title: The prognostic value of endogenous hypoxia-related markers for head and neck squamous cell carcinomas treated with ARCON.
abstract: OBJECTIVE
  Hypoxic radioresistance is an important cause for treatment failure in a number of tumor types including head and neck cancers. Recent studies suggest that outcome can be improved by oxygenation modifying treatments such as ARCON. A robust endogenous marker of hypoxia might be a valuable aid to select patients for such treatments. The aim of this investigation was to study associations between the putative endogenous hypoxia markers CA-IX, Glut-1 and Glut-3 and clinical tumor and patient characteristics and to evaluate the prognostic value of these markers.
  
  
  METHODS
  Tumor biopsies from 58 patients treated with ARCON in a phase II trial were included. Tumor sections were immunohistochemically stained for CA-IX, Glut-1 and Glut-3. Sections were scored for relative tumor area stained by the markers (CA-IX and Glut-3) and for intensity of staining (Glut-1 and Glut-3). Further, sections were stained for CD34, an endothelial marker to assess microvascular density.
  
  
  RESULTS
  Staining of CA-IX and Glut-3 was observed at some distance from vessels and adjacent to necrosis. Glut-1 staining was generally very diffuse. The distribution of clinical characteristics was equal between tumors with high and low marker expression. Significant differences were found for locoregional control (P = 0.04) and for freedom of distant metastases (P = 0.02) in favour of patients with high CA-IX positivity (>25% of tumor area). High Glut-3 expression was associated with a better locoregional control (P = 0.04). Higher Glut-1 intensity was associated with an increased rate of distant metastases (P = 0.0005) and a worse overall survival (P = 0.001).
  
  
  CONCLUSIONS
  The inconsistent associations with outcome of CA-IX and the glucose transporters indicate that different factors play a role in up-regulation of these markers. Compared to studies with conventional treatment, the correlation between CA-IX expression and Glut-3 expression and outcome was reversed after treatment with ARCON. This does not support the potential of any of these proteins as very specific and robust hypoxia markers.
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Jonathan
authors.forename: Karien I E M
authors.initials: KI
authors.lastname: Wijffels
authors.forename: Wenny
authors.initials: W
authors.lastname: Peeters
authors.forename: Peter C M
authors.initials: PC
authors.lastname: de Wilde
authors.forename: Henri A M
authors.initials: HA
authors.lastname: Marres
authors.forename: Matthias A W
authors.initials: MA
authors.lastname: Merkx
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.forename: Albert J
authors.initials: AJ
authors.lastname: van der Kogel
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D002245:Carbon Dioxide / Q000008:administration & dosage*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000473:pathology / Q000532:radiotherapy*; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D051272:Glucose Transporter Type 1 / Q000032:analysis / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000032:analysis / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage*; D010100:Oxygen / Q000008:administration & dosage*; D011237:Predictive Value of Tests; D011379:Prognosis; D011829:Radiation Dosage; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D002245:Carbon Dioxide; D009536:Niacinamide; C011700:carbogen; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D010100:Oxygen