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.


METHODS
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.


METHODS
Six adult male cynomolgus monkeys (Macaca fascicularis) weighing 4 to 6 kg (3 received carboplatin treatment and 3 served as normal controls).


METHODS
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.
May
Bradford J
BJ
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA. bmay@jhu.edu
Guarnieri
Michael
M
Carson
Benjamin S
BS
Bachani
Abdul
A
Jallo
George I
GI
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001306:Auditory Pathways / Q000187:drug effects; D001309:Auditory Threshold / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects*; D016190:Carboplatin / Q000633:toxicity*; D016503:Drug Delivery Systems; D006309:Hearing / Q000187:drug effects*; D036502:Infusions, Intralesional; D008252:Macaca fascicularis; D008297:Male
D000970:Antineoplastic Agents; D016190:Carboplatin