Phase 1 Study of Tirapazamine in Combination With Radiation and Weekly Cisplatin in Patients With Locally Advanced Cervical Cancer
- 1 June 2010
- journal article
- Published by BMJ in International Journal of Gynecologic Cancer
- Vol. 20 (5), 827-833
- https://doi.org/10.1111/igc.0b013e3181dc827e
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/m2 on weeks 1 to 6 and weekly intravenous tirapazamine, 290 mg/m2 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/m2 dose of cisplatin and a 260-mg/m2 dose of tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level −1a: a 35-mg/m2 dose of cisplatin and a 260-mg/m2 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/m2 and cisplatin 30 mg/m2. Further study of this weekly schedule is not warranted.Keywords
This publication has 17 references indexed in Scilit:
- Phase II Study of Tirapazamine, Cisplatin, and Etoposide and Concurrent Thoracic Radiotherapy for Limited-Stage Small-Cell Lung Cancer: SWOG 0222Journal of Clinical Oncology, 2009
- When is being in a hurry going too fast? Lessons learned from clinical trials in cervical cancerGynecologic Oncology, 2009
- Tirapazamine, Cisplatin, and Radiation Versus Fluorouracil, Cisplatin, and Radiation in Patients With Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02)Journal of Clinical Oncology, 2005
- Tumor Hypoxia Has Independent Predictor Impact Only in Patients With Node-Negative Cervix CancerJournal of Clinical Oncology, 2002
- Tirapazamine Plus Cisplatin Versus Cisplatin in Advanced Non–Small-Cell Lung Cancer: A Report of the International CATAPULT I Study GroupJournal of Clinical Oncology, 2000
- Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for Locally Advanced Cervical CancerThe New England Journal of Medicine, 1999
- Pelvic Radiation with Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical CancerThe New England Journal of Medicine, 1999
- Intratumoral PO2 Histography as Predictive Assay in Advanced Cancer of the Uterine CervixAdvances in experimental medicine and biology, 1994
- SR 4233 (Tirapazamine): a new anticancer drug exploiting hypoxia in solid tumoursBritish Journal of Cancer, 1993
- Prediction of Creatinine Clearance from Serum CreatinineNephron, 1976