Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer

Purpose: To determine the maximum-tolerated dose of tirapazamine when combi ned with cisplatin and radiation in patients with T3/4 and/or N2/3 squamous cell carcinoma of the head and neck. Patients and Methods: The starting schedule was conventionally fractionated radiotherapy (70 Gy in 7 weeks) with concomitant cisplatin 75 mg/m(2) and tirapazamine 290 mg/m(2) (before cisplatin) in weeks 1, 4, and 7 and tirapa zamine alone 160 mg/m(2) three times a week in weeks 2, 3, 5, and 6. Positr on emission tomography scans for tumor hypoxia (F-18 misonidazole) were per formed before and during radiotherapy. Results: We treated 16 patients with predominantly oropharyngeal primary tu mors, including 10 patients with T4 or N3 disease. Febrile neutropenia occu rred toward the end of radiotherapy in three out of six patients treated on the initial dose level. Two of these patients also developed grade 4 acute radiation reactions. Another 10 patients were treated with the same doses, but the week 5 and week 6 tirapazamine doses were omitted. This resulted i n less neutropenia and only one dose-limiting toxicity (DLT) (febrile neutr openia), and eight out of 10 patients completed treatment without any dose omissions. In these 10 patients, the acute radiation toxicities were not ob viously enhanced compared with chemoradiotherapy regimens using concurrent platinum and fluorouracil. F-18 misonidazole scans detected hypoxia in 14 o f 15 patients at baseline, with only one patient having detectable hypoxia at the end of treatment. With a median follow-up of 2.7 years, the 3-year f ailure-free survival rate was 69%(SE, 12%), the 3-year local progression-fr ee rate was 88% (SE, 8%), and the 3-year overall survival rate was 69% (SE, 12%). Conclusion: DLT was due unexpectedly to febrile neutropenia, which could be overcome by omitting tirapazamine in weeks 5 and 6. The combination of tir apazamine, cisplatin, and radiotherapy resulted in remarkably good and dura ble clinical responses in patients with very advanced head and neck cancers . It warrants further investigation. J Clin Oncol 19:535-542. (C) 2001 by A merican Society of Clinical Oncology.