Pilot study of nimorazole as a hypoxic-cell sensitizer with the "CHART" regimen in head and neck cancer

Purpose: A potential disadvantage of accelerated fractionation in radiotherapy is the lack of time for reoxygenation, so that hypoxia becomes a more potent cause of failure. Accordingly, we have combined nimorazole, the only hypoxic radiosensitizer shown to significantly improve local control in head and neck cancer, with continuous hyperfractionated accelerated radiation therapy (CHART). Methods and Materials: Twenty-two patients with locally advanced (stage IV) squamous cell carcinoma of the head and neck were treated with escalating doses of nimorazole given concomitantly with CHART (three fractions of 1.5 Gy per day, spaced 5 1/2 hours apart, on 12 consecutive days). All patients received 1.2 g/m(2) nimorazole 90 minutes before each first daily fraction. Seventeen patients received a further 0.6 g/m(2) before each second daily fraction and six of these patients received an additional dose of 0.6 g/m(2) before each third fraction. Results: The three times daily schedule yielded mean plasma drug concentrations at the time of irradiation of 37.7 mu g/ml with the morning fractions, 31.2 mu g/ml with the afternoon fractions, and 30.4 mu g/ml with the evening fractions, In view of these results the midday dose was increased to 0.9 mu g/m(2) in an ongoing Phase II study. Drug toxicity was limited to nausea and vomiting apart from two cases of mild paraesthesia at the highest dose level. Conclusions: Comparison with a historical group of patients, treated with the CHART regimen alone and matched for irradiation volume and technique, showed that nimorazole did not increase the severity of acute normal tissue radiation effects. Encouraging tumor responses have been seen in the patients receiving nimorazole with every radiotherapy fraction. (C) 1998 Elsevier Science Inc.