Dose-related alpha-difluoromethylornithine ototoxicity

Abstract

We assessed the ototoxicity associated with oral alpha-difluoromethylornithine (DFMO) administration in 58 patients with metastatic malignant melanoma. One hundred seventy-nine sequential audiograms obtained from patients treated with DFMO alone (16 patients) or in combination with alpha 2b-interferon (42 patients) were evaluated. DFMO doses ranged from 2 to 12 g/m2/d and were given over periods of 2 to 50 weeks. Total doses ranging from 60 g/m2 to 1390 g/m2 were correlated with clinical effects and pure tone audiometric changes. By regression analysis cumulative DFMO dose showed a consistent and statistically significant positive relationship to hearing loss at multiple frequencies (500, 1000, 2000, 4000, and 8000 Hz). Patients with normal (threshold less than 30 db) baseline audiograms demonstrated more hearing loss than those with abnormal (threshold greater than or equal to 30 db) baseline audiograms at the higher frequency levels. Of the patients with normal prestudy hearing thresholds 10% or less developed a demonstrable hearing deficit at cumulative DFMO doses below 150 g/m2. Conversely, up to 75% of the patients who received more than 250 g/m2 developed a clinically demonstrable hearing loss. Other factors which adversely affected hearing included age, male gender, and the concomitant use of alpha 2b-interferon. In summary, the risk of clinically significant hearing loss in patients treated with DFMO was primarily related to dose and the presence of a pre-existing hearing deficit.