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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

Danny Rischin, Rodney J. Hicks, Richard Fisher, David Binns, June Corry, Sandro Porceddu, Lester J. Peters

From the Division of Haematology and Medical Oncology, Centre for Molecular Imaging, Division of Radiation Oncology, and Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre; University of Melbourne, Melbourne; and Trans-Tasman Radiation Oncology Group, Newcastle, Australia.

Address reprint requests to Danny Rischin, MBBS, FRACP, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag No. 1, A'Beckett St, Melbourne 8006, Australia; e-mail: Danny.Rischin{at}petermac.org

PURPOSE: 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).

PATIENTS AND 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).

CONCLUSION: 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.

Supported in part by Sanofi-Aventis.

Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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