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When to Use Cetuximab or Chemotherapy in HNSCC

Insights From: Ezra Cohen, MD, UC San Diego Moores Cancer Center; Robert L. Ferris, MD, PhD, FACS, University of Pittsburgh Cancer Institute; Jared Weiss, MD, University of North Carolina School of Medicine
Published: Monday, Jun 20, 2016


Transcript:

Ezra Cohen, MD:
In terms of deciding what to use for patients—whether it should be cetuximab or cytotoxic chemotherapy—unfortunately, we don’t have a biomarker to go on in squamous cell carcinoma of the head and neck, as opposed to, for instance, colorectal cancer—where clearly, if there’s a KRAS mutation, one should not administer cetuximab to that patient because there will be no benefit. RAS mutations do occur in patients with head and neck cancer, but very infrequently. And KRAS mutations almost never occur; it’s usually the HRAS mutation.

For head and neck cancer, unfortunately, we don’t have a biomarker yet. We have some hints at biomarkers, but nothing definitive. So, what we do is we depend on clinical parameters to decide. In the locally advanced setting, it’s usually patients who are not good candidates for a platinum-based therapy, patients who have borderline renal failure, patients who may have borderline hearing function or some of the other toxicities that we worry about when we administer cisplatin. And those are patients that we would often treat with cetuximab. In the recurrent metastatic setting, cetuximab becomes either part of the first-line chemotherapy, because of the EXTREME trial, or often a preferred second-line agent because it really does tend to be very well tolerated as a single agent with quite manageable toxicities. But, in terms of deciding which patients to use it on, it really comes down to clinical parameters for the most part.

In terms of HPV status and response to cetuximab, I would say that this still a controversial issue, and there is evidence on both sides suggesting that it doesn’t matter, and there’s evidence suggesting that it does matter. Let’s look at the data as best we can. In the locally advanced setting, the best data set we have is from the so-called Bonner study, or the study that added cetuximab to radiation therapy. And in an analysis that was recently done, looking at HPV status, it looked like HPV-positive and HPV-negative patients had the same degree of benefit with the addition of cetuximab. HPV-positive patients did better, no surprise there. We know they’re a better prognostic group, but when we look at the degree of benefit—the separation in the curves, if you will—that separation appeared to be the same. So, in the locally advanced setting with about 8 weeks of cetuximab delivered with radiation, it doesn’t seem to make a difference with the best data set that we have.

In the recurrent and metastatic setting, that’s where it begins to get a little bit trickier. There are some studies that have suggested that for HPV-positive patients, cetuximab does not work so well. And if we look at the biology of HPV-positive disease, we begin to see that, for the most part, it’s not an EGFR-driven tumor. We don’t see EGFR gene copy number increases or EGFR amplification. We see other types of alterations that appear to be tumor drivers that are not affected by inhibition of EGFR, that are not affected by cetuximab. And that’s led some people to think that in the HPV-positive patients, cetuximab may be less effective.

The problem is that we don’t really have great data. We don’t have prospective data that has taken patients with HPV-positive cancers and randomized them to cetuximab versus something else. The best data set that we do have employs a drug called afatinib, which is a small molecular inhibitor of EGFR and its family of receptors, not a monoclonal antibody. And, for afatinib, it does appear that HPV-positive patients do not benefit as much as their HPV-negative counterparts. But if we could extend that to a drug like cetuximab, we’re not sure.

The differences in quality of life and toxicities between cetuximab and cytotoxic chemotherapy are really quite apparent. We know that cetuximab has associated toxicities, of course. Most typically that’s a rash and the so-called acneiform rash. It can have hypomagnesaemia and other changes to the integumentary system. But, for the most part, these toxicities are manageable. Now that we’ve recognized them, we’ve learned to deal with them, we’ve learned to, in fact, in some cases, prevent them from getting worse. I would say it’s unusual in our practice to have a patient actually come off cetuximab purely for toxicity. It still happens once in a while, but it’s quite unusual. For the most part, cetuximab is actually a pretty well-tolerated agent.

