ASCO Guidelines

An interview with Dr. Yinghong Wang from MD Anderson Cancer Center, author on "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update." She discusses the identification, evaluation, and management of gastrointestinal toxicities in patients receiving ICPis, including colitis and hepatitis in Part 4 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey. And today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Yinghong Wang from the University of Texas MD Anderson Cancer Center in Houston, Texas, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on gastrointestinal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Wang. YINGHONG WANG: Thank you, Brittany. It's my great pleasure to be invited to participate in this education event. I'm happy to share my experience and the knowledge that I learned over all the research studies in this field and share with the readers or the community providers on this specific topic. BRITTANY HARVEY: Great. Thank you. Then, first, before we get into the content, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Wang, do you have any relevant disclosures that are directly related to these guidelines? YINGHONG WANG: I do have consulting services to two pharmaceuticals, but they're not related to the current guidelines that are published from the ASCO. They're Tillotts Pharma and Athenex Pharma. BRITTANY HARVEY: OK. Thank you. Then, let's talk about these gastrointestinal toxicities. So first, what are the immune-related gastrointestinal toxicities addressed in this guideline? YINGHONG WANG: So these particular guidelines have provided very detailed description on the incidence and clinical presentations and also recommendations on the evaluation and treatment for the upper and the lower gastrointestinal adverse events and the liver and even other organ toxicity, including the exocrine pancreas toxicities that are being categorized as GI field related to checkpoint inhibitor treatments. BRITTANY HARVEY: OK. And then what are the key recommendations for the identification, evaluation, and management of colitis? YINGHONG WANG: So colitis is definitely one of the most common organ to be involved in this category of toxicity-related checkpoint inhibitors. And that's why a lot more studies have been studied because the patient volume can allow enough power to run a lot of analysis. I think the summary that I would say-- the recommendations from the current ASCO Guidelines include the early recognition and evaluation with close monitoring for people who had suspicious symptoms for gastrointestinal adverse events and early stool inflammatory marker evaluation even in patients who had grade 1 symptoms. And very important to rule out alternative causes of the symptom presented, like infections or cancer metastases or some other medication-related side effects other than checkpoint inhibitors. And the other important component of evaluation is endoscopy and the pathological evaluation for patients who had a positive stool inflammatory markers or if the patient has a presentation of colitis symptoms like bleeding. And also, the presence of ulcers on the endoscopy usually has been found to predict a steroid refractory disease course. Therefore, the early initiation of more potent treatment like biologic agents, such as infliximab or vedolizumab, is very critical. The other alternative medical treatment, like ustekinumab or tofacitinib or even fecal transplantation for refractory cases, should also be considered in the small portion of patients. The disease monitoring while on the medical treatment is critical via the repeat endoscopy or following the fecal calprotectin level to guide the duration of treatment and the time to resume immune checkpoint inhibitor treatments if indicated. The rechallenge of these checkpoint inhibitors is possible among patients with GI toxicities, and the risk of GI toxicities is completely manageable. That's the brief summary of the GI recommendations. BRITTANY HARVEY: Yeah. Thank you for that summary. And then just in addition to those key recommendations, is there anything additional about the identification, evaluation, and management of hepatitis? YINGHONG WANG: Yeah. The hepatitis-- the incidence is not as common as colitis but can be severe in extreme cases. So it requires the equal attention to recognize and evaluate for liver toxicity after checkpoint inhibitors with close monitoring. We also need to rule out other alternative causes of the symptoms, including the infections, alcohols, iron overload, thromboembolic events, cancer metastases, et cetera. The imaging, on the other hand, is more critical for liver toxicity evaluation. This is a little bit different from using the endoscopy and biopsy for luminal GI tract toxicities. And the liver biopsy should also be considered in certain select cases through all other differential diagnosis and also the other alternative treatment other than corticosteroid, including azathioprine and mycophenolate mofetil, that are mentioned in the small case series and also listed in the current ASCO Guidelines. BRITTANY HARVEY: Great. Thank you for that overview for both colitis and hepatitis. So then, in your view, how will these recommendations for the management of gastrointestinal toxicities impact both clinicians and patients? YINGHONG WANG: Yeah. Given the increasing volume of patients experiencing the GI adverse events related to the checkpoint inhibitor cancer therapies and their related morbidities, so both the clinicians and patients need to be familiar with the clinical presentations and the time frame of onset to ensure early recognition and early diagnosis, especially serious complication and even mortality can occur due to the significant delay in appropriate treatment in extreme cases. So the updated guideline provided by ASCO and also other professional societies in the US or internationally can provide a great resources to the academic and community clinicians when they encounter these cases in their practice. So ultimately, the implementation of appropriate management and future prospective clinical trials in this field for these challenging conditions should improve the patient's outcome of toxicities and also cancer. And that's the goal of our clinicians and academia providers, to be able to serve the patient better in the future. BRITTANY HARVEY: Definitely. Well, thank you for sharing this summary with us today, for all of your work on these guidelines, and for taking the time to speak with me today, Dr. Wang. YINGHONG WANG: Thank you very much for this opportunity. Please let me know if you have any questions. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Milan Anadkat from Washington University & Dr. Aung Naing from MD Anderson Cancer Center, authors on "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update." They discuss recommendations for cutaneous toxicities in patients receiving ICPis, including rash, bullous dermatoses & SCAR in Part 3 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey. And today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Milan Anadkat from Washington University in St. Louis, Missouri. And Dr. Aung Naing from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, authors on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on cutaneous toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here Dr. Anadkat and Dr. Naing. AUNG NAING: Thank you for having us. MILAN ANADKAT: Thank you. BRITTANY HARVEY: I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Anadkat, do you have any relevant disclosures that are directly related to these guidelines? MILAN ANADKAT: As listed in the document, I don't have any direct disclosures. I do have a number of indirect disclosures, as I've consulted on similar topics in the past. BRITTANY HARVEY: Thank you. Then Dr. Naing, do you have any relevant disclosures that are related to these guidelines? AUNG NAING: I do not have. BRITTANY HARVEY: Great, then let's get into the content of this guideline and the cutaneous toxicities that we're here today to talk about. So Dr. Naing, what are the immune-related cutaneous toxicities addressed in this guideline? AUNG NAING: Well, with the advancement of immunotherapy, we've seen better response in our cancer patients. However, together with such positive outcomes, we are also seeing side effects caused by the immunotherapy. Disruption of the homeostatic mechanisms include a unique spectrum of side effects or immune related adverse events, commonly called IRAEs. The most common immune related adverse events in patients receiving checkpoint inhibitors are dermatitis, enterocolitis, transmitis, and endocrinopathies. However, if you look at the most commonly reported IRAE of any grade, it is dermatologic toxicity. So here in this guideline, we addressed how to take care of the patients when they are having these side effects, particularly with the cutaneous toxicities. So when you look at that time to median onset of skin toxicities, it ranges from two to five weeks. And using CTCAE criteria for grading is a challenge for skin toxicity, as it may not reflect the true picture. So, therefore, severity may be graded based on body surface area, tolerability, mobility, and durations. Those are the points also we discuss in this guideline. Broadly speaking, they are three groups of cutaneous IRAEs. They are rash inflammatory dermatitis, bullous dermatoses, and finally, Severe Cutaneous Adverse Reactions, SCAR. It is important to have thorough physical exam and rule out any other etiology of skin problems. In general, it's also important to work closely with our colleagues from dermatology. While some of those low grade skin toxicities could be treated in outpatient setting, consulting the cases with dermatologists is important for higher grades of skin toxicities, such as bullous dermatoses and SCAR. My colleague, Dr. Milan Anadkat, will follow with a discussion on the role of dermatologists in taking care of patients with cutaneous toxicities caused by immunotherapy. BRITTANY HARVEY: Thank you, Dr. Naing for reviewing those. So then you just mentioned three categories of toxicity. And I'd like to review the key recommendations for each. So Dr. Anadkat, starting with what is recommended for the identification, evaluation, and management of rash or inflammatory dermatitis? MILAN ANADKAT: Thank you, Brittany. And thank you Dr. Naing for teeing up this discussion. I think, as was mentioned, there are three major categories of cutaneous toxicity that are seen from immunotherapy. By and large, the most common is rash or inflammatory dermatitis, from which there are multiple different phenotypes or looks by which physicians may be seeing. The most common phenotypes within rash or inflammatory dermatitis, which account for over 90% of the cutaneous toxicity seen from immunotherapy, include lichenoid, which is a purple, flat topped bumpy rash that can involve the skin or the mucosal membranes. The psoriasiform, which resembles psoriasis, morbilliform, or oftentimes, maculopapular, which resembles a measles-like pink exanthem over the trunk, or generalized eczema and itching. So what's important is identifying the particular phenotype and categorizing it as an inflammatory dermatosis and excluding the other two phenotypes of cutaneous toxicity, such as bullous dermatoses or Severe Cutaneous Adverse Reactions. BRITTANY HARVEY: Great, and then moving into that second category that you both mentioned, what are the key recommendations for bullous dermatoses? MILAN ANADKAT: And so the key phenotypes for bullous dermatoses, by and large, is bullous pemphagoid, which is the most common phenotype seen in this category. Although other phenotypes resembling autoimmune bullous diseases, such as pemphigus or bullous drug reactions may also be seen. With bullous pemphigoid we see tense blisters, or tense bullae, frequently overlying a bed of erythema on the skin. Patients typically complain of considerable itching, far more than pain, with this category of eruption. BRITTANY HARVEY: Got it. Thank you for reviewing that for bullous dermatoses. So then the third group is Severe Cutaneous Adverse Reactions. So what are the key recommendations there? MILAN ANADKAT: And so the third group, being Severe Cutaneous Adverse Reactions, is a term used worldwide to encompass conditions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and DRESS or drug reaction with eosinophilia and systemic symptoms. These are, fortunately, rare, but can be life threatening skin eruptions. They account for less than 1% of all skin reactions seen from immunotherapy. When practitioners are approaching a patient who may potentially have one of these conditions, patients typically will exhibit symptoms of malaise, fatigue, fever, and a dramatic cutaneous eruption, which will either present with peeling or sloughing of the top layers of the skin, or a generalized erythema covered with multiple sterile pinpoint pustules. Oftentimes, there are associated symptoms of lymphadenopathy and organ toxicity that is noticed simultaneously, such as hepatotoxicity, or eosinophilia, or acute renal failure. BRITTANY HARVEY: Great, I appreciate you reviewing the identification of all three of those groups. So then I'd like to hear from you both on this last question. But in your view, how will these recommendations for the management of cutaneous toxicities impact both clinicians and patients? AUNG NAING: I would say that recognition of the toxicity is really important, particularly if you can actually catch the toxicity when it is in the mild grade. If you take care of them, then you can actually stop them from being mild to severe toxicity. That's number one. Number 2 is in that way, we may not have to halt or stop the immunotherapy treatment that could be beneficial to the patients. And also, working together with the dermatologists is very important, because as I discussed earlier, some of them, we could take care of as an outpatient. But there will be certain dermatology toxicities, where we need to work closely with our dermatologists. And please also remember that these are the guidelines. You will be seeing the patient in the setting. So I think using that guideline and clinical judgment, that would actually help our patients at large. MILAN ANADKAT: I think that's excellent. One, I think, important aspect of these guidelines is not only to correctly identify the phenotypes of cutaneous toxicity, but as Dr. Naing mentioned, it assists in management of these toxicities. The goal of these guidelines, especially as it pertains to the skin toxicity, is to accurately identify what toxicity is occurring for the patient, but then more importantly, to guide on appropriate management strategies to allow the patient to continue on immunotherapy and minimize or avoid unnecessary treatment interruption or treatment discontinuation. The guidelines assist in management strategies according to the severity by which patients present. And as mentioned, I think ultimate priority will be given to the practitioner directly treating the patient. But consideration towards not only extent of body surface area involved, but severity of cutaneous eruption is thoroughly reviewed. And in addition to phenotype, including such patient reported outcomes, such as degree of pain, itch, or interruption on activities of daily living help guide the degree of management that can be provided. BRITTANY HARVEY: Those are excellent points. I want to thank you so much for your work on these guidelines and for taking the time to speak with me today, Dr. Naing and Dr. Anadkat. AUNG NAING: Thank you. MILAN ANADKAT: Thank you. