Promising results in a randomized phase II trial with the hypoxic cytotoxin tirapazamine (TPZ) combined with cisplatin (CIS) and radiation led to this phase III trial.

Patients with previously untreated stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either CIS (100 mg/m²) on day 1 of weeks 1, 4, and 7 or CIS (75 mg/m²) plus TPZ (290 mg/m²/d) on day 1 of weeks 1, 4, and 7 and TPZ alone (160 mg/m²/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS). The primary end point was overall survival (OS). The planned sample size was 850, estimated to result in 334 deaths, which would provide 90% power to detect a difference in 2-year survival rates of 60% v 70% for CIS versus TPZ/CIS, respectively (hazard ratio = 0.69).

Eight hundred sixty-one patients were accrued from 89 sites in 16 countries. In an intent-to-treat analysis, the 2-year OS rates were 65.7% for CIS and 66.2% for TPZ/CIS (TPZ/CIS – CIS: 95% CI, −5.9% to 6.9%). There were no significant differences in failure-free survival, time to locoregional failure, or quality of life as measured by Functional Assessment of Cancer Therapy–Head and Neck.

We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS.