Long-term effects of carboplatin brainstem infusions on hearing thresholds in monkeys

Objective: To isolate the central auditory neurotoxicity of carboplatin from its well-established ototoxic effects. Design: The "best-case scenario" of targeted drug delivery to brain cancer was simulated by infusing carboplatin directly into the brainstem of cynomolgus monkeys with chronically implanted catheters. Because this manner of drug administration produced low levels of carboplatin in spinal fluid and blood, it was assumed that resulting deficits were dictated by the central auditory neurotoxicity of platinum compounds and not peripheral ototoxic effects. The magnitude of this hearing loss was estimated by comparing the auditory brainstem response thresholds of treated monkeys with results from normal controls. Subjects: Six adult male cynomolgus monkeys (Macaca fascicularis) weighing 4 to 6 kg (3 received carboplatin treatment and 3 served as normal controls). Intervention: Brainstem infusions of carboplatin. Results: The average threshold of carboplatin-treated monkeys was elevated 8.8 dB (SD = 7.3 dB) relative to normal controls 6 months after the termination of drug delivery and increased to 10.7 dB with less variation between subjects (SD = 5.6 dB) 1 year after drug treatment. Although small in magnitude, the hearing loss was statistically significant (P<.05). Conclusions: Brainstem infusions of carboplatin induced some degree of hearing impairment in all treated monkeys. These threshold elevations were modest compared with the ototoxic effects that have been reported after systemic doses of carboplatin. Our findings suggest that the neurotoxic sensitivity of cochlear hair cells is not shared by neurons in the central auditory pathways. As a result, methods for reducing the ototoxic effects of chemotherapy remain a viable strategy for preserving auditory function in patients with brain cancer.