Robert Ferris, MD, PhD, Head and Neck Cancer Surgeon, Director of the UPMC Hillman Cancer Center, talks about lowering radiation for head and neck cancers.
Can you talk about the type of cancer that you and your colleagues are studying?
DR FERRIS: We generally think of head and neck cancer as cancers of the lining of the mouth, the throat, and the voice box. Those are three different areas with the mouth being the front part, the throat being the middle part, and then further down in the voice box where we form sound and breathe. Those are how we divide the three regions of the head and neck. The tumor type is called squamous cell carcinoma.
Are you seeing an increase in this kind of cancer?
DR FERRIS: Yes, because in western countries, there are two types of head and neck squamous cell carcinoma. The traditional type caused by carcinogens like smoking and alcohol, which has been declining in parallel with good public health efforts to reduce tobacco exposure. There’s been an increase in the second type caused by a virus, human papillomavirus. So, we’re seeing an overall increase in head and neck squamous cell carcinomas primarily because the human papillomavirus subtype has been so prevalent.
Is this a cancer that’s striking people in their younger years or middle age?
DR FERRIS: Typically, the more traditional smoking HPV-negative head-neck cancer shows up in the early to mid-60’s. The HPV positive, the one that’s been increasing so much, is about 10 years earlier, 50 to 55. Although, as we get an older population, we’re seeing more older patients with HPV-positive head-neck cancers. It’s just growing dramatically.
What’s the standard diagnosis and treatment?
DR FERRIS: Most patients with a head and neck squamous cell carcinoma arrive at their doctor because they have a lump in the neck. That generally means the tumor has spread to a lymph node. So, you tend to show up to an ear, nose, and throat doctor, and that’s the surgeon. But we have surgical therapy and non-surgical therapy, such as radiation and chemo. The radiation oncologist and the medical oncologist who gives the chemotherapy will treat the patient together. The best way to treat a head and neck cancer patient is for that patient to meet all of the doctors to decide whether an initial surgical treatment is ideal or an upfront radiation with or without chemotherapy may be a better way to treat it. That decision is done through a consensus we call a multidisciplinary evaluation by all the doctors.
In terms of a combination of surgery and chemotherapy, what is traditionally the path that people with this kind of cancer will go?
DR FERRIS: We think for a couple of reasons surgical therapy is the bedrock of treatment for this disease. Number one is that it gives us the ability to assess the risk level. That tends to come with what surgery brings, which is the specimen out of the body that can be examined under a microscope. CAT scans or MRI or PET scans are only so good. So, surgical therapy up front allows us to do the risk category because we have the actual lymph nodes of the neck to be examined under the microscope. A pathologist looking at 20 lymph nodes will tell you beyond a shadow of a doubt if there is a single lymph node positive with cancer. And the more lymph nodes positive, the higher the risk we think. When there’s higher risk, we traditionally add more types of treatment. We add radiation, for instance, after surgery or chemotherapy plus radiation for the highest risk. We think surgery may give us the ability to reduce the need for radiation and chemotherapy because the side effects of surgery are very well-known. Human beings have all had a cut, and our body heals. What we know less as humans is the side effects of something like radiation because most of us don’t have that kind of an injury unless we end up with a cancer. It turns out that the side effects of radiation are very different than surgery and can be long-standing, can occur a year or three or five years later, and can be irreversible. So, the other benefit of surgery is the potential to reduce the need for radiation or reduce the dose.
What is the survival rate of the HPV-positive cancer?
DR FERRIS: There is a bit of a mixture of the HPV-positive group, depending on the bulk of disease a patient may have, or depending on whether they’re a smoker. I’ve presented it as you’re either a smoker or you’re either HPV-positive. Some people are both. It seems like the survival is a little bit in the middle between the two. But in general, a simple way to think about it is 40 to 50 percent survival for the HPV-negative, the traditional head and neck cancer patient, 80 to 90 percent survival for the HPV-positive patient.
Could you tell me about the clinical trial you and your colleagues conducted?