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast. And be sure to subscribe, so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center and Dr. Monalisa Ghosh from the University of Michigan Health System, authors on "Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline." They discuss recommendations for management of irAEs in patients treated with CAR T-Cell Therapy in Part 2 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network. A collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today we're continuing our series on the management of immune-related adverse events. ASCO has developed two guidelines for the management of immune-related adverse events-- one for patients treated with immune checkpoint inhibitor therapy and a second for patients treated with CAR T-cell therapy. In our last episode, you heard an overview of the Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Today, we'll be focusing on the Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline, and we'll have authors join us for future episodes to discuss the key recommendations for organ-specific management for patients treated with immune checkpoint inhibitor therapy. Today, I am joined by Dr. Monalisa Ghosh, from the University of Michigan Health System in Ann Arbor, Michigan and Dr. Bianca Santomasso from Memorial Sloan Kettering Cancer Center in New York, New York, authors on both Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline and Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Thank you both for being here, Dr. Ghosh and Dr. Santomasso. In addition, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Ghosh, do you have any relevant disclosures that are directly related to this guideline? MONALISA GHOSH: No. I do not have any relevant disclosures. BRITTANY HARVEY: Thank you. And, Dr. Santomasso, do you have any relevant disclosures that are directly related to this guideline? BIANCA SANTOMASSO: Yes. I'd like to disclose that I've served as a paid consultant for Celgene, Janssen Pharmaceutical, and Legend Biotech for advising them on the topics of CAR T-cell therapy side effects. BRITTANY HARVEY: Thank you. Then, getting into these immune-related adverse events-- first, Dr. Ghosh, can you give us an overview of the scope and purpose of this guideline? MONALISA GHOSH: Sure. The purpose of this guideline is to offer expert guidance and recommendations on the management of immune-related adverse events in patients treated with chimeric antigen receptor or CAR T-cell therapy. This guideline offers guidance on the diagnosis, evaluation, and management of the most common toxicities of CAR T-cell therapy, which includes Cytokine Release Syndrome-- or CRS-- and immune effector associated neurologic syndrome-- or ICANS. As well as other potential, but less common toxicities, such as Hemophagocytic Lymphohistiocytosis-- or HLH-- B-cell aplasia, prolonged and recurrent cytopenias, Disseminated Intravascular Coagulation-- or DIC-- and infections. BRITTANY HARVEY: Great. Thank you. Then, Dr. Santomasso-- looking at this guideline, there's a few overarching recommendations. So, what are those general recommendations for the management of immune-related adverse events in patients receiving CAR T-cell therapy? BIANCA SANTOMASSO: Yes. The overarching recommendations are, really, first to recognize that these side effects exist. And that, as such, it's important to recognize that patients who develop these toxicities or side effects after CAR T-cell therapy need to be evaluated, or managed in, or transferred to a specialty center that has experience with the management of these toxicities. They're new toxicities. This is a new therapy. And patients are increasingly going to be managed in, or treated in, the outpatient setting, and, as such, they need to remain within a short distance of the treating center for about four to eight weeks post-therapy, and they should then return to their treating center upon experiencing any toxicities. Finally, as its flu season and infection season, it is recommended that inactivated influenza and COVID-19 vaccination be performed on patients and also family members as well. And any patient who does have an active infection, the CAR T-cell infusion should be delayed until that infection has been successfully treated or controlled. I often make a final point, which is that the immunogenicity of and efficacy of COVID-19 vaccines is uncertain in these patients with these agents, but the potential benefits outweigh the risks and uncertainties for most patients. BRITTANY HARVEY: Thank you. Those are important points for patients and treating clinicians. So then, Dr. Ghosh-- as you mentioned, this guideline addresses the seven most common CAR-T-related toxicities, and I'd like to review the key recommendations for each of those. So let's start with, what are the key recommendations for identification, evaluation, and management of cytokine-release syndrome? MONALISA GHOSH: Well, Cytokine Release Syndrome is one of the two major toxicities that occur immediately or within a short time period after infusion of CAR T-cells. We have defined Cytokine Release Syndrome, or CRS, as an immune-mediated phenomenon that's characterized by various symptoms that are indicative of immune activation and inflammation. And patients may experience signs and symptoms that could include fever, hypotension, hypoxia, tachycardia, shortness of breath, rash, nausea, headache, and various other symptoms that are a little less common. These symptoms are caused primarily by the release of cytokines. Cytokines are the messengers of the immune system, and most of them are released by bystander immune and non-immune cells. We know that the onset of Cytokine Release Syndrome is variable depending on the CAR T-cell product that's used, as well as the patient population that's treated. But it generally occurs anywhere from two to seven days after infusion of CAR T-cells, and in some rare cases can occur even a little bit later. A standard grading system has been developed and grade CRS, or Cytokine Release Syndrome, based on three parameters-- fever, hypotension, or low blood pressure; and hypoxia or low oxygen levels. CRS is primarily managed with IL-6 antagonists because IL-6 is an inflammatory cytokine that has been shown to mediate a lot of the systemic effects that we see from Cytokine Release Syndrome. And one of the treatments is the monoclonal antibody tocilizumab, which acts against-- or blocks-- the IL-6 receptor. CRS that is refractory to tocilizumab is generally treated with steroids. Then there's limited experience with additional therapies, especially in the setting of CRS, that does not respond to tocilizumab or steroids. There are other anti IL-6 therapies available. For example, siltuximab, which binds to IL-6 itself rather than the IL-6 receptor. However, there have been no direct comparative studies of these agents. Anakinra, which is also an IL-1 receptor antagonist has also been shown to mitigate CRS in some CAR T-cell recipients that have high grade CRS. BRITTANY HARVEY: OK. Thank you for reviewing those management strategies. So, following that-- Dr. Santomasso, what are key recommendations for identification, evaluation, and management of immune effector cell-associated neurotoxicity syndrome? BIANCA SANTOMASSO: Sure. Immune Effector Cell-associated Neurotoxicity Syndrome-- also known as ICANS-- is the second most frequent severe toxicity that can be seen after CAR T-cell therapy. So, what is ICANS? These are transient neurological symptoms that occur in the days after infusion, most commonly with CD19 CAR T-cell therapy. And the clinical manifestations of ICANS include encephalopathy, which is confusion, behavioral changes, expressive aphasia, or other language disturbance, change in handwriting or other fine motor impairment or weakness, and tremor and headache can also be seen. In more severe cases, patients can become obtunded with a depressed level of consciousness or even develop seizures, and they may require a higher level of ICU care, such as intubation for airway protection. And in very rare cases, malignant cerebral edema may develop, which may be fatal. ICANS can occur at the same time as Cytokine Release Syndrome, or can also occur several days after or shortly after CRS resolves, so it's important to have a high index of suspicion even after Cytokine Release Syndrome has resolved, but typically the side effects are self-limited and occur within the one month after infusion. Most symptoms lasts between 5 and 17 days, and the time of onset duration and severity of ICANS may really vary depending on the CAR T-cell product used or the disease state of the patient. So, what do I mean by that? Patients with high disease burden seem to be at increased risk for severe ICANS, so kind of knowing the disease that the patient has and the burden of disease is important. And then also there may be product-specific differences as well, so reviewing the product label is important as well because each may have its own risk evaluation and mitigation strategies that inform both the duration and the frequency of monitoring for ICANS after infusion. For evaluation of ICANS, we recommend, again, the ASTCT ICANS grading system. These allow for monitoring of several different aspects of neurologic function in these patients. Mental status changes are really what define the onset of ICANS. So for CRS, it's fever; for ICANS, it's mental status changes. And the severity of the mental status change can be determined by a standardized score known as the ICE score, which stands for Immune Effector Cell-associated Encephalopathy score. This is a simple 10-point scoring metric where points are assigned for orientation to year, month, city, hospital, ability to name three objects, ability to follow simple commands, write a standard sentence, and count backwards from 100 by tens. And for children younger than age 12 or those with developmental delay, The Cornell Assessment of Pediatric Delirium, also known as the CAPD, can be used in placement of the ICE assessment. Prior to CAR infusion, patients should be evaluated, including with an ICE score, for their baseline neurologic status. And what's nice is that this ICE assessment can be used as a daily screen after CAR infusion for the onset of ICANS during at-risk period. Then, other than the ICE score, there are four other neurologic domains that contribute to ICANS grading, and that's level of consciousness, seizures, severe motor weakness, and signs and symptoms of elevated intracranial pressure or cerebral edema, and patients are graded according to the most severe symptom in any of the five domains. So for patients who develop ICANS, it's recommended that they have workup, including blood work, CRP, CBC, comprehensive metabolic panel, fibrinogen, and coagulation tests. Neuroimaging with a non-contrast CT of the brain should be done and considering MRI of the brain in patients who are stable enough. In addition, electroencephalogram and lumbar puncture should be considered. And the electroencephalogram is really to rule out subclinical seizures, and the lumbar puncture is to assess the opening pressure-- or the pressure within the central nervous system-- and also to send studies to rule out infection. And again, these all have to be considered on an individual case by case basis, but are things to keep in mind. So for treatment of ICANS, the mainstay of treatment is, really, supportive care and corticosteroids. Tocilizumab, while it seems to rapidly resolve Cytokine Release Syndrome and most symptoms, actually does not resolve ICANS and may worsen it, so steroids are really typically used. The typical steroid is dexamethasone at a dose of 10 milligrams, and the interval really depends on the grade of the ICANS. Because of the possibility that tocilizumab may worsen neurotoxicity, ICANS really takes precedence over low grade CRS when the two occur simultaneously. And patients who don't show improvement within 24 hours after starting steroids or other supportive measures should have CSF evaluation and neuroimaging. Often treatment of seizures-- many patients are put on Keppra and levetiracetam or other anti-seizure medicine if they develop ICANS, and patients with grade 3 or greater ICANS may need an ICU level of care and escalation of steroid doses. The steroids are continued until ICANS improves to grade 1 and then tapered as clinically appropriate. And the most important thing to remember is that ICANS just needs to be monitored very closely as patients may worsen as some steroids are tapered. They also may improve rapidly after steroids are started, so steroids should be tapered quickly as patients improve. And, again, as with CRS, there's limited experience with other agents, such as Anakinra and siltuximab, but those could be considered in severe or refractory cases. BRITTANY HARVEY: Understood. I appreciate you going through when and how clinicians should screen for ICANS and those key management points. So, in addition to that-- Dr. Ghosh, what are the key recommendations regarding cytopenias? MONALISA GHOSH: So cytopenias can occur post-CAR T-cell infusion, and they can occur either in the early phase or in the later phase after CAR T-cell infusion. Meaning that they can occur early within the first few days to weeks post-CAR T-cell therapy or could even occur months to years later. These cytopenias include anemia, thrombocytopenia, leukopenia, neutropenia. Many patients may present with fatigue, weakness, shortness of breath, lightheadedness, frequent infections, fevers, bruising, and bleeding, and the symptoms usually are consistent with how they would present otherwise with anemia, thrombocytopenia, or neutropenia. Acute cytopenias within three months of CAR T-cell therapy are more common. This is due to usually the lymphodepleting chemotherapy that is administered prior to CAR T-cell therapy. Most patients receive a combination of fludarabine and cyclophosphamide prior to CAR T-cell infusion, or they may receive another agent, such as bendamustine. Most patients also come into CAR T-cell therapy with low lymphocyte counts from previous therapies. Early cytopenias, as I mentioned, are generally due to lymphodepleting chemotherapy or other recent therapies. There also could be an immune-mediated process due to the CAR T-cells. Usually prolonged cytopenias which occur beyond three months post-CAR T-cell infusion can be seen in a small number of patients. And the mechanism of prolonged cytopenias is really unclear at this time, but likely multifactorial. Most recipients of CAR T-cells who have prolonged cytopenias beyond three months post-CAR T-cell infusion should have a standard workup to rule out other common causes, such as vitamin or nutritional deficiencies. They should also have testing such as bone marrow biopsy and scans to rule out relapse disease-- relapse lymphoma or leukemia, for instance, that could be causing these cytopenias. Other examples would be myelodysplastic syndrome or other bone marrow failure syndromes. So cytopenias are generally managed with supportive care including growth factor and transfusion support. This applies to both cytopenias in the early period post-CAR T-cell therapy or more delayed prolonged cytopenias. In patients who have prolonged cytopenias of unclear cause that could be immune-mediated, other interventions such as high dose IVIG or even steroids could be considered depending on the situation. For those that have cytopenias in the first few months post-CAR T-cell therapy, generally they are monitored and treated with supportive care, and these cytopenias eventually resolve in the majority of patients. BRITTANY HARVEY: Great. Those are important considerations. Then, Dr. Santomasso, what are the key recommendations regarding Hemophagocytic Lymphohistiocytosis? BIANCA SANTOMASSO: The major recommendations for the identification, evaluation, and management of Hemophagocytic Lymphohistiocytosis, or HLH-- this is also known as macrophage activation syndrome. First, let's just start by saying that this is a dysfunctional immune response, and it's basically characterized by macrophages which are revved up and hyperactive and also possibly lymphocytes as well. There are high levels of pro-inflammatory cytokines during this state and tissue infiltration, and hemophagocytosis, and organ damage. This can occur outside of the context of CAR T-cell therapy, either as a primary HLH or secondary HLH that can be either triggered by infections, or autoimmune disease, or cancer-- especially hematological malignancies, but HLH has also been observed as a rare complication of CAR T-cell therapy. And outside of the setting of CAR T-cell therapy, HLH is defined by fever, cytopenias, hyperferritinemia-- or high ferritin level-- as well as bone marrow hemophagocytosis. And what's interesting is that this is very similar to what's seen during Cytokine Release Syndrome, and that can make it difficult for patients who have moderate to severe CRS to distinguish that from HLH. The laboratory results may be very similar. So the key to recognizing HLH is really to have it on your differential even though it occurs rarely after CAR T-cell therapy. It may occur with slightly different timing and may require more aggressive treatment. The lab alterations can include, again, as I mentioned, these elevated levels of several cytokines, such as interferon gamma. We can't normally send those in the hospital or the clinic, but sometimes soluble IL-2 receptor alpha can be sent and serum ferritin can be sent, and that's an especially useful marker. There have been diagnostic criteria for CAR T-cell-induced HLH that have been proposed, and these conclude very high ferritin levels-- over 10,000-- and at least two organ toxicities that are at least grade 3, such as transaminitis, increased bilirubin, renal insufficiency or oliguria, or a pulmonary edema, or evidence of hemophagocytosis in bone marrow or organs. Unlike other forms of HLH that occur outside of the context of CAR T-cell therapy, the patients may not have hepatosplenomegaly, lymphadenopathy, or overt evidence of hemophagocytosis. So just because a patient may not show those yet doesn't mean that HLH shouldn't be considered. If we see patients that have a persistent fever without an identified infection source or worsening fever, we basically should be considering HLH and doing the appropriate workup and treatment. Patients with HLH often have low fibrinogen, high triglycerides, and also cytopenias as well. The treatment-- just as there's an overlap kind of in the signs and symptoms, the treatment and the clinical management overlaps as well with CRS, so tocilizumab is typically administered. But corticosteroids should really be added for these patients, especially if there's clinical worsening or grade 3 or greater organ toxicity. And if there's insufficient response after 48 hours of corticosteroid therapy plus tocilizumab, many centers consider adding another medication such as Anakinra. I'll finally make a comment that, outside of the context of CAR T-cell therapy, HLH is sometimes treated with cytotoxic chemotherapy, such as etoposide. This approach generally is not used as a first line for patients undergoing CAR T-cell therapy due to etopiside's documented toxicity to T lymphocytes. And generally, the corticosteroids, plus the anti IL-6 agent, plus Anakinra is considered the first line of management. BRITTANY HARVEY: Got it. That's an important note on the management of HLH, and a great note on distinguishing CRS and HLH. So in addition, Dr. Ghosh-- what are the recommendations for management of B-cell aplasia? MONALISA GHOSH: B-cell aplasia, it's a disorder that's caused by low numbers or absent B-cells. And this is particularly relevant to CD19 directed CAR T-cell therapy, which is what most of the CAR T-cell therapies that are available right now target. They target CD19, and CD19 is present on normal as well as malignant B-cells. So most patients who receive anti-CD19 CAR T-cell therapy will develop B-cell aplasia at some point, and B-cell aplasia may be temporary or prolonged. It usually does, on one hand, indicate ongoing activity of the CD19 CAR T-cells and can be used as a surrogate marker. And increase in CD19 CAR T-cells could, in some patients, signal impending relapse, or dysfunction, or absence of activity of CD19 CAR T-cells. B-cell aplasia in CAR T-cell recipients is really due to, as I mentioned, an on-target, off-tumor effect. It can be prolonged and there is variability in rates of prolonged B-cell aplasia. The most significant consequence of B-cell aplasia is that it can lead to low immunoglobulin production. And immunoglobulin production is a very important part of the immune response by providing antibody-mediated immunity, so patients may present with frequent infections and low immunoglobulin levels. For most CAR T-cell recipients, this can be managed with infusions of Intravenous Immunoglobulins-- IVIG. However, the presence of B-cell aplasia can also present other challenges-- especially during this current pandemic, as Dr. Santomasso alluded to earlier, that it is unclear if patients will be able to mount a sufficient enough antibody response to the COVID-19 vaccines available since they cannot produce significant amounts of antibodies. This is an active area of research. However, we do advise that all CAR T-cell recipients do get the COVID vaccine and also other seasonal vaccines, such as the influenza vaccine. So it remains to be seen. We need some more long-term follow-up studies on how many people who receive CD19-directed CAR T-cell therapy will have prolonged B-cell aplasia and what the consequences will be. At this time, it is suggested that patients have their IgG levels monitored and-- if possible-- their actual B-cell numbers monitored. And if their IgG levels drop below a certain number, then they may receive IVIG infusions intermittently. We recommend in this guideline using 400 as a possible cutoff for IgG levels prior to administering IVIG. However, if patients have higher IgG levels and they have recurrent or life threatening infections, infusion of IVIG is recommended as a consideration to help boost the antibody response. BRITTANY HARVEY: OK. As you mentioned, those challenges are particularly relevant now. So then, Dr. Santomasso, what are the key recommendations regarding Disseminated Intravascular Coagulation? BIANCA SANTOMASSO: Disseminated Intravascular Coagulation is a disorder that's characterized by systemic pathological activation of blood clotting mechanisms, which results in both clot formation throughout the body and also bleeding. There's an increased risk of hemorrhage as the body is depleted of platelets and other coagulation factors. So it's basically important for clinicians to be aware that DIC-- or Disseminated Intravascular Coagulation-- can occur after CAR T-cell therapy, and it can occur either with or without concurrent Cytokine Release Syndrome. The treatment is primarily supportive care and replacing the factors, such as fibrinogen-- based on the levels-- and also replacing factors based on partial thromboplastin time and bleeding occurrences. But corticosteroids and IL-6 antagonist therapy can be used if there is concurrent CRS or in the setting of severe bleeding complications. There is limited evidence for other interventions. BRITTANY HARVEY: Great. Appreciate you reviewing those. So then, the last category of toxicity addressed in this guideline-- Dr. Ghosh, what are the key recommendations for identification, evaluation, and management of infections? MONALISA GHOSH: So a variety of infections can be seen after CAR T-cell therapy. And there are many factors that can lead to infection after CAR T-cell therapy including the presence of cytokines, such as neutropenia or leukopenia and B-cell aplasia that we earlier discussed-- leading to low immunoglobulin production and protection. As well as the increased risk of infection due to use of high-dose steroids to treat CAR T-cell-related toxicities, such as ICANS or CRS. Early after the infusion of CAR T-cell therapy-- that is, within three months-- patients often develop neutropenia due to lymphodepleting chemotherapy and/or the CAR T-cells themselves. And these patients are particularly susceptible to infection, so most of the infections that occur early on tend to be bacterial infections, and a few fungal infections have been observed as well. Patients who receive high-dose steroids for high grade CRS or ICANS have been shown to have increased serious infectious complications including bacterial infections, fungal infections, as well as viral reactivations. Infectious complications that occur later are often due to hypogammaglobulinemia due to B-cell aplasia and reduced production of immunoglobulins. And treatment is typically directed at the infectious source, as it would be even if these patients did not have CAR T-cell therapy. There are some prophylactic antimicrobials that are recommended for CAR T-cell recipients who have prolonged cytopenias. Especially those with prolonged neutropenia should be on some sort of bacterial and/or fungal prophylactic antimicrobials. Patients should also be monitored for hypogammaglobulinemia long term and should receive intravenous immunoglobulins as needed. As we have mentioned a couple of times already, being very aware that these patients are also more susceptible to seasonal infection, such as influenza, is important, and so vaccinations are very important for this patient population. Vaccinating against influenza and vaccinating against COVID-19. BRITTANY HARVEY: Thank you both for reviewing those key points for the most common CAR T-related toxicities. So, just to wrap us up-- Dr. Santomasso-- in your view, how will this guideline impact both clinicians and patients? BIANCA SANTOMASSO: Well, I think we've seen now that cell therapy is really one of the major advances in cancer treatment in the past decade. And I think it's reasonable to expect more of these cell therapies to be developed, and we'll hopefully see their use extend beyond very specialized centers. But CAR T-cell therapy side effects are manageable if they're recognized, so I think this guideline helps that, and they're reversible with proper supportive care. They can be serious and they require close vigilance and prompt treatment. But, again, we believe this guideline and recommendations will help members of clinical teams with both the recognition and management of all of these toxicities, and that will help patients by increasing their safety. BRITTANY HARVEY: Great. That's important to note that these toxicities can be severe, but are also manageable. So I want to thank you both for your work on these guidelines and for taking the time to speak with me today, Dr. Santomasso and Dr. Ghosh. BIANCA SANTOMASSO: Our pleasure. MONALISA GHOSH: Absolutely. It was my pleasure. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events in patients treated with immune checkpoint inhibitors. To read the full guidelines, go to www.asco.org/supportive care guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Bryan Schneider from the University of Michigan Health System and Dr. Kathryn Bollin from Scripps MD Anderson Cancer Center, co-chairs of the Management of Immune-Related Adverse Events Guideline Expert Panel. They discuss an overview of the "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update" in Part 1 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and I want to introduce you to our series on the Management of Immune-Related Adverse Events. ASCO has developed two guidelines for the management of immune-related adverse events, one for patients treated with immune checkpoint inhibitor therapy and a second for patients treated with CAR T-cell therapy. Today, we'll be focusing on an overview of the Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. And we'll have authors join us for future episodes to discuss the key recommendations for organ-specific management for patients treated with immune checkpoint inhibitor therapy and an episode to discuss the management of immune-related adverse effects in patients treated with CAR T-cell therapy. Today, I am joined by Dr. Bryan Schneider from the University of Michigan Health System in Ann Arbor, Michigan, and Dr. Kathryn Bollin from Scripps MD Anderson Cancer Center in San Diego, California, co-chairs on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy, ASCO Guideline Update and authors of the Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy, ASCO Guideline. Thank you for being here, Dr. Schneider and Dr. Bollin. BRYAN SCHNEIDER: Thank you, Brittany. KATHRYN BOLLIN: Thank you for having us. BRITTANY HARVEY: I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Schneider, do you have any relevant disclosures that are related to this guideline? BRYAN SCHNEIDER: I have research funding to my institution from Bristol Myers Squibb and Genentech Roche at the time of panel formation. BRITTANY HARVEY: Thank you. And, Dr. Bollin, do you have any relevant disclosures that are directly related to this guideline? KATHRYN BOLLIN: No disclosures. BRITTANY HARVEY: Thank you. Then, let's talk about this guideline. So first, Dr. Schneider, what prompted this update to the Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy Guideline last published in 2018? BRYAN SCHNEIDER: Yeah. The previous guideline was widely used and consistently one of the top read articles of the JCO over the last couple of years. And since the original guideline publication in 2018, new data have emerged on the management of immune checkpoint inhibitor toxicities. So our goal was to build on the original guideline with more treatment options, especially for patients who fail initial steroid treatment. New strategies have developed for the management of many toxicities, especially GI, cardiac, and heme toxicities. And ASCO and the panel felt it was important to present these new options to the providers in the community. We also wanted to add sections that the providers would find valuable, including a table with many of the immunosuppressive agents used with typical dosages and schedules. We also added a table of commonly conducted testing while patients are on high-dose steroids as this is something many medical oncologists may not be used to handling as we typically do not have patients on steroids at high doses for several weeks or even months. BRITTANY HARVEY: Understood. Then, in addition to those updates that Dr. Schneider just mentioned, Dr. Bollin, what is the general scope and purpose of this guideline? KATHRYN BOLLIN: Yes. So the immune-related adverse event management guideline update and the CAR T-cell toxicity guideline serve to provide physicians that are prescribing these therapies with an understanding of the wide range of known potential toxicities of these agents and the best available evidence-based and expert opinion recommendations for their management. So up to 70% of patients treated with immune checkpoints will experience some form of immune-related adverse event, and nearly all patients getting CAR T-cell therapies experience toxicity. So recognition of the occurrence of these toxicities and appropriate management are essential for optimizing patient outcomes. BRITTANY HARVEY: Definitely, those are key points. So then, Dr. Schneider, what are the overarching recommendations for the management of immune-related adverse events irrespective of the affected organ? BRYAN SCHNEIDER: I think early recognition of the side effect is critical. So the guideline has typical signs and symptoms of each toxicity to help clinicians decide if this is occurring in their patients. Second, I think it's critical to grade the toxicity. We often don't do that with side effects related to traditional chemotherapy outside of clinical trials. So for example, if a patient has a platelet count of 75, I can't think off the top of my head what grade that is. I just know I'm going to hold chemotherapy for a week or two. But grading of the toxicity of these immune checkpoint therapies really is very important to decide whether patients can just be watched, whether they need to start steroids or whether they need to be admitted. I think still corticosteroids and dose holds are the first steps that clinicians will do. The majority of these toxicities-- although it would be nice if we could personalize the treatment based on the particular side