title: Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose of tirapazamine when combined with cisplatin and radiation in patients with T3/4 and/or N2/3 squamous cell carcinoma of the head and neck.
  
  
  METHODS
  The starting schedule was conventionally fractionated radiotherapy (70 Gy in 7 weeks) with concomitant cisplatin 75 mg/m2 and tirapazamine 290 mg/m2 (before cisplatin) in weeks 1, 4, and 7 and tirapazamine alone 160 mg/m2 three times a week in weeks 2, 3, 5, and 6. Positron emission tomography scans for tumor hypoxia (18F misonidazole) were performed before and during radiotherapy.
  
  
  RESULTS
  We treated 16 patients with predominantly oropharyngeal primary tumors, including 10 patients with T4 or N3 disease. Febrile neutropenia occurred 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 in less neutropenia and only one dose-limiting toxicity (DLT) (febrile neutropenia), and eight out of 10 patients completed treatment without any dose omissions. In these 10 patients, the acute radiation toxicities were not obviously enhanced compared with chemoradiotherapy regimens using concurrent platinum and fluorouracil. 18F misonidazole scans detected hypoxia in 14 of 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 failure-free survival rate was 69% (SE, 12%), the 3-year local progression-free rate was 88% (SE, 8%), and the 3-year overall survival rate was 69% (SE, 12%).
  
  
  CONCLUSIONS
  DLT was due unexpectedly to febrile neutropenia, which could be overcome by omitting tirapazamine in weeks 5 and 6. The combination of tirapazamine, cisplatin, and radiotherapy resulted in remarkably good and durable clinical responses in patients with very advanced head and neck cancers. It warrants further investigation.
authors.affiliation: Division of Hematology and Medical Oncology, and Statistical Centre, Peter MacCallum Cancer Institute, Melbourne, Australia. drischin@petermarc.unimelb.edu.au
authors.forename: D
authors.initials: D
authors.lastname: Rischin
authors.forename: L
authors.initials: L
authors.lastname: Peters
authors.forename: R
authors.initials: R
authors.lastname: Hicks
authors.forename: P
authors.initials: P
authors.lastname: Hughes
authors.forename: R
authors.initials: R
authors.lastname: Fisher
authors.forename: R
authors.initials: R
authors.lastname: Hart
authors.forename: M
authors.initials: M
authors.lastname: Sexton
authors.forename: I
authors.initials: I
authors.lastname: D'Costa
authors.forename: R
authors.initials: R
authors.lastname: von Roemeling
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D015687:Cell Hypoxia; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D019788:Fluorodeoxyglucose F18; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D008875:Middle Aged; D008920:Misonidazole / Q000031:analogs & derivatives*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D019275:Radiopharmaceuticals; D016019:Survival Analysis; D000077704:Tirapazamine; D014055:Tomography, Emission-Computed; D014227:Triazines / Q000008:administration & dosage
chemical_list: D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D014227:Triazines; C031843:fluoromisonidazole; D019788:Fluorodeoxyglucose F18; D000077704:Tirapazamine; D008920:Misonidazole; D002945:Cisplatin