Patients with recurrent or second primary head and neck cancer who previously received radiation therapy to the head and neck region—especially those with unresectable tumors—have typically had a dismal prognosis and limited treatment options. Although radiation therapy offers high rates of local disease control, re-irradiating the region is usually avoided for fear of damaging previously irradiated healthy tissue, including vital structures such as the carotid arteries and neural structures. But advanced imaging and radiation therapy techniques are now being used to re-irradiate recurrent tumors while sparing nearby critical structures in patients with head and neck cancer.
For previously irradiated patients with recurrent head and neck cancer, surgery is historically considered the only potentially curative option. When these recurrent tumors are unresectable, chemotherapy provides a median survival of only 9–11 months—just a few months longer than with supportive care.
“These patients with unresectable tumors don’t have many options, and they die of very morbid disease,” said Jack Phan, M.D., Ph.D., an assistant professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center.
But Dr. Phan and colleagues have shown that re-irradiating recurrent tumors, if done safely, can provide local tumor control and relieve symptoms. With the goal of also prolonging patients’ survival, Dr. Phan is now leading a clinical trial that explores re-irradiation in patients with unresectable recurrent head and neck cancer.
Overcoming challenges to re-irradiation
In the 1990s, several clinical trials studied re-irradiating recurrent head and neck tumors with conventional two-dimensional and three-dimensional conformal radiation therapy. “It did improve outcomes in a select group of patients, but the side effects were pretty horrendous,” Dr. Phan said. The practice was restricted to very high risk cases.
In 2013, believing that advances in technology could improve patient safety, MD Anderson physicians began using stereotactic techniques for re-irradiation in patients with unresectable recurrent head and neck cancers. Dr. Phan and colleagues visualize these tumors by creating a composite three-dimensional image from magnetic resonance imaging, computed tomography, and positron emission tomography–computed tomography scans taken with the patient in the treatment position. The composite image is used to plan the delivery of stereotactic body radiation therapy (SBRT) with a linear accelerator or stereotactic radiosurgery with a Gamma Knife.
“We’re at a point now where we can target the tumor with stereotactic precision and avoid the nearby normal, critical tissues,” Dr. Phan said. “We previously couldn’t visualize the tumor very well. Advances in radiation therapy are very closely tied to advances in medical imaging.”
Both stereotactic modalities deliver high doses of radiation to the tumor in very few fractions—typically three to five for SBRT and one to three for radiosurgery—with minimal doses to nearby structures. The patient is re-imaged in the treatment position before each treatment session to ensure precise targeting. SBRT is used for most recurrent head and neck tumors, with stereotactic radiosurgery reserved for small skull base tumors.
Clinical benefits of re-irradiation
Patients who previously received radiation therapy to the head and neck region and receive re-irradiation for recurrent head and neck cancer at MD Anderson are enrolled in an observational study. Data from this study are showing that patients benefit from re-irradiation.
“We currently re-irradiate about 100 patients a year—an increase from about 20 patients a year prior to 2011,” Dr. Phan said. “Many folks we treated 3–5 years ago with SBRT are still alive and doing well.”
In addition to potentially prolonging survival, re-irradiation can provide symptom relief. Dr. Phan and colleagues recently analyzed the outcomes of patients who received stereotactic radiosurgery as a palliative treatment for facial pain from unresectable recurrent skull base tumors. Most patients had significantly lower self-reported pain scores 6 months after treatment. Furthermore, many patients were able to reduce their doses of pain medication, and some patients were able to discontinue their pain medications altogether.
“This was the first study to document a decrease in narcotic use after palliative-intent re-irradiation for patients with pain from recurrent head and neck cancer,” Dr. Phan said. “And in our current clinical trial, re-irradiation with SBRT is being done with the goal of long-term cancer control.”
The current trial (No. 2016-1065) is enrolling patients who have one to three sites of unresectable recurrent or second primary head and neck cancer who previously received at least 30 Gy of radiation therapy for head and neck cancer. Each tumor must be smaller than 60 cm3, and the total tumor volume must be less than 100 cm3.
Patients enrolled in the trial are randomly assigned to one of two treatment groups. One group receives SBRT at a dose of 45 Gy in five fractions over 2 weeks, and the other group receives intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT) at a dose of 60–70 Gy in 33–35 fractions over 6 or 7 weeks.
The trial’s outcome measures include toxic effects, local tumor control, and patient-reported symptoms. “All three modalities used in the trial are highly conformal,” Dr. Phan said. “The question we have is, which modality will give better local tumor control and a better side effect profile?”
