Double-Blind, Randomized Phase 3 Trial of Low-Dose 13-Cis Retinoic Acid in the Prevention of Second Primaries in Head and Neck Cancer: Long-Term Follow-Up of a Trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590)

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Abstract

13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS).In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5?mg or 10?mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups.13-CRA neither significantly reduced the cumulative incidence of SPT (P?=?.61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P?=?.61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P?=?.14), particularly among patients whose index tumor was surgically excised (N?=?26; HR, 0.50; P?=?.057) and among women (N?=?39; HR, 0.44; P?=?.065) and never/former smokers (N?=?129; HR, 0.61; P?=?.055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis.Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women 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. Cancer 2017;123:4653-4662. © 2017 American Cancer Society.

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