title: Prognostic and predictive significance of plasma HGF and IL-8 in a phase III trial of chemoradiation with or without tirapazamine in locoregionally advanced head and neck cancer.
abstract: OBJECTIVE
  Hepatocyte growth factor (HGF) is a hypoxia-induced secreted protein that binds to cMet and regulates interleukin (IL)-8 expression. We evaluated the role of circulating HGF and IL-8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin.
  
  
  METHODS
  Patients with stages III to IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or CIS plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma sample availability for HGF and IL-8 assay by ELISA and no major radiation deviations (N = 498). Analyses included adjustment for major prognostic factors. p16(INK4A) staining (human papillomavirus surrogate) was carried out on available tumors. Thirty-nine patients had hypoxia imaging with (18)F-fluoroazomycin arabinoside ((18)FAZA)-positron emission tomography.
  
  
  RESULTS
  Elevated IL-8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (P = 0.053); elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16(INK4A)-negative patients. Four subgroups defined by high and low HGF/IL-8 levels were examined for TPZ effect; the test for interaction with arm was P = 0.099. TPZ/CIS seemed to be beneficial for patients with high HGF and IL-8 but adverse for low HGF and high IL-8. Only HGF correlated with (18)FAZA tumor standard uptake value.
  
  
  CONCLUSIONS
  IL-8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL-8/HGF levels seemed to do better with TPZ/CIS while others did worse, highlighting the complexity of hypoxia targeting in unselected patients.
authors.affiliation: Radiation Oncology & Pathology, Stanford University, Stanford, CA, USA. qle@stanford.edu
authors.forename: Quynh-Thu
authors.initials: QT
authors.lastname: Le
authors.forename: Richard
authors.initials: R
authors.lastname: Fisher
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Oliner
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Young
authors.forename: Hongbin
authors.initials: H
authors.lastname: Cao
authors.forename: Christina
authors.initials: C
authors.lastname: Kong
authors.forename: Edward
authors.initials: E
authors.lastname: Graves
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Lester
authors.initials: L
authors.lastname: Peters
authors.forename: Brian
authors.initials: B
authors.lastname: O'Sullivan
authors.forename: Amato
authors.initials: A
authors.lastname: Giaccia
authors.forename: Danny
authors.initials: D
authors.lastname: Rischin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D002294:Carcinoma, Squamous Cell / Q000097:blood* / Q000401:mortality / Q000628:therapy*; D059248:Chemoradiotherapy; D005260:Female; D006258:Head and Neck Neoplasms / Q000097:blood* / Q000401:mortality / Q000628:therapy*; D017228:Hepatocyte Growth Factor / Q000097:blood; D006801:Humans; D016209:Interleukin-8 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage*
chemical_list: D014408:Biomarkers, Tumor; D016209:Interleukin-8; D014227:Triazines; D000077704:Tirapazamine; D017228:Hepatocyte Growth Factor