ASCO Guidelines

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 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. 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. 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/podcasts. 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 are 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 177Lutetium-PSMA-617, what are the updated recommendations from the guideline panel? Dr. Rohan Garje: The panel recommends the use of 177Lutetium-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 taxane-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 radiotracers 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 myelosuppression 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: 177Lutetium-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.