Now, the same is true for cytotoxic chemotherapy, but those side effects can be sometimes a little bit harder to manage. Cisplatin has associated nephropathy, for instance, that can be hard to manage. Electrolyte abnormalities, especially in the locally advanced setting, can be difficult because these patients often don’t drink very well because of the mucositis, they don’t eat very well because of the mucositis. And those toxicities can get patients in trouble and, in fact, even can lead to hospitalization or more serious than that. Cytotoxic chemotherapy can be myelosuppressive, so neutropenia, thrombocytopenia, and anemia. Of course, we’ve known about it for decade, but it still poses a problem in patients we’re treating for either locally advanced or recurrent metastatic disease.

I would say, in general, cetuximab tends to be better tolerated than cytotoxic chemotherapy, and the toxicities are manageable. There is one toxicity, though, that we do need to be aware of with cetuximab in the locally advanced setting, and that’s radiation dermatitis. A few studies, more recently, have demonstrated pretty consistently that the addition of cetuximab to radiation does increase radiation dermatitis. Again, this is something that’s manageable, it’s preventable, but we have to know about it in order to do that, and awareness is the most important thing.

Jared Weiss, MD: We don’t have an absolute standard of care of defined surveillance regimens. The most important point to be made is that it is important to do surveillance after treatment. In terms of immediately after treatment, I think the first most important lesson is not to do a PET too soon if you’re going to do a PET. In our practice, the very earliest we’ll obtain them is 2 months out. Otherwise, you get a lot of false-positives that can lead to unnecessary salvage surgeries, with a lot of morbidity from doing that. And then, in my practice, we surveil patients every 3 months for at least the first 2 years, and the modalities by which you do this are nasopharyngeal laryngoscopy for patients with mucosal tumors that you can see, as well as imaging.

The other point I’d like to make is that for the smoking-driven head and neck cancer patient, there can be value in surveillance imaging of the lungs, as well. And here again, not so much looking for metastatic spread from your original tumor as a new stage I lung cancer. The National Lung Screening Trial (NLST) finally gave us data on surveillance of patients with heavy smoking histories. Most of these patients meet the NLST criteria anyway, and even for those who don’t, we know that there’s such a high rate of new stage I lung cancer that I do get annual low-dose CT scans.

Robert L. Ferris, MD, PhD, FACS: After we treat a patient with head and neck cancer, based on the high- or low-risk stratification, then the level of concern for surveillance comes into play. When we say somebody has a long-term survival of 50%, well, our hope is to identify recurrence early enough that we can intervene and hopefully apply a second swing at the ball, a second effort to cure or implement a palliative therapy—a salvage therapy—soon enough that we may have a chance of really prolonging life. So, surveillance is important. Traditionally, we’ve used CT scans of the neck or chest. PET/CT scans have been used for the past 10 or 15 years, in part because they give functional imaging in addition to anatomic imaging. Often times, lymph nodes in the neck shrink back down to a centimeter, but they don’t go away. So, having the ability to see FDG avidity, PET avidity, helps us to say that a lymph node doesn’t disappear, but it’s not avid on a PET scan, and so it’s likely benign. Whereas, when you just had CT scans, that lymph node may have shrunken down but not disappeared, and we didn’t really know and often had to remove lymph nodes in the neck 3 months after treatment to ask whether we had a complete response.

A study was presented at ASCO last year using the PET scan in the surveillance setting, in a randomized fashion, showing that you really could avoid those unnecessary surgical procedures on the neck. And the PET scan was an accurate way to perform posttreatment surveillance.

Jared Weiss, MD: The first question to ask in seeing a case of a recurrence is whether it’s locally only recurrent and whether there might still be a curative option. So, we have an old historic literature showing us that for recurrent or persistent disease after chemoradiotherapy, that surgical salvage can result in a cure. If surgery is not possible, the next question is whether re-irradiation might be possible for the local-only recurrent. And this is really a conversation to have with the radiation oncologist. But if the fields are different or if a lot of time has passed, then it generally often can be and can result in a cure. Now, for the patient who truly has no local option or who has metastatic disease, then at that point, you’re talking about systemic palliative chemotherapy.

