title: Phase 1 study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. danny.rischin@petermac.org
authors.forename: Danny
authors.initials: D
authors.lastname: Rischin
authors.forename: Kailash
authors.initials: K
authors.lastname: Narayan
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.forename: Linda
authors.initials: L
authors.lastname: Mileshkin
authors.forename: David
authors.initials: D
authors.lastname: Bernshaw
authors.forename: Jimin
authors.initials: J
authors.lastname: Choi
authors.forename: Rodney
authors.initials: R
authors.lastname: Hicks
authors.forename: Bev
authors.initials: B
authors.lastname: McClure
authors.forename: Anthony
authors.initials: A
authors.lastname: Fyles
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D018307:Neoplasms, Squamous Cell / Q000628:therapy*; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage; D002583:Uterine Cervical Neoplasms / Q000628:therapy*
chemical_list: D014227:Triazines; D000077704:Tirapazamine; D002945:Cisplatin