effect and what we see under the microscope if the particular affected organ is biopsied, I think, in broad strokes, corticosteroids can be implemented easily, and a lot of our oncologists can be comfortable doing this potentially without subspecialty help. Having said that, I think multidisciplinary care is a must for the higher-grade side effects as, in oncology, we can't pretend to also be cardiologists, gastroenterologists, neurologists, dermatologist, and so on. And although there may be varying degrees of comfort from our subspecialists regarding the management of these toxicities, we do need their help for shared decision making, especially for the steroid refractory toxicities. We always want to emphasize a slow steroid taper oftentimes over at least four to six weeks. We get into trouble when we try to get them off the steroid quickly because they do have side effects that the patient may not enjoy. But oftentimes, we try to taper them quickly, and the side effect comes roaring back. And then, finally, to escalate immunosuppression quickly if no improvement with high-dose steroids is observed, oftentimes, that's done even within just a few days. But commonly, in practice, there's still hope that the steroid will kick in two or three weeks down the road, and that's not a good strategy. If the patient's having significant symptoms and steroids aren't helping, they do need to go on to a more important immunosuppressant. BRITTANY HARVEY: Those are important notes on the overarching management, particularly on how the adverse effects are different than those in patients treated with chemotherapy and the importance of multidisciplinary care. So then, Dr. Bollin, in your view, how will this guideline impact clinical practice? KATHRYN BOLLIN: So the impact of this guideline update is actually very broad. As with the previous guideline, as Dr. Schneider alluded to earlier, it's been very frequently accessed by readers since it offers symptom outlines and algorithmic recommendations for early identification and the management of immune-related adverse events based on the severity and organ system involved. What's really important to understand is that while initially, as hematology-oncology physicians prescribing these agents, we're doing so in the setting of early phase clinical trials. We were learning about the toxicities, and those physicians were often managing the toxicities themselves. But now, with the exponential increase and the therapeutic indications for immune checkpoint therapies in cancer, the experience with the toxicities and their management and the questions have also followed suit with an exponential rise. With this guideline update, we have experts among all of the internal medicine subspecialties that are now guiding the hematology-oncology physicians in immune-related adverse event management. We enlisted the experts in crafting this guideline update. So in summary, this serves not only as a tool for the prescribing hematology-oncology physicians but also for all of the subspecialists in the community and within academic centers for optimizing patient outcomes in the setting of immune-related adverse events. BRITTANY HARVEY: Great. Yeah, it sounds like this update will be hugely important for practicing clinicians. So then, in addition to those points raised by Dr. Bollin, Dr. Schneider, what are the implications for patients receiving immune checkpoint inhibitor therapy? BRYAN SCHNEIDER: So we really hope this will be an essential tool to help providers quickly treat patients when these toxicities present. Often, this is unexpected, and busy clinicians may be blindsided by these issues. So these guidelines will provide a quick resource to guide the workup and formulate a treatment plan that will expedite patient recovery. And ultimately, this should help promote quality of life for patients on these therapies and may help reduce trips to the emergency department, hospitalizations, and potentially allow the safe rechallenge of immune checkpoint therapy after resolution of the side effect. Many centers have the advantage of subspecialty support with experience in managing these toxicities. But for providers who may not have immediate access to, say, hepatology or endocrinology, we hope these guidelines will help the oncology providers provide the best treatment to facilitate the optimal clinical outcome. BRITTANY HARVEY: Absolutely, those are key for optimal care. Then, finally, Dr. Bollin, looking toward the future, what are the important outstanding questions and developing areas of research for the management of immune-related adverse events? KATHRYN BOLLIN: So while our recognition of immune-related adverse events, the testing for them, and management strategies have greatly improved with the expanded use of and experience with these therapies, large gaps in our knowledge remain. Translational and basic science research efforts are underway to understand these gaps, such as with the intrinsic and extrinsic drivers of autoimmunity, such as those with HLA allelic variations and the microbiomes interplay with our immune systems. There are also research efforts underway to develop rapid diagnostic tests to deploy early in the onset of irAE signs and symptoms and for the development of biomarkers and modeling tools that will aid us in predicting which patients are likely to experience immune-related adverse events. There have also been some interventional protocols that have attempted to prevent these immune-related adverse events by incorporating immune suppressants along with therapeutic agents. But so far, promising results with this strategy remain elusive. In regard to treatment for immune-related adverse events, investigators are working to learn the best strategies for selective immune suppression rather than just the use of glucocorticoids that will control immune-related adverse events while maintaining the clinical benefit of these incredible anticancer therapies. BRITTANY HARVEY: Thank you for highlighting those research gaps and both of you for your efforts to lead this guideline update. We'll be joined by authors on the guideline over the next episodes to review the key recommendations for organ-specific management in patients treated with immune checkpoint inhibitors and to review the recommendations for patients receiving CAR T-cell therapy. Stay tuned for these episodes highlighting the sections of the guidelines. And thank you for your time today, Dr. Schneider and Dr. Bollin. KATHRYN BOLLIN: Thank you so much. BRYAN SCHNEIDER: Thank you. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Manish Shah from New York Hospital and Weill Cornell Medicine, co-chair on "Immunotherapy in Patients with Locally Advanced Esophageal Carcinoma: ASCO Guideline Rapid Recommendation Update." He discusses the results of the Checkmate 577 trial and the updated recommendation of the Treatment of Locally Advanced Esophageal Carcinoma Guideline. For more information, visit www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at ASCO.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Manish Shah from New York Hospital and Weill Cornell Medicine in New York, NY, co-chair of the Locally Advanced Esophageal Carcinoma guideline expert panel and lead author on the Immunotherapy in Patients with Locally Advanced Esophageal Carcinoma: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Shah. MANISH SHAH: Absolutely. Thank you very much for having me. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline is available online. Dr. Shah, do you have any relevant disclosures that are directly related to this guideline? MANISH SHAH: Yes, so I do have relationships with many of the companies that make checkpoint inhibitors. And in fact, we are being supported by Bristol Myers Squibb on a first-line study of chemotherapy with nivolumab. We've also been supported by Merck on a pre-operative study of chemotherapy with radiation and pembrolizumab. BRITTANY HARVEY: Thank you for that information. Then so what prompted this rapid update to the Treatment of Locally Advanced Esophageal Carcinoma: ASCO Guideline? MANISH SHAH: Yes, so recently there was a landmark study that was practice-changing in the space, published in the New England Journal of Medicine by Ronan Kelly and colleagues. And this was the report of CheckMate 577, the use of adjuvant nivolumab in resected esophageal or gastroesophageal junction carcinoma. And this was a positive study that led to important changes in practice. And we felt that this was worthy and worthwhile of getting it out there to the community. BRITTANY HARVEY: Great. Then based off this new data from CheckMate 577 on nivolumab, what is the updated recommendation? MANISH SHAH: Sure. So previously, the data available was that patients who receive chemotherapy and radiation and then went on to receive surgery, that those patients with esophageal cancer had no further treatment recommendations. This study, CheckMate 577, actually examined nivolumab in that context. So patients who received chemotherapy and radiation and then underwent surgery, if they had some residual disease at the time of the surgical resection, even if they had a major response but there was some residual cancer in the surgical specimen, patients were eligible for randomization. And about 800 patients were randomized, 2 to 1, to receive nivolumab versus placebo in this context. And the primary endpoint in the study was disease-free survival. And patients who received nivolumab had a median disease-free survival of 22.4 months compared to placebo, which was the previous standard of care. The median disease-free survival in that group was 11.0 months, so almost a doubling of the disease-free survival. The hazard ratio was 0.69. And that was highly significant, with a p value of 0.001. So there was a 31% improvement in reducing the risk of recurrence with adjuvant nivolumab. So based on that trial, we have updated the guideline to recommend adjuvant nivolumab for patients who have received chemotherapy and radiation and surgery, and then had some residual disease in the surgical specimen. A key distinction is that about 20% to 30% of patients will have had a pathologic complete response. These patients were not eligible for the trial. And so at this time, patients who have had a complete response, the current guidelines remain the same, where there's no further treatment indicated. BRITTANY HARVEY: OK, it seems like this study provided a strong signal to update that recommendation. I appreciate you going through the details of that study, and particularly the patients that were eligible to participate. So then, how will this guideline impact patients with locally advanced esophageal cancer? MANISH SHAH: Yeah, I think that this is a key thing. Because 70% to 75% of patients have residual disease at the time of resection. And still, even if you've had a major pathologic response, the risk of recurrence for many patients is still high, greater than 50%. Of note also I'd highlight that the study included adenocarcinoma and squamous cell cancer. And the results were positive in both groups. So based on that, I think that this will be highly impactful for a majority of patients with esophageal cancer, both adenocarcinoma and squamous cell cancer, who, as I said, underwent chemoradiation and surgery and had residual disease in the surgical pathologic specimen. BRITTANY HARVEY: That's good to hear that this will have a positive impact for these patients. So then what are the outstanding clinical questions regarding treatment of these patients? MANISH SHAH: Yeah, so I think that there are a lot of outstanding questions. I think one question which is currently being studied is the use or integration of checkpoint inhibition therapy prior to surgery. So that's being examined in an inter-group study in the United States, as well as several company-sponsored studies across the globe. And a concept there is that, if you're giving chemotherapy with radiation and a checkpoint inhibitor all combined, you might be able to have even the higher benefit from activation of the immune system against the cancer than in the adjuvant setting where you're trying to treat microscopic minimal disease. So that's one question. And the other key question, which was actually raised by the clinical trial itself was the CPS scoring system. So CPS means Combined Positive Score. This is a way to examine the level of PD-L1 expression in the tumor and its microenvironment. And it's not a great biomarker, but it's the best biomarker available. And it is predictive of who would benefit. So patients who have a higher CPS score are more likely to benefit from a checkpoint inhibitor. A post hoc analysis of this study suggested that tumors that had a CPS score of less than 5 had less benefit. So although the FDA approval for adjuvant nivolumab was independent of the CPS score, I think, with time, we'll have more information on the potential impact of CPS or other biomarkers on which patients really may benefit from adjuvant therapy. So I think, on the positive end, patients now have options. And I think they're clinically significant and meaningful. But it does, as you point out, highlight new questions that will be answered in due course. BRITTANY HARVEY: Great. And we'll look forward to the results of those studies that address some of those questions. So thank you for your efforts to issue this rapid update and for taking the time to speak with me today, Dr. Shah. MANISH SHAH: Oh, absolutely. It was a pleasure to be here. Thanks so much, Brittany. 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. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Nadine Tung and Dr. Dana Zakalik, co-chairs on "Adjuvant PARP Inhibitors in Patients with High-risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update." They discuss the results and impact of the OlympiA trial, the updated recommendation, and outstanding questions on the use of PARP inhibitors in the adjuvant setting. For more information, visit www.asco.org/breast-cancer-guidelines. TRANSCRIPT [MUSIC PLAYING] ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.ASCO.org. My name is Brittany Harvey, and today I'm interviewing Dr. Nadine Tung from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and Dr. Dana Zakalik from Beaumont Health in Royal Oak, Michigan, co-chairs of the Management of Hereditary Breast Cancer Guideline Expert Panel and this rapid recommendation update, Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Guideline Recommendation Update. Thank you for being here, Dr. Tung and Dr. Zakalik. DR. ZAKALIK: Thank you for having us. DR. TUNG: Thank you so much. Pleasure 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 online. Dr. Tung, do you have any relevant disclosures that are directly related to this guideline topic? DR. TUNG: I do receive research funding from AstraZeneca, as I run a trial using a PARP inhibitor in breast cancer. BRITTANY HARVEY: Thank you. And Dr. Zakalik, do you have any relevant disclosures? DR. ZAKALIK: I do not. BRITTANY HARVEY: Thank you. Then let's get into the meat of this rapid recommendation update. So, Dr. Tung, what prompted this rapid update to a recommendation from the Management of Hereditary Breast Cancer Guideline? DR. TUNG: The OlympiA Trial, which was presented at ASCO this past June and published the same day in the "New England Journal of Medicine." OlympiA was a large Phase III trial, which demonstrated that a year of adjuvant olaparib, a PARP inhibitor, significantly improved both invasive disease-free survival by nearly 9%, and distant disease-free survival by a similar improvement, in germline BRCA mutation carriers with HER2-negative breast cancer and a high risk of recurrence. Overall survival was numerically better with olaparib, but it didn't yet reach significant improvement as a stringent p-value was required for this early reporting. And I say early reporting because the trial was reported early after the first event-driven interim analysis showed a benefit with olaparib. 