ASCO Guidelines Podcast Series podkast

Renal Toxicities: Management of irAEs Guideline (Part 8)

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An interview with Dr. Umang Swami from the Huntsman Cancer Institute, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” He discusses the identification, evaluation, and management of renal toxicities in patients receiving ICPis, focusing on nephritis/acute kidney injury in Part 8 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

 

TRANSCRIPT

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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.

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BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, we're continuing our series on the management of immune-related adverse events.

I am joined by Dr. Umang Swami from the Huntsman Cancer Institute at the University of Utah in Salt Lake City, Utah, author on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update, and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T Cell Therapy: ASCO Guideline. And today, we're focusing on renal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Swami.

UMANG SWAMI: Thank you, Brittany. And I appreciate the invitation to be here today.

BRITTANY HARVEY: Great. Then first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Swami, do you have any relevant disclosures that are directly related to these guidelines?

UMANG SWAMI: No, I do not have any relevant disclosures that are directly related to these guidelines.

BRITTANY HARVEY: Thank you. Then let's dive into what we're here today to talk about. So what are these immune-related renal toxicities that are addressed in this guideline?

UMANG SWAMI: So this guideline focuses on nephritis, or acute kidney injury, as an adverse event due to immunotherapy. Acute kidney injury, or AKI, is an uncommon complication of immune checkpoint inhibitor therapy. Just to give a little context before we start, the incidence of any grade AKI is around 1% to 2% in patients treated with a single agent immune checkpoint inhibitor, such as ipilimumab, nivolumab, or pembrolizumab, and 4.5% in those treated with anti-CTLA-4 for and anti-PD-1 combination of nivolumab plus ipilimumab therapy. The incidence of grade 3 or grade 4 AKI is very low. I will say less than 1% with single agents, and around 1.6% with the combination of nivolumab plus ipilimumab.

While initial studies had quoted a small incidence of AKI with immune checkpoint inhibitor use, emerging data now suggests that a higher incidence might be present, which might range between 9.9% to around 29% of AKI with the immune checkpoint inhibitors. However, most of this extra toxicity is grade 1. The median time to onset of renal toxicity with these agents is around 14 weeks, but can range from 6.5 to 21 weeks.

BRITTANY HARVEY: Thank you for that background information. I think it's helpful for clinicians to understand how rare or common these adverse events are. So then, what are the key recommendations for identification, evaluation, and management of nephritis or acute kidney injury?

UMANG SWAMI: That's a great question. Presenting symptoms related to immune therapy-induced renal toxicities may include urinary frequency, dark, cloudy urine, fluid retention, or edema of face, abdomen, extremities. There might be sudden weight gain. There might be associated abdominal or pelvic pain. Patients might have nausea, vomiting, high blood pressure, or they may have a change in mental status such as drowsiness. However, we should remember that a vast majority of them will be asymptomatic at presentation. Therefore, patients should have their renal function, that is, serum creatinine, checked prior to administration of each dose of checkpoint inhibitor therapy.

For patients with new elevations in creatinine, one should consider holding checkpoint inhibitor therapy while other potential causes are evaluated. These other causes may include recent IV radiographic contrast administration, dehydration, urinary tract infection, other natural toxic medications, including concurrent chemotherapy, herbals, or other supplements. Patients without their obvious causes or who don't respond to alternative treatment measures should be presumed to have immune-related renal toxicity and treated empirically depending on the grade of AKI.

Safe treatment of autoimmune component is important. So with regards to the grading of AKI, grade 1 means a creatinine level increase of more than 0.3 milligrams per deciliter, or creatinine 1.5 to two times above baseline. And in this situation, physicians should consider temporarily holding checkpoint inhibitor therapy and evaluating other potential contributing agents in combination regimes, pending consideration of potential alternative pathologies. A change that is still less than 1.5 times of upper limit of normal could be meaningful and should be remembered.

For grade 2 AKI, which is creatinine two to three times above baseline, apart from holding immune checkpoint inhibitor and evaluating for alternative causes, nephrology should be consulted. If other etiologies are ruled out, administer 0.5 to 1 milligram per kg per day prednisone or its equivalent. If kidney function worsens or does not improve after one week, increase the dose of prednisone to 1 to 2 milligrams per kg per day or its equivalent, and permanently discontinue immune checkpoint inhibitor.

