ASCO Guidelines Podcast Series podkast

Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Guideline Update

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An interview with Dr. Harold Burstein from Dana Farber Cancer Institute in Boston, MA, chair on “Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Update.” This guideline updates recommendations on use of alpelisib, and the role of biomarkers and CDK4/6 inhibitors. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.

 

TRANSCRIPT

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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 podcasts.asco.org.

My name is Brittany Harvey. And today I'm interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute in Boston, Massachusetts, chair and lead author on endocrine treatment and targeted therapy for hormone receptor-positive HER2 negative metastatic breast cancer ASCO guideline update. Thank you for being here, Dr. Burstein.

HAROLD BURSTEIN: Glad to be with you.

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

HAROLD BURSTEIN: I do not.

BRITTANY HARVEY: Great, thank you. Then let's delve into the content of this guideline. So first, what prompted the update of this guideline and what is the focus of this update?

HAROLD BURSTEIN: So this guideline focuses on metastatic breast cancer, and in particular, estrogen receptor-positive HER2 negative metastatic breast cancer. Worldwide in 2021, actually breast cancer became the most commonly diagnosed cancer in the world, excepting superficial skin cancers.

And so it is a true global health problem. And the most common type of breast cancer is estrogen receptor-positive HER2 negative breast cancer, which accounts for 70% to 75% of all cancer diagnoses in the breast cancer space, and as a consequence, also accounts for 70% to 75% of the cases of metastatic breast cancer. So it's really important from a public health point of view and a quality point of view, both in the United States and globally, to have current up-to-date guidance for the management of this most common form of breast cancer that we have.

In addition, there have been several innovations in the way of targeted therapies that are coming into place for advanced ER-positive breast cancer. And increasingly, we are using genomic tests to help us understand how best to treat patients with advanced ER-positive breast cancer. So those two initiatives-- the interest in genomic testing and the use of targeted therapies-- all warranted and justified an update to the guidelines.

BRITTANY HARVEY: Great. Thank you for reviewing that landscape of where we are in clinical practice for this guideline. So then I'd like to review the key recommendations that this guideline addresses. So first, should alpelisib be given to post-menopausal women and to male patients with hormone receptor-positive HER2 negative PIK3CA-mutated advanced or metastatic breast cancer?

HAROLD BURSTEIN: So alpelisib, as you indicated, is a new drug. It is now FDA approved. And it is a protein kinase targeted inhibitor. And it goes after the PIK3CA-mutated tumors. And in a seminal study called the SOLAR-1 study, there was randomization to endocrine therapy alone with fulvestrant or endocrine therapy plus alpelisib for ER-positive HER2 negative breast cancer.

And that study showed two important things. First was that in women whose tumors did not have a PIK3CA mutation, there was no benefit for alpelisib. However, in the women whose tumors did have a PIK3CA mutation, there was an improvement in progression-free survival with the use of this targeted drug alpelisib.

So based on that, the guidelines now incorporate alpelisib into the treatment algorithm. And as a corollary, it means that all patients who have ER-positive metastatic breast cancer now need testing of the tumor to see if they have a PIK3CA mutation because that's going to guide therapy.

In the guideline, we now suggest that this be a standard thing to do-- to test all tumors for PIK3CA mutation. And in those cases where there is a PIK3CA mutation to add alpelisib-based therapy with endocrine treatment typically in second or subsequent lines of therapy.

BRITTANY HARVEY: Great. And thank you for reviewing the evidence base behind that recommendation. So next, what is recommended regarding the role of biomarkers in treatment selection for patients with hormone receptor-positive metastatic breast cancer?

HAROLD BURSTEIN: So there are two different ways of thinking about biomarkers. One is traditional biomarkers, such as estrogen receptor, progesterone receptor, and HER2. Those are familiar to all clinicians who have been dealing with breast cancer. The second is to think about some of the newer technologies, including tumor genomic sequencing and the kind of mutational analysis we just discussed with the PIK3CA mutations.

So in the breast cancer space, there are some important innovations in that latter genomic or genetic testing. One, of course, is the PIK3CA mutation testing that we now recommend for all cancers. That can be done on the primary tumor, or it can be done on cell-free or circulating tumor DNA samples from the bloodstream in most cases.

