title: The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy +/- chemotherapy.
abstract: BACKGROUND
  Several parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols. The purpose of this study was to investigate the inter-relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma (HNSCC) treated by radiotherapy +/- chemotherapy.
  
  
  METHODS
  We used two subgroups of a retrospective series for which CT-determined tumoral perfusion correlated with local control. In the first subgroup (n = 67), immunohistochemistry for carbonic anhydrase IX (CA IX) and glucose transporter-1 (GLUT-1) was performed on the pretreatment tumor biopsy. In the second subgroup (n = 34), enzyme linked immunosorbent assay (ELISA) was used to determine pretreatment levels of the cytokines vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated.
  
  
  RESULTS
  For CA IX and GLUT-1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control (p = 0.02) and disease-free survival (p = 0.04) with a trend for regional control (p = 0.06). In the second subgroup, IL-6 pretreatment serum level above the median was the only independent predictor of local control (p = 0.009), disease-free survival (p = 0.02) and overall survival (p = 0.005).
  
  
  CONCLUSIONS
  To our knowledge, we are the first to report a link in HNSCC between IL-6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL-6 with local control, known to be the most important parameter to judge radiotherapy responses. Furthermore, the combined assessment of CA IX and GLUT-1 correlated independently with prognosis. This is a valuable indication that a combined approach is important in the investigation of prognostic markers.
authors.affiliation: Department of Radiation Oncology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. harlinde.deschutter@uz.kuleuven.ac.be
authors.forename: Harlinde
authors.initials: H
authors.lastname: De Schutter
authors.forename: Willy
authors.initials: W
authors.lastname: Landuyt
authors.forename: Erik
authors.initials: E
authors.lastname: Verbeken
authors.forename: Laurence
authors.initials: L
authors.lastname: Goethals
authors.forename: Robert
authors.initials: R
authors.lastname: Hermans
authors.forename: Sandra
authors.initials: S
authors.lastname: Nuyts
mesh_terms: D000951:Antigens, Neoplasm / Q000097:blood*; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000097:blood*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000097:blood*; D006258:Head and Neck Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood*; D015999:Multivariate Analysis; D010477:Perfusion; D011379:Prognosis; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases