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Debates Surrounding Induction Chemotherapy in HNSCC

Panelists: Ezra Cohen, MD, UC San Diego Moores Cancer Center; Viktor Grünwald, MD, Medical School Hannover; Kevin Harrington, MD, PhD, The Royal Marsden NHS Foundation; Tanguy Y. Seiwert, MD, The University of Chicago Medical Center
Published: Friday, Dec 30, 2016


Transcript:

Ezra Cohen, MD:
The other potential place for chemotherapy is as neoadjuvant or induction. Tanguy, what do you think about that and how do you approach the use of induction chemotherapy?

Tanguy Y. Seiwert, MD: Well, I think with induction, there has been a fair amount of interest in this, and I think the rationale actually sounds quite good. The problem—as we’ve gotten much better locoregional control—is that, increasingly, we are starting to see patients who have distant failure, and that’s what we’re most afraid of because that’s when patients become incurable. So, the idea was why not give systemically active doses of chemotherapy after chemoradiation? That’s quite difficult, but we could do it before and that’s what we call neoadjuvant or induction. However, we have 3 phase III studies about this, and it remains controversial.

In fact, Ezra, you led one of the really important deciding phase III studies called the DeCIDE trial. There was PARADIGM, and then there was an Italian study. And at least the first 2 studies were negative. However, I would argue that the studies were negative in part because they were underpowered, they were too small, and they had large fractions of HPV-positive patients who have better outcomes. At least in a subgroup analysis of the DeCIDE study, it seems like patients who were at the highest risk of failing distally saw N3 disease, N2C disease, and HPV-negative disease arguably. Those actually seemed to have a decrease of distant metastatic failure. So, the short answer is, I think it is one option for patients who are at high risk of distant metastatic failure. But, it remains controversial.

The other controversy then is, what type of induction do you use? In those studies, TPF was used—docetaxel, cisplatin, and 5-FU—which is a relatively aggressive regimen. And, again, the debate is, do you have to use TPF? And the danger is that patients have so many side effects that they might not go on to the curative setting and then therapy. So, we use some induction for high-risk patients, and we oftentimes use carboplatin/Taxol. There’s actually little evidence other than the SIRO phase II studies. I think it’s something that the controversy will continue. And there are different practice patterns. The Italian study, interestingly, was positive for induction, although we haven’t seen the final, final data. And, again, I think the controversy remains.

Ezra Cohen, MD: So, for the most advanced patients, I’m hearing you say use TPF or a carboplatin/paclitaxel regimen for those that are non-TPF eligible.

Tanguy Y. Seiwert, MD: Yes, I think that’s very true. I think there’s clearly an interest in taxanes. In fact, we’ve seen studies that compared platinum 5-FU versus the same plus a taxane. And there was a clear benefit to adding a taxane. So, I think there’s something about taxanes, although we don’t exactly know how to best do it.

The other setting where I believe induction may play a role is actually the exact opposite: patients who have a really good prognosis with HPV-positive tumors. We don’t know this for sure, but one de-escalation strategy may be to use induction chemotherapy and identify those patients that actually have more febrile tumors.

Again, this is something that is done as part of clinical trials. And patients who have a really good response, as was done on the ECOG 1308 study, may actually get away with substantially less radiation. And so, it’s a de-escalation strategy, thinking that maybe the radiation is actually the most toxic long-term problem and maybe we can reduce it. Again, I think we have to wait for the final data, and it should be done as a trial.

Ezra Cohen, MD: Using response to induction almost as a biomarker to decide to stratify patients.

Tanguy Y. Seiwert, MD: There’s actually a biologic dynamic biomarker. Exactly.

Ezra Cohen, MD: We talked, Viktor, a lot now about cytotoxic chemotherapy, but, of course—and you mentioned this earlier—there is another option with respect to concurrent treatment, and that’s EGFR inhibition. How do you use EGFR inhibitors, how do you use cetuximab, and what goes into the equation there?

Viktor Grünwald, MD: When we speak about localized disease, the question would be, would you use radioimmunotherapy given the antibody cetuximab or would you do a radiochemotherapy approach? And as Kevin said, you barely do radioimmunotherapy and so do we. Whenever it’s possible, we do radiochemotherapy because we think that’s the best way to treat our patients. And I think there’s enough evidence to suggest that assumption actually. So, we really rarely do EGFR inhibition in the context of radiotherapy when it’s definite for the treatment. For localized disease, I think it has a diminishing role, and the only context I could envision is that if you consider a patient ineligible for cisplatin and doing radiochemotherapy, there might be a role for adding in cetuximab instead. But, again, we touched on this before. And as Kevin said, we’d be more eager to change our chemotherapy partner than we would switch to an EGFR inhibitor, actually. So, we would do the same thing. We would go for either carboplatin or we’d go to a weekly dose of cisplatin. Because then we can deliver that in a more safe way.

Transcript Edited for Clarity
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Transcript:

Ezra Cohen, MD:
The other potential place for chemotherapy is as neoadjuvant or induction. Tanguy, what do you think about that and how do you approach the use of induction chemotherapy?

Tanguy Y. Seiwert, MD: Well, I think with induction, there has been a fair amount of interest in this, and I think the rationale actually sounds quite good. The problem—as we’ve gotten much better locoregional control—is that, increasingly, we are starting to see patients who have distant failure, and that’s what we’re most afraid of because that’s when patients become incurable. So, the idea was why not give systemically active doses of chemotherapy after chemoradiation? That’s quite difficult, but we could do it before and that’s what we call neoadjuvant or induction. However, we have 3 phase III studies about this, and it remains controversial.

In fact, Ezra, you led one of the really important deciding phase III studies called the DeCIDE trial. There was PARADIGM, and then there was an Italian study. And at least the first 2 studies were negative. However, I would argue that the studies were negative in part because they were underpowered, they were too small, and they had large fractions of HPV-positive patients who have better outcomes. At least in a subgroup analysis of the DeCIDE study, it seems like patients who were at the highest risk of failing distally saw N3 disease, N2C disease, and HPV-negative disease arguably. Those actually seemed to have a decrease of distant metastatic failure. So, the short answer is, I think it is one option for patients who are at high risk of distant metastatic failure. But, it remains controversial.

The other controversy then is, what type of induction do you use? In those studies, TPF was used—docetaxel, cisplatin, and 5-FU—which is a relatively aggressive regimen. And, again, the debate is, do you have to use TPF? And the danger is that patients have so many side effects that they might not go on to the curative setting and then therapy. So, we use some induction for high-risk patients, and we oftentimes use carboplatin/Taxol. There’s actually little evidence other than the SIRO phase II studies. I think it’s something that the controversy will continue. And there are different practice patterns. The Italian study, interestingly, was positive for induction, although we haven’t seen the final, final data. And, again, I think the controversy remains.

Ezra Cohen, MD: So, for the most advanced patients, I’m hearing you say use TPF or a carboplatin/paclitaxel regimen for those that are non-TPF eligible.

Tanguy Y. Seiwert, MD: Yes, I think that’s very true. I think there’s clearly an interest in taxanes. In fact, we’ve seen studies that compared platinum 5-FU versus the same plus a taxane. And there was a clear benefit to adding a taxane. So, I think there’s something about taxanes, although we don’t exactly know how to best do it.

The other setting where I believe induction may play a role is actually the exact opposite: patients who have a really good prognosis with HPV-positive tumors. We don’t know this for sure, but one de-escalation strategy may be to use induction chemotherapy and identify those patients that actually have more febrile tumors.

Again, this is something that is done as part of clinical trials. And patients who have a really good response, as was done on the ECOG 1308 study, may actually get away with substantially less radiation. And so, it’s a de-escalation strategy, thinking that maybe the radiation is actually the most toxic long-term problem and maybe we can reduce it. Again, I think we have to wait for the final data, and it should be done as a trial.

Ezra Cohen, MD: Using response to induction almost as a biomarker to decide to stratify patients.

Tanguy Y. Seiwert, MD: There’s actually a biologic dynamic biomarker. Exactly.

Ezra Cohen, MD: We talked, Viktor, a lot now about cytotoxic chemotherapy, but, of course—and you mentioned this earlier—there is another option with respect to concurrent treatment, and that’s EGFR inhibition. How do you use EGFR inhibitors, how do you use cetuximab, and what goes into the equation there?

Viktor Grünwald, MD: When we speak about localized disease, the question would be, would you use radioimmunotherapy given the antibody cetuximab or would you do a radiochemotherapy approach? And as Kevin said, you barely do radioimmunotherapy and so do we. Whenever it’s possible, we do radiochemotherapy because we think that’s the best way to treat our patients. And I think there’s enough evidence to suggest that assumption actually. So, we really rarely do EGFR inhibition in the context of radiotherapy when it’s definite for the treatment. For localized disease, I think it has a diminishing role, and the only context I could envision is that if you consider a patient ineligible for cisplatin and doing radiochemotherapy, there might be a role for adding in cetuximab instead. But, again, we touched on this before. And as Kevin said, we’d be more eager to change our chemotherapy partner than we would switch to an EGFR inhibitor, actually. So, we would do the same thing. We would go for either carboplatin or we’d go to a weekly dose of cisplatin. Because then we can deliver that in a more safe way.

Transcript Edited for Clarity
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