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
Open accessAbstract
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.
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There is increasing evidence that tumors with more hypoxic cells are poorly responsive to radiation therapy.
“There is increasing evidence that tumors with more hypoxic cells are poorly responsive to radiation therapy.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [337]
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References 43 · Cited by 289
- Authors
- Koukourakis, M. I., Bentzen, S. M., Giatromanolaki, A., Wilson, G. D., Daley, F. M., Saunders, M. I., Dische, S., Sivridis, E., & Harris, A. L.
- Affiliations
- Democritus University of Thrace (GR)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2006-02-10
- Volume
- 24
- Issue
- 5
- Pages
- 727-735
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2170212327
- Cited by
- 289
- References
- 43
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 13 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 12 · 2019: 7 · 2018: 12 · 2017: 9 · 2016: 23 · 2015: 14 · 2014: 16 · 2013: 14 · 2012: 14
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Trakya Üniversitesi
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
- Keywords
- head and neck squamous cell carcinoma, tumor hypoxia, HIF-2α, carbonic anhydrase IX, HIF-1α, accelerated radiotherapy, radiotherapy failure, locoregional control, prognostic factors, pre-treatment biopsy
- MeSH terms
- Carbonic Anhydrase IX, Endothelial PAS Domain-Containing Protein 1, Antigens, Neoplasm, Biopsy, Carbonic Anhydrases, Head and Neck Neoplasms, Humans, Immunohistochemistry, Retrospective Studies, Biomarkers, Tumor, Cell Hypoxia, Treatment Outcome, Dose Fractionation, Radiation, Gene Expression Profiling, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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