Balancing the risks and benefits of concurrent reirradiation and chemotherapy for recurrent head and neck cancers is difficult for physicians at even the most experienced centers. Research recently published in Cancer, however, suggests that selection of patients who may benefit from this therapy should be based on the patient’s previous treatment and the amount of time that has elapsed since initial treatment (Choe KS, Haraf DJ, Solanki A. [Published online ahead of print June 13, 2011.]
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September 2011Patients being considered for reirradiation start with a poor prognosis, said Douglas Frank, MD, chief of the division of head and neck surgery at Long Island Jewish Medical Center and associate professor in the department of otolaryngology-head and neck surgery at Albert Einstein College of Medicine in New York. “What we struggle with as clinicians is that we know that there is somewhat of a desperation to it,” he said. “We have to be very judicious in offering this type of treatment, knowing which patients are least likely to benefit and who will have the most complications.”
The retrospective study, conducted at the University of Chicago, included data from nine consecutive phase 1 and 2 protocols with 166 patients who had recurrent or second primary squamous cell carcinoma in a region that had previously been irradiated. Eighty-one of the patients had had surgical resection or de-bulking before enrollment. All patients received reirradiation as well as concurrent chemotherapy, which generally comprised 5-fluorouracil, hydroxyurea and a third agent. After a median follow-up of 53 months, median overall survival (OS) was 10.3 months. The two-year OS rate was 24.8 percent.
A subgroup analysis found that four prognostic factors were significantly linked with survival: surgical resection before protocol, reirradiation dose ≥ 60 Gy, an interval ≥ 36 months since prior radiation therapy and no previous chemoradiation therapy. The OS rate was 63.6 percent for the 11 patients in the study who had all of those variables.
Survival was lower in the patients who had previously been treated with concurrent chemoradiotherapy, however. For those initially treated with chemoradiotherapy, the two-year OS rate was 10.8, compared with 28.4 percent for those who had not received that concurrent therapy. In a subgroup analysis of the 11 patients who had undergone previous chemoradiation therapy and had a reirradiation dose < 60 Gy, the median survival was only 1.2 months, and none of those patients survived for two years.
Combining chemotherapy with reirradiation for treatment of recurrent or second cancer, although beneficial for some patients, carries with it significant risk. The mortality rate from treatment-related toxicities was 19.9 percent in the retrospective study. Among the 40 patients who had previously been treated with chemoradiotherapy, 30 percent experienced grade 5 toxicity. More than 66 percent of all patients at the last follow-up required a gastrostomy tube for feeding. Other adverse events included 15 episodes of carotid hemorrhage, with 10 of those fatal, and 18 patients who developed osteoradionecrosis requiring surgical intervention.
“The patients who tend to fail after chemoradiotherapy tend to fail in a much more widespread pattern, and those people don’t do well.”—David Schwartz, MD
Joseph K. Salama, MD, assistant professor in the department of radiation oncology at Duke University Medical Center in Durham, N.C., and one of the investigators in the study, said the research highlights the need to “appropriately select who gets this treatment. More and more patients are having initial chemotherapy and radiation together. Our study shows that for those patients who go on to have recurring cancer or a second cancer, prior treatment with both chemotherapy and radiation therapy means they may not do as well.”
The data suggest that a patient can be considered for a second course of chemotherapy and radiation if the tumor recurs in a previously irradiated area and if the patient does not have evidence of a distant cancer. However, patients who are incapacitated, those who have tumors that cannot be irradiated and those with recurrence very shortly after the initial treatment should be considered for a different type of treatment, Dr. Salama said
Patient Selection Is Critical
According to Matthew Fury, MD, PhD, assistant attending physician in the head and neck service at Memorial Sloan-Kettering Cancer Center in New York, the research results, although not surprising to experienced centers, “help us at least pull together the available information to select patients. If you have that rare patient who has all four favorable prognostic factors, you can go forward with reirradiation with some degree of confidence.”
David Schwartz, MD, associate professor and vice chair in the departments of radiation medicine, otolaryngology, and molecular medicine at Hofstra North Shore-Long Island Jewish School of Medicine in New York, said appropriate patient selection is critical. “It is widely known that people who are heavily pretreated and recur do worse with salvage treatment,” he said. “The patients who tend to fail after chemoradiotherapy tend to fail in a much more widespread pattern, and those people don’t do well.”
Jonas Johnson, MD, professor and chair of otolaryngology at the University of Pittsburgh School of Medicine, said patients who require a second treatment and don’t have a very good prognosis are more likely to die of cancer and to have treatment-related side effects and complications.
This paper clarifies the risks imposed by reirradiation and chemotherapy, but the surgical option also extracts a large price, Dr. Johnson said. “The surgeries are almost always more difficult, more likely to have complications and side effects, and the cure rate, although better than 25 percent, is not better than 50 percent,” he said.
Research reported by Goodwin in 2000 found that salvage surgery came at great cost to patients (Laryngoscope. 2000;110(suppl 93):1-18). Following salvage surgery, the researchers found that about 33 percent of people with stage III recurrent cancer lived at least two years, but 30 percent had significant complications, and fewer than 25 percent of patients with stage IV recurrent cancer lived for at least two years, and 30 percent had significant complications. In patients with stages I and II recurrent cancer, the results of salvage surgery were better: They had a 70 percent chance of living for at least two years without recurrence of their cancer and a 60 percent to 85 percent change of a successful outcome with respect to their quality of life.
Dr. Schwartz’s research has looked at using intensity-modulated radiotherapy (IMRT) as reirradiation therapy for patients with recurrent or second primary head and neck cancers (Int J Radiat Oncol Biol Phys. 2009;73(2):399-409). In that study, data from 78 consecutive patients reirradiated with IMRT for recurrent head and neck cancer were reviewed. Median time interval between the initial radiation and reirradiation was 46 months, and median reirradiation dose was 60 Gy. The two-year OS rate was 58 percent, and the locoregional control rate was 64 percent. Twenty percent of the patients had severe reirradiation-related toxicity.
Because prognosis is poor, the balance between risks and benefits is complex and ability to select patients is limited. Patients undergoing treatment for recurrent cancer should, in an ideal world, be treated in a clinical trial, Dr. Fury said. “When you look at the studies, the probability of getting meaningful disease-free survival is the same as the probability of dying from toxicity of treatment,” he added. “That gives us pause.”
One outcome of this research, according to Dr. Frank, is that physicians have more information for open discussions with their patients. “There has been great interest in the past few years about reirradiation, and that’s a very difficult discussion to have with patients,” he said. “It’s extremely morbid. For the patient who is not resectable and has been treated previously with chemoradiation, this allows us to present a more honest discussion about treatment. Maybe, some of those patients would opt instead for something more palliative or [for] pain hospice care.” ENT TODAY