The other kind of testing we do relates to ESR1 mutations. And one of the reasons that tumors become resistant to aromatase inhibitors is that they acquire mutations in the estrogen receptor itself, so-called ESR1 activating mutations. Those mutations mean that the estrogen receptor is on even in the absence of estrogen. And that accounts for probably 50% to 60% of the resistance that we see in treatment with aromatase inhibitors.

So the panel really struggled with this because, on the one hand, this is not a uniformly accepted way to decide how to treat patients. On the other hand, there are a lot of data that women whose tumors have ESR1 mutations get negligible benefit from ongoing use of aromatase inhibitor therapy.

So this recommendation fell into sort of our practice suggestions, which is that if you have the information on ESR1, then it probably is the case that there's very little, if any, role for ongoing aromatase inhibitor treatment. This fell short of the highest level in endorsement because, first, it's not a uniformly tested assay. And secondly, it's important to remember that these tumors can still benefit from ongoing anti-estrogen therapy with different anti-estrogens like fulvestrant.

And finally, and perhaps this is the most practical issue, the way you become ESR1 mutated is usually through exposure to aromatase inhibitors. And if you've already had a patient with extensive exposure to AIs, and they need ongoing anti-estrogen therapy in the metastatic setting, it usually means you're switching treatment anyway. So that's an example of where we're sort of on the frontier of thinking about dynamic changes in the tumor as a way to select treatment for ER-positive metastatic disease.

BRITTANY HARVEY: Great. That's helpful for a clinical interpretation of the recommendations and incorporating these into practice. So the final question that was addressed in this focused update was, what is the role of CDK4/6 inhibitors in the treatment of patients with hormone receptor-positive metastatic breast cancer?

HAROLD BURSTEIN: So CDK4/6 inhibitors are another tyrosine kinase inhibitor class of drugs that has really emerged as an important part of first-line therapy for ER-positive metastatic disease. There have been multiple randomized trials looking at either first-line therapy with an aromatase inhibitor with or without a CDKI4/6 inhibitor, or second-line treatment typically with fulvestrant with or without a CDKI4/6 inhibitor in the metastatic setting. And the panel was able to update the guidance here based on the maturation of multiple randomized trials, as well as extensive subset analyses that have been performed by investigators associated with the individual pharmaceutical-led studies and by the FDA itself.

So here are some important takeaways. The first is that in long-term follow-up, these drugs as a class are improving overall survival for women with ER-positive HER2 negative metastatic breast cancer. And for that reason, they are a very important part of the standard armamentarium for ER-positive disease. It's important to say that they also delay the onset of need for chemotherapy, and in general, are associated with a very well preserved quality of life. So this is a big win for patients with ER-positive metastatic breast cancer.

We typically recommend them in the first-line setting. So if a patient has de novo metastatic disease, then they should get an endocrine therapy such as an aromatase inhibitor with a CDK4/6 inhibitor. If they've previously had adjuvant aromatase inhibitor treatment or recur while on adjuvant endocrine therapy, we often move to fulvestrant plus a CDKI4/6 inhibitor. Both settings have shown substantial benefit for this class of drugs.

It's important that clinicians understand the side effects of these drugs. Neutropenia and diarrhea are common side effects associated with the various drugs. And because of the prevalence of ER-positive metastatic disease, it's really important for clinicians and all those who care for advanced breast cancer patients to know how to manage those side effects carefully.

The panel discussed controversial issues, I suppose you might say, in the management. What about patients who have truly minimal metastatic disease? There aren't a lot of data on how best to think about those patients. And we all can imagine on a case-by-case basis an individual who might not need a CDK4/6 inhibitor at a given moment in time.

But what was impressive when we pulled all the data was that in subset analyses, it's really hard to find a group of patients that does not benefit from the incorporation of these drugs. So that included premenopausal women who also get concurrent ovarian suppression and then endocrine therapy plus the CDK4/6 inhibitor. It included women with bone-only metastatic disease. It included women whose tumors were ER-positive but PR negative, or had other variations in ER expression. It included patients who had less rather than more metastatic cancer, including visceral disease.

So in the literature, one is hard-pressed to see a subset that does not benefit meaningfully from this class of drugs. So we really wanted to reiterate in the algorithms just how important these are. They should be the standard first-line treatment for metastatic disease either paired with an AI or with fulvestrant.

