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Role of Surgery in the Management of Advanced Melanoma

Panelists:Keith T. Flaherty, MD, Massachusetts General Hospital; Rene Gonzalez, MD, University of Colorado Melanoma Research Clinics; Jason J. Luke, MD, FACP, University of Chicago Medicine; Jeffrey S. Weber, MD, PhD, NYU Langone Medical Center
Published: Monday, Jan 18, 2016


Transcript:

Keith Flaherty, MD:
Brain metastases have always been kind of the bane of our existence in this disease. Let’s step back from the hope for abscopal effects being really commonplace. If you have a patient in front of you, and let’s say they are BRAF wild-type, what are your rules of thumb in terms of the role of surgery?

Who needs surgery as an upfront approach before initiating therapy versus who would you think about initiating systemic therapy and radiating, perhaps stereotactic? Who are the patients you’d actually feel comfortable waiting? Again, this is the BRAF wild-type population where immune therapy is going to be front and center of your option.

Jason Luke, MD, FACP: Well, this is an area where we might get some robust discussion. In my practice, I would say if the patient has a symptomatic lesion, then I would send them to the OR to try to have that lesion removed. Outside of that, we try to be as aggressive as possible with stereotactic approaches to individual lesions, assuming that it’s a number that we can actually do, not 10 or something.

But if it’s three, or something along those lines, we definitely try to get those. Now, the question about should you do that first and then wait? I think that’s less clear to me. I think that a little bit is dictated by what else is going on. If the patient, otherwise, has disease all over their body that’s all growing fast, sometimes I feel like we’ve just got to get going. If there’s time and there’s less disease, then I sometimes will do that first to try to make sure that we’re going one step at a time.

It doesn’t happen uncommonly with patients who are getting radiation, that they need steroids for some period of time. That can interrupt your ability to give immunotherapy if the idea is to give concomitant immunotherapy. But, again, it goes to the clinical situation. If we have to just get going, then we just get going. But if we can, we separate it out a little bit.

And then the question becomes, in these patients, what is the best agent? Because we don’t have a lot of great data for pembrolizumab or nivolumab in brain metastases. We do have data for ipilimumab, suggesting that it works slightly less well than in the body. I am sometimes slowed down by that to say which one is actually best for this patient. Systemically, I would give PD-1 as frontline therapy, but in a patient with brain-only disease, and then you radiate it, what do you want to do then? That involves a lot more nuances, and I think we’re not going to know that for a couple of years.

Keith Flaherty, MD: As you are alluding to, we do have at least some phase II data with ipilimumab showing that there is a tail of the curve there for patients who started with asymptomatic non-steroid requiring brain metastases. So at least there is some evidence, and we need that data for the PD-1 antibodies, and ideally, a little bit of follow-up time to get a sense that we can get the same kind of profile of treatment effect.

But I agree, we’re not there yet. There has been some consideration of the idea of using surgery—leave aside the brain metastases population—as a consolidation approach, for patients who have excellent responses, maybe sustained remission, but are now resectable.

Rene, we don’t have any clinical trial evidence to guide decisions, but I’m interested in your thoughts about the role of surgery there. I want to tuck in that the patient has had both immunotherapy and targeted BRAF therapy. You have a patient who has had a nice durable remission, 20 sites of disease, but is now progressing at a single site. So, there’s something going on there in terms of concern of loss of control but maybe just at a single site.

How enthusiastic do you feel about the idea of surgery as a way of clearing that lesion and maybe getting on a path towards continued response elsewhere?

Rene Gonzalez, MD: I think it’s a good idea, and it’s been used in other tumors where effective therapies have been out there. To bring up an old idea, when we didn’t have effective therapy, we did that with biochemotherapy to basically get a maximum response, and then resect the residual disease. There are ongoing studies right now looking at both neoadjuvant immunotherapy and targeted agents in patients with big, bulky disease that the surgeons can go in, but they’re probably going to leave tumor behind. And it’s ultimately the systemic thing that’s going to be a problem. So, I think it’s good, and you find a number of complete pathologic responses, which may correlate with outcome. We don’t know that, but there are ongoing trials, and I think it’s an exciting new field.

Keith Flaherty, MD: You look at the data as it emerges, pretty clearly with the targeted therapies, it’s hard to know yet with the immune checkpoints, still, whether a complete response from drug therapy alone is the most powerful predictor of long-term benefit. But it raises the question of whether converting a partial response to a complete response with a scalpel is really functionally the same or not. If the patient didn’t have such a robust response, does that worry you about microscopic disease elsewhere?