1,800 patients had been enrolled with a median follow up of 2 and 1/2 years at the reporting. But the follow up was 3 and 1/2 years for the first 900 patients enrolled, known as the maturity cohort. And it was comforting that the significant improvement in invasive disease-free survival and distant disease-free survival was also seen when just looking at that maturity cohort. So for those who might think that it's too early and that these benefits might not hold up with longer follow up, it's very comforting that in that maturity cohort with longer follow up, the results were really the same. And last year, ASCO published guidelines on managing patients with hereditary breast cancer, including women with inherited BRCA mutations, meaning a pathogenic or likely pathogenic variant. At that time, PARP inhibitors were recommended only for BRCA carriers with metastatic disease, based on the OlympiAD and EMBRACE trials. So when OlympiA was published, we felt the need to update the guidelines to recommend olaparib in the early-stage setting for some germline BRCA carriers. BRITTANY HARVEY: So then, based off this new data from the OlympiA trial, Dr. Zakalik, what is the updated recommendation from the guideline expert panel? DR. ZAKALIK: The updated recommendation states that for patients with early-stage, HER2-negative breast cancer with a high risk of recurrence, and who carry a germline BRCA1 or 2 mutation, one year of adjuvant olaparib should be offered after completion of adjuvant or neoadjuvant chemotherapy and local treatment, including radiation therapy. And this data was specific to a high risk of recurrence subgroup of these patients, defined as, for those with triple-negative breast cancer having a tumor over two centimeters, or with any involved lymph nodes, or for those who received neoadjuvant chemo, any residual disease in the triple-negative setting was sufficient to qualify. For patients with hormone receptor positive disease, these were high-risk patients for recurrence, again, and that was defined as having at least four positive lymph nodes, or any residual disease following neoadjuvant therapy. But in addition, having a clinical stage and pathologic stage estrogen receptor status and tumor grade, otherwise called the CPS+EG score, of greater than or equal to three, which is really defined as looking at estrogen receptor status grade and clinical and pathologic stage. So again, a high-risk group for risk of recurrence was included in this study. And again, in order to apply these findings, we have to be mindful of patients who meet these inclusion criteria as being high-risk for recurrence. Again, both in the triple-negative hormone receptor-positive setting, if they met these criteria, there was a significant benefit in terms of outcome in lowering the risk of recurrence. BRITTANY HARVEY: I appreciate you going through that recommendation. So then, given that updated recommendation. Dr. Tung, what should clinicians know as they implement the use of adjuvant olaparib into clinical practice? DR. TUNG: For those who have not used olaparib, it's worth saying that it's an oral medication. Typically patients take two pills twice a day. And it's important to be familiar with the side effects. I would say that generally, olaparib is well-tolerated. But it can have side effects. And the two most common are nausea, and then anemia. So for the nausea, we use the typical antiemetics we would use for any chemotherapy. And it's worth saying to patients who do have nausea that quite often, that lessens with time. It decreases. So I would say nausea's one of the side effects. Some patients can have fatigue, although I don't think that's all that common. And anemia is the other one. And we do check bloodwork monthly for patients on olaparib. The anemia can come suddenly, even after months of really not having any. And grade 3 anemia was probably the most common, grade 3 or higher, toxicity that was seen in OlympiA, although it's only 9% of patients that had grade 3 or higher anemia. But I would say those are the two side effects to look for most. And then I think one other thing that's worth saying is that for the BRCA carriers with triple-negative breast cancer, currently our standard therapy for patients who have residual disease after neoadjuvant chemotherapy is capecitabine. But olaparib should not be given with capecitabine. There is no safety data for that. So oncologists are going to need to choose between what I think is our standard therapy right now, capecitabine, and olaparib. And there's no data directly comparing these two medications in the early-stage setting. But in the metastatic setting in BRCA carriers, in both OlympiAD and EMBRACE, olaparib was compared to chemotherapy. And olaparib with superior. And in both of those studies, about half the women in the chemotherapy arms received capecitabine. And olaparib, again was superior. So olaparib may be the better choice in the early-stage setting. But I can't say that there's any direct data. But the message would be not to give them together. And I think it would be better probably not to give capecitabine first and then olaparib, because there's some data that the earlier you give a PARP inhibitor the better. BRITTANY HARVEY: Those are important notes for clinicians and particularly for safety. So then building on that, Dr. Zakalik, how will this update impact patients with breast cancer? DR. ZAKALIK: This data will significantly impact the therapeutic options that we have for patients with high-risk disease in the setting of a BRCA germline mutation. And that will happen in the sense that patients who have these certain specific features that render them high-risk will now be able to be offered a very impactful therapy that has been shown in this landmark study to significantly decrease their risk of recurrence. And these are patients who otherwise would face a significant risk of potentially facing a recurrence in the future. So the outcomes we anticipate to be dramatically improved for patients who have triple-negative or high-risk hormone receptor-positive breast cancer in the setting of a BRCA germline mutation. But furthermore, whereas genetic testing in the past was predominantly focused on identifying individuals who are at high risk for developing breast cancer so that we can offer early detection or prevention options, this is the first time that we're able to broadly apply the benefit of molecular genetic testing for hereditary risk to therapy for patients with early nonmetastatic breast cancer. So as clinicians who see patients with breast cancer, it is further made more important to recognize what the guidelines are for genetic testing. To think of whether a patient meets criteria that are currently outlined for genetic testing, as this will have a significant potentially major impact on patients' outcome. And already in the clinic, we have been focused on recognizing who may have a BRCA mutation. Obviously, this data will make that even more important, because this therapy is so beneficial for patients. And I think going forward, it will fuel a discussion of possibly reevaluating who gets genetic testing, now that it's particularly important not to miss patients who have BRCA mutations when they develop breast cancer. So I think that physicians who are in the clinic will not only have a therapeutic option, but also will be hopefully recognizing more patients who have a BRCA mutation in that the therapy is so markedly better now with this new data. And in the future, we may possibly expand our guidelines for testing. And I think that remains to be determined, based on a number of factors that go into this decision. BRITTANY HARVEY: Well then, you've both touched on this a bit, regarding outstanding questions for both genetic testing and the use of capecitabine. But finally, Dr. Tung, given this recent study and guideline update, what are the outstanding questions regarding the use of PARP inhibitors in the adjuvant setting? DR. TUNG: Right. We have already listed a couple. The capecitabine question is one that I won't repeat. And I think who gets tested would be another one that Dana just mentioned. I think a big one, as of yesterday, is immune therapy. Yesterday, the FDA approved pembrolizumab, based on the KEYNOTE-522 study for patients with triple-negative breast cancer. And that population in KEYNOTE was very similar to the one in OlympiA for BRCA carriers, namely patients with T2 tumors, or involved axillary lymph nodes. So for BRCA carriers, we're going to have to make some decisions here, namely, should they receive pembrolizumab and olaparib together, for those who have residual disease after neoadjuvant chemotherapy. I think everyone right now is digesting KEYNOTE-522 and this FDA approval. And so that's something that will have to be worked out. I know in other diseases there is safety data for the combination of pembrolizumab and olaparib. But again, I think that's something that we're all going to have to sort out. I don't think there's going to be any data forthcoming immediately about the use of pembro, olaparib, and the combination, et cetera for our patients. So that's a big one I think another question that comes up is, how long after a BRCA carrier finishes their chemotherapy and local therapy are they eligible to take olaparib? What about patients that finished six months ago, or a year ago, or longer? And again, I don't think there are any data for that, and we're going to have to use some clinical judgment. There was precedent for this kind of question when adjuvant trastuzumab was approved and in 2005, when the adjuvant trials demonstrating such an impressive benefit for trastuzumab were announced and published. I remember that we were administering trastuzumab to patients who'd completed their chemotherapy within the last year. So I think for many, that may be a timeline that makes sense. But again, there are no data. So still questions, and we're going to as always have to use some clinical judgment. And others, Dana, that you can think of? DR. ZAKALIK: No. I think this is tremendously exciting new data. It really provides hope for patients who are young, often, when they're diagnosed. Because hereditary breast cancer tends to manifest itself at a young age. And so for our women in the prime of their life, when they have high risk and develop breast cancer, I think this just really gives us tremendous hope and opportunity for improving the lives and saving lives in the future of patients who have high-risk disease. Very exciting data. DR. TUNG: Yeah, I agree completely. I think the investigators are really to be congratulated. This was a very large study. 1,800 BRCA carriers, international study. Very hard to do with a situation, a disease that's relatively uncommon. Only 3% to 5% of all breast cancer. So really a terrific effort with a significant, major impact for our BRCA carriers with breast cancer. BRITTANY HARVEY: Definitely. This is an exciting update for patients with breast cancer. And we'll look forward to hearing more research about those outstanding questions that you mentioned. So I want to thank you both for your efforts to update this guideline recommendation so quickly, and provide evidence-based recommendations for both clinicians and patients. And thank you for taking the time to speak with me today, Dr. Zakalik and Dr. Tung. DR. ZAKALIK: Thank you. DR. TUNG: My pleasure. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. For more information, visit www.ASCO.org/breast-cancer-guidelines. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Beverly Moy from Massachusetts General Hospital, co-chair on "Chemotherapy and Targeted Therapy for Patients With HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update." Updated guidance addresses optimal sequence of therapy & indications for treatment regimens. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey. TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey. And today I'm interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, co-chair and lead author on chemotherapy and targeted therapy for patients with HER2 negative metastatic breast cancer that is either endocrine pre-treated or hormone receptor negative ASCO guideline update. Thank you for being here, Dr. Moy. BEVERLY MOY: Thanks for having me, Brittany. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic? BEVERLY MOY: I do not have any relevant disclosures related to this guideline topic. BRITTANY HARVEY: Great. Thanks so much. Then let's get into what this update covers. So first, what prompted the update of this ASCO guideline and what does the scope of this guideline update? BEVERLY MOY: So this guideline update was developed to address both chemotherapy and targeted therapy for women with advanced HER2 negative breast cancer that is either endocrine pre-treated or hormone receptor negative. So it really focuses on chemo and targeted therapy. The original ASCO clinical treatment guideline was published in 2014 and really focused on chemotherapy, since that was generally the standard of care at that time. Since 2014, however, there have been several important new therapies that have become available based on robust evidence from numerous clinical trials. These include, but are not limited to, BOLERO-6 and PEARL trials for hormone receptor positive HER2 negative metastatic breast cancer, the ASCENT and EMBRACE trials for triple negative metastatic breast cancer, and the EMBRACA trial for metastatic breast cancer associated with germline BRCA1 or 2 mutations. So it really was important to update the guideline in a fairly urgent matter. BRITTANY HARVEY: Great. Well, then this guideline addresses four overarching clinical questions. For each of these, I'd like to review the key recommendations for our listeners. So starting with question one, is there an optimal sequence of chemotherapy and/or targeted therapy for patients with triple negative metastatic breast cancer either with or without BRCA1 or BRCA2 germline mutations? BEVERLY MOY: So clinical question one really focused on patients with metastatic triple negative breast cancer. So for patients with metastatic triple negative disease, the first key question is, what is the Programmed cell Death Ligand 1, or what we call PD-L1 status? If the disease is PD-L1 positive, then patients may be offered first line therapy with an immune checkpoint inhibitor plus chemotherapy. And that's a very important development. If the disease, however, is PD-L1 negative, patients should be offered single agent chemotherapy rather than combination chemotherapy, unless they have symptomatic or immediately life-threatening disease, and you really need to get a response more quickly. In those cases, combination chemotherapy can be used. After the first line, if patients with metastatic triple negative breast cancer have received at least two prior therapies, then they should be offered treatment with the new antibody drug conjugate called sacituzumab govitecan, which is a very exciting development in the treatment of metastatic triple negative breast cancer. If the patient has a germline BRCA1 or 2 mutation and has metastatic triple negative disease and have been previously treated with chemotherapy, then they may be offered treatment with an oral PARP inhibitor rather than chemotherapy, also a very exciting development that this guideline update addresses. BRITTANY HARVEY: Great. Thank you for reviewing those recommendations for triple negative metastatic breast cancer. So then next for clinical question two, what are the indications for chemotherapy versus endocrine therapy in endocrine pre-treated estrogen receptor positive metastatic breast cancer? BEVERLY MOY: So clinical question two focuses on women or patients with metastatic hormone receptor positive breast cancer who have developed progressive disease on a prior endocrine therapy with or without targeted therapy. So really is focusing on patients with metastatic hormone receptor positive breast cancer that have become fairly resistant