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The purpose of this study was to determine the efficacy and toxicities of single-agent weekly cisplatin for patients with squamous cell carcinoma of the head and neck treated definitively with radiation therapy (RT).Thirty-five patients with American Joint Committee of Cancer stage II (3%), stage III (14%), or stage IV (83%) squamous cell carcinoma of the oropharynx, larynx, or hypopharynx treated from June 2000 to November 2003 at the University of Florida were retrospectively reviewed. Subjects received radiation therapy (RT; median, 74.4 Gy) and cisplatin, 30 mg/m2/wk. Altered fractionation was used in 34 of 35 (97%) patients. The endpoints were best response, percentage of grade III or IV toxicities, local-regional control, disease-free survival, cause-specific survival, and overall survival.The median number of cycles of cisplatin administered was 6. Grade III or IV toxicities were: anemia, 11%; thrombocytopenia, 6%; leukopenia, 26%; and mucositis, 23%. No patients had renal failure and 1 patient (3%) died because of therapy-related complications. Responses to therapy included 71% complete response, 17% partial response, and 6% stable disease. Median follow-up for all patients was 1.8 years (range, 0.1–7.8 years); median follow-up for living patients was 4.4 years (range, 2.6–7.8 years). The 3-year outcomes were: local-regional control, 85%; disease-free survival, 56%; cause-specific survival, 59%; and overall survival, 40%.Concomitant weekly CDDP with definitive RT is feasible, tolerable, highly active, and comparable with more complex, costly, and toxic regimens. Intercurrent disease was a significant contributor to mortality in our population. Our regimen is an attractive alternative to sequential chemoradiotherapy programs.