Hypoxia inducible factor (HIf1alpha and HIF2alpha) and carbonic anhydrase 9 (CA9) expression and response of head-neck cancer to hypofractionated and accelerated radiotherapy

Int J Radiat Biol. 2008 Jan;84(1):47-52. 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 HIF1alpha, HIF2alpha 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 HIF1alpha, HIF2alpha and CA9, was performed in formalin-fixed paraffin-embedded tissues obtained prior to radio-chemotherapy.

Results: HIF1alpha and HIF2alpha were expressed in the nuclei and cytoplasm of cancer cells, while CA9 had a membrane reactivity. A high expression of HIF1alpha, HIF2alpha 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 HIF1alpha was marginally related with persistent disease after RT (p = 0.05). HIF1alpha was significantly associated with poor local relapse free survival (LRFS) (p = 0.006) and overall survival (p = 0.008), whilst HIF2alpha 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 HIF1alpha and CA9 in HNC predict resistance to platinum based radio-chemotherapy. Whether HIF2alpha expressing tumors are more sensitive to larger radiotherapy fractions, compared to standard radiotherapy fractionation, is an issue that deserves further investigation.

MeSH terms

  • Amifostine / therapeutic use
  • Antigens, Neoplasm / metabolism*
  • Antineoplastic Agents / therapeutic use
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biomarkers, Tumor / metabolism*
  • 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, Radiation
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / radiotherapy*
  • Humans
  • 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, Conformal


  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Organoplatinum Compounds
  • Radiation-Protective Agents
  • endothelial PAS domain-containing protein 1
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • Amifostine