to endocrine therapy alone. These patients may be offered treatment with either endocrine therapy with or without a targeted therapy or single agent chemotherapy. Brittany, I think it's important for listeners to realize that there is another important clinical practice guideline update that's being released simultaneously with this guideline. And that one is called endocrine therapy and targeted therapy for hormone receptor positive metastatic breast cancer. This other guideline update will describe in detail recommendations for the various targeted therapies that can be used with endocrine therapy, such as CDK4/6 inhibitors, PI 3-kinase inhibitors, and others. So I encourage everyone to read this guideline as well. Importantly, both guidelines state that treatment choice should be based on individualized patient and provider assessment of preferences, risks, and benefits. BRITTANY HARVEY: Great. And thank you for pointing out that companion guideline. Listeners can also listen to a podcast episode with Dr. Burstein on that particular guideline, which will be available in our podcast feed. So then next, what are the key recommendations for the third question in the guideline, which is, is there an optimal sequence of non-endocrine agents for patients with hormone receptor positive but HER2 negative metastatic breast cancer who are no longer benefiting from endocrine therapy, either with or without BRCA1 or BRCA2 germline mutations? BEVERLY MOY: So this third question really focuses on patients with hormone receptor positive HER2 negative disease and the optimal sequence. Essentially what we recommend is that germline BRCA1 or 2 patients with metastatic hormone receptor positive HER2 negative breast cancer who are no longer benefiting from endocrine therapy, those patients may be offered an oral PARP inhibitor in the first through third line setting rather than chemotherapy. And that is evidence that is evolving and important, and that's what the guideline recommends at this time. BRITTANY HARVEY: Great. And then clinical question four was the last question addressed in this guideline update. And what did the panel say regarding at what point should a patient be transitioned to hospice or best supportive care only? BEVERLY MOY: So this obviously is an incredibly important question for clinicians and oncologists to consider. The current literature and evidence does not allow us, at this time, to make a firm recommendation regarding at which point a patient's care should be transitioned to hospice or best supportive care only. When to transition is a decision that really needs to be shared between the patient and clinician in the context of an ongoing conversation regarding goals of care. The conversation of that integration of supportive care and eventual consideration of hospice care really should start early in the management of metastatic breast cancer. And these conversations have to occur throughout. I would also refer listeners to other important clinical treatment guidelines on the ASCO website about incorporation of palliative and supportive care for patients with metastatic cancer. I think those are incredibly valuable guidelines. BRITTANY HARVEY: And then you've touched on this a bit as you've talked about the recommendations, but in your view, what is the importance of this guideline update? And how will these updated recommendations impact both clinicians and patients? BEVERLY MOY: I think that this is an extremely important guideline update. It provides really important clinical guidance about the new use of immune checkpoint inhibitors, which really is the first time immune checkpoint inhibitors are clearly recommended for the treatment of breast cancer. It also provides important clinical guidance about this new antibody drug conjugate, sacituzumab govitecan, and PARP inhibitors for the treatment of metastatic breast cancer. These are all important and effective new treatments for breast cancer. And every clinician should be aware of their optimal uses. I will point out that many unanswered questions remain. And that was really an exciting part of doing this guideline update to look at these unanswered questions, such as what we described earlier, the optimal time to transition to best supportive care only and the widespread use of molecular tumor profiling. As treatments get more complicated and the entire oncology community are increasingly tasked to absorb new data, ASCO guidelines are enormously helpful in giving people an easy to access tool that takes into account the latest data. BRITTANY HARVEY: Great. Thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Moy. BEVERLY MOY: Thank you. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at surveymonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss episode. [MUSIC PLAYING]

An interview with Dr. Harold Burstein from Dana Farber Cancer Institute in Boston, MA, chair on "Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Update." This guideline updates recommendations on use of alpelisib, and the role of biomarkers and CDK4/6 inhibitors. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey. TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcasts.asco.org. My name is Brittany Harvey. And today I'm interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute in Boston, Massachusetts, chair and lead author on endocrine treatment and targeted therapy for hormone receptor-positive HER2 negative metastatic breast cancer ASCO guideline update. Thank you for being here, Dr. Burstein. HAROLD BURSTEIN: Glad to be with you. BRITTANY HARVEY: First I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Burstein, do you have any relevant disclosures that are related to this guideline topic? HAROLD BURSTEIN: I do not. BRITTANY HARVEY: Great, thank you. Then let's delve into the content of this guideline. So first, what prompted the update of this guideline and what is the focus of this update? HAROLD BURSTEIN: So this guideline focuses on metastatic breast cancer, and in particular, estrogen receptor-positive HER2 negative metastatic breast cancer. Worldwide in 2021, actually breast cancer became the most commonly diagnosed cancer in the world, excepting superficial skin cancers. And so it is a true global health problem. And the most common type of breast cancer is estrogen receptor-positive HER2 negative breast cancer, which accounts for 70% to 75% of all cancer diagnoses in the breast cancer space, and as a consequence, also accounts for 70% to 75% of the cases of metastatic breast cancer. So it's really important from a public health point of view and a quality point of view, both in the United States and globally, to have current up-to-date guidance for the management of this most common form of breast cancer that we have. In addition, there have been several innovations in the way of targeted therapies that are coming into place for advanced ER-positive breast cancer. And increasingly, we are using genomic tests to help us understand how best to treat patients with advanced ER-positive breast cancer. So those two initiatives-- the interest in genomic testing and the use of targeted therapies-- all warranted and justified an update to the guidelines. BRITTANY HARVEY: Great. Thank you for reviewing that landscape of where we are in clinical practice for this guideline. So then I'd like to review the key recommendations that this guideline addresses. So first, should alpelisib be given to post-menopausal women and to male patients with hormone receptor-positive HER2 negative PIK3CA-mutated advanced or metastatic breast cancer? HAROLD BURSTEIN: So alpelisib, as you indicated, is a new drug. It is now FDA approved. And it is a protein kinase targeted inhibitor. And it goes after the PIK3CA-mutated tumors. And in a seminal study called the SOLAR-1 study, there was randomization to endocrine therapy alone with fulvestrant or endocrine therapy plus alpelisib for ER-positive HER2 negative breast cancer. And that study showed two important things. First was that in women whose tumors did not have a PIK3CA mutation, there was no benefit for alpelisib. However, in the women whose tumors did have a PIK3CA mutation, there was an improvement in progression-free survival with the use of this targeted drug alpelisib. So based on that, the guidelines now incorporate alpelisib into the treatment algorithm. And as a corollary, it means that all patients who have ER-positive metastatic breast cancer now need testing of the tumor to see if they have a PIK3CA mutation because that's going to guide therapy. In the guideline, we now suggest that this be a standard thing to do-- to test all tumors for PIK3CA mutation. And in those cases where there is a PIK3CA mutation to add alpelisib-based therapy with endocrine treatment typically in second or subsequent lines of therapy. BRITTANY HARVEY: Great. And thank you for reviewing the evidence base behind that recommendation. So next, what is recommended regarding the role of biomarkers in treatment selection for patients with hormone receptor-positive metastatic breast cancer? HAROLD BURSTEIN: So there are two different ways of thinking about biomarkers. One is traditional biomarkers, such as estrogen receptor, progesterone receptor, and HER2. Those are familiar to all clinicians who have been dealing with breast cancer. The second is to think about some of the newer technologies, including tumor genomic sequencing and the kind of mutational analysis we just discussed with the PIK3CA mutations. So in the breast cancer space, there are some important innovations in that latter genomic or genetic testing. One, of course, is the PIK3CA mutation testing that we now recommend for all cancers. That can be done on the primary tumor, or it can be done on cell-free or circulating tumor DNA samples from the bloodstream in most cases. The other kind of testing we do relates to ESR1 mutations. And one of the reasons that tumors become resistant to aromatase inhibitors is that they acquire mutations in the estrogen receptor itself, so-called ESR1 activating mutations. Those mutations mean that the estrogen receptor is on even in the absence of estrogen. And that accounts for probably 50% to 60% of the resistance that we see in treatment with aromatase inhibitors. So the panel really struggled with this because, on the one hand, this is not a uniformly accepted way to decide how to treat patients. On the other hand, there are a lot of data that women whose tumors have ESR1 mutations get negligible benefit from ongoing use of aromatase inhibitor therapy. So this recommendation fell into sort of our practice suggestions, which is that if you have the information on ESR1, then it probably is the case that there's very little, if any, role for ongoing aromatase inhibitor treatment. This fell short of the highest level in endorsement because, first, it's not a uniformly tested assay. And secondly, it's important to remember that these tumors can still benefit from ongoing anti-estrogen therapy with different anti-estrogens like fulvestrant. And finally, and perhaps this is the most practical issue, the way you become ESR1 mutated is usually through exposure to aromatase inhibitors. And if you've already had a patient with extensive exposure to AIs, and they need ongoing anti-estrogen therapy in the metastatic setting, it usually means you're switching treatment anyway. So that's an example of where we're sort of on the frontier of thinking about dynamic changes in the tumor as a way to select treatment for ER-positive metastatic disease. BRITTANY HARVEY: Great. That's helpful for a clinical interpretation of the recommendations and incorporating these into practice. So the final question that was addressed in this focused update was, what is the role of CDK4/6 inhibitors in the treatment of patients with hormone receptor-positive metastatic breast cancer? HAROLD BURSTEIN: So CDK4/6 inhibitors are another tyrosine kinase inhibitor class of drugs that has really emerged as an important part of first-line therapy for ER-positive metastatic disease. There have been multiple randomized trials looking at either first-line therapy with an aromatase inhibitor with or without a CDKI4/6 inhibitor, or second-line treatment typically with fulvestrant with or without a CDKI4/6 inhibitor in the metastatic setting. And the panel was able to update the guidance here based on the maturation of multiple randomized trials, as well as extensive subset analyses that have been performed by investigators associated with the individual pharmaceutical-led studies and by the FDA itself. So here are some important takeaways. The first is that in long-term follow-up, these drugs as a class are improving overall survival for women with ER-positive HER2 negative metastatic breast cancer. And for that reason, they are a very important part of the standard armamentarium for ER-positive disease. It's important to say that they also delay the onset of need for chemotherapy, and in general, are associated with a very well preserved quality of life. So this is a big win for patients with ER-positive metastatic breast cancer. We typically recommend them in the first-line setting. So if a patient has de novo metastatic disease, then they should get an endocrine therapy such as an aromatase inhibitor with a CDK4/6 inhibitor. If they've previously had adjuvant aromatase inhibitor treatment or recur while on adjuvant endocrine therapy, we often move to fulvestrant plus a CDKI4/6 inhibitor. Both settings have shown substantial benefit for this class of drugs. It's important that clinicians understand the side effects of these drugs. Neutropenia and diarrhea are common side effects associated with the various drugs. And because of the prevalence of ER-positive metastatic disease, it's really important for clinicians and all those who care for advanced breast cancer patients to know how to manage those side effects carefully. The panel discussed controversial issues, I suppose you might say, in the management. What about patients who have truly minimal metastatic disease? There aren't a lot of data on how best to think about those patients. And we all can imagine on a case-by-case basis an individual who might not need a CDK4/6 inhibitor at a given moment in time. But what was impressive when we pulled all the data was that in subset analyses, it's really hard to find a group of patients that does not benefit from the incorporation of these drugs. So that included premenopausal women who also get concurrent ovarian suppression and then endocrine therapy plus the CDK4/6 inhibitor. It included women with bone-only metastatic disease. It included women whose tumors were ER-positive but PR negative, or had other variations in ER expression. It included patients who had less rather than more metastatic cancer, including visceral disease. So in the literature, one is hard-pressed to see a subset that does not benefit meaningfully from this class of drugs. So we really wanted to reiterate in the algorithms just how important these are. They should be the standard first-line treatment for metastatic disease either paired with an AI or with fulvestrant. And so one of the other nice things that the update gave us was the opportunity to put in some fresh sort of algorithm flow sheets. I would very much encourage people to look at that. They make fantastic PowerPoint or downloadable Twitter documents if you are so inclined. But it's very clear the way the treatment should flow, which is the initial therapy is endocrine treatment plus a CDK4/6 inhibitor. While the patients are getting that, we typically test for PIK3CA mutations. In second line, if it's a PIK3CA mutated, you have the option of using alpelisib. You also might consider an older drug for PIK3CA wild type tumors called everolimus. We reiterated that recommendation in the guideline. Finally, one more thing to touch on that is emerging in the guidelines we generated and in the parallel guideline process for the ASCO guidance on chemotherapy-resistant or refractory breast cancer