ALPHA-DIFLUOROMETHYLORNITHINE OTOTOXICITY - CHEMOPREVENTION CLINICAL-TRIAL RESULTS

Objectives: To determine the effects of low-dose oral eflornithine hyd rochloride (difluoromethylornithine [DFMO]) administration on hearing and to identify factors that influence those effects. Design: Combined data from 2 studies: a prospective, randomized phase 1 clinical trial of eflornithine (n = 26 subjects) and a prospective, randomized, plac ebo-controlled phase 2 clinical trial of eflornithine (n = 40 subjects ) Setting: Ambulatory academic tertiary care referral center. Particip ants: Sixty-six volunteer subjects who had previously treated bladder, prostate, or colon cancer with no current evidence of neoplastic dise ase, or who were healthy individuals at increased risk for colon cance r, all without need of hearing amplification. Interventions: Subjects were randomized to receive oral eflornithine at daily doses between 0. 5 and 3 g per square meter of body surface area (g/m(2)) for 6 to 12 m onths (phase 1 study) or randomized to receive placebo or eflornithine , 0.5 g/m(2) for 12 months (phase 2 study). Outcome Measures: Auditory thresholds were measured before, during, and after eflornithine admin istration. Auditory thresholds and threshold shifts were evaluated wit h regard to eflornithine dose, serologic variables, and demographic fa ctors. Results: Predictable shifts in auditory thresholds occurred fol lowing administration of eflornithine. As the daily dose of eflornithi ne increased, the magnitude and incidence of threshold shift increased , and the time until onset of threshold shift decreased. Threshold cha nges were greater in the lower frequencies than in the higher frequenc ies. Subjects' sex, age, and renal function had no effect on eflornith ine-associated threshold shifts. Threshold shifts were reversible afte r eflornithine treatment was discontinued. Conclusions: Administration of eflornithine is associated with a predictable shift in auditory th resholds. The magnitude and incidence of threshold shift correlate wit h the daily eflornithine dose.