Transcript:Ezra Cohen, MD: For patients with recurrent or metastatic squamous cell carcinoma of the head and neck, we really should think about that same first question: is the patient in front of me curable? Unfortunately, for patients with recurrent disease, the answer will usually be no. But there’s about 10% to15%, maybe 20%, of patients who we can salvage with either surgery or re-radiation. And at the very least, we need to have a discussion with the patient about that. But let’s talk about the larger group of patients who, unfortunately, are not going to be curable in the recurrent or metastatic setting. How do we approach those? Then we take into account things like patient preferences, their performance status, and their ability to tolerate different chemotherapy agents. With all things being equal for the most part, we usually start with either a doublet or triplet chemotherapy regimen that is platinum-containing; so carboplatin, paclitaxel, cisplatin, docetaxel, regimens like that. Of course, the EXTREME regimen that incorporates cetuximab is approved for first-line recurrent metastatic head and neck cancer, the regimen that improved survival from seven-and-a-half months to 10 months—incorporating platinum, 5-FU, and cetuximab—with cetuximab extended as maintenance after the 6 cycles of the triplet combinations.

When patients have progressive disease after first-line therapy, often we’ll use a single-agent therapy based on what they have not had in the first-line setting or in the initial curative setting. And single agents that have activity in head and neck cancer include the taxanes, the platinums, the fluoropyrimidines, 5-FU and capecitabine, cetuximab, and methotrexate. And those are all agents with low-level activity, but real activity that can offer a benefit to patients. Fortunately, we’re seeing emerging data about immunotherapy in recurrent metastatic head and neck cancer, and it looks like those agents will be a large part of our armamentarium. In fact, it looks like they may be even more effective than what we currently have.

This balance between the desire to cure the patient and the need to preserve quality of life for the long-term is something that we’ve always struggled with in head and neck cancer. Let’s remember that for the head-and-neck cancer patient, not only does the disease, but also the treatment profoundly affects how we define ourselves as human beings. It affects the way we interact with each other. It affects our speech. It affects our swallowing. So, we know from studies that head and neck cancer has the most profound effect on quality of life of any malignancy and the most profound effect on social interaction of any malignancy, and among the most dramatic effect on financial outcome and financial health, if you will, in the long-term. These are all issues that we need to keep in mind when approaching a patient. When we ask patients what do they want out of therapy, in almost every study that’s been done, the answer has been cure. That makes sense, and that’s what we always try to think about and is paramount in our minds. How do we cure this patient? We realize we can cure the patient with modifications in the therapy that will also hopefully preserve their quality of life in the long term. So, what we’ve gotten away from in the last couple of decades are very extensive surgeries—for instance, laryngectomies or total glossectomies—with a realization that we can take nonsurgical approaches to patients who would have otherwise needed those surgeries and preserve their organs, preserve their function.

There’s a big push to stratify patients into low-risk, intermediate-risk, and high-risk with a thought that we can de-intensify for the low-risk patients and preserve those cure rates. That’s not part of standard management yet. We’re beginning to see more and more prospective data on de-intensification approaches—approaches that, for instance, lower the radiation therapy dose, change the radiation therapy volume, or modify the systemic therapy, all in an effort to de-intensify therapy and preserve cure rates. If I had to guess, those will be part of standard therapy probably in the next few years, certainly within the next 5 years. But we don’t have enough data to change standard management yet.

For HPV-positive patients, we now realize quite clearly that their prognosis is much better, and that for many patients with HPV-positive disease, we are likely over treating. We don’t need to be as aggressive as we are when we’re looking at cure rates approaching 90%. So, with that in mind, we began to hypothesize whether we could reduce the intensity of therapy, de-intensify and maintain the cure rates. When we think about how to do that and what the most morbid parts of our therapy are, we begin to think about things, like reducing the radiation dose or modifying the radiation volume or integrating minimally invasive surgery for these patients who often have small tumors but more extensive neck disease, in an effort to try to reduce some of the other modalities.