is the importance of genetic testing all patients who have metastatic breast cancer to look for the possibility of a BRCA1 or BRCA2 deleterious mutation, because there now is FDA approval for PARP inhibitors in the setting of metastatic disease. And one of the interesting things is that as we test more and more, we're seeing that not all the patients who are found to have a BRCA1 or 2 mutation meet the classic criteria for genetic testing-- strong family history, or say, triple-negative breast cancer. So it's really important to test, because that class of drugs, the PARP inhibitors, can be immensely helpful in women with ER-positive metastatic disease when they harbor a BRCA1 or 2 mutation. One of the things the guideline panel wrestled with and ended up putting into the sort of clinical discussion, as opposed to the strong guidance, was the 1% of patients who have PALB2 mutations. So PALB2 mutation, another hereditary predisposing factor for breast cancer. Most tumors that arise in PALB2 mutation carriers are in fact estrogen receptor positive. And a very small study, now published in the JCO, has suggested that those patients have a very high likelihood of response to PARP inhibitors. Because there were only like 15 patients in that cohort, we didn't feel that this warranted clear endorsement in the guidelines. But at the same time, everyone on the panel acknowledges that this is an active drug in that rare subset of tumors with PALB2 mutations in addition to the BRCA1 or 2 mutations. So the takeaway here is that genetic testing should be standard for all patients with advanced metastatic breast cancer to see if the patient is a candidate for a PARP inhibitor-based therapy. BRITTANY HARVEY: Definitely. Well, thank you for reviewing all of those updated recommendations and highlighting some of the ones that were still relevant to this guideline. HAROLD BURSTEIN: Work in progress. BRITTANY HARVEY: Yeah, definitely. And then finally, what is the importance of this guideline update? And how will it impact both clinical practice and what does it mean for patients? HAROLD BURSTEIN: Well, I think guidelines like this have multiple purposes. The first is to sort of describe the state of the art. And while breast cancer is a very common disease, and most clinicians who take care of a lot of cancer patients will see a lot of advanced breast cancer, I think it's still helpful to articulate the rationale for these treatment recommendations. And one of the great things about the ASCO guideline process is the thoroughness of the literature review, the thoroughness of the search to make sure we're including all important publications, and the thoughtfulness that the panel, which includes experts, patient advocates, quality of life expertise, all those things bring to bear on really thinking through what makes sense and what does not for our patients based on the best science available. So I think it is an important activity to really sort of benchmark where we're at. The second thing we've tried to do in the guideline is to introduce areas of nuanced discussion, because not every patient is the same. And I think for those who are interested and take the time to read the guideline, there really is a very nice discussion about how our panel thought about when best to use this approach and when to use a different approach. Third, there's extensive discussion of the side effects and the appropriate management of the side effects. These are drugs that do carry risks. And while by oncology standards, many of them are, quote, "well tolerated," unquote, there's no doubt that there are side effects to these drugs. And it's important for clinical teams to know how to manage them. Finally, I think by putting forward all the evidence, you make clear to investigators, to drug companies, to patients and advocates, and others who are involved in the review of new drugs what the benchmarks are and what the criteria should be for designing clinical trials and for approving new drugs. And I think we've done a nice job of framing that discussion quite handsomely in this guideline and to all of the ASCO guidelines. BRITTANY HARVEY: Great. Well, thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Burstein. HAROLD BURSTEIN: Happy to join you and thanks very much. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at SurveyMonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Robin Zon from Michiana Hematology Oncology in Mishawaka, IN, co-chair on "Telehealth in Oncology: ASCO Standards and Practice Recommendations." The standards address telehealth implementation, doctor-patient relationships, roles of advanced practice providers & allied health professionals, multidisciplinary cancer conferences, and teletrials. Read the standards at www.asco.org/standards. Suggest a topic for standards development at www.surveymonkey.com/r/standardssurvey. TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcasts.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Robin Zon from Michiana Hematology Oncology in Mishawaka, Indiana, co-chair on the "Telehealth in Oncology: ASCO Standards and Practice Recommendations." Thank you for being here Dr. Zon. ROBIN ZON: Thank you so very much for having me here with you, to discuss this very important topic and work, which was undertaken by an expert panel of ASCO incredible volunteers and ASCO staff lead, Erin Kennedy. BRITTANY HARVEY: Great. Then first I'd like to note that ASCO takes great care in the development of its standards and ensuring that the ASCO conflict of interest policy is followed. The full conflict of interest information for the expert panel is available online with the publication of the standards in the JCO Oncology Practice. Dr. Zon, do you have any relevant disclosures that are directly related to these standards? DR. ROBIN ZON: No. I do not have any relationships to disclose related to the subject. BRITTANY HARVEY: Thank you. Then let's get into the content of these telehealth standards. So first, can you give us a general overview of the purpose and scope of these standards for telehealth in oncology? DR. ROBIN ZON: Well, absolutely. The service background, pre-pandemic, telehealth was utilized less than 1% of the time for oncology ambulatory visits. With, of course, a subsequent rapid adoption of digital health, in response to the public health emergency. This uptake of technology intervention was then further facilitated by the Centers for Medicare and Medicaid Services increased flexibility and reimbursement for these services. In response to the COVID-19 pandemic, ASCO published an interim policy statement on telemedicine. The signal is positions on emerging policy issues, as well as the road to recovery report, which presented ASCO's recommendations for modifying pre-pandemic policies and practices to improve high-quality patient care, wherein ASCO membership identified a need for more detailed oncology-based telemedicine. So these standards were created in response to this need. It is important to note that these standards include an endorsement of existing general guidelines as published by the American Medical Association Telehealth Implementation Playbook and the American Telemedicine Association's Quickstart Guide. BRITTANY HARVEY: That background and context is helpful for our listeners. So, then these standards, reading through them, they address six questions. I'd like to review the key points in each section for our listeners. So the first section, which patients should be seen via telehealth versus in-person? And what are the important implementation considerations for oncology telehealth visits? DR. ROBIN ZON: Those are great questions, Brittany. Generally speaking, patients should always have the option for in-person visits when feasible. But when appropriate infrastructure and personnel are available, telehealth visits are suitable for treatment or long term management visits, in addition to family conferences, genetic counseling, second opinion evaluations, consent form discussions for pre-research trial participation, or when care access issues exist. I would refer the audience to the bottom line box which highlights the 18 described visits, as well as the preferred in-person consultation recommendations. So from an operations standpoint, the standards include recommendations for practices to develop their own policies and procedures for these types of visits, frequency of visits, and documentation requirements for all clinical visits. Additionally, patients need to be oriented to the technology being utilized and have real time access to troubleshoot and support, if there are technology issues. The panel strongly advocated the quality of care should be equivalent to in-person visits. Thus to support this concept, the standards include, key performance indicators evaluation, policies for interventions delivered asynchronously, automated reminders, and inclusion of patients and caregivers involvement, if new technologic interventions are developed. BRITTANY HARVEY: Great. I think those specifics you outlined will be helpful both for clinicians and practices, as they implement telehealth. So then, how should the establishment of the physician-patient relationship occur within the context of telehealth in oncology. DR. ROBIN ZON: Well, both state and federal policies permitting telemedicine to cross state lines, should include a provision requiring that the doctor-patient relationship be established, prior to provision of any telemedicine services. As a reminder to the listener, the ASCO position statement, Telemedicine Cross-State Licensure, was recently approved by the Board of Directors and references a valid doctor-patient relationship as outlined by the American Medical Association. This includes establishment of relationship by face-to-face examination or consultation with another physician, who has an ongoing doctor-patient relationship with the patient, or meets the standards of establishing a doctor-patient relationship, if included, in clinical practice guidelines developed by a major medical specialty society. I would refer the audience then to this ASCO position statement, for a much more detailed discussion regarding this topic. Importantly, the doctor-patient relationship should include the usual follow-up and care responsibilities and include opportunity for in-person visits at the physical location of the physician practice. BRITTANY HARVEY: Then following those recommendations for the physician-patient relationship, what is the guidance for when patients may see an advanced practice provider? DR. ROBIN ZON: Well, the panel recommends that practices follow established standards, policies, and algorithms that govern when Advanced Practice Providers, also known as APPs, or physicians should conduct the televisit based on the disease, treatment, or decision inflection point. However, the panel advises that practices should also review and comply with state and local regulations, for advanced practice provider supervision, including on how the APPs and physicians form teams. BRITTANY HARVEY: Understood. And then further, in addition to those, what is the role of allied health professionals in oncology-specific telehealth interventions? DR. ROBIN ZON: And just to orient the audience, when we refer to allied health professionals, we are referring to health professionals who are valued oncology team members. But they're distinct from physicians and nurses. That said, the expert panel referred to the Clinical Oncology Society of Australia, also known as COSA, Tele-oncology Guidelines, which provides guidance for oncology telehealth in rural and remote Australia. This evidence base was the largest for allied health professionals supportive interventions, delivered by both telephone and video conferencing. So due to the strength of the COSA evidence base, the expert panel endorses these recommendations, and refers to the utilization of telephone-based support systems, computerized screening, hybrid tele-practice systems, and video conferencing, as instruments for allied services delivery. BRITTANY HARVEY: Great. And then the standards went into specifics regarding multidisciplinary cancer conferences. So how should discussion occur at virtual multidisciplinary cancer conferences, compared to in-person MCC meetings? DR. ROBIN ZON: Well, as many of you know, many practices, in both academia and community settings, consider cancer conferences, which we also refer to as tumor boards, as essential for high quality patient care. Therefore, virtual cancer conferences replace these face-to-face meetings. The expert panel endorses the recommendations by the University of Pittsburgh Medical Center, for implementation of a virtual cancer conference. These include finalization of the agenda, one day in advance, secure video conferencing software, prioritizing complicated cases, and documentation and evaluation guidance. The expert panel also suggests that practices follow institutional guidelines, allowing the discussion to be directed by the presenter. And that there be no recording of the conference taking place without prior legal review. BRITTANY HARVEY: Once again I find those specifics will be very helpful and explicit for clinicians. So then the last question that was addressed in these standards, how can telehealth be incorporated into clinical trials in oncology? DR. ROBIN ZON: Well, utilization of telehealth and clinical trials are recommended, as a method for increasing recruitment, while reducing patient burden. Importantly, I want to emphasize that the expert panel endorses these recommendations prevail, beyond COVID-19 pandemic restrictions. This includes consideration for a hub and spoke model for patient enlistment. As well as recommendations to facilitate the conduct of teletrials, which are modifications intended to reduce risk during the pandemic, but also results in increased accessibility, reduced costs, and are less time-consuming. BRITTANY HARVEY: Thank you for reviewing all of those key statements that were highlighted in the standards. So then, in your view, Dr. Zon, what is the importance of these standards to clinicians, and how will their implementation impact clinical practice? DR. ROBIN ZON: Well, as I mentioned earlier, telehealth was very uncommonly utilized in cancer care, prior to the pandemic. However, with the soaring use of this intervention, there was a noted gap specific to oncology standards beyond the general telehealth guidance. These standards, then, are designed to assist the cancer care team in delivering the highest quality patient care, similar to the face-to-face quality care the oncologists strive to provide on a daily basis. Furthermore, what we have witnessed, from both the practice responses and the convening of many experts in the delivery of telecare, is the flexibility to swiftly change and harness innovation among our colleagues worldwide. Telehealth, then, has the potential to improve care beyond the pandemic. And these standards serve as a roadmap for telecare best practices to continue to develop and address the needs for rural communities, patients with poor access to care, increase overall clinical trial participation, support patient education, and become one strategy, in a toolbox of other strategies, to help narrow the gap in disparate care. BRITTANY HARVEY: Great. And then you've started to touch on this already, and talking about access to telehealth and how that impacts patients. But finally, how will these standards affect patients? DR. ROBIN ZON: With regards to patients, what we learned from this evidence review, is that patient satisfaction is high. And they appreciate the convenience, flexibilities, and time and cost savings, as a result of telehealth options. I can share from my own practice that my patients were very grateful that we were able to provide telecare during the pandemic, and even now, as restrictions lessen, they're very thankful to have that opportunity. Many oncology patients want this option to continue for the future, and do not believe their clinical care was compromised. However, oncology patient-reported outcomes and ongoing patient satisfaction evaluations must continue, along with the assessment of how the continuing challenges of broadband access, lack of technologic devices, or even familiarity with some technology, may serve as barriers to this care model. These standards are meant to assure the same high quality care for patients who choose to use this intervention, as they would if it were in person. BRITTANY HARVEY: Definitely. Well, thank you for your work on these evidence-based standards directed at delivering high quality and accessible oncology care. And thank you for taking the time to speak with me today Dr. Zon. DR. ROBIN ZON: And thank you so very much for this opportunity. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the standards go to www.asco.org/standards. Additionally, our annual survey for standard topics is open for submissions suggest a topic for standard development at www.surveymonkey.com/r/standardssurvey. Our standards survey. The link is also available in the episode notes of this podcast. If you have enjoyed what you heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode. [MUSIC PLAYING]

An interview with Dr. Valeria Mercadante from University College London, Dr. Siri Beier Jensen from Aarhus University, and Dr. Douglas Peterson from UConn Health, authors on "Salivary Gland Hypofunction and/or Xerostomia Induced by Non-Surgical Cancer Therapies: ISOO/MASCC/ASCO Guideline." This guideline provides evidence-based recommendations for interventions to prevent, minimize, and manage salivary gland hypofunction and xerostomia in patients receiving nonsurgical cancer therapy. Read the full guideline at www.asco.org/supportive-care-guidelines. Suggest a topic for guideline development at www.surveymonkey.com/r/ascoguidelinesurvey. TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcasts.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Valeria Mercadante from University College London and University College London Hospitals Trust in London, United Kingdom, Dr. Siri Beier Jensen from Aarhus University in Aarhus, Denmark, and Dr. Douglas Peterson from the School of Dental Medicine and Neag Comprehensive Cancer Center UConn Health in Farmington, Connecticut, authors on "Salivary Gland Hypofunction and/or Xerostomia Induced by Non-Surgical Cancer Therapies: International Society of Oral Oncology, Multinational Association of Supportive Care in Cancer, and American Society of Clinical Oncology Guideline." Thank you for being here, Dr. Mercadante, Dr. Beier Jensen, and Dr. Petersen. DR. VALERIA MERCADANTE: Thank you. It's a pleasure to be here. DR. DOUGLAS PETERSON: Thank you. DR. SIRI BEIER JENSEN: 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. Mercadante, do you have any relevant disclosures that are directly related to this guideline topic? DR. VALERIA MERCADANTE: No, I do not have any relevant disclosure. BRITTANY HARVEY: Thank you. And Dr. Beier Jensen, do you have any relevant disclosures that are directly related to this guideline? DR. SIRI BEIER JENSEN: No, I have no conflicts to declare related to this guideline topic. BRITTANY HARVEY: Thank you. And finally, Dr. Peterson, do you have any relevant disclosures that are related to this guideline topic? DR. DOUGLAS PETERSON: No. No related conflicts to declare. BRITTANY HARVEY: Thank you. Then let's delve into some of the content of the guideline. First, Dr. Mercadante, can you give us an overview of this guideline's scope and purpose? DR. VALERIA MERCADANTE: Of course. These clinical practice guidelines focus on the prevention and management of salivary gland hypofunction and xerostomia due to non-surgical cancer therapies. This is something we are deeply passionate about because nonsurgical cancer therapies, including all type of radiation regimens, chemotherapy, and biological cancer therapy, can damage the glands in our mouth that produce saliva, resulting in xerostomia, which we define as patient-reported subjective sensation of dryness and salivary gland hypofunction, which we define as reduced salivary flow rate as measured objectively. And this condition may last for several months or may become permanent. And because saliva serves so many important function, xerostomia may lead to a range of other symptoms that can impact patient quality of life. And therefore, ASCO, MASCC, and ISOO decided to update the findings of their two previous systematic reviews published in 2010 and provide a practical, evidence-based approach in a multidisciplinary setting to address this important topic. BRITTANY HARVEY: Great. Thank you for that background. So then I'd like to review the key recommendations of this guideline. This guideline covers two clinical questions, one on prevention and one on management. So Dr. Peterson, starting with prevention, what are the key recommendations regarding pharmacologic and non-pharmacologic interventions for the prevention of salivary gland hypofunction and/or xerostomia induced by non-surgical cancer therapies? DR. DOUGLAS PETERSON: Thank you, Brittany. As you've noted, the guideline is framed in the context of two clinical questions, prevention, and then followed by the management once the condition has occurred. Relative to prevention, there were eight recommendations, all of which were directed to reducing the risk of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer. And as with other ASCO guidelines, each of these recommendations was in turn supported by text directed to literature review and analysis and clinical interpretation. So let me just briefly highlight the eight recommendations on prevention. Recommendation 1.1 was that intensity-modulated radiation therapy, IMRT, should be used to spare major and minor salivary glands from a higher dose of radiation. This was a very strong, well-evidenced recommendation. The evidence quality was high. The strength of the recommendation was strong. Recommendation 1.2 is that other radiation modalities that limit cumulative dose to an irradiated volume of major and minor salivary glands as one or more effectively than IMRT may be offered. Recommendation 1.3 reads that acupuncture may be offered during radiation therapy for head and neck cancer to reduce the risk of developing the symptom of xerostomia. Recommendation 1.4, systemic administration of the sialogogue bethanechol may be offered during radiation therapy for head and neck cancer. Recommendation 1.5-- and this is an important different type of recommendation-- vitamin E or other antioxidants should not be used to reduce the risk of radiation-induced salivary gland hypofunction and xerostomia. And this is because of the potential adverse impact of these antioxidants on cancer-related outcomes and the lack of evidence of benefit. In addition to those five recommendations, there were three recommendations for which the evidence was insufficient. In the panel's view, it was important to delineate these three recommendations in the context of current clinical practice as well as opportunities for future research that we'll talk about in a little bit. The three recommendations for which there was insufficient evidence are 1.6. -- The panel was unable to make a recommendation for or against the use of submandibular gland transfer administered before head and neck cancer treatment. This limitation is due to the current amount of evidence associated with this surgical intervention, submandibular gland transfer, in relation to ever-evolving contemporary radiation modalities. Recommendation 1.7-- evidence remains insufficient for a recommendation for or against use of the following three interventions during radiotherapy for head and neck cancer. The three interventions are oral pilocarpine, amifostine in association with contemporary radiation modalities, and low-level laser therapy. And then, finally, Recommendation 1.8-- the evidence remains insufficient for or against the use of several interventions, including selected radiation technology, for example, boost radiation or hyper or hypofractionated radiation therapy, Transcutaneous Electrical Nerve Stimulation or TENS, human epidermal growth factor, and selected complementary medicines. And again, the evidence is insufficient in the panel's view for a recommendation for or against these and several other interventions that are listed in the guideline. So I'll now turn the microphone back to Brittany. BRITTANY HARVEY: Great. Thank you for reviewing those prevention recommendations and explaining the evidence that supported those as well. That's very helpful. So following that, Dr. Beier Jensen, what are the key recommendations on pharmacologic and non-pharmacologic interventions for the management of salivary gland hypofunction and/or xerostomia induced by non-surgical cancer therapies? DR. SIRI BEIER JENSEN: The key recommendations for the management of salivary gland hypofunction and xerostomia induced by cancer therapies are based on the principles of stimulation of the salivary reflex and lubrication of the oral tissues of, say, the mucosa and the teeth. The recommendations 2.2, 2.3, 2.4, and 2.5 address this stimulatory approach. If there is residual secretory capacity of the salivary glands, stimulation of natural saliva secretion may be provided by chewing or taste stimuli. This can be regular use of sugar-free lozenges, sugar-free candies, or sugar-free non-acidic chewing gum. In patients who have their natural teeth, it's important to be aware that if acidic candies are used to stimulate saliva secretion, then it should be a special nonerosive preparation for dentate patients that will say that they do not dissolve the tooth substance. Pharmacological stimulation is also an option by prescription medication such as oral pilocarpine and cevimeline in countries where this is available. This may result in systemic adverse effects that limit use in some patients. So the gustatory and masticatory salivary reflex stimulation, Recommendation 2.2, the evidence-based quality was intermediate, and the strength of the recommendation was moderate. And for the pharmacological stimulation by pilocarpine and cevimeline, it was evidence-based, high-quality, and strong recommendation strength. For patients who have salivary gland hypofunction or xerostomia induced by radiation therapy for head and neck cancer, stimulation of saliva secretion may also be provided by acupuncture, transcutaneous electrical stimulation, or acupuncture-like transcutaneous electrical stimulation, although the evidence base here is less strong than for the other stimulatory management options mentioned. This is addressed in Recommendation 2.4 and 2.5. If the residual secretory capacity of the salivary glands is low or maybe even nonexistent, then regular lubrication of the oral mucosa and teeth is of relevance. This is addressed in Recommendation 2.1. Such lubrication may be provided by topical application of mucosal lubricants and saliva substitutes, which are agents directed at ameliorating xerostomia and other salivary gland hypofunction-related symptoms. It is of importance to notice that available stimulatory and lubricating options all provide transitory increased salivary flow rates and transitory relief from xerostomia. If you would like to review the specific recommendations, they can be found in the manuscript. BRITTANY HARVEY: Great. Thank you for reviewing those recommendations on the management of salivary gland hypofunction and/or xerostomia. So Dr. Peterson, you mentioned this earlier, but there are some cases in the guideline in which evidence was insufficient to make recommendations. And you went through a few of these areas. So what areas of future research did the panel discuss? DR. DOUGLAS PETERSON: Thanks, Brittany. The panel worked very carefully to relate the quality of evidence to strength of each of the recommendations. In addition to providing important context regarding clinical prevention and treatment of xerostomia salivary hypofunction, novel directions for future research were therefore identified. And I'll just briefly delineate these future directions. Studies directed to the continued, rapidly-evolving radiation technology such as proton therapy and volumetric modulated art therapy or VMAT, as well as the length of time after this treatment is completed, for example, one to five years after completion of treatment, these studies are needed to assess the relationship of this rapidly-evolving technology to the long-term adverse oral events such as salivary gland hypofunction and xerostomia as well as advanced dental disease and osteoradionecrosis as well. Importantly, and the panel spent quite a bit of time deliberating this, ethical considerations must continue to be paramount in the study designs. And this is pertinent relative to this guideline. An important issue is that implementation of randomized clinical trials comparing current and novel radiation therapy modalities is typically precluded for ethical reasons. So this is a barrier to address, and the panel wanted to call attention to the scientific and clinical community. In addition to the radiation technology itself, two additional future research directions also represent potential strategic advances in the field as well. First, radiosensitivity of parotid gland stem cells. For example, it has been recently shown that not all constituents of the parotid gland are equally radiosensitive because of an unequal distribution of the stem cells within the gland. This and related biologic concepts should be incorporated in future randomized controlled trials of head and neck cancer patients. Secondly, novel regenerative medicine options may be used to spare, optimize, or restore salivary gland function after treatment. The guideline addresses these innovative treatment approaches in the context of both the current state of the science as well as opportunities for future research. I'll turn the microphone back to Brittany. BRITTANY HARVEY: Great. Thank you, Dr. Peterson, for reviewing those areas where additional research would be helpful. So next, in your view, Dr. Mercadante, what is this guideline's importance and how will it affect clinicians? DR. VALERIA MERCADANTE: Thank you for this question. We believe these guidelines offer an opportunity for any clinician involved in non-surgical cancer therapies-- oncologists, dentists, dental specialists, dental hygienists, oncology nurses, clinical researchers, advanced practitioners. We all have an essential role in supporting our patients for the entire journey by optimizing symptoms management and improve our patients quality of life. These guidelines thus suggest a preventative and treatment course, but we've also delineated what we feel is common practice between experts and what areas would need further research to provide, as Dr. Peterson beautifully described, an ethical framework for future studies in this field. BRITTANY HARVEY: Great. Thank you so much. So finally, Dr. Beier Jensen, how will these guideline recommendations impact patients? DR. SIRI BEIER JENSEN: Well, for patients who live with these complications during cancer treatment or as [INAUDIBLE] of cancer therapies, these guideline recommendations on prevention and management of salivary gland hypofunction and xerostomia will enable them evidence-based and with the help of professional health care providers to support the natural functions of saliva and promote their oral comfort and health. BRITTANY HARVEY: Great. Well, thank you all, Dr. Mercadante, Dr. Beier Jensen, and Dr. Peterson for taking the time to work on this guideline and produce evidence-based recommendations for clinicians and patients. And thank you for taking the time to speak with me today. DR. BEIER JENSEN: Thank you. DR. DOUGLAS PETERSON: 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/supportive-care-guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at www.SurveyMonkey.com/r/ascoguidelinesurvey by August 1st. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]