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Immunotherapy Toxicity Management in Bladder Cancer

Panelists: Daniel P. Petrylak, MD, Yale University Cancer Center; Dean F. Bajorin, MD, Memorial Sloan Kettering Cancer Center; Robert Dreicer, MD, MS, Virginia Cancer Center; Arjun V. Balar, MD, Laura and Isaac Perlmutter Cancer Center; Elizabeth R. Plimack, MD, MS, Fox Chase Cancer Center; David I. Quinn, MBBS, PhD, USC Norris Cancer Hospital
Published Online: Tuesday, Apr 18, 2017



Transcript:

Daniel P. Petrylak, MD:
Dean, maybe you can make a comment about management of toxicities with PD-1s or PD-L1s. What’s your experience?

Dean F. Bajorin, MD: I would say it has become common sense for us. If we take a look at the toxicities or the immune-related adverse events, they’re ranging from roughly around 5% to up to 10%, depending on the study. And the things that we see that are most concerning in terms of toxicity that we should really worry about, pneumonitis is, in my opinion, the one that I really worry about because patients can have subtle shortness of breath, etc, that may reflect pneumonitis, and it can happen quickly. So, I think a high index of suspicion should be there for all treating physicians. The second one that we typically worry about is the colitis. There might be a little diarrhea that might be a grade 1 or 2, but it also can be fulminant, and we need to be aware of that. And there are clear-cut paradigms for intervention in terms of grade of toxicity, whether you simply withdraw the drug and observe or whether you institute steroids, and I would highly recommend for treating physicians that they really become very familiar with those.

Then, there are the other subtle immune-related events that we may not pick up so quickly. For example, we see patients with fatigue, but a point of fact, hypothyroidism is reasonably common in these patients. We personally program in our thyroid function tests on a regular basis, that is included in a number of trials. And so, we highly recommend that. And then, occasionally, you’ll see patients with adrenal insufficiency and panhypopituitarism. Those kinds of things should also be, at least, in the area of heightened awareness with regard to immune-related events. There are others that we have seen. There has been a report of myositis, etc. These are very rare, actually, but I think that the majority of patients do well, and we get comfortable with that. But there are a small number of patients who can’t have these immune-related events. Our approach is that everyone gets a thorough education. Our nurses speak with our patients about what to call in about. Even though it may seem subtle to them, we really want to know about it. And so, I think for the treating oncologist, it’s a matter of training the staff to make sure they can pick up these nuances.

Arjun V. Balar, MD: I think there’s another key point here. In the era of chemotherapy, we had a sense of who was going to have a tough time with chemotherapy, who was going to do OK, and who was just going to fly through it. And that’s how we formulate some of the cisplatin-eligible or cisplatin-ineligible criteria. The challenge with immunotherapy is we can’t predict reliably who is going to get immune-related toxicity or not. And, in fact, I’ve had patients in their young 80s who have tolerated immunotherapy exceptionally well, had very few adverse events, and then we have 50-year-olds who otherwise had great performance status and have had significant autoimmune toxicities. That’s one of the key messages here, that we can’t predict who is going to get some of these toxicities.

Daniel P. Petrylak, MD: Absolutely. I think the other thing, too, is we have to take a careful history in our patients to be sure they’ve had no other autoimmune disorders that may actually be worsened by some of these treatments. In fact, most of the trials have excluded these patients. We don’t know what the effect of checkpoint inhibitors is going to be in this situation. Truly, as Dean pointed out, the only irreversible side effect is the panhypopituitarism that we can see.

Arjun V. Balar, MD: And thyroidism.

Daniel P. Petrylak, MD: Thyroidism, right.

Elizabeth R. Plimack, MD, MS: Having worked with these in renal cell and many other diseases for a long time, patients sometimes die of these. It’s not that they’re not potentially reversible, it’s just they didn’t get there in time or their particular pneumonitis didn’t resolve. And I think it becomes especially more relevant as we move this to the adjuvant setting, for instance. Melanoma has a long experience with this, giving high doses of ipilimumab in the adjuvant setting. There are treatment-related deaths on those studies, we should anticipate that we’re going to see them, too, and we should let our patients know.

