Phase 1 study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer

Abstract

Introduction: Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. The aim of this phase I study was to develop a well-tolerated regimen that added tirapazamine to the standard regimen of radiation and weekly low-dose cisplatin.

Methods: Eligible patients had previously untreated carcinoma of the cervix, stages IB2 to IVA. The starting schedule was radiotherapy (45-50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly intravenous cisplatin, 40 mg/m on weeks 1 to 6 and weekly intravenous tirapazamine, 290 mg/m in weeks 1 to 5.

Results: Eleven patients were enrolled. The median age was 52 years (range, 31-65 years). Ten patients had squamous cell carcinoma and 1 patient had adenocarcinoma; 5 patients had stage 1B2 disease, 1 had stage IIA, 3 had stage IIB-3, 1 had stage IIIB, and 1 had stage IVA. The first 2 patients on dose level 1 experienced a dose-limiting toxicity (DLT): 1 experienced grade 3 alanine amino transferase elevation and grade 4 pulmonary embolism, and 1 experienced grade 3 ototoxicity. Doses were decreased to dose level -1 with a 30-mg/m dose of cisplatin and a 260-mg/m dose of tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a: a 35-mg/m dose of cisplatin and a 260-mg/m doses of tirapazamine with 2 DLTs--grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. Three of 10 evaluable patients have experienced locoregional failure.

Conclusions: The combination of weekly tirapazamine and cisplatin with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being tirapazamine 260 mg/m and cisplatin 30 mg/m. Further study of this weekly schedule is not warranted.