Transcript Edited for Clarity
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Transcript:

Ezra Cohen, MD:
In terms of deciding what to use for patients—whether it should be cetuximab or cytotoxic chemotherapy—unfortunately, we don’t have a biomarker to go on in squamous cell carcinoma of the head and neck, as opposed to, for instance, colorectal cancer—where clearly, if there’s a KRAS mutation, one should not administer cetuximab to that patient because there will be no benefit. RAS mutations do occur in patients with head and neck cancer, but very infrequently. And KRAS mutations almost never occur; it’s usually the HRAS mutation.

For head and neck cancer, unfortunately, we don’t have a biomarker yet. We have some hints at biomarkers, but nothing definitive. So, what we do is we depend on clinical parameters to decide. In the locally advanced setting, it’s usually patients who are not good candidates for a platinum-based therapy, patients who have borderline renal failure, patients who may have borderline hearing function or some of the other toxicities that we worry about when we administer cisplatin. And those are patients that we would often treat with cetuximab. In the recurrent metastatic setting, cetuximab becomes either part of the first-line chemotherapy, because of the EXTREME trial, or often a preferred second-line agent because it really does tend to be very well tolerated as a single agent with quite manageable toxicities. But, in terms of deciding which patients to use it on, it really comes down to clinical parameters for the most part.

In terms of HPV status and response to cetuximab, I would say that this still a controversial issue, and there is evidence on both sides suggesting that it doesn’t matter, and there’s evidence suggesting that it does matter. Let’s look at the data as best we can. In the locally advanced setting, the best data set we have is from the so-called Bonner study, or the study that added cetuximab to radiation therapy. And in an analysis that was recently done, looking at HPV status, it looked like HPV-positive and HPV-negative patients had the same degree of benefit with the addition of cetuximab. HPV-positive patients did better, no surprise there. We know they’re a better prognostic group, but when we look at the degree of benefit—the separation in the curves, if you will—that separation appeared to be the same. So, in the locally advanced setting with about 8 weeks of cetuximab delivered with radiation, it doesn’t seem to make a difference with the best data set that we have.

In the recurrent and metastatic setting, that’s where it begins to get a little bit trickier. There are some studies that have suggested that for HPV-positive patients, cetuximab does not work so well. And if we look at the biology of HPV-positive disease, we begin to see that, for the most part, it’s not an EGFR-driven tumor. We don’t see EGFR gene copy number increases or EGFR amplification. We see other types of alterations that appear to be tumor drivers that are not affected by inhibition of EGFR, that are not affected by cetuximab. And that’s led some people to think that in the HPV-positive patients, cetuximab may be less effective.

The problem is that we don’t really have great data. We don’t have prospective data that has taken patients with HPV-positive cancers and randomized them to cetuximab versus something else. The best data set that we do have employs a drug called afatinib, which is a small molecular inhibitor of EGFR and its family of receptors, not a monoclonal antibody. And, for afatinib, it does appear that HPV-positive patients do not benefit as much as their HPV-negative counterparts. But if we could extend that to a drug like cetuximab, we’re not sure.

The differences in quality of life and toxicities between cetuximab and cytotoxic chemotherapy are really quite apparent. We know that cetuximab has associated toxicities, of course. Most typically that’s a rash and the so-called acneiform rash. It can have hypomagnesaemia and other changes to the integumentary system. But, for the most part, these toxicities are manageable. Now that we’ve recognized them, we’ve learned to deal with them, we’ve learned to, in fact, in some cases, prevent them from getting worse. I would say it’s unusual in our practice to have a patient actually come off cetuximab purely for toxicity. It still happens once in a while, but it’s quite unusual. For the most part, cetuximab is actually a pretty well-tolerated agent.

