Predictive Classifier for Intensive Treatment of Head and Neck Cancer

Background: Predictors to identify which patients with locoregionally advanced head and neck cancer (LAHNC) benefit from intensive treatment are lacking. We sought to test the hypothesis that patients with a higher risk of cancer recurrence relative to competing mortality (ω score) selectively benefit from altered fractionation (AFX; MARCH data) and/or chemotherapy (MACH-NC data). Methods: We analyzed 22,339 LAHNC patients treated on 81 randomized trials testing AFX (MARCH data set) or chemotherapy (MACH-NC dataset). We applied generalized competing event regression to the control arms in MARCH, stratifying patients by tertile according to ω score. Model covariates were age, performance status (PS), sex, site, T and N category, p16 status, and smoking history. We externally validated the classifier on the MACH-NC dataset. We tested for interactions between ω score and treatment effects on overall survival (OS). Findings: Factors associated with a higher ω score were lower age, better PS, oral cavity site, higher T/N category, and p16 negative/unknown status. The effect of AFX on OS was greater in patients with high (hazard ratio [HR], 0.92; 95% CI, 0.85 to 0.99) and medium (HR, 0.91; 95% confidence interval [CI], 0.84 to 0.98) vs. low ω score (HR, 0.97; 95% CI, 0.90 to 1.05; p=0.086 for interaction). The effect of chemotherapy on OS was significantly greater in patients with high (HR, 0.81; 95% CI, 0.75 to 0.88) and medium (HR, 0.86; 95% CI, 0.78 to 0.88) vs. low ω score (HR, 0.96; 95% CI, 0.86 to 1.08; p=0.011 for interaction). Interpretation: LAHNC patients with a higher risk of cancer progression relative to competing mortality - as reflected by a higher ω score - selectively benefit from more intensive treatment. Funding Statement: Ligue National Contre le Cancer, Institut National du Cancer (PHRC-K 10-02-58; PHRC-K-15-189), Programme d'Actions Integrees de Recherche (2011-1-VADS-04), UC San Diego Head and Neck Cancer Center. Declaration of Interests: KZ, BL, LKV, QTL, VG, JO, AH, BZ, MKBP, BB, MGG, GS, BO, CF, JB, HS, JH, SM, JPP, LKM – none; FR is an employee of Innate Pharma, Marseille (France). Ethics Approval Statement: Analysis and reporting conformed to the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, and followed a pre-specified protocol for the analysis.