Double blind phase III trial of effects of low dose 13-cisretinoic acid on prevention of second primaries in stages I-II head and neck cancer: A trial of the ECOG-ACRIN Cancer Research Group (C0590).

Abstract

1507 Background: 13-Cisretinoic acid (13-CRA) is a synthetic derivative of Vitamin A. Trials of high-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHN) showed encouraging results. We report the results of a long-term Phase III randomized trial that compared low-dose 13-CRA versus placebo, among patients with early-stage SCCHN in development of second primary tumors (SPTs) and overall survival (OS). Methods: 176 patients treated for Stage I/II SCCHN were randomized to low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for two years, with additional 5 years of follow-up. The Kaplan-Meier method was used to estimate the survival distribution of time to SPTs and time to all-cause death (OS). Results: 13-CRA did not significantly reduce the number of SPTs (22/91 in the 13-CRA vs 23/85 in the placebo arm, p = 0.73). The most common sites of SPTs were head and neck (11) and lung (10). No significant differences in second primary-free survival between the arms were noted (Hazard ratio (HR) 0.79, 95% confidence interval (CI) = 0.44 to 1.42, p= 0.42). Despite limited power, there was a trend to improved OS for the 13-CRA arm (HR 0.75, 95% CI 0.51 to 1.10, p = 0.14) particularly among female patients (N=39, HR 0.44, 95% CI 0.18 to 1.05, p = 0.065) and never/former smokers (N=129, HR 0.61, 95% CI 0.37 to 1.01, p = 0.055), at 15 years. HRs for death comparing never-smokers vs current and former smokers vs current smokers were 0.05 and 0.26, respectively (p=0.003 and p<0.0001, respectively). 77% patients received at least 1 year of treatment and 52% completed 2 years. Main 13-CRA related toxicites were fatigue, dry skin, cheilitis, nausea and elevated triglycerides and were mostly low-grade. Conclusions: Low-dose 13-CRA for 2 years did not demonstrate a significant benefit in decreasing the incidence of SPTs or prolonging OS, despite some potential survival advantages observed among female patients and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials.