Functional and morphological effects of fotemustine on the auditory system of the rat

This study aimed to elucidate the potential inner-ear effects of fotemustine, a chemotherapeutic agent which crosses the blood-brain barrier and is used in the treatment of primary and metastatic brain tumours and metastatic melanoma. This study utilised distortion product otoacoustic emissions and transmission electron microscopy in order to conduct electrophysiological and morphological assessments, using a rat experimental model. Twelve ears of six male rats were examined two months following intraperitoneal slow infusion of fotemustine (100 mg/m2 or 7.4 mg/kg). Pre- and post-treatment measurements were compared. Finally, electron microscopy was performed on three rat temporal bones. After infusion of fotemustine, distortion product otoacoustic emissions revealed a significant reduction in signal-to-noise ratios only at 3600 Hz (from 11.95 +/- 7.52 to -0.26 +/- 9.45 dB) and at 3961 Hz (from 18.09 +/- 7.49 to 6.74 +/- 12.11 dB) (referenced to 2f1 - f2). Transmission electron microscopy of the temporal bone revealed ultrastructural changes in the outer hair cells, stria vascularis and cochlear ganglion at the cochlear basal turn. The ganglion cell perikarya were unaffected. Fotemustine was administered via intraperitoneal slow infusion in a rat experimental model. Twelve ears of six survivors, from 10 rats, were evaluated at the second month. Fotemustine was determined to have a potential for ototoxicity at 3600 and 3961 Hz. Three randomly chosen rats underwent electron microscopy for morphological analysis. Morphological effects in the cochlear basal turn were observed. Oedematous intracytoplasmic spaces and perivascular areas of the stria vascularis, as well as distorted chromatin content, were detected, thereby suggesting potential ototoxic effects for this agent. Further experimental and clinical studies are required in order to determine whether the effect seen in this pilot study is reversible, and to analyse effects in humans.