them to be recognized just as a organization, broadly speaking, and then on an individual basis. They are on the ground doing the hard work, making the phone calls, making the partnerships, raising the money. They're really doing incredible, incredible work for people out there who have no other options. It's not enough. As I mentioned earlier, these are local solutions to statewide issues. If you look at Alabama, it's a non-expansion state, unfortunately. The patients in Jefferson County here where Birmingham is, they benefit from Public Access, but the patients in Shelby County might not. So it's a statewide issue for the states that don't have Medicaid expansion, and then even a small population in the states that do. One thing that we can do is we can look at the examples that have been set by Project Access centers who have partnered with these hospitals and collaborate and say, listen, we're a Project Access center that has not had any luck. Please share with us how you were successful in providing oncology care to your patients. My hope is that this project provides a list where collaboration can begin. And these places can learn from each other. NATHAN PENNELL: Well, I think that this is fantastic. And I'm really happy that we're going to be able to highlight Project Access and your manuscript so more people are aware of this and hopefully can start shining lights on their own local Project Access programs. JAMEY HAMMOCK: Right, right. NATHAN PENNELL: Well, Jamey, thank you so much for joining me on the podcast today. JAMEY HAMMOCK: Thank you for having me. I thoroughly enjoyed it and love talking about Project Access and access to care. And I really appreciate it. NATHAN PENNELL: Until next time, I also want to thank our listeners for checking in on this JCO Oncology Practice podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts, or wherever you listen. While you're there, be sure to subscribe so you never missed an episode. JCO OP podcasts are just one of ASCO's many podcasts programs. You can find all recordings at podcast.asco.org. The full text of this paper is available online at ascohubs.org/journal/op. This is Dr. Nate Pennell for the JCO Oncology Practice signing off. PRESENTER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care. And is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

Dr. Pennell and Dr. Friedman discuss the variety of ethical dilemmas for health care providers brought on by COVID-19. NATE PENNELL: Hello, and welcome to the latest JCO Oncology Practice Podcast, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all recordings, including this one, at podcast.asco.org My name is Dr. Nate Pennell, Medical Oncologist at the Cleveland Clinic, and consultant editor for the JCOOP. I have no conflicts of interest related to this podcast, and a complete list of disclosures is available at the end of the podcast. Today I want to talk about a very serious topic that all of us who care for cancer patients really had at the front of our minds back in the spring of 2020. While it may already seem like a long time ago, when the COVID pandemic was at its peak in the United States, New York City was being inundated with of COVID. And for a while there was quite a bit of uncertainty about whether they might run out of personal protective equipment or ventilators. And there were very serious discussions happening about allocation of resources. I personally remember patients asking me, even here in Ohio, if they might not be offered a ventilator if they became sick, because of their cancer diagnosis. And while this certainly never came close to happening in Ohio, I think it actually came closer than we'd like to admit in places like New York. With me today to discuss this really fascinating topic is Liz Blackler, who is the program manager for the Ethics Committee and Consult Service at Memorial Sloan Kettering Cancer Center in New York City. We'll be discussing the upcoming manuscript from her and her colleagues titles, "COVID-19-related Ethics Consultations at a Cancer Center in New York City-- a Content Review of Ethics Consultations During the Early Stages of the Pandemic," which was published online August 27, 2020 in the JCOOP. Welcome Liz, and thank you for joining me on the podcast. LIZ BLACKLER: Thank you so much for having me here today. I'm definitely looking forward to discussing our manuscripts with you. Just to note, I do not have any relationships or disclosures related to this study. NATE PENNELL: Thank you. So what was it like to be really in the epicenter of the COVID pandemic back in the spring? LIZ BLACKLER: There was a lot of uncertainty. We were all just trying to find our way, to figure it all out. Staff was just reconciling what was happening in real time in the city and the world, and then looking into our own hallways, seeing what was happening there. I would say it was both chaotic and eerily quiet. Our ethics consultation service, as with many ethics consultation services in the hospital, went virtual. So only those people who needed to be on site were there. And the rest of us were working from home. And so I think as a staff, we were adjusting to doing our jobs remotely, and also watching and feeling the enormity of what was happening at the hospital with patients, and feeling just a little bit far away. NATE PENNELL: So you are in charge of the ethics consult service. I think anyone who's ever been involved in a case that needs to involve the ethics consult service knows how incredibly interesting a job that must be, and complicated. Can you just, before we get into the COVID thing, explain what an inpatient ethics consult team does, and who is on that team? LIZ BLACKLER: Sure. So ethics consultations are most frequently requested to help analyze and resolve complex value-laden concerns that arise between or among clinicians, and patients, and/or families. Anyone-- clinicians, non-clinician staff, patients, family members, health care agents, surrogate decision makers can request an ethics consultation. And depending on the situation, the consultant may facilitate communication between the stakeholders. This also involves clarifying treatment options and prognosis. Our consultants also help opine moral reasoning and ethical principles to certain situations. And we spend quite a bit of time confirming and clarifying state and federal laws, and hospital policy, and how it relates to the specific patient at hand. In general, the ethics consultants work closely with all parties to help identify acceptable courses of action. Our clinical ethics consultation team is a standing subgroup of the ethics committee. And the group is voluntary, and is comprised of 10 MSK employees from a variety of disciplines. These consultants are additionally trained in clinical ethics. And currently we have nurses and physician assistants, nurse practitioners, social workers, and physicians representing psychiatry and critical care medicine. So we work in a single-modeled service, meaning consultants work independently, and then reach out to other consultants for assistance as needed. So we are a busy service at baseline. And during COVID, our ethics consultations actually doubled. NATE PENNELL: Yeah, I can see that when you start to delve into your paper, and the issues that came up. And what are the special ethical concerns that arose that might involve COVID in patients with cancer that differed from the usual things you would see patients about in the hospital? LIZ BLACKLER: Sure, it was actually what spurred us to do a retrospective review on our ethics consultation service. We encountered two, I would think, unique issues that came up that we had not previously seen before on the ethics consultation service. Our very first COVID-19-related ethics consult focused on a patient with decisional capacity who was admitted to the floor, and wanted to be discharged against medical advice while he was waiting for his COVID-19 test to come back. In the beginning, it was taking a couple of days to get those results back. Staff was very concerned if a patient would not adequately quarantine at home, while we are waiting for the results. In fact, he said he would not quarantine, that he would be out in the subway, and this and that. So we were called in to assist in clarifying whether respecting this patient's autonomy to leave the hospital AMA outweighed our obligation to keep the patient in isolation, and prevent him from potentially spreading the infection. We had never encountered an issue like that before. So in that case, we were able to support the patient, and help him understand the reasoning why he needed to stay. In the early days of the pandemic, as we were just sorting out what was causing the spread of COVID, I think we would have likely leaned towards figuring out a way to keep him, as long as we could. It's always tricky in that we don't want to override someone's autonomy, unless absolutely necessary. And so there were two cases like this, where we really had to weigh the risk to the public against individual autonomy of the patient. NATE PENNELL: Yeah, I know. It's very interesting to think about something like that. At first blush, it seems as though there would be no legal way to keep someone if they wanted to leave. But then switch it out and say, well this patient has Ebola now, and wants to go out on their own. And suddenly it jumps to the front of your mind that maybe it's not quite so simple. It also, I think, illustrates nicely what the ethics team does, which is not necessarily to come in and deliver an academic treatise on the ethical principles of who's right and who's wrong, but to help negotiate the different parties to come to an acceptable agreement. LIZ BLACKLER: Exactly. And in a similar case, we had a family who was wanting to leave the hospital, and go to a local hotel. But at the time, the hotels were either COVID-positive hotels or COVID-negative hotels. And this family insisted on having their loved ones stay at the hotel that was a COVID negative hotel. And so the staff called a similar consult line to know whether they had an obligation to share the patient's medical status with the hotel. And in a similar mind, we did just what you said. We pulled the whole team together. We met with the patient and family, expressed our concerns, and actually helped identify an acceptable hotel that would make a concession, that was in the geographic location of where they wanted to be, that would in fact sterilize and come up with its own private entrance for this patient. So everybody was happy, right? We knew he would be safe, and the family got to have this loved one closer to home. NATE PENNELL: I'm sure that doesn't always end up with such a good result at the end. But that sounds like a good job. So you had some fascinating consults. So most of your manuscript is describing some of the examples of the types of scenarios that you had to address. So can you take us through some of those, both just like the general themes and then maybe some specific examples? LIZ BLACKLER: Of course. So like I said, we performed a retrospective review of all of our COVID-19 ethics-related consults that happened between mid-March and the end of April. There were 26 consults total performed on 24 unique patients. The most common ethical issue was related to code status. So these were patients. Staff members were concerned about incubating, or performing cardiopulmonary resuscitation, because of the high risk for aerosolizing procedures. If you remember, at the beginning of the pandemic, there was a high level of anxiety about supply shortage of personal protective equipment. So staff was very concerned about whether it was ethically appropriate to provide CPR for our patients with poor prognosis, because many, if not most of our patients at that time, not only had advanced cancer, but they had concurrent COVID-19 infection. They had a poor prognosis. Because there was a lot of risks to providing the CPR and intubation with minimal benefit, and so more than half of our consults came through that were questioning that, this idea of non-beneficial treatment. NATE PENNELL: Well, I guess it's hard not to stop, and talk about that a little bit. So you've got a patient with advanced cancer, who presumably wants to be full code, but is COVID positive. How do you even start to address something like that with the patient and the staff who are worried? LIZ BLACKLER: As you know, many of our patients with advanced cancer and respiratory distress, it's quite hard to have conversations with them for lots of reasons. I think complicating the situation was we had a zero visitor policy at that time at the hospital. So all hospitals in the state had zero visitor policies. There was no family or caregivers or agents at bedside. We had family at home listening to the news, and they're recognizing how important something like a ventilator was for patients with COVID, as a bridge to recovery. And many family members very much wanted to give their loved one an opportunity to recover from COVID, despite something like a stage 4 lung cancer diagnosis with no [INAUDIBLE] And so as you can imagine, on a day-to-day basis pre-COVID, we do a lot of goals of care discussion. So we spend a lot of time with patients and families trying to help them understand the limitations to treatment at the end of life, and what is ethically and morally appropriate, and what may not be the right thing to do. And so we had to apply all of those same tactics in a very expedited fashion, talking with family who were isolated and removed from the situation, who could not be at bedside with their loved one to try to help them come to terms with what was happening. What you may not know is New York state has a law that says full code, cardiopulmonary resuscitation is the de facto intervention for all patients, unless they consent specifically to a do-not-resuscitate order. So we were obligated by law to perform cardiopulmonary resuscitation on all patients with families who wanted it. And so we spent a lot of time talking with our families to help them understand what's happening. And some of those patients did have cardiopulmonary resuscitation, and others understood the gravity of the situation, and were more amenable to do-not-resuscitate orders. NATE PENNELL: Yeah, it must have been incredibly challenging. But any other themes that arose in terms of the consults that you received? LIZ BLACKLER: Interestingly we had three or four consults that came through by staff that were concerned that patients were requesting a do-not-resuscitate order prematurely, that it was not standard of care for their clinical situation. What we suspected that it was the converse of what was happening. Patients and families had this altruistic response to the local and national focus on scarce resources. So saying, wow, we understand how difficult things are right now. We're OK. Please focus your resources on someone else. NATE PENNELL: Wow. LIZ BLACKLER: So that was-- NATE PENNELL: Yeah, I can imagine that would have been-- well hopefully, I guess, that might not have been quite as challenging. Because maybe some of that might have been a lack of understanding about the prognosis, and people who actually did have a reasonable prognosis might-- I don't know if they were convinced to change their minds, or they generally just supported their decision. LIZ BLACKLER: We did a little of both. I think in two of the situations, we were able to help families understand the nuances of the situation, and they agreed to a trial intubation. Other families were insistent that this was not in line with their loved one's wishes, which might have been separate from the COVID-19 pandemic. One thing we did do with the hospitals early in the pandemic, we requested, mandated if you will, that all outpatient oncologists communicate and document the goals of care conversation with their patients on admission within 24 hours. And so each patient that was admitted to the hospital had a discussion. All those who could had