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De-Escalation of Therapy for HPV-Positive HNSCC

Panelists:Ezra Cohen, MD, FRCPSC, FASCO, UC San Diego; Joshua M. Bauml, MD, University of Pennsylvania; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center; Barbara A. Burtness, MD, Yale University School of Medicine
Published: Tuesday, Aug 29, 2017



Transcript:

Joshua M. Bauml, MD: I think it’s really important to emphasize talking about de-escalation of HPV-associated head and neck cancers. It echoes the efforts that have been done in Hodgkin’s disease and others. But, in lymphoma, you generally have 2 shots on goal, so I think that it’s important to remember that here, we usually only have 1 shot to cure this. So, I think that the concept in the community would be that if we want a de-escalation approach, it’s essential that it’s done on a clinical trial. We should not be uniformly—I don’t believe—de-escalating patients with HPV-associated head and neck cancers simply because of their HPV-positive status, but I think that the de-escalation efforts on clinical trials are critical to advancing the field.

Jared Weiss, MD: This is so important and might be worth saying yet a third time, and really, really directly. Outside of a clinical trial, 70 gray is the standard radiation. One could argue that maybe high 60 is, but full dose radiation with bolus cisplatin or perhaps with cetuximab remains the standard of care for an HPV-positive patient outside of a clinical trial. We have yet to do the study that you reference, which is a phase III study of standard of care. We could argue what that is, but certainly bolus cisplatin and 70 gray might be a standard that is perhaps most endorsed in the United States versus a de-escalated attempt. Right now, all of these studies are uncontrolled phase IIs.

Barbara A. Burtness, MD: But I think it’s worth saying that the patients in the studies, that have been reported to date, have done well.

Jared Weiss, MD: Absolutely.

Barbara A. Burtness, MD: RTOG 1016 was a thousand-patient study doing a different de-escalation, putting cetuximab in place of cisplatin. It hasn’t been reported yet, but it certainly wasn’t stopped early because of bad results. My experience is that patients are often quite grateful to have the opportunity to go on a trial that offers them de-escalation, and I think as a physician, you can feel OK about making that recommendation because the results to date have been good.

Joshua M. Bauml, MD: I think that within the confines of a clinical trial, I’m in full agreement with that concept. I wonder, though, what you think about cetuximab as a true de-escalation, or a choose-your-poison situation. It’s different toxicities. I’m not sure if it’s less, but it’s different.

Barbara A. Burtness, MD: And that’s the reason that RTOG 1016, De-ESCALaTE, and the TROG study were so important to do. My impression is that the side effects are completely different. You get more mucositis; you get more rash. I practice in New England, so we don’t get a ton of high-grade allergic reactions.

Jared Weiss, MD: Although, we have the alpha-Gal assay now, which has 100% negative predictive value against the grade 3/4 reactions.

Barbara A. Burtness, MD: OK, but I think that we do not see loss of renal function. We don’t see a lot of loss of hearing function.

Jared Weiss, MD: The permanent stuff.

Barbara A. Burtness, MD: Right. And I have a soft impression that the in-field chronic toxicity is a little bit better. I don’t think that’s been documented yet. Hopefully, De-ESCALaTE and RTOG 1016 will give us some data about that. We do have 10-year data on the Bonner study, which had not suggested this increased non-cancer mortality that has been a concern with platinum. So, if the studies pan out, I do think it will offer some long-term toxicity advantages.

Ezra Cohen, MD: Barbara, now you’ve touched on it, what do you think the role of cetuximab is currently as we’re waiting for these trials to read out? What’s the role of cetuximab now in locally advanced head and neck cancer?

Barbara A. Burtness, MD: Cetuximab is a radiation sensitizer that will improve locoregional control and overall survival compared to radiation alone. The trial that established that did not actually allow you to only pick patients who weren’t platinum candidates. To get on that study, you had to have a reasonable renal function, and the benefit was not particularly greater in the elderly patients than in others. However, I think that a lot of us do turn to cetuximab when we have a patient who’s not a candidate for getting cisplatin or getting their carboplatin doublet during radiation, because it’s something that’s validated to be better than radiation alone.

There was a post hoc analysis of the Bonner trial that seemed to suggest the impact of adding cetuximab to radiation was greater in the HPV-associated cancers than in the HPV-negative cancers. RTOG 1016 fully accrued in HPV-positive. We used cetuximab in E1308 in HPV-positive patients. I think we still don’t completely understand why that difference might be, and it’s different than the impact of HPV with the tyrosine kinase inhibitors, as you know. Maybe it’s PTEN loss, PTEN mutation, and things that mirror the same causes of resistance to cetuximab that KRAS has in colon cancer, for example. So, I think that we remain a little bit uncertain until we see RTOG 1016. I think that in clinical trial design, one might actually consider dealer’s choice: radiation, and then the investigator can choose platinum or cetuximab for a given patient, given the state of the data. But it will be great to see the results of these big studies.

