RESULTS OF AN RTOG PHASE-III TRIAL (RTOG-85-27) COMPARING RADIOTHERAPY PLUS ETANIDAZOLE WITH RADIOTHERAPY ALONE FOR LOCALLY ADVANCED HEAD AND NECK CARCINOMAS

Purpose: The objectives of this study were to determine the efficacy a nd toxicity of Etanidazole (ETA), a hypoxic cell sensitizer, when comb ined with conventional radiotherapy (RT) in the management of advanced head and neck carcinomas. Methods and Materials: From March 1988 to S eptember 1991, 521 patients who had Stage III or IV head and neck carc inomas were randomized to receive conventional RT alone (66 Gy in 33 f ractions to 74 Gy in 37 fractions, 5 fractions per week) or RT+ETA (2. 0 g/m(2) thrice weekly for 17 doses), of whom 504 were eligible and an alyzable. Treatment assignments were stratified before randomization a ccording to the primary site (oral cavity + hypopharynx vs. supraglott ic larynx + oropharynx + nasopharynx), T-stage (T1-3 vs. T4), and N-st age (N0-2 vs. N3). Pretreatment characteristics were balanced. In the RT-alone arm, 39% of patients had T3 and 34% had T4 disease, whereas i n the RT+ETA arm, 42% of patients had T3 and 33% had T4 disease. Thirt y-eight percent of the RT-alone patients and 37% of the RT+ETA patient s had N3 disease. The median fellow-up of surviving patients was 3.38 years, with a range between 0.96 and 5.63 years. Results: One hundred and ninety-four of the 252 (77%) RT+ETA patients received at least 14 doses of the drug. Overall RT protocol compliance rate was 82% in the RT-alone arm and 86% in the RT+ETA arm. No Grade 3 or 4 central nervou s system or peripheral neuropathy was observed in the RT+ETA arm. Eigh teen percent of the patients developed Grade 1 and 5% developed Grade 2 peripheral neuropathy. Other drug related toxicities included nausea /vomiting (27%), low blood counts (15%), and allergy (9%). Most of the se toxicities were Grade 1 and 2. The incidence of severe acute and la te radiation effects were similar between the two arms. The 2-year act uarial local-regional control rate (LCR) was 40% for the RT-alone arm and 40% for the RT+ETA arm, Two-year actuarial survival was 41% for th e RT-alone arm and 43% for the RT+ETA arm (p = 0.65). Multivariate ana lyses were performed to investigate the influence of covariates on tre atment effects. A strong treatment interaction with N-stage was reveal ed: LCR (50% vs. 40% at 2 years), RT+ETA improved for patients with N0 -2 disease but not for N3 patients (22% for RT+ETA and 40% for RT). Fu rther analyses showed that RT+ETA was more advantageous in N0-1 patien ts, with a 2-year LCR of 55% for RT+ETA vs. 37% for RT only (p = 0.03) . A similar phenomenon was observed when using survival as the end poi nt. Conclusion: The results showed that adding Etanidazole to conventi onal RT produced no global benefit for patients who had advanced head and neck carcinomas. There was a suggested benefit for patients who ha d N0-1 disease, and that needs to be confirmed by another study.