So, some of the efforts that have been aimed at doing that have included minimally invasive surgery, so transoral robotic surgery, for instance, or modifications of the radiation. We saw some very interesting data recently—one from ECOG and another from a group at the University of North Carolina with the University of Florida—that essentially reduced the dose of radiation, and, at least, the prospective outcomes for these patients appear to be maintained, outcomes in terms of cure rates. At the University of Chicago, we undertook a slightly different approach, and what we hypothesized was that these cancers would require the same dose of radiation to kill a cancer cell, but that we may be able to spare the other parts of the neck, specifically PTV2, the parts of the neck that are at risk for microscopic disease but we don’t see any disease at this point. And we hypothesized that we could actually eliminate radiation to those areas and improve quality of life in the long run. We were just able to present our data now with significant follow-up showing that that, in fact, appears to be the case. We’re able to maintain local regional control, maintain progression-free survival and overall survival in these patients, spare the PTV2, the microscopic areas, and actually end up with much lower G-tube rates and better quality of life a year after therapy.

Robert L. Ferris, MD, PhD, FACS: The treatment options for locally advanced head and neck cancer usually entail two of the three modalities. For stage III and IV head and neck cancers, we’re likely to use surgery as long as it’s not going to be debilitating and disfiguring, followed by radiotherapy alone. Radiation in the postoperative setting is a bit lower dose than the radiation in the locally advanced setting. Another option for certain cancers, particularly those in the voice box or the oropharynx, is a nonsurgical approach. We don’t usually use chemotherapy and radiation primarily for the mouth, for the oral cavity. That’s, in part, because it’s extremely difficult for the patient to have the whole mouth radiated. There is a chance that the jawbone and other bony structures can have osteonecrosis, and die and get infected. The dry mouth and caries and so on, the xerostomia associated with radiating the mouth, tend to lead us away from that approach. So, we tend to have a surgical approach for the oral cavity. The oropharynx and the larynx have both options, and we choose surgery if it can be done functionally up front, or, if not, we would prefer radiation with chemotherapy. Transoral robotic surgery or transoral laser surgery is a common way to access the oropharynx and the larynx. And just because it’s at the far back of the throat doesn’t mean that we don’t have surgical options. And technology over the past 10 or 15 years has enabled the surgeons to have operating instruments down at the end of a dark hole with lighted binocular instruments. The first surgical robot was FDA-approved in 2009.

There’s now another technology, or robot-assisted device, that was approved in the summer of 2015. So, we had lots of surgical technologies that we can apply for a functional removal of locally advanced head and neck cancers. Nonetheless, those patients are likely to get postoperative radiation therapy, and if there are worrisome prognostic factors—such as multiple lymph nodes, or positive margins, or extranodal extension—then we would add chemotherapy on top in the postoperative setting. If it’s a morbid functional surgical procedure, then we would prefer to use chemotherapy and radiation and cetuximab and radiation. Cetuximab was FDA-approved in 2006 in the Bonner trial, where the addition of cetuximab to radiotherapy had an absolute 10% survival benefit. This held up in the 5-year analysis and report. So, this was quite promising because in patients who are chemotherapy-intolerant, up to 30% now have a curative option that can enhance the effect of radiotherapy.

In addition, we have these two standards of care and the fact that HPV-positive patients are comprising an increasing subset of head and neck cancers. So, the question arises, do HPV-positive patients do just as well with cetuximab as they do with cisplatin, the other chemotherapy that’s a standard regimen? It appears that they do. There has been a head-to-head clinical trial performed. It’s completed accrual. It has not yet reported out, so we are left with independent studies. And looking at the so-called hazard ratio, or the statistical benefit of adding cetuximab to radiation versus comparing it to cisplatin chemotherapy radiation, it appears that the survival benefit is the same or roughly equivalent by adding cetuximab to radiation compared with adding cisplatin chemotherapy to radiation.

Now, the issue of HPV status, because these patients are at lower risk for recurrence, versus HPV-negative patients that are at higher risk for recurrence, we feel like we should intensify therapy for patients who have higher-risk disease. I also mentioned that HPV-positive patients are not always low, low risk. There is an intermediate group that has the bulky nodal disease, that has a T4, and that has smokers, heavy smokers. So, clinical trials right now are testing whether we should alter the dose for higher-risk, intermediate-risk, and lower-risk patients. Those subgroups exist based on prognostic factors. But we want to make sure we select the appropriate treatment that’s just enough to cure the disease without causing morbidity and functional impairments that will persist for the life of that patient.

Transcript Edited for Clarity