-Difluoromethylornithine Ototoxicity: Chemoprevention Clinical Trial Results

Abstract

To determine the effects of low-dose oral eflornithine hydrochloride (difluoromethylornithine [DFMO]) administration on hearing and to identify factors that influence those effects. Combined data from 2 studies: a prospective, randomized phase 1 clinical trial of eflornithine (n = 26 subjects) and a prospective, randomized, placebo-controlled phase 2 clinical trial of eflornithine (n = 40 subjects). Ambulatory academic tertiary care referral center. Sixty-six volunteer subjects who had previously treated bladder, prostate, or colon cancer with no current evidence of neoplastic disease, or who were healthy individuals at increased risk for colon cancer, all without need of hearing amplification. Subjects were randomized to receive oral eflornithine at daily doses between 0.5 and 3 g per square meter of body surface area (g/m2) for 6 to 12 months (phase 1 study) or randomized to receive placebo or eflornithine, 0.5 g/m2 for 12 months (phase 2 study). Auditory thresholds were measured before, during, and after eflornithine administration. Auditory thresholds and threshold shifts were evaluated with regard to eflornithine dose, serologic variables, and demographic factors. Predictable shifts in auditory thresholds occurred following administration of eflornithine. As the daily dose of eflornithine increased, the magnitude and incidence of threshold shift increased, and the time until onset of threshold shift decreased. Threshold changes were greater in the lower frequencies than in the higher frequencies. Subjects' sex, age, and renal function had no effect on eflornithine-associated threshold shifts. Threshold shifts were reversible after eflornithine treatment was discontinued. Administration of eflornithine is associated with a predictable shift in auditory thresholds. The magnitude and incidence of threshold shift correlate with the daily eflornithine dose.