And so one of the other nice things that the update gave us was the opportunity to put in some fresh sort of algorithm flow sheets. I would very much encourage people to look at that. They make fantastic PowerPoint or downloadable Twitter documents if you are so inclined. But it's very clear the way the treatment should flow, which is the initial therapy is endocrine treatment plus a CDK4/6 inhibitor. While the patients are getting that, we typically test for PIK3CA mutations. In second line, if it's a PIK3CA mutated, you have the option of using alpelisib. You also might consider an older drug for PIK3CA wild type tumors called everolimus. We reiterated that recommendation in the guideline.

Finally, one more thing to touch on that is emerging in the guidelines we generated and in the parallel guideline process for the ASCO guidance on chemotherapy-resistant or refractory breast cancer is the importance of genetic testing all patients who have metastatic breast cancer to look for the possibility of a BRCA1 or BRCA2 deleterious mutation, because there now is FDA approval for PARP inhibitors in the setting of metastatic disease.

And one of the interesting things is that as we test more and more, we're seeing that not all the patients who are found to have a BRCA1 or 2 mutation meet the classic criteria for genetic testing-- strong family history, or say, triple-negative breast cancer. So it's really important to test, because that class of drugs, the PARP inhibitors, can be immensely helpful in women with ER-positive metastatic disease when they harbor a BRCA1 or 2 mutation.

One of the things the guideline panel wrestled with and ended up putting into the sort of clinical discussion, as opposed to the strong guidance, was the 1% of patients who have PALB2 mutations. So PALB2 mutation, another hereditary predisposing factor for breast cancer. Most tumors that arise in PALB2 mutation carriers are in fact estrogen receptor positive.

And a very small study, now published in the JCO, has suggested that those patients have a very high likelihood of response to PARP inhibitors. Because there were only like 15 patients in that cohort, we didn't feel that this warranted clear endorsement in the guidelines. But at the same time, everyone on the panel acknowledges that this is an active drug in that rare subset of tumors with PALB2 mutations in addition to the BRCA1 or 2 mutations.

So the takeaway here is that genetic testing should be standard for all patients with advanced metastatic breast cancer to see if the patient is a candidate for a PARP inhibitor-based therapy.

BRITTANY HARVEY: Definitely. Well, thank you for reviewing all of those updated recommendations and highlighting some of the ones that were still relevant to this guideline.

HAROLD BURSTEIN: Work in progress.

BRITTANY HARVEY: Yeah, definitely. And then finally, what is the importance of this guideline update? And how will it impact both clinical practice and what does it mean for patients?

HAROLD BURSTEIN: Well, I think guidelines like this have multiple purposes. The first is to sort of describe the state of the art. And while breast cancer is a very common disease, and most clinicians who take care of a lot of cancer patients will see a lot of advanced breast cancer, I think it's still helpful to articulate the rationale for these treatment recommendations.

And one of the great things about the ASCO guideline process is the thoroughness of the literature review, the thoroughness of the search to make sure we're including all important publications, and the thoughtfulness that the panel, which includes experts, patient advocates, quality of life expertise, all those things bring to bear on really thinking through what makes sense and what does not for our patients based on the best science available. So I think it is an important activity to really sort of benchmark where we're at.

The second thing we've tried to do in the guideline is to introduce areas of nuanced discussion, because not every patient is the same. And I think for those who are interested and take the time to read the guideline, there really is a very nice discussion about how our panel thought about when best to use this approach and when to use a different approach.

Third, there's extensive discussion of the side effects and the appropriate management of the side effects. These are drugs that do carry risks. And while by oncology standards, many of them are, quote, "well tolerated," unquote, there's no doubt that there are side effects to these drugs. And it's important for clinical teams to know how to manage them.

Finally, I think by putting forward all the evidence, you make clear to investigators, to drug companies, to patients and advocates, and others who are involved in the review of new drugs what the benchmarks are and what the criteria should be for designing clinical trials and for approving new drugs. And I think we've done a nice job of framing that discussion quite handsomely in this guideline and to all of the ASCO guidelines.

BRITTANY HARVEY: Great. Well, thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Burstein.

