• 3/25/2003
  • Cleveland
  • Daniel Nester
  • Journal of Clinical Onocology

Standard radiation treatment combined with a single high dose of chemo increases survival rates.

Although it also increases toxicity rates, the addition of concurrent high-dose, single-agent cisplatin (Platinol, Bristol-Myers Squibb) to conventional radiation treatment significantly improves survival rates in patients with head and neck cancer. A new study has found that the three-year projected overall survival rate of patients who received the combination treatment was 37%, compared with 23% in those patients who received radiation alone.

Another arm of the seven-year study showed no improvement in efficacy from the use of multi-agent chemotherapy with a split-course of radiation despite the possibility of midcourse surgery. The three-year survival rate for that group was 27%.

The study proves that “concurrent chemotherapy and radiation can be safely administered with acceptable toxicity in a multi-institutional, cooperative oncology group trial,” said David J. Adelstein, MD, from the Cleveland Clinic Foundation, and lead researcher of the study. More investigation of this combination is needed, he said, but the results demonstrate the treatment “significantly improves survival.”

Materials and methods

Adelstein and colleagues at the Head and Neck Intergroup — comprising the Eastern Cooperative Oncology Group and the Southwest Oncology Group — were following-up their previous studies that have compared the standard care of radiation treatment and a combination of radiation and chemotherapy in patients with unresectable head and neck cancer. Those studies demonstrated increased response rates compared with radiation alone, but survival differences were statistically insignificant, Adelstein said. Overall survival rates of patients receiving radiation alone for unresectable disease, he pointed out, have in general been less than 25%.

Researchers conducted a randomized, phase-3 study that examined results of 295 patients (271 evaluable) with unresectable squamous cell head and neck cancer between 1992 and 1999. Patients were randomly assigned to a control group of patients who received a single, daily fractionated radiation (70 Gy at 2 Gy/d); a second group that received the identical radiation therapy along with concurrent bolus cisplatin (given on days 1, 22 and 43); or a third group that received a split course of a single daily fractionated radiation treatment and three concurrent cycles of fluorouracil and bolus cisplatin chemotherapy (30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle).

Surgical resection was encouraged if possible, Adelstein said, after the second chemotherapy cycle in the multiagent split course group and, if necessary, as a salvage therapy in all three treatment groups.

Increased toxicity and survival

With a median follow-up of 41 months for patients who were still alive, researchers found that the three-year projected overall survival for the control arm was 23% with a median survival of 12.6 months. The survival of patients in the group given concurrent single-agent cisplatin was “significantly better” than controls, with a three-year projection of 37%, a median of 19.1 months (P=0.014).

Complete responses bore out similar results. Researchers reported a complete response in 27.4% of control patients receiving radiation alone, 40.2% in the single-agent cisplatin group, and 49.4% in the multiagent-split-course group. The difference between controls and the multiagent-split-course group was statistically significant (P=0.002), but was only “marginally significant” between controls and the single-agent cisplatin patients (P=0.07). The complete response rate for the split course group included patients who underwent midcourse surgical resection, Adelstein said.

Three-year disease-specific survival rates were 33% in controls, 51% in the single agent cisplatin group, and 41% in the multiagent split course group. Toxicity rates of grade 3 or worse occurred in 51% of controls, 85% in the combination group (P < 0.0001), and 72% in the split course group (P < 0.001).

“The toxicity was manageable,” he said, “and the benefit clear.”

Obstacles of definition

One of the major obstacles to the study, Adelstein said, as well as all studies of patients with unresectable head and neck cancer, is the definition of the term “unresectability.” The anatomic criteria for the term are “not standard and vary from surgeon to surgeon and institution to institution,” Adelstein said. Age and performance status of the patient, and the willingness to accept surgical morbidity also affects resectability, all of which “makes interpretation of the literature difficult,” he said.

Chemotherapy’s role in the definitive management of patients with squamous head and neck cancer “has undergone intensive investigation during the last 30 years,” Adelstein said. Despite “surprising chemosensitivity,” extensive phase-3 testing of induction chemotherapy “has failed to demonstrate any reproducible survival benefit,” he said. Concurrent chemotherapy and radiation, however, “has been a more consistently successful treatment.”

Another question raised in the present study is why the multiagent-split-course group’s three-year survival rates were not as successful as the single-agent cisplatin arm. Some reasons, Adelstein said, could include the use of the split-course radiation therapy schedule, a strategy employed with the hope that mid-course surgery would be possible. It is, however, “a suboptimal way to deliver radiation.”

For more information:

* Adelstein DJ. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21(1):92-98.