Hypoxia inducible factor (HIF1α and HIF2α) and carbonic anhydrase 9 (CA9) expression and response of head-neck cancer to hypofractionated and accelerated radiotherapy

• Published in: International journal of radiation biology 2008, Vol.84 (1), p.47-52
• Main Authors: Koukourakis, Michael I., Giatromanolaki, Alexandra, Danielidis, Vassilios, Sivridis, Efthimios
• Format: Article
• Language: English
• Subjects: acceleration; Amifostine - therapeutic use; Antigens, Neoplasm - metabolism; Antineoplastic Agents - therapeutic use; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biomarkers, Tumor - metabolism; carbonic anhydrase; Carbonic Anhydrase IX; Carbonic Anhydrases - metabolism; Cell Hypoxia; Cell Membrane - metabolism; Cell Membrane - pathology; Cell Nucleus - metabolism; Cell Nucleus - pathology; Combined Modality Therapy; Cytoplasm - metabolism; Cytoplasm - pathology; Cytoprotection; Dose Fractionation; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - radiotherapy; HNC; Humans; hypofractionation; hypoxia inducible factor; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Neoplasm Recurrence, Local - prevention & control; Organoplatinum Compounds - therapeutic use; Prospective Studies; Radiation Tolerance; Radiation-Protective Agents - therapeutic use; Radiotherapy; Radiotherapy, Conformal; Space life sciences
• ISSN: 0955-3002; 1362-3095
• DOI: 10.1080/09553000701616114

Purpose: Tumor hypoxia and low intrinsic radiosensitivity may counteract the efficacy of standard radiotherapy for locally advanced head and neck cancer (HNC). We investigated the involvement of hypoxia-regulated proteins (Hypoxia inducible factors HIF1α, HIF2α and carbonic anhydrase CA9) in HNC resistance to accelerated and hypofractionated radiotherapy. Materials and methods: Thirty-nine patients with locally advanced HNC received 15 daily fractions of 3.4 Gy amounting to a total tumor dose of 51 Gy (equivalent to 63 Gy in four weeks - one week split); this was combined with platinum chemotherapy and amifostine cytoprotection administered subcutaneously. Immunohistochemical analysis of hypoxia-regulated proteins, namely HIF1α, HIF2α and CA9, was performed in formalin-fixed paraffin-embedded tissues obtained prior to radio-chemotherapy. Results: HIF1α and HIF2α were expressed in the nuclei and cytoplasm of cancer cells, while CA9 had a membrane reactivity. A high expression of HIF1α, HIF2α and CA9 was noted in 21 39 (53.8%), 20 39 (51.3%) and 23 39 (58.9%) cases, respectively. Complete response was obtained in 85.2% of patients and HIF1α was marginally related with persistent disease after RT (p = 0.05). HIF1α was significantly associated with poor local relapse free survival (LRFS) (p = 0.006) and overall survival (p = 0.008), whilst HIF2α was not. A significant association of CA9 expression with poor LRFS was noted (p = 0.01). Conclusion: In accord with previously reported studies, high levels of the hypoxia regulated proteins HIF1α and CA9 in HNC predict resistance to platinum based radio-chemotherapy. Whether HIF2α expressing tumors are more sensitive to larger radiotherapy fractions, compared to standard radiotherapy fractionation, is an issue that deserves further investigation.