If the AKI improves to grade 1 or less, taper steroids over at least four weeks, otherwise we might see recurrence. If there is no recurrence, a physician might discuss resumption of immune checkpoint inhibitor with patient after taking into account what are the risks and what are the benefits. Resumption of immune checkpoint inhibitor can be considered once steroids have been successfully tapered to 10 milligrams per day or less, or discontinued. However, if elevation persists for more than seven days or worsens, and no cause is found, then the grade 2 AKI needs to be treated as grade 3.

Now grade 3 and grade 4 AKI are managed similarly. Grade 3 AKI is defined as creatinine more than three times the baseline, or more than 4 milligrams per deciliter, or when hospitalization is indicated. And grade 4 AKI defined as an AKI associated with life-threatening consequences, when dialysis is indicated, or creatinine six times above baseline.

Management includes nephrology consult, evaluation for alternative causes, and permanent discontinuation of immune checkpoint inhibitor. If they are directly implicated in renal toxicity, the administration of corticosteroids in grade 3 or grade 4 AKI is at an initial dose of 1 to 2 milligrams per kg per day of prednisone or its equivalent. If and when the AKI improves to grade 1, corticosteroids can be tapered over at least four weeks.

However, if elevation persists for more than three to five days for grade 3 or more than two to three days for grade 4 or worsens, we should consider additional immunosuppression, such as infliximab as a time frame, cyclophosphamide, cyclosporine, or mycophenolate. Usually, reflex renal biopsy is typically not necessary or recommended unless the AKI is refractory to steroids or other immunosuppressive agents.

BRITTANY HARVEY: I appreciate your reviewing those details for immune-related renal toxicity. So then, in your view, Dr. Swami, how will these recommendations for the management of renal toxicities impact both clinicians and patients?

UMANG SWAMI: This guideline presents a concise, up to date, and a stepwise approach to diagnose, grade, and treat this rare, but serious side effect of immunotherapy. In my view, this would be immensely helpful to clinicians in busy practices.

Prompt identification and treatment is also expected to help our patients experiencing immune related kidney injury. For patients, it will provide a readily available document to refer to for information regarding side effects of immune checkpoint inhibitor therapy. I applaud the efforts by the ASCO and the authorship team in developing the patient-focused version of this guideline. This may allow patients, especially when between clinic visits, to identify this unusual condition and seek medical help in a timely fashion.

BRITTANY HARVEY: Great. Thank you for highlighting the importance of this guideline, for all your work you did on this guideline, and for your time today, Dr. Swami.

UMANG SWAMI: Thanks so much, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can find many of our guidelines and interactive resources in the free ASCO guidelines app, available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

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  • ASCO Guidelines Podcast Series podkast

    Adjuvant Therapy for Stage II Colon Cancer Guideline Update

    17:42

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

    Management of Stage III NSCLC Guideline

    11:44

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

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  • ASCO Guidelines Podcast Series podkast

    Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline

    15:53

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

    Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline

    16:36

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

    Abemaciclib with Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer: ASCO Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Rapid Recommendation Update

    8:55

    An interview with Dr. Sharon Giordano, co-chair on “Abemaciclib with Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer: ASCO Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Rapid Recommendation Update.” Dr. Giordano discusses the results and impact of the monarchE trial, the updated recommendations on the use of abemaciclib, and impact for clinicians and patients. For more information, visit www.asco.org/breast-cancer-guidelines.
  • ASCO Guidelines Podcast Series podkast

    Considerations for the Use of Steroids: Management of irAEs Guideline (Part 13)

    8:58

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

    Ocular Toxicities: Management of irAEs Guideline (Part 12)

    6:39

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

    Cardiovascular Toxicities: Management of irAEs Guideline (Part 11)

    12:27

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

    Hematologic Toxicities: Management of irAEs Guideline (Part 10)

    18:34

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

    Nervous System Toxicities: Management of irAEs Guideline (Part 9)

    20:11

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

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