Originally published as JCO Early Release 10.1200/JCO.2005.02.7474 on January 17 2006

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Endogenous Markers of Two Separate Hypoxia Response Pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) Are Associated With Radiotherapy Failure in Head and Neck Cancer Patients Recruited in the CHART Randomized Trial

From the Departments of Radiotherapy/Oncology and Pathology, Democritus University of Thrace, Alexandroupolis, Greece; Gray Cancer Institute and the Cancer Centre, Mount Vernon Hospital; University College London; Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom; and the Barbara Ann Karmanos Cancer Institute, Detroit, MI

Address reprint requests to Adrian L. Harris, MD, Cancer Research UK, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom, OX3 7LJ; e-mail: aharris.lab{at}cancer.org.uk

PURPOSE: Randomized controlled trials have generally shown a benefit from accelerated radiotherapy in head and neck squamous cell carcinoma (HNSCC). However, the large randomized United Kingdom trial CHART (Continuous Hyperfractionated Accelerated Radiotherapy) failed to show a benefit of strongly accelerated over standard radiotherapy (RT) in 918 patients with HNSCC. In this study, we investigated the impact of tumor hypoxia on the outcome of HNSCC patients in the CHART trial. There are two distinct hypoxia inducible factors (HIFs) that control different gene response pathways and we assessed them both with endogenous markers of hypoxia, hypoxia inducible factor HIF-2 alpha (HIF-2) and carbonic anhydrase CA9, an indicator of HIF-1 alpha (HIF-1) function.

METHODS: Tissue from pre-RT biopsies performed in 198 of 918 patients recruited was analyzed for the immunohistochemical expression of HIF-2 and CA9.

RESULTS: A significant association of high HIF2 and of high CA9 reactivity with poor locoregional control (P < .0001 and P = .0002, respectively) and poor survival (P = .0004 and 0.002, respectively) was noted. In multivariate analysis, HIF-2 and CA9 maintained their independent prognostic significance. Coexpression of both pathways had an additive effect, supporting their independent role. The uni-directional hypothesis, that a benefit from randomization to CHART should be seen in the nonhypoxic tumors, was supported by the data (one-tailed P = .04).

CONCLUSION: Expression of endogenous markers of hypoxia for the HIF-1 and HIF-2 pathway is strongly associated with radiotherapy failure. Using immunohistochemical methods it is possible to identify subgroups of HNSCC patients who are highly curable with radiotherapy, or who are excellent candidates for clinical trials on hypoxia-targeting drugs in two distinct pathways.

Supported by the University of Thrace (M.I.K., A.G., and E.S.), the National Health Service (S.M.B., S.D., M.I.S., and F.M.D.), the University of Oxford (A.L.H.), the Medical Research Council, the Tumor and Angiogenesis Research Group, Cancer Research UK, and European Union grant Euroxy.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

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

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