Fosfomycin prevents cisplatin-induced ototoxicity: Results of a randomized, double blind, placebo controlled trial

Abstract

9041 Background: Cisplatin is one of the most frequently used chemotherapy agents. The main dose-limiting toxicity for its use is hearing-loss, present in 40–100% of patients. To date, no treatment has proven efficacy in preventing or reducing cisplatin acoustic damage. Fosfomycin, acting as a free-radical scavanger, has shown to reduce cisplatin-induced ototoxicity and nephrotoxicity in animal models, without affecting its antineoplastic activity. This trial evaluated the effect of fosfomycin in cisplatin-induced ototoxicity. Methods: 22 chemotherapy naive patients with normal audition, scheduled to receive cisplatin-based chemotherapy (cumulative dose =200mg/m2) were randomized to receive placebo (n=11) or 1g of IV fosfomycin concurrent with each cisplatin administration (2–4 cycles). Primary outcome was ototoxicity when comparing audiometric studies (low and high frequencies and otoaccustic emissions) at baseline and at completion of chemotherapy. With β=0.8 and a=0.05 the study was powered to detect differences =20 dB at any given frequency. Fisher's test, Wilcoxon and Mann-Whitney test were used. Results: Groups were balanced for baseline characteristics, cisplatin dose and response rates. No differences were found when comparing ototoxicity at low frequency ranges. When analyzing high frequencies and otoaccustic emissions, 9 patients (82%) in the placebo group developed ototoxicity vs 4 (36%) in the fosfomycin group (p=0.04). The degree of hearing-loss, evaluated by comparing percentage of change in each evaluated frequency, was significantly lower in patients receiving fosfomycin (p=0.04). Other chemotherapy toxicities were similar in both groups. Conclusions: In patients with audiometric integrity, the concurrent administration of fosfomycin with cisplatin significantly reduces ototoxicity. The degree of hearing-loss is lower in patients receiving fosfomycin than in those receiving placebo. The use of fosfomycin in combination with cisplatin is safe and does not interfere with its antineoplastic activity. To our knowledge this is the first clinical-trial that demonstrates prevention and reduction of cisplatin-induced hearing-loss. No significant financial relationships to disclose.