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Alternative Adjuvant Approaches in Stage III Melanoma

Panelists: Robert H.I. Andtbacka, MD, CM, Huntsman Cancer Institute; Michael A. Davies, MD, PhD, MD Anderson Cancer Center; Antoni Ribas, MD, PhD, University of California Los Angeles; Georgina Long, MD, Melanoma Institute of Australia; Michael Postow, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Jan 30, 2017


Transcript:

Robert H.I. Andtbacka, MD, CM:
Tony, this patient also, now with the recurrence with the macroscopic disease, is a stage IIIc equivalent patient—not a stage IIIc, but stage IIIc equivalent. You’re also head of the melanoma group in SWOG, and we had the SWOG 0008 study. Do you want to comment a little bit on that, what that study showed in terms of this adjuvant setting?

Antoni Ribas, MD, PhD: SWOG 0008 was a study that was planned and conducted 15 years ago, and, at that time, it predated the majority of the active therapies that we have now. At that time, a combination of chemotherapy and cytokines—interleukin-2/interferon—called biochemotherapy was being used in metastatic disease with evidence of responses that seem to be beyond what chemotherapy or cytokine therapy would do by itself, but also with little evidence that led to long-lasting responses. That was tested in the adjuvant setting, and this study compared biochemotherapy with high-dose interferon. The readout is that for relapse-free survival, it was superior for biochemotherapy, but for overall survival, it was completely the same. If it was anything else, we’d have changed our standard of care, but it’s biochemotherapy. That needs to be put in the context of randomized trials in metastatic disease comparing biochemotherapy with chemotherapy alone or cytokine therapy alone. There were a number of those trials, none of which demonstrated improvement in overall survival. So, I think our interpretation, and the interpretation of the majority of practicing oncologists who see melanoma, is that the benefit of biochemotherapy with probably the higher initial benefit is not long lasting, and that may not be beneficial to patients.

Robert H.I. Andtbacka, MD, CM: Okay. So, at the moment then, I understand you would not use biochemotherapy for this patient.

Antoni Ribas, MD, PhD: Right.

Robert H.I. Andtbacka, MD, CM: Mike, for MD Anderson, you used a lot of biochemotherapy at MD Anderson. Would you use this in an adjuvant setting for this patient?

Michael A. Davies, MD, PhD: No. I think, again, the randomized trial showed that although there was a very notable difference in relapse-free survival, the fact that that didn’t translate into a difference in overall survival, to me, is actually somewhat concerning. The question is, how would that have not actually converted into a benefit in overall survival? I would note though that it is actually, to this point, the only adjuvant therapy that’s been shown to be superior to interferon. And, again, with the ipilimumab trial, we have to remember it was high-dose ipilimumab versus high-dose placebo, which was the standard of care in Europe. So, it will be interesting, in the ECOG trial, having that interferon arm there as a control. Now, I think at this point, with the data really showing no impact at all on overall survival, we would not recommend biochemotherapy. I think in the broader sense, the care and the treatment option for patients with stage IV melanoma has been absolutely revolutionized over the last 5 to 6 years. This is really the time where our emphasis is enrolling patients in clinical trials for these adjuvant therapies to see if we can similarly transform adjuvant therapy for earlier stages of disease.

Robert H.I. Andtbacka, MD, CM: So, with that then, is there any role right now outside of a clinical trial to give this patient anti-PD-1 therapy?

Michael A. Davies, MD, PhD: No. And, actually, the one question in the management of a patient like this would be on the role of adjuvant radiation therapy. I don’t know. At your center, would you recommend radiation therapy for this patient?

Robert H.I. Andtbacka, MD, CM: Yes. Actually, if we look at the patient, this patient would fall into a study that was done with radiation called the TROG study, which was done in New Zealand and Australia, but it also had a few sites outside of there. And this patient had recurrence of their melanoma and would have met the criteria for this. Now, what the TROG study showed is that radiation done to the regional lymph node basin decreased the risk of recurrence in that basin, but had no impact on overall survival, which we would expect with radiation. I’m not surprised by that. We also know that the area of radiation makes a big difference in terms of toxicity. So, at our institution, patients with head and neck melanoma were more likely to have a discussion with radiation, and potentially consider it; the same thing with the axilla. With the groin, on the other hand, our experience is that the risk of having infections, having a lymphedema, and having adverse side effects, most of the time, outweigh the potential benefit. We have really decreased the amount of radiation that we do for the groin. Additionally, I also think it’s important to recognize, as we’ve said, that if these patients were to recur, the current therapies that we have for metastatic and recurrent melanoma is vastly different than it was previously. So, we really have gone away from radiating the groin for that reason.

Michael A. Davies, MD, PhD: If the pathology report from surgery, and, again, whether it was here in the axilla, showed evidence of extranodal extension, would that change your recommendation at all?

Robert H.I. Andtbacka, MD, CM: Yes. So, there is an indication. The number of lymph nodes and extranodal extension then would increase the risk of the recurrence. And it traditionally may have changed in our decision of radiation. Even with extranodal extension in the groin, we would still be very reluctant to radiate this. In the axilla and the neck, as I said, we would definitely consider it and we would discuss it. But, in the groin, I think our experience has been that it can be a very difficult area because of the side effects.

Transcript Edited for Clarity
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Transcript:

Robert H.I. Andtbacka, MD, CM:
Tony, this patient also, now with the recurrence with the macroscopic disease, is a stage IIIc equivalent patient—not a stage IIIc, but stage IIIc equivalent. You’re also head of the melanoma group in SWOG, and we had the SWOG 0008 study. Do you want to comment a little bit on that, what that study showed in terms of this adjuvant setting?

Antoni Ribas, MD, PhD: SWOG 0008 was a study that was planned and conducted 15 years ago, and, at that time, it predated the majority of the active therapies that we have now. At that time, a combination of chemotherapy and cytokines—interleukin-2/interferon—called biochemotherapy was being used in metastatic disease with evidence of responses that seem to be beyond what chemotherapy or cytokine therapy would do by itself, but also with little evidence that led to long-lasting responses. That was tested in the adjuvant setting, and this study compared biochemotherapy with high-dose interferon. The readout is that for relapse-free survival, it was superior for biochemotherapy, but for overall survival, it was completely the same. If it was anything else, we’d have changed our standard of care, but it’s biochemotherapy. That needs to be put in the context of randomized trials in metastatic disease comparing biochemotherapy with chemotherapy alone or cytokine therapy alone. There were a number of those trials, none of which demonstrated improvement in overall survival. So, I think our interpretation, and the interpretation of the majority of practicing oncologists who see melanoma, is that the benefit of biochemotherapy with probably the higher initial benefit is not long lasting, and that may not be beneficial to patients.

Robert H.I. Andtbacka, MD, CM: Okay. So, at the moment then, I understand you would not use biochemotherapy for this patient.

Antoni Ribas, MD, PhD: Right.

Robert H.I. Andtbacka, MD, CM: Mike, for MD Anderson, you used a lot of biochemotherapy at MD Anderson. Would you use this in an adjuvant setting for this patient?

Michael A. Davies, MD, PhD: No. I think, again, the randomized trial showed that although there was a very notable difference in relapse-free survival, the fact that that didn’t translate into a difference in overall survival, to me, is actually somewhat concerning. The question is, how would that have not actually converted into a benefit in overall survival? I would note though that it is actually, to this point, the only adjuvant therapy that’s been shown to be superior to interferon. And, again, with the ipilimumab trial, we have to remember it was high-dose ipilimumab versus high-dose placebo, which was the standard of care in Europe. So, it will be interesting, in the ECOG trial, having that interferon arm there as a control. Now, I think at this point, with the data really showing no impact at all on overall survival, we would not recommend biochemotherapy. I think in the broader sense, the care and the treatment option for patients with stage IV melanoma has been absolutely revolutionized over the last 5 to 6 years. This is really the time where our emphasis is enrolling patients in clinical trials for these adjuvant therapies to see if we can similarly transform adjuvant therapy for earlier stages of disease.

Robert H.I. Andtbacka, MD, CM: So, with that then, is there any role right now outside of a clinical trial to give this patient anti-PD-1 therapy?

Michael A. Davies, MD, PhD: No. And, actually, the one question in the management of a patient like this would be on the role of adjuvant radiation therapy. I don’t know. At your center, would you recommend radiation therapy for this patient?

Robert H.I. Andtbacka, MD, CM: Yes. Actually, if we look at the patient, this patient would fall into a study that was done with radiation called the TROG study, which was done in New Zealand and Australia, but it also had a few sites outside of there. And this patient had recurrence of their melanoma and would have met the criteria for this. Now, what the TROG study showed is that radiation done to the regional lymph node basin decreased the risk of recurrence in that basin, but had no impact on overall survival, which we would expect with radiation. I’m not surprised by that. We also know that the area of radiation makes a big difference in terms of toxicity. So, at our institution, patients with head and neck melanoma were more likely to have a discussion with radiation, and potentially consider it; the same thing with the axilla. With the groin, on the other hand, our experience is that the risk of having infections, having a lymphedema, and having adverse side effects, most of the time, outweigh the potential benefit. We have really decreased the amount of radiation that we do for the groin. Additionally, I also think it’s important to recognize, as we’ve said, that if these patients were to recur, the current therapies that we have for metastatic and recurrent melanoma is vastly different than it was previously. So, we really have gone away from radiating the groin for that reason.

Michael A. Davies, MD, PhD: If the pathology report from surgery, and, again, whether it was here in the axilla, showed evidence of extranodal extension, would that change your recommendation at all?

Robert H.I. Andtbacka, MD, CM: Yes. So, there is an indication. The number of lymph nodes and extranodal extension then would increase the risk of the recurrence. And it traditionally may have changed in our decision of radiation. Even with extranodal extension in the groin, we would still be very reluctant to radiate this. In the axilla and the neck, as I said, we would definitely consider it and we would discuss it. But, in the groin, I think our experience has been that it can be a very difficult area because of the side effects.

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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