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Nuclear Factor-B–Related Serum Factors as Longitudinal Biomarkers of Response and Survival in Advanced Oropharyngeal Carcinoma

Authors' Affiliations: ¹ Tumor Biology Section, Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders and ² Biometrics Research Branch, National Cancer Institute, NIH, Bethesda, Maryland and ³ Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Carter Van Waes, Tumor Biology Section, Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders, 10 Center Drive, CRC Room 4-2732, Bethesda, MD 20892. Phone: 301-402-4216; Fax: 301-402-1140; E-mail: vanwaesc{at}nidcd.nih.gov.

Purpose: Cytokines and growth factors modulated by transcription factor nuclear factor-B and secreted by tumor and stromal cells are detectable in serum of patients with advanced cancers, including head and neck squamous cell carcinomas (SCC). Longitudinal changes in these serum factors could be early biomarkers of treatment response and survival.

Experimental Design: Interleukin (IL)-6, IL-8, growth-related oncogene-1 (GRO-1), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) concentrations were determined by Luminex multiplex assay using serum obtained at baseline and every 3 months in a prospective study of 30 patients with locally advanced (stage III/IV) oropharyngeal SCC receiving chemoradiation therapy. The relationship between baseline and direction of change in individual and multiple cytokines with cause-specific and disease-free survival was determined by Cox proportional hazards models and Kaplan-Meier survival analysis. Statistical analyses included adjustment for smoking status and response to chemoradiation.

Results: Three-year cause-specific and disease-free survival was 74.4% and 68.9%. Nonsmoking history (P = 0.05) and higher baseline VEGF (P = 0.003) correlated with increased survival. Longitudinal increases in levels of individual factors predicted decreased cause-specific survival when adjusted for smoking history [IL-6: relative risk (RR), 3.8; 95% confidence interval (95% CI), 2.0-7.4; P = 0.004; IL-8: RR, 1.6; 95% CI, 1.2-2.2; P = 0.05; VEGF: RR, 3.0; 95% CI, 1.6-5.6; P = 0.01; HGF: RR, 2.9; 95% CI, 1.9-4.4; P = 0.02; and GRO-1: RR, 1.2; 95% CI, 1.1-1.3; P = 0.02]. For a given individual, large increases in the upper quartile for any three or more factors predicted poorer cause-specific survival compared with patients with two or fewer large increases in factor levels (P = 0.004).

Conclusions: Pretreatment VEGF levels and longitudinal change in IL-6, IL-8, VEGF, HGF, and GRO-1 may be useful as biomarkers for response and survival in patients with locally advanced oropharyngeal and head and neck SCC treated with chemoradiation.

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