DR FERRIS: This is a clinical trial through the ECOG-ACRIN which is a committee funded by the federal government and National Cancer Institute. It has a committee focused on head and neck cancer. We set out 10 or so years ago to design clinical trials to de-intensify therapy. This was called ECOG 3311 to test whether upfront surgery using a minimally invasive technique called transoral robotic surgery, abbreviated TORS, to remove all the visible cancer in the throat and the neck because head and neck cancer tends to be localized in the head and neck above the collar bones. To do accurate disease staging, surgery is very helpful. Once we removed the tumor, the specimen was analyzed by the pathologist and allowed us to classify patients based on their risk. So, low risk has the least amount of disease burden. Intermediate has, as it sounds like, a sort of middle extent. Then there’s the high risk, which has lots of disease burden. All of this is measured by if the surgeon could get the tumor out completely. We call that the margin status, positive margins, or negative margins. We removed lymph nodes on all patients. And generally, we needed to remove around 20. And out of those 20, whether there was a single lymph node positive, which would make you low risk, whether there was two, three, or four lymph nodes positive, that’s intermediate risk, and greater than four lymph nodes positive, major high risk. There was also another feature as to whether those tumor cells in the lymph nodes had escaped outside of the capsule of the lymph node. We think of a lymph node like an orange. It has a rind on it, a capsule. If the tumor had spread outside of the capsule or the rind of the orange, that’s called extranodal extension. We divided up extranodal extension to less than a millimeter outside of the lymph node or greater than a millimeter outside lymph node. Less than a millimeter is intermediate risk. Greater than a millimeter is high risk. With those risk categories, we then assigned a post-operative radiation dose. If a patient had upfront transoral surgery and was deemed low risk, meaning no more than a single positive lymph node with no extranodal extension, they got no further therapy and no radiation at all. On the ECOG 3311 trial, that was about 10 or 11 percent of the patients who got no further therapy. Their survival rate, we think successfully regarding the trial, was about 95 to 96 percent. For the intermediate risk, this was the group with up to four metastatic lymph nodes and less than a millimeter of extranodal extension, those patients had a 95 percent survival. But the key is they were randomized to either the standard dose of 60 of radiation or our experimental lower intensity dose of 50. It turns out that on this clinical trial with about 100 in each arm of the 50 or the 60, there was no detectable difference in survival. Both had about 95 percent survival when we looked at two years or at three years after surgery.
What’s the benefit of having less radiation?
DR FERRIS: Well, it’s interesting. The dose difference of 60 and 50 may not seem so different. That’s a full week less radiation but it’s because the treatment is basically two per day. So, five times two is 10 less treatments. So, it is faster. It turns out if you ask any cancer patient, the first few weeks of radiation are reasonably tolerable. But then it gets progressively harder. That final week is a lot in terms of the short-term acute side effects or toxicity. The goal of the trial is to ask is it better in terms of long-term toxicity? We think it will be because less radiation is always better. We shouldn’t necessarily have to have data to show that 10 less of radiation is just as good. We need to have some data to say why should we even give any more treatment? So, if a dose of 50 gives us 95 percent survival, I think that most of the field feels like that may establish a safe new standard. This was a medium-sized phase two trial. Usually, we want to see a phase three trial to change practice. But because it was a good-sized phase two trial, we may see this changes practice in some centers across the U.S. When we looked at what it would take to do a new phase three trial to confirm these results, it was 1,500 to 2,000 patients. I think most doctors feel like in the absence of data that says you must give 60, it seemed like 50 was just as good. And it seems safe if you have just as high a survival, you’re always going to have lower side effects by giving less radiation. And none of the patients got chemotherapy in the intermediate risk group. Even that less than a millimeter has been a reason to give chemo in the past. In this trial, we didn’t need to give it and could still maintain high survival.
Has that changed practice here at UPMC?
DR FERRIS: Well, we were the number one accruing center. We put on 50 or so patients of this 500-person trial. So, it has certainly changed our practice. We’re still discussing at our tumor conference, have we solved every risk group? Is there a separate risk group that we can still study? We’re looking at whether we can replace chemotherapy with the new immunotherapies, which is a less toxic way for the high-risk category. So, we still think there’s work to be done to figure out what we need to give the high-risk group. But for the intermediate risk group, we’re certainly comfortable with a dose of 50. We and others are asking whether you can get away with 30 or 40. So the field is moving. I would summarize by saying we need a phase three trial to practice changing and a big trial like this with the very successful results of 95 percent survival.
Will there be a phase three trial?
DR FERRIS: The phase three trial that the ECOG is designing would take as the standard arm surgery with a dose of 50 radiation post-operatively and now compare it to a completely non-surgical treatment type, which would be no surgery but with radiation and chemo and compare those two against each other. So, randomizing a patient to surgery versus no surgery is challenging, but the ECOG is going to try.
What does ECOG stand for?
DR FERRIS: Eastern Cooperative Oncology Group.
Is there anything else you want to make sure people know?
DR FERRIS: I think it’s important just to reiterate, as we said at the beginning, that patients with a head and neck cancer should meet all of the doctors, the surgeon, the medical and the radiation oncologist, and have their case discussed in a multidisciplinary treatment forum to get the best recommended treatment. In many cases, that’s surgery upfront, but maybe not always. And having the team confer, evaluate, and individualize care gives the highest quality.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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