title: Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02.
abstract: OBJECTIVE
  To determine the association between tumor hypoxia, treatment regimen, and locoregional failure (LRF) in patients with stage III or IV squamous cell carcinoma of the head and neck randomly assigned to radiotherapy (70 Gy in 35 fractions over 7 weeks) plus either tirapazamine and cisplatin in weeks 1, 4, and 7 and tirapazamine alone in weeks 2 and 3 (TPZ/CIS) or cisplatin and infusional fluorouracil during weeks 6 and 7 (chemoboost).
  
  
  METHODS
  Forty-five patients were enrolled onto a hypoxic imaging substudy of a larger randomized trial. Pretreatment and midtreatment [18F]-fluoromisonidazole positron emission tomography scans (FMISO-PET) were performed 2 hours after tracer administration, with qualitative scoring of uptake in both primary tumors and nodes.
  
  
  RESULTS
  Thirty-two patients (71%) had detectable hypoxia in either or both primary and nodal disease. In patients who received chemoboost, one of 10 patients without hypoxia had LRF compared with eight of 13 patients with hypoxia; the risk of LRF was significantly higher in hypoxic patients (exact log-rank, P = .038; hazard ratio [HR] = 7.1). By contrast, in patients who received the TPZ/CIS regimen, only one of 19 patients with hypoxic tumors had LRF; risk of LRF was significantly higher in chemoboost patients (P = .001; HR = 15). Similarly, looking at the primary site alone, in patients with hypoxic primaries, zero of eight patients treated with TPZ/CIS experienced failure locally compared with six of nine patients treated with chemoboost (P = .011; HR = 0).
  
  
  CONCLUSIONS
  Hypoxia on FMISO-PET imaging, in patients receiving a nontirapazamine-containing chemoradiotherapy regimen, is associated with a high risk of LRF. Our data provide the first clinical evidence to support the experimental observation that tirapazamine acts by specifically targeting hypoxic tumor cells.
authors.affiliation: Division of Haematology and Medical Oncology, Centre for Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia. Danny.Rischin@petermac.org
authors.forename: Danny
authors.initials: D
authors.lastname: Rischin
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.forename: Richard
authors.initials: R
authors.lastname: Fisher
authors.forename: David
authors.initials: D
authors.lastname: Binns
authors.forename: June
authors.initials: J
authors.lastname: Corry
authors.forename: Sandro
authors.initials: S
authors.lastname: Porceddu
authors.forename: Lester J
authors.initials: LJ
authors.lastname: Peters
mesh_terms: D015687:Cell Hypoxia; D003131:Combined Modality Therapy; D005260:Female; D019788:Fluorodeoxyglucose F18; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008920:Misonidazole / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011379:Prognosis; D000077704:Tirapazamine; D017211:Treatment Failure; D014227:Triazines / Q000627:therapeutic use*
chemical_list: D014227:Triazines; D019788:Fluorodeoxyglucose F18; D000077704:Tirapazamine; D008920:Misonidazole