HAROLD BURSTEIN: Happy to join you and thanks very much.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at SurveyMonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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

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    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. 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    Ocular Toxicities: Management of irAEs Guideline (Part 12)

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    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. 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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.
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    Cardiovascular Toxicities: Management of irAEs Guideline (Part 11)

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    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]
  • ASCO Guidelines Podcast Series podkast

    Renal Toxicities: Management of irAEs Guideline (Part 8)

    10:47

    An interview with Dr. Umang Swami from the Huntsman Cancer Institute, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” He discusses the identification, evaluation, and management of renal toxicities in patients receiving ICPis, focusing on nephritis/acute kidney injury in Part 8 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING]   BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Umang Swami from the Huntsman Cancer Institute at the University of Utah in Salt Lake City, Utah, author on Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update, and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T Cell Therapy: ASCO Guideline. And today, we're focusing on renal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Swami. UMANG SWAMI: Thank you, Brittany. And I appreciate the invitation to be here today. BRITTANY HARVEY: Great. Then first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Swami, do you have any relevant disclosures that are directly related to these guidelines? UMANG SWAMI: No, I do not have any relevant disclosures that are directly related to these guidelines. BRITTANY HARVEY: Thank you. Then let's dive into what we're here today to talk about. So what are these immune-related renal toxicities that are addressed in this guideline? UMANG SWAMI: So this guideline focuses on nephritis, or acute kidney injury, as an adverse event due to immunotherapy. Acute kidney injury, or AKI, 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. [MUSIC PLAYING]
  • ASCO Guidelines Podcast Series podkast

    Musculoskeletal Toxicities: Management of irAEs Guideline (Part 7)

    10:20

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

    Endocrine Toxicities: Management of irAEs Guideline (Part 6)

    14:06

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

    Lung Toxicities: Management of irAEs Guideline (Part 5)