discussions with their outpatient primary oncologist about diagnosis, treatment options at present, and what their wishes were regarding goals of care. And that very much helped the ethics consultation service and the services in the hospital provide care that was aligned with not only treatment options, but the patient's and family's wishes. NATE PENNELL: That's really interesting. Because many people were listening to this podcast might think, well, gosh. Shouldn't you do that anyway when someone gets admitted to the hospital with advanced cancer? But perhaps the pandemic offered an opportunity, because patients were thinking about it now, as opposed to oftentimes when they get admitted and it suddenly is a bit of a shock to be presented with the question of what they would want if they needed to be resuscitated. LIZ BLACKLER: Agreed. I think it's a natural opportunity for us to continue to strengthen our need for and goals of care conversations for all of our patients, whether they're stage one cancers or stage four cancers. And so I think it was this natural time where everybody was talking about it. And it just felt it was-- it was just made sense for us to do. And it is something that we've been trying to continue as a hospital. These conversations are hard to have. Patients and families are not always receptive. Clinicians are not always ready to have those conversation either. And so if anything, the pandemic brought us all together, and we all recognize in the anticipation of scarce resources how can we best take care of these patients. What's first and foremost is we have to have a better understanding of what our patient's wishes and preferences are. NATE PENNELL: One of the things that continues, at least to some extent in a lot of places, is the restrictions on visitors and caregivers in the hospital, although perhaps not as strict as it was back in the spring. How did the inability of caregivers and powers of attorney and things like that to physically be present impact your job? And I guess more broadly, how does being forced to work over a sort of video conferencing impact these conversations? LIZ BLACKLER: Sure. I think the level of distress secondary to the limited or lack of visitors at bedside, was palpable. So the nursing staff, the clinical staff, and non-clinical staff who were in the hospital at bedside every day were very upset. It was an incredibly sad time. And that in itself led to more ethics consultations, the amount of distress. And so we as a consultation service, worked hard in our virtual platform to provide extra support to staff who were trying to manage these patients to really take care of them in a way, in a kind and compassionate way in the midst of all of this chaos. We started something called a virtual ethics open office hours. We actually set up a virtual Zoom twice a week where my consultants would sit on the Zoom call and just field questions, general questions that were coming up from staff. Because there was a lot of anticipation of what was to come, and how the hospital was prepared, how we were prepared to take care of patients, if we were to not have enough ventilators, or if we were not have enough blood products. And so the anticipation of all of that was very extremely stressful for staff, and I think compounded by the fact that there was no support at bedside for the patients. I would say as a consultant service, going virtual certainly had its hiccups at first. But I actually think in the long run, we were able to really support patients and caregivers in a different way. There were more families that were able to participate in some of the family meetings, if they were scattered around the tri-state area or the country even. And so once everybody was acclimated to using these platforms, staff and family alike, then there were more opportunities for families to engage and participate in these family meetings. We were able to outfit many of our rooms with video access so that the patients who were able to participate were also able to participate, to be there [INAUDIBLE] NATE PENNELL: It sounds like you did the best with what you could. And certainly it was tough on our patients, because they didn't have anyone to be there with them. But I can see the benefits of bringing people in who otherwise might have had trouble participating. So I wanted to just briefly touch upon something that I'm not sure if everyone realized this. But in anticipation of being completely inundated and running out of ventilators and whatnot, some hospitals were putting together protocols on how they would allocate resources. And it sounds like you may have been part of putting something like that together for your hospital. I know it was never needed. But can you talk a little bit about that? LIZ BLACKLER: Sure. I think one of our obligations as an ethics committee is we have a duty to plan, and a duty to steward resources, and a duty to be transparent about it. So early in the pandemic, the ethics committee was asked to draft allocation policy in the event that we had a scarcity of equipment, or staff, resources, blood products. I remember being sent home from the office to start writing that policy. And I actually haven't been back since. What I will say is although an incredibly difficult policy to write, it was heart-wrenching for all of the reasons that you can