Transcript Edited for Clarity

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Transcript:

Joshua M. Bauml, MD: I think it’s really important to emphasize talking about de-escalation of HPV-associated head and neck cancers. It echoes the efforts that have been done in Hodgkin’s disease and others. But, in lymphoma, you generally have 2 shots on goal, so I think that it’s important to remember that here, we usually only have 1 shot to cure this. So, I think that the concept in the community would be that if we want a de-escalation approach, it’s essential that it’s done on a clinical trial. We should not be uniformly—I don’t believe—de-escalating patients with HPV-associated head and neck cancers simply because of their HPV-positive status, but I think that the de-escalation efforts on clinical trials are critical to advancing the field.

Jared Weiss, MD: This is so important and might be worth saying yet a third time, and really, really directly. Outside of a clinical trial, 70 gray is the standard radiation. One could argue that maybe high 60 is, but full dose radiation with bolus cisplatin or perhaps with cetuximab remains the standard of care for an HPV-positive patient outside of a clinical trial. We have yet to do the study that you reference, which is a phase III study of standard of care. We could argue what that is, but certainly bolus cisplatin and 70 gray might be a standard that is perhaps most endorsed in the United States versus a de-escalated attempt. Right now, all of these studies are uncontrolled phase IIs.

Barbara A. Burtness, MD: But I think it’s worth saying that the patients in the studies, that have been reported to date, have done well.

Jared Weiss, MD: Absolutely.

Barbara A. Burtness, MD: RTOG 1016 was a thousand-patient study doing a different de-escalation, putting cetuximab in place of cisplatin. It hasn’t been reported yet, but it certainly wasn’t stopped early because of bad results. My experience is that patients are often quite grateful to have the opportunity to go on a trial that offers them de-escalation, and I think as a physician, you can feel OK about making that recommendation because the results to date have been good.

Joshua M. Bauml, MD: I think that within the confines of a clinical trial, I’m in full agreement with that concept. I wonder, though, what you think about cetuximab as a true de-escalation, or a choose-your-poison situation. It’s different toxicities. I’m not sure if it’s less, but it’s different.

Barbara A. Burtness, MD: And that’s the reason that RTOG 1016, De-ESCALaTE, and the TROG study were so important to do. My impression is that the side effects are completely different. You get more mucositis; you get more rash. I practice in New England, so we don’t get a ton of high-grade allergic reactions.

Jared Weiss, MD: Although, we have the alpha-Gal assay now, which has 100% negative predictive value against the grade 3/4 reactions.

Barbara A. Burtness, MD: OK, but I think that we do not see loss of renal function. We don’t see a lot of loss of hearing function.

Jared Weiss, MD: The permanent stuff.

Barbara A. Burtness, MD: Right. And I have a soft impression that the in-field chronic toxicity is a little bit better. I don’t think that’s been documented yet. Hopefully, De-ESCALaTE and RTOG 1016 will give us some data about that. We do have 10-year data on the Bonner study, which had not suggested this increased non-cancer mortality that has been a concern with platinum. So, if the studies pan out, I do think it will offer some long-term toxicity advantages.

Ezra Cohen, MD: Barbara, now you’ve touched on it, what do you think the role of cetuximab is currently as we’re waiting for these trials to read out? What’s the role of cetuximab now in locally advanced head and neck cancer?

Barbara A. Burtness, MD: Cetuximab is a radiation sensitizer that will improve locoregional control and overall survival compared to radiation alone. The trial that established that did not actually allow you to only pick patients who weren’t platinum candidates. To get on that study, you had to have a reasonable renal function, and the benefit was not particularly greater in the elderly patients than in others. However, I think that a lot of us do turn to cetuximab when we have a patient who’s not a candidate for getting cisplatin or getting their carboplatin doublet during radiation, because it’s something that’s validated to be better than radiation alone.

There was a post hoc analysis of the Bonner trial that seemed to suggest the impact of adding cetuximab to radiation was greater in the HPV-associated cancers than in the HPV-negative cancers. RTOG 1016 fully accrued in HPV-positive. We used cetuximab in E1308 in HPV-positive patients. I think we still don’t completely understand why that difference might be, and it’s different than the impact of HPV with the tyrosine kinase inhibitors, as you know. Maybe it’s PTEN loss, PTEN mutation, and things that mirror the same causes of resistance to cetuximab that KRAS has in colon cancer, for example. So, I think that we remain a little bit uncertain until we see RTOG 1016. I think that in clinical trial design, one might actually consider dealer’s choice: radiation, and then the investigator can choose platinum or cetuximab for a given patient, given the state of the data. But it will be great to see the results of these big studies.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations Across Lung, Head and Neck, and Bladder CancersApr 28, 20182.0
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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