Antioxidants in the Prevention of Cisplatin-Induced Hearing Loss: A Systematic Review and Meta-Analysis

Abstract

Background Cisplatin is a commonly used chemotherapeutic drug that is associated with irreversible hearing loss. A number of antioxidants have been investigated for prevention, but data have so far been inconclusive. Objective The objective of this study was to assess the efficacy of various antioxidant therapies in preventing hearing loss among adult patients treated with cisplatin. Methodology We searched for controlled clinical trials evaluating various antioxidants as prevention against cisplatin-induced hearing loss in adults. The primary outcome is the proportion of patients with hearing loss. Secondary outcomes include audiometric threshold shifts, tinnitus, tumor response, adverse events, and quality of life. Results Thirteen randomized trials comprising of nine antioxidant therapies were included. Only coenzyme Q with multivitamins demonstrated significant benefit in preventing cisplatin-induced hearing loss (relative risk: 0.15, 95% confidence interval: 0.04–0.58) in a small study, while data for the rest of the agents were inconclusive. Audiometric threshold shifts were significantly lower in the intervention arm for aspirin, vitamin E, and transtympanic dexamethasone. The available data on tumor response was inconclusive, with no definite evidence of diminished tumor response noted. Adverse events noted include mild ear pain particularly for transtympanic therapies. There was no data available on quality of life. Conclusion The current available evidence is so far insufficient to establish any benefit for antioxidant therapies for the prevention of cisplatin-induced hearing loss. More high-quality studies are needed to fill in the identified gaps in knowledge.

Efficacy and Mechanisms of Antioxidant Compounds and Combinations Thereof against Cisplatin-Induced Hearing Loss in a Rat Model

“…In sum, many studies support increased oxidative stress as a main cisplatin ototoxicity mechanism [13,24]. Therefore, efforts have focused on neutralizing oxidative stress damage in the cochlea with antioxidant compounds [20,25,26]. From a biomedical perspective, antioxidants are chemical species which counteract and regulate biological oxidations, keeping ROS/RNS and other reactive free radicals and non-radicals within the levels required to maintain the physiological redox state and signaling.…”

“…Histological preservation of hair cells and supporting structures, threshold recovery in auditory brainstem responses (ABRs), preservation of distortion product otoacoustic emissions, and recovery of antioxidant enzyme activity or combinations thereof have been reported after antioxidant administration [13,19,28]. However, this is still not mirrored by conclusive evidence in the clinical setting [25,35], which stresses the need for more experimental, pre-clinical studies contributing further evidence on otoprotective activity and mechanisms of antioxidant therapies.…”

“…We have tested whether a similar principle may apply to antioxidant otoprotection in cisplatin ototoxicity. Despite still-inconclusive clinical evidence, it is interesting that a combination of coenzyme Q and multivitamins [41] has been the only one to show, in a small trial, significant benefit in preventing cisplatin-induced hearing loss in a recent meta-analysis of thirteen randomized trials [25].…”

“…Therefore, NAC shares free radical scavenging properties with non-enzymatic antioxidant vitamins A, C, and E (see below), and it also promotes enzymatic antioxidant defenses by regenerating a key substrate such as glutathione. Pre-clinical experimental evidence of otoprotection [46][47][48], along with its wide availability and limited adverse effects, make NAC a potentially useful otoprotective antioxidant, although evidence for clinical use in cisplatin ototoxicity still is inconclusive [25].…”

Efficacy and Mechanisms of Antioxidant Compounds and Combinations Thereof Against Cisplatin Induced Hearing Loss in a Rat Model

“…In sum, many studies support increased oxidative stress as a main cisplatin ototoxicity mechanism [13,24]. Therefore, efforts have focused on neutralizing oxidative stress damage in the cochlea with antioxidant compounds [20,25,26]. From a biomedical perspective, antioxidants are chemical species which counteract and regulate biological oxidations, keeping ROS/RNS and other reactive free radicals and non-radicals within levels required to maintain physiological redox state and signaling.…”