These are topics we’ll maybe want to revisit when we think about the systemic therapies, which is where I think we should turn.
                                                                                                                                                                                                                                                                                                      
Transcript Edited for Clarity
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Transcript:

Keith Flaherty, MD:
Brain metastases have always been kind of the bane of our existence in this disease. Let’s step back from the hope for abscopal effects being really commonplace. If you have a patient in front of you, and let’s say they are BRAF wild-type, what are your rules of thumb in terms of the role of surgery?

Who needs surgery as an upfront approach before initiating therapy versus who would you think about initiating systemic therapy and radiating, perhaps stereotactic? Who are the patients you’d actually feel comfortable waiting? Again, this is the BRAF wild-type population where immune therapy is going to be front and center of your option.

Jason Luke, MD, FACP: Well, this is an area where we might get some robust discussion. In my practice, I would say if the patient has a symptomatic lesion, then I would send them to the OR to try to have that lesion removed. Outside of that, we try to be as aggressive as possible with stereotactic approaches to individual lesions, assuming that it’s a number that we can actually do, not 10 or something.

But if it’s three, or something along those lines, we definitely try to get those. Now, the question about should you do that first and then wait? I think that’s less clear to me. I think that a little bit is dictated by what else is going on. If the patient, otherwise, has disease all over their body that’s all growing fast, sometimes I feel like we’ve just got to get going. If there’s time and there’s less disease, then I sometimes will do that first to try to make sure that we’re going one step at a time.

It doesn’t happen uncommonly with patients who are getting radiation, that they need steroids for some period of time. That can interrupt your ability to give immunotherapy if the idea is to give concomitant immunotherapy. But, again, it goes to the clinical situation. If we have to just get going, then we just get going. But if we can, we separate it out a little bit.

And then the question becomes, in these patients, what is the best agent? Because we don’t have a lot of great data for pembrolizumab or nivolumab in brain metastases. We do have data for ipilimumab, suggesting that it works slightly less well than in the body. I am sometimes slowed down by that to say which one is actually best for this patient. Systemically, I would give PD-1 as frontline therapy, but in a patient with brain-only disease, and then you radiate it, what do you want to do then? That involves a lot more nuances, and I think we’re not going to know that for a couple of years.

Keith Flaherty, MD: As you are alluding to, we do have at least some phase II data with ipilimumab showing that there is a tail of the curve there for patients who started with asymptomatic non-steroid requiring brain metastases. So at least there is some evidence, and we need that data for the PD-1 antibodies, and ideally, a little bit of follow-up time to get a sense that we can get the same kind of profile of treatment effect.

But I agree, we’re not there yet. There has been some consideration of the idea of using surgery—leave aside the brain metastases population—as a consolidation approach, for patients who have excellent responses, maybe sustained remission, but are now resectable.

Rene, we don’t have any clinical trial evidence to guide decisions, but I’m interested in your thoughts about the role of surgery there. I want to tuck in that the patient has had both immunotherapy and targeted BRAF therapy. You have a patient who has had a nice durable remission, 20 sites of disease, but is now progressing at a single site. So, there’s something going on there in terms of concern of loss of control but maybe just at a single site.

How enthusiastic do you feel about the idea of surgery as a way of clearing that lesion and maybe getting on a path towards continued response elsewhere?

Rene Gonzalez, MD: I think it’s a good idea, and it’s been used in other tumors where effective therapies have been out there. To bring up an old idea, when we didn’t have effective therapy, we did that with biochemotherapy to basically get a maximum response, and then resect the residual disease. There are ongoing studies right now looking at both neoadjuvant immunotherapy and targeted agents in patients with big, bulky disease that the surgeons can go in, but they’re probably going to leave tumor behind. And it’s ultimately the systemic thing that’s going to be a problem. So, I think it’s good, and you find a number of complete pathologic responses, which may correlate with outcome. We don’t know that, but there are ongoing trials, and I think it’s an exciting new field.

Keith Flaherty, MD: You look at the data as it emerges, pretty clearly with the targeted therapies, it’s hard to know yet with the immune checkpoints, still, whether a complete response from drug therapy alone is the most powerful predictor of long-term benefit. But it raises the question of whether converting a partial response to a complete response with a scalpel is really functionally the same or not. If the patient didn’t have such a robust response, does that worry you about microscopic disease elsewhere?

These are topics we’ll maybe want to revisit when we think about the systemic therapies, which is where I think we should turn.
                                                                                                                                                                                                                                                                                                      
Transcript Edited for Clarity
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TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
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