    10:47

    An interview with Dr. Jarushka Naidoo from Johns Hopkins University, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She discusses the identification, evaluation, and management of lung toxicities in patients receiving ICPis, focusing on pneumonitis in Part 5 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines   TRANSCRIPT [MUSIC PLAYING]   SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING]   BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network-- a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Jarushka Naidoo from Johns Hopkins University in Baltimore, Maryland, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And, today, we're focusing on lung toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Naidoo. JARUSHKA NAIDOO: Thank you. It's my pleasure to share updates on this guideline. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with a publication of the guidelines in the Journal of Clinical Oncology. Dr. Naidoo, do you have any relevant disclosures that are directly related to these guidelines? JARUSHKA NAIDOO: Yes. So I have research funding in the last two years from Merck, AstraZeneca, and Bristol Myers Squibb. And I also have served in a consulting role-- or an advisory board capacity-- for Merck, AstraZeneca, Bristol Myers. And not specifically related to this work, but also Pfizer, Takeda, Daiichi Sankyo, and Kaleido Biosciences. BRITTANY HARVEY: OK. Thank you for those disclosures. Then-- getting into the content of this guideline-- what are the immune-related lung toxicities addressed in this guideline? JARUSHKA NAIDOO: Thanks, Brittany. So the main lung toxicity that is addressed in this guideline is immune checkpoint inhibitor pneumonitis, which-- as this audience knows-- is an uncommon, but potentially fatal toxicity particularly associated with anti-PD-1 or PD-L1 monotherapy, but can also occur with combination immunotherapy approaches. In the guideline, we go through what is known about the natural history, risk factors, and then, of course, our comprehensive approach to identifying, evaluating, and managing this toxicity, which is defined as a focal or diffuse inflammation of the lung parenchyma. We also identify that, while pneumonitis is the quintessential lung toxicity that can occur with immune checkpoint inhibitors, we also note that there are some other lung toxicities that have been reported on, but for which known we relatively little. And this includes sarcoid-like granulomatous reactions, including subpleural micronodular opacities and hilar lymphadenopathy, as well as pleural effusions. And these have been associated with both CTLA-4 and the PD-1, PD-L1 immune checkpoint inhibitor therapies. BRITTANY HARVEY: I appreciate that overview. So then, you mentioned the main toxicity here is pneumonitis. What are the key recommendations for identification, evaluation, and management of pneumonitis? JARUSHKA NAIDOO: Thanks, Brittany. So yeah, this is a key focus of the guideline. So, as we're aware, pneumonitis is defined as a focal or diffused inflammation of the lung parenchyma and is a toxicity that was identified as one of the early toxicities in the early clinical trials of the PD-1 inhibitors. The incidence of this toxicity is estimated at anywhere between 0% and 10%, and in large meta analyses, looks to be around 2% to 3% in terms of incidence. In terms of how to evaluate patients with suspected immune-related pneumonitis, the common symptoms would be cough, shortness of breath, fever, and chest pain. And in a patient who has suspected pneumonitis, some of the first tests to be done would be to take a pulse oximetry and to do some chest imaging. Chest imaging is preferable with a CT scan with contrast in order to rule out alternative etiology, such as pulmonary embolus For patients who are symptomatic-- which means CTCAE grade 2 or greater-- we also recommend a standard infectious workup, which is guided by institutional guidelines. But based on our ASCO guideline, we outline that this should include, at a minimum, a nasal swab, sputum culture and sensitivity, blood culture and sensitivity, and urine culture and sensitivity, as well as a standard COVID-19 evaluation. When we come to the diagnosis of pneumonitis, we then evaluate that in terms of CTCAE grade. Where the grade of pneumonitis refers, firstly, to whether a patient has symptoms, and the proportion of the lung parenchyma that may be involved with pneumonitis on chest imaging. Broadly speaking, patients with grade 1 pneumonitis are asymptomatic and usually identified on radiographic imaging almost incidentally. For these patients, we would recommend either holding immunotherapy or proceeding with close monitoring. And we recommend that patients should have weekly physical exams and pulse oximetry offered, and consideration of further chest imaging if the diagnosis is uncertain, or to follow progress-- usually around every three to four weeks-- or, if a patient becomes symptomatic, it may be more often than this. We also recommend that we may consider doing spirometry or DLCO evaluation as a repeat in these patients. Broadly, again, in terms of the evaluation of patients-- if patients are symptomatic from pneumonitis, which means they have a symptom related to radiographic features, then this would be called grade 2. And usually, radiographically, patients have more of the lung parenchyma involved-- greater than 25%-- and require a medical intervention. And the management would be prednisone, 1 to 2 milligrams per kilogram per day, that is then tapered over 4 to six weeks, and immunotherapy is held during that time. Importantly, in order to knuckle down the diagnosis of pneumonitis, we recommend consideration of doing a bronchoscopy with bronchoalveolar lavage sampling in order to truly rule out alternative infectious diagnoses or lymphangitis carcinomatosis. And for this reason, a transbronchial biopsy can also be considered. In some cases, we also consider treating with empiric antibiotics to cover infection if we feel that this remains in the differential diagnosis. If patients do not clinically improve after 48 to 72 hours on prednisone, then we recommend treating at a higher grade, meaning grade 3, where patients have severe symptoms, hospitalization is required, and a larger proportion of the lung parenchyma is involved. For these patients who have grade 3 or greater pneumonitis, we recommend permanently discontinuing immunotherapy, administering a higher dose of steroids at methylprednisolone, 1 to 2 milligrams per kilogram per day. And, once again-- if there is no improvement after 48 hours, we recommend a range of potential additional immunosuppressive approaches, which include either infliximab, mycophenolate mofetil, intravenous immunoglobulin, or cyclophosphamide. And there are currently no recommendations as to which may be the optimum immunosuppressive approach, but there are a number of clinical trials aiming to elucidate the answer to this. Importantly, overall in patients who are symptomatic, it may also be appropriate to consult pulmonary medicine and infectious diseases teams to weigh in on the diagnosis and management going forward. BRITTANY HARVEY: Great. Thank you for that clear, step-wise approach to the evaluation and management of pneumonitis. So then, in your view, Dr. Naidoo-- how will these recommendations for the management of lung toxicities impact both clinicians and patients? JARUSHKA NAIDOO: I think it's very important for both clinicians and patients to be aware of the potential side effects of the treatment that patients are receiving with immune checkpoint inhibitors. We know that some toxicities from immunotherapy tend to be mild and can be managed quite well with corticosteroids or other approaches. What we understand about lung toxicities is that, thankfully-- in the majority of cases-- pneumonitis will be well-controlled with corticosteroids and holding of immunotherapy. However, in a proportion of patients, pneumonitis may become severe and may even lead to treatment-related deaths. And for that reason, both patients and clinicians need to be aware of what to look out for in terms of the symptoms of pneumonitis, and how to diagnose and manage this toxicity quickly and efficiently in order to avoid poor outcomes. BRITTANY HARVEY: Absolutely. Those are excellent points for both clinicians and patients to keep in mind. So I really want to thank you for all of your work on these guidelines and for taking the time to speak with me today, Dr. Naidoo. JARUSHKA NAIDOO: You're very welcome, Brittany. And thank you to the ASCO oncology community for the opportunity to share this important work. BRITTANY HARVEY: And thank you to all of our listeners for tuning into 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

    Gastrointestinal Toxicities: Management of irAEs Guideline (Part 4)

    8:37

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

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