So far, patients in both treatment groups are doing well. “We only have 1 year of follow-up, but the local tumor control rate for all patients is 80%–90%,” Dr. Phan said, emphasizing that these results are too early for meaningful analysis. “We don’t know how these patients will do 5 years from now, but it’s promising.”
In the 1990s, re-irradiation for head and cancer was believed to cause carotid artery damage in 8%–13% of patients; however, Dr. Phan and his colleagues have not seen any carotid artery damage in patients in the observational study or the current clinical trial.
Other clinical trials of stereotactic radiation techniques are expected to begin enrolling previously irradiated patients with head and neck cancer in the near future. Some of these trials will combine radiation therapy with immunotherapy.
A phase I trial will combine SBRT and an immune checkpoint inhibitor for patients with recurrent head and neck cancer and one to three head and neck lesions who have previously undergone radiation therapy to the head and neck region. “Head and neck tumors have a high risk of spreading regionally and distantly,” Dr. Phan said. “We hope the immunotherapy will help the body target any stray tumor cells outside the radiation field.” The researchers also hope that the radiation therapy will create an abscopal effect, i.e., that antigens released by the irradiated tumors will enhance the effect of immunotherapy on the non-irradiated metastatic lesions.
Dr. Phan and colleagues also want to see if re-irradiation plus immunotherapy can benefit patients with resectable disease. A trial combining re-irradiation and immunotherapy will enroll patients with resectable recurrent head and neck cancer who previously underwent radiation therapy. After resection of the recurrent disease, patients will receive lower-dose SBRT in combination with immunotherapy drugs. One of these drugs is a novel immune checkpoint inhibitor that also has the potential to reduce radiation-related inflammation. “This is exciting because re-irradiated patients have a high risk of severe scarring, and this scarring comes from inflammation,” Dr. Phan said.
Dr. Phan and his colleagues’ goal is to use highly conformal re-irradiation techniques to prolong survival without causing debilitating pain or scarring for patients with recurrent head and neck cancer. “We only have SBRT re-irradiation follow-up data up to 5 years, and we don’t know what long-term effects we may see,” Dr. Phan said. “But at the same time, many of these folks probably would have had 6 months to live without treatment.”
For more information, contact Dr. Jack Phan at 713-792-5373 or firstname.lastname@example.org. To learn more about clinical trials for patients with head and neck cancer, visit www.clinicaltrials.org and search by trial number or cancer type.
Phan J, Pollard C III, Brown PD, et al. Stereotactic radiosurgery for trigeminal pain secondary to recurrent malignant skull base tumors. J Neurosurg. In press.
OncoLog, April 2018, Volume 63, Issue 4
Stereotactic Radiation for Newly Diagnosed Head and Neck Tumors
While much of Dr. Phan’s research in stereotactic treatments has focused on recurrent disease, he believes such treatments could eventually become standard first-line therapies for some head and neck cancers. His current dose-escalation trial of SBRT as organ-preserving therapy in newly diagnosed patients with laryngeal cancer is a step in that direction.
The phase I trial (No. 2016-1023) is enrolling patients with previously untreated T1, N1, M0 or T2–4a, N0–1, M0 squamous cell carcinoma of the larynx. All patients receive SBRT at a minimum dose of 40 Gy in five fractions. “The goal is to avoid surgery while eliminating the tumor in order to preserve swallowing function, which is very important for quality of life,” Dr. Phan said.
The study’s outcome measures are the maximum tolerated dose, toxic effects, and complete response rate. Early results are not yet available, but Dr. Phan is optimistic about the patients’ outcomes.
Another trial, which is still in the planning stages, will enroll patients with newly diagnosed nasopharyngeal cancer. Patients will receive an upfront stereotactic radiation boost followed by induction therapy with an immune checkpoint inhibitor and then standard treatment with chemotherapy plus IMRT or IMPT. The researchers plan to obtain blood and tissue samples as well as imaging scans at baseline, after induction therapy, and after the completion of chemoradiation to search for biomarkers that may predict patients’ outcomes. The imaging biomarker study will be headed by Clifton David Fuller, M.D., Ph.D., an associate professor in the Department of Radiation Oncology and the medical director of the Program for Image-Guided Cancer Therapy.
“I believe we can treat these patients with limited side effects so that we don’t impair their quality of life,” Dr. Phan said.