imagine. It felt important to at least have a framework in place just in case. And so we made a decision as an ethics committee and consultation service to model the framework after the New York State ventilator guidelines that were published in 2015. We made some slight modifications to address our unique cancer patient population. We chose the New York State guidelines, because they were developed just a few years before with support from our state government. The guidelines were also publicly available, and we assumed had passed with public support. There are no perfect guidelines. And so for us, in many ways we were lucky to have had a blueprint, something to work with in our state. While acknowledging that without state support, we were fully aware that if the crisis standards of care were needed, they needed to be implemented statewide with consistency. We also struggled with trying to recognize that the policies needed to take into account inequities in access and delivery of health care, with special considerations for inherent bias, based on socioeconomic, racial, ethnic, age, and others with disabilities. I think as a bioethics community, we're working to update allocation policy that acknowledges and begins to rectify such bias. And so we're able to think about that now, looking back on what's happened a few months ago. But in real time, what we had with the New York state guidelines, which I think is a good start, those guidelines are your classic guidelines that look to maximize benefit of resource in order to save as many lives as possible. The [INAUDIBLE] is given to patients for whom resources would most likely be lifesaving. We put into place a classic triage process that was grounded in a clinical scoring system. And we also made sure to remove the triage decisions from the bedside clinician, instead relying on a triage committee that would be made up of critical care physicians, administration, ethics consultants, or committee members, and other senior staff from the hospital to help make these determinations based on this clearly spelled out criteria, knowing that there were flaws in those criteria. And so we did put together a policy. We thankfully did not have to implement that policy. But we have the policy put into place. NATE PENNELL: And that, I think, leads us really nicely into my last question, which is really what did you learn from all of this going forward? So if this happens again, hopefully not with COVID, but another emergency or something that leads to strained resources; what take-home lessons can you take from this that will make that perhaps an easier situation the next time? LIZ BLACKLER: Sure I'll approach it from a macro and a micro standpoint. So within the hospital, one of the things that we learned is that our clinician's preoccupation and distress when confronted with these difficult choices in the pandemic, with the anticipation of a scarce resource, was palpable. And that as an ethics consultation service, we have an obligation to put together a center-based initiative to really support staff in real time. And so going virtual quickly, setting up services for staff that are proactive instead of reactive, it has been very helpful. And so I mentioned the virtual ethics clinics or office hours as one way to reach a lot of staff quickly, and to provide support in real time. I think the other issue I touched on briefly, and that is working within the state and the country to come up with acceptable allocation policies that acknowledge bias, that acknowledged disparities in health care, and delivery of health care, and access to health care are extremely important. So one thing that has come out of this that I'm very proud of, as a hospital we at Memorial Sloan Kettering, we reached out to all of our colleagues in the city and upstate New York, and have recently just for formed an Empire State Bioethics Consortium. So all of the chairs of the bioethics departments from around the state, we now meet on a regular Monday night phone calls, to talk about what's happened, anticipation for future, and really working on a broad range of ethical issues that affect New York State. NATE PENNELL: Liz, thank you so much for joining me on the podcast today. LIZ BLACKLER: Thank you so much for having me. I really appreciate it. NATE PENNELL: I'm glad we're going to have the opportunity to highlight your manuscript, which I think is really going to be beneficial to people who hopefully will not be presented with this in the future. But if they are, it's something to get them thinking. And until next time, I want to thank our listeners for listening to the JCO Oncology Practice podcast. If you enjoyed what you heard today, don't forget to give us a rating or a review on Apple podcasts, or wherever you listen. While you're there, be sure to subscribe, so you never miss an episode. JCOOP podcasts are just one of ASCO's as many podcast programs. You can find all the recordings at podcast.asco.org. And the full text of this paper is available online at ascopubs.org, backslash journal, backslash op. And this is Dr. Nate Pennell for the JCO Oncology Practice signing off. Thanks for listening. SPEAKER 1: 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. For more original research, editorials, and review articles; please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.