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


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).


CONCLUSIONS
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.
Koukourakis
Michael I
MI
Department of Radiotherapy/Oncology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece. targ@her.forthnet.gr
Giatromanolaki
Alexandra
A
Danielidis
Vassilios
V
Sivridis
Efthimios
E
D004999:Amifostine / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D015687:Cell Hypoxia; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003131:Combined Modality Therapy; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D019610:Cytoprotection; D019583:Dose Fractionation, Radiation; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011446:Prospective Studies; D011836:Radiation Tolerance; D011837:Radiation-Protective Agents / Q000627:therapeutic use; D020266:Radiotherapy, Conformal; D000099162:Endothelial PAS Domain-Containing Protein 1
D004999:Amifostine; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009944:Organoplatinum Compounds; D011837:Radiation-Protective Agents; D000099162:Endothelial PAS Domain-Containing Protein 1; C089226:CA9 protein, human