Study Warns Against De-Intensifying Treatment for Certain Oropharyngeal Cancer Patients

A little over a decade ago, oncologists began to realize that not all oropharyngeal cancer patients were the same. Those who acquired the disease through the human papillomavirus (HPV) often had much better survival rates than those who acquired the disease differently.

This dichotomy has led to calls for the de-intensification of treatment for HPV-associated oropharyngeal patients so that these highly curable patients might be spared the side effects that come with aggressive chemoradiation regimens.

New studies involving HPV-positive patients treated with newer targeted drugs, however, have added a wrinkle to de-intensification plans by showing that not all HPV-positive patients do well on a less intense treatment regimen.

“There has been evidence, and I think it’s ever increasing, that there’s a group of patients that don’t do great on the less intensive treatment regimens,” says Brian Burkey, MD, MEd, Vice-chairman and Section head of the Section of Head and Neck Surgery and Oncology at Cleveland Clinic’s Head & Neck Institute. “They’re usually active smokers, those with very large primary disease and those who got a certain kind of (cancer-fighting) drug.”

Antibody drug vs. chemotherapy

Dr. Burkey and several Cleveland Clinic colleagues including Shlomo Koyfman, MD, radiation oncologist, recently published a retrospective study in Head & Neck. It showed certain HPV-positive head-and-neck cancer patients had a higher risk of developing distant metastases when they received radiation along with the drug cetuximab instead of radiation along with the gold standard cisplatin, a type of chemotherapy.

Cetuximab is an antibody medicine that works primarily to sensitize cancer cells to radiation so oncologists can kill more cancer cells with the same amount of radiation. Because cetuximab is a targeted therapy, patients are not subjected to the risks of kidney damage, hearing loss and infections that are associated with traditional cisplatin chemotherapy. “We tend not to give cisplatin to patients who are older than 75 or to patients who have renal insufficiency because we know cisplatin is toxic to the kidneys,” Dr. Burkey says. “We tend to give those patients cetuximab knowing that we may lose some benefit.”

Dr. Burkey and Dr. Koyfman’s study followed a number of investigations looking at de-intensification. One study out of the Eastern Cooperative Oncology Group gave all enrolled patients induction chemotherapy and then split them into two groups: those who responded well and those who didn’t. The former group received reduced doses of radiation and cetuximab and did quite well; the latter group received standard dose radiation and cetuximab and had inferior outcomes.

Another study, the clinical trial RTOG 1016, gave all patients a standard dose of radiation and then half received cetuximab and half received cisplatin. The results from that investigation won’t be available for another year; however, Dr. Koyfman had patients in that study and he began to worry when some of them developed cancer in their lungs and bones. “I did a little gut check,” he says, “and I had a hunch that this was happening more in the patients who received cetuximab.” This hunch prompted the design of their study recently published in Head & Neck.

Dr. Koyfman says cetuximab works along with radiation to fight cancer at the original site but may not be effective when cancer cells escape into the blood stream and end up in other parts of the body. “Is it enough to kill cancer on its own?” he says. “That’s not clear.”

Not all patients should get de-intensified regimen

Those earlier studies convinced Dr. Koyfman, Dr. Burkey and their colleagues to do the retrospective study to see if they could figure out what predicted the cancer coming back elsewhere in the body. “What we found was pretty dramatic,” Dr. Koyfman says. “The No. 1 predictor was use of cetuximab instead of cisplatin.”

Their data showed patients who received that regimen more than doubled their chances of developing a distant metastases, from 11 percent to 23 percent. It also showed an elevated risk if the patient had large tumors and if they smoked heavily.

Dr. Koyfman says the results of the RTOG 1016 trial will give them the final answer, but he believes the evidence is indicating that a significant subset of HPV-patients should not be included in de-intensified treatments.

“You have to be really smart and careful about who you try to de-intensify,” he says. “There are people who not only do not need de-intensification, they probably need additional intensified therapies specifically for distant metastases.

National groups are now designing different clinical trials for lower risk and higher risk patients with virus-associated head and neck cancer, he says. “The key is that until we have final results from the recently completed studies, we should continue using cisplatin-based chemotherapy ad not cetuximab in these patients.”