Now, the same is true for cytotoxic chemotherapy, but those side effects can be sometimes a little bit harder to manage. Cisplatin has associated nephropathy, for instance, that can be hard to manage. Electrolyte abnormalities, especially in the locally advanced setting, can be difficult because these patients often don’t drink very well because of the mucositis, they don’t eat very well because of the mucositis. And those toxicities can get patients in trouble and, in fact, even can lead to hospitalization or more serious than that. Cytotoxic chemotherapy can be myelosuppressive, so neutropenia, thrombocytopenia, and anemia. Of course, we’ve known about it for decade, but it still poses a problem in patients we’re treating for either locally advanced or recurrent metastatic disease.

I would say, in general, cetuximab tends to be better tolerated than cytotoxic chemotherapy, and the toxicities are manageable. There is one toxicity, though, that we do need to be aware of with cetuximab in the locally advanced setting, and that’s radiation dermatitis. A few studies, more recently, have demonstrated pretty consistently that the addition of cetuximab to radiation does increase radiation dermatitis. Again, this is something that’s manageable, it’s preventable, but we have to know about it in order to do that, and awareness is the most important thing.

Jared Weiss, MD: We don’t have an absolute standard of care of defined surveillance regimens. The most important point to be made is that it is important to do surveillance after treatment. In terms of immediately after treatment, I think the first most important lesson is not to do a PET too soon if you’re going to do a PET. In our practice, the very earliest we’ll obtain them is 2 months out. Otherwise, you get a lot of false-positives that can lead to unnecessary salvage surgeries, with a lot of morbidity from doing that. And then, in my practice, we surveil patients every 3 months for at least the first 2 years, and the modalities by which you do this are nasopharyngeal laryngoscopy for patients with mucosal tumors that you can see, as well as imaging.

The other point I’d like to make is that for the smoking-driven head and neck cancer patient, there can be value in surveillance imaging of the lungs, as well. And here again, not so much looking for metastatic spread from your original tumor as a new stage I lung cancer. The National Lung Screening Trial (NLST) finally gave us data on surveillance of patients with heavy smoking histories. Most of these patients meet the NLST criteria anyway, and even for those who don’t, we know that there’s such a high rate of new stage I lung cancer that I do get annual low-dose CT scans.

Robert L. Ferris, MD, PhD, FACS: After we treat a patient with head and neck cancer, based on the high- or low-risk stratification, then the level of concern for surveillance comes into play. When we say somebody has a long-term survival of 50%, well, our hope is to identify recurrence early enough that we can intervene and hopefully apply a second swing at the ball, a second effort to cure or implement a palliative therapy—a salvage therapy—soon enough that we may have a chance of really prolonging life. So, surveillance is important. Traditionally, we’ve used CT scans of the neck or chest. PET/CT scans have been used for the past 10 or 15 years, in part because they give functional imaging in addition to anatomic imaging. Often times, lymph nodes in the neck shrink back down to a centimeter, but they don’t go away. So, having the ability to see FDG avidity, PET avidity, helps us to say that a lymph node doesn’t disappear, but it’s not avid on a PET scan, and so it’s likely benign. Whereas, when you just had CT scans, that lymph node may have shrunken down but not disappeared, and we didn’t really know and often had to remove lymph nodes in the neck 3 months after treatment to ask whether we had a complete response.

A study was presented at ASCO last year using the PET scan in the surveillance setting, in a randomized fashion, showing that you really could avoid those unnecessary surgical procedures on the neck. And the PET scan was an accurate way to perform posttreatment surveillance.

Jared Weiss, MD: The first question to ask in seeing a case of a recurrence is whether it’s locally only recurrent and whether there might still be a curative option. So, we have an old historic literature showing us that for recurrent or persistent disease after chemoradiotherapy, that surgical salvage can result in a cure. If surgery is not possible, the next question is whether re-irradiation might be possible for the local-only recurrent. And this is really a conversation to have with the radiation oncologist. But if the fields are different or if a lot of time has passed, then it generally often can be and can result in a cure. Now, for the patient who truly has no local option or who has metastatic disease, then at that point, you’re talking about systemic palliative chemotherapy.

Transcript Edited for Clarity
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