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

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Quynh-Thu Le, Richard Fisher, Kelly S Oliner, Richard J Young, Hongbin Cao, Christina Kong, Edward Graves, Rodney J Hicks, Grant A McArthur, Lester Peters, Brian O'Sullivan, Amato Giaccia, Danny Rischin
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 6 Pg. 1798-807 (Mar 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22383739 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Biomarkers, Tumor
• Interleukin-8
• Triazines
• Tirapazamine
• Hepatocyte Growth Factor

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (blood)
• Carcinoma, Squamous Cell (blood, mortality, therapy)
• Chemoradiotherapy
• Female
• Head and Neck Neoplasms (blood, mortality, therapy)
• Hepatocyte Growth Factor (blood)
• Humans
• Interleukin-8 (blood)
• Male
• Middle Aged
• Positron-Emission Tomography
• Tirapazamine
• Triazines (administration & dosage)