Daniel P. Petrylak, MD: Absolutely.

Dean F. Bajorin, MD: And that’s where education is really key. I can tell you our nurses spend a great deal of time on education. We’ll go over it in detail, but they go over it in exquisite detail. And I think the 2 things that we’ve learned is education and reeducation for our patients. Then, the other issue that we’re seeing is that you might be suspicious of hypothyroidism. And I have a case. For example, we’re suspicious of adrenal insufficiency. Of course, all was fine, but 6 weeks later, there was adrenal insufficiency. When you think about it, think about it yet again. Don’t put it on the shelf.

Arjun V. Balar, MD: And early recognition and aggressive management. That’s what has to be done.

Daniel P. Petrylak, MD: In fact, the other thing, too, we talk a lot about hypothyroidism. I’ve seen hyperthyroidism develop first, then the patients become hypothyroid. So, you have to be flexible. But it reflects the point that you have to listen to your patients carefully and also emphasize—you can become complacent in some respects—that this is not chemotherapy and relax a little bit. That’s when trouble happens, so you’ve got to be really careful.

Robert Dreicer, MD, MS: And ultimately, other challenges we all deal with is that we share our patients with primary care doctors. Our patients are seen in emergency rooms when they’re ill, and sometimes there’s yet a lack of full understanding of the appreciation of immune toxicity by the community of physicians who are engaged in the care of patients. So, that actually is also something that we need to be actively engaged in trying to bring up to a level, that wherever the patient is seen, there’s an appreciation this is not chemotherapy.

Elizabeth R. Plimack, MD, MS: I’ll just tell a quick anecdote about that. I had a patient on an immunotherapy trial who went to an excellent academic emergency room with diarrhea. And they looked up the drug he was on and it said it can cause diarrhea. They said, “It’s your drug, go home.” Because, that’s what you would do with chemotherapy: go home and call your oncologist. So, it’s one of those things. You need to act on that adverse event where you didn’t with chemotherapy. And that paradigm shift that you were talking about, how we think about things and have to think about them different, it’s going to take a while to relay it to all those ancillary services.

Daniel P. Petrylak, MD: Exactly. And I think that what we tell our patients is if they do go to the emergency room, call the doctor who’s on call from the oncology group. Make sure that there’s contact made. I think that’s a really, really crucial point.

Transcript Edited for Clarity

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Transcript:

Daniel P. Petrylak, MD:
Dean, maybe you can make a comment about management of toxicities with PD-1s or PD-L1s. What’s your experience?

Dean F. Bajorin, MD: I would say it has become common sense for us. If we take a look at the toxicities or the immune-related adverse events, they’re ranging from roughly around 5% to up to 10%, depending on the study. And the things that we see that are most concerning in terms of toxicity that we should really worry about, pneumonitis is, in my opinion, the one that I really worry about because patients can have subtle shortness of breath, etc, that may reflect pneumonitis, and it can happen quickly. So, I think a high index of suspicion should be there for all treating physicians. The second one that we typically worry about is the colitis. There might be a little diarrhea that might be a grade 1 or 2, but it also can be fulminant, and we need to be aware of that. And there are clear-cut paradigms for intervention in terms of grade of toxicity, whether you simply withdraw the drug and observe or whether you institute steroids, and I would highly recommend for treating physicians that they really become very familiar with those.

Then, there are the other subtle immune-related events that we may not pick up so quickly. For example, we see patients with fatigue, but a point of fact, hypothyroidism is reasonably common in these patients. We personally program in our thyroid function tests on a regular basis, that is included in a number of trials. And so, we highly recommend that. And then, occasionally, you’ll see patients with adrenal insufficiency and panhypopituitarism. Those kinds of things should also be, at least, in the area of heightened awareness with regard to immune-related events. There are others that we have seen. There has been a report of myositis, etc. These are very rare, actually, but I think that the majority of patients do well, and we get comfortable with that. But there are a small number of patients who can’t have these immune-related events. Our approach is that everyone gets a thorough education. Our nurses speak with our patients about what to call in about. Even though it may seem subtle to them, we really want to know about it. And so, I think for the treating oncologist, it’s a matter of training the staff to make sure they can pick up these nuances.

Arjun V. Balar, MD: I think there’s another key point here. In the era of chemotherapy, we had a sense of who was going to have a tough time with chemotherapy, who was going to do OK, and who was just going to fly through it. And that’s how we formulate some of the cisplatin-eligible or cisplatin-ineligible criteria. The challenge with immunotherapy is we can’t predict reliably who is going to get immune-related toxicity or not. And, in fact, I’ve had patients in their young 80s who have tolerated immunotherapy exceptionally well, had very few adverse events, and then we have 50-year-olds who otherwise had great performance status and have had significant autoimmune toxicities. That’s one of the key messages here, that we can’t predict who is going to get some of these toxicities.

Daniel P. Petrylak, MD: Absolutely. I think the other thing, too, is we have to take a careful history in our patients to be sure they’ve had no other autoimmune disorders that may actually be worsened by some of these treatments. In fact, most of the trials have excluded these patients. We don’t know what the effect of checkpoint inhibitors is going to be in this situation. Truly, as Dean pointed out, the only irreversible side effect is the panhypopituitarism that we can see.

Arjun V. Balar, MD: And thyroidism.

Daniel P. Petrylak, MD: Thyroidism, right.

Elizabeth R. Plimack, MD, MS: Having worked with these in renal cell and many other diseases for a long time, patients sometimes die of these. It’s not that they’re not potentially reversible, it’s just they didn’t get there in time or their particular pneumonitis didn’t resolve. And I think it becomes especially more relevant as we move this to the adjuvant setting, for instance. Melanoma has a long experience with this, giving high doses of ipilimumab in the adjuvant setting. There are treatment-related deaths on those studies, we should anticipate that we’re going to see them, too, and we should let our patients know.

Daniel P. Petrylak, MD: Absolutely.

Dean F. Bajorin, MD: And that’s where education is really key. I can tell you our nurses spend a great deal of time on education. We’ll go over it in detail, but they go over it in exquisite detail. And I think the 2 things that we’ve learned is education and reeducation for our patients. Then, the other issue that we’re seeing is that you might be suspicious of hypothyroidism. And I have a case. For example, we’re suspicious of adrenal insufficiency. Of course, all was fine, but 6 weeks later, there was adrenal insufficiency. When you think about it, think about it yet again. Don’t put it on the shelf.

Arjun V. Balar, MD: And early recognition and aggressive management. That’s what has to be done.

Daniel P. Petrylak, MD: In fact, the other thing, too, we talk a lot about hypothyroidism. I’ve seen hyperthyroidism develop first, then the patients become hypothyroid. So, you have to be flexible. But it reflects the point that you have to listen to your patients carefully and also emphasize—you can become complacent in some respects—that this is not chemotherapy and relax a little bit. That’s when trouble happens, so you’ve got to be really careful.

Robert Dreicer, MD, MS: And ultimately, other challenges we all deal with is that we share our patients with primary care doctors. Our patients are seen in emergency rooms when they’re ill, and sometimes there’s yet a lack of full understanding of the appreciation of immune toxicity by the community of physicians who are engaged in the care of patients. So, that actually is also something that we need to be actively engaged in trying to bring up to a level, that wherever the patient is seen, there’s an appreciation this is not chemotherapy.

Elizabeth R. Plimack, MD, MS: I’ll just tell a quick anecdote about that. I had a patient on an immunotherapy trial who went to an excellent academic emergency room with diarrhea. And they looked up the drug he was on and it said it can cause diarrhea. They said, “It’s your drug, go home.” Because, that’s what you would do with chemotherapy: go home and call your oncologist. So, it’s one of those things. You need to act on that adverse event where you didn’t with chemotherapy. And that paradigm shift that you were talking about, how we think about things and have to think about them different, it’s going to take a while to relay it to all those ancillary services.

Daniel P. Petrylak, MD: Exactly. And I think that what we tell our patients is if they do go to the emergency room, call the doctor who’s on call from the oncology group. Make sure that there’s contact made. I think that’s a really, really crucial point.

Transcript Edited for Clarity
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