Cisplatin is a commonly used chemotherapeutic agent [1–3]. Its main reported side effects are nephrotoxicity, peripheral neurotoxicity, and ototoxicity [1, 2]. Cisplatin-induced hearing loss occurs as the result of cochlear damage [4] which typically begins at the base of the cochlea and penetrates towards the apex with increasing cumulative exposure [5]. Cochlear damage includes injury to the stria vascularis [4], spiral ganglion neurons [6] inner and outer hair cells [7] as well as supporting cells [8]. The degree of cisplatin ototoxicity is dose dependent, but also varies, though to a lesser extent, with different treatment schedules and administration routes [7, 9].
In clinical use, cisplatin causes a symmetric hearing loss in 69% of patients, measuring between 15 and 65 dB in the 4,000- to 8,000-Hz range, and in 100% of patients if extended high-frequency audiometry (> 8,000 Hz) is used. In general, hearing loss is permanent, with some sporadic and partial recovery [10]
As the mechanism of cisplatin ototoxicity lies primarily in oxidative damage to the outer hair cells, previous animal studies have evaluated the administration of antioxidants for preventing cisplatin-induced ototoxicity. Systemic administration of either L- or D-methionine before Cisplatin treatment reduced ototoxic and nephrotoxic side effects but were also associated with an unwanted partial tumor-sparing effect [11]. Similar decreased chemotherapeutic efficacy of cisplatin has been reported for sodium thiosulfate co-treatment [12–13].
Aspirin, and its active ingredient, salicylate, is a commonly used antipyretic, analgesic and anti-inflammatory drug. In contrast to forementioned antioxidants (methionine and sodium thiosulfate), aspirin did not inhibit the anti-tumor efficacy of cisplatin [14, 15]. Several studies evaluated the protective effect of aspirin on the ototoxic effect of cisplatin. Li et al. [14] and Minami et al. [16] demonstrated aspirin protective effect on cisplatin ototoxicity in rats. Both used a short regimen of aspirin treatment and followed the animals for a short period of time and demonstrated significant although partial otoprotection.
Beyond its antioxidative effect, aspirin affects uniquely the inner ear. Continuous aspirin administration at high doses induces for itself hearing loss and tinnitus [17, 18]. However, its effect is reversible [14, 16, 19]. In humans receiving high doses of 4g daily, temporary threshold shift (TTS) of 10-40dB develops and persists throughout the period of drug administration. Hearing thresholds typically returns to their pre-treatment level after aspirin administration is stopped [18, 20, 21]. TTS induced by high doses of aspirin can theoretically be associated with reduced metabolic activity of cochlear elements and may be associated with improved resilience of the cochlea to damaging insults. Such resilience is similar to tissue preservation achieved in brain and cardiac surgeries using hypothermia to reduce metabolic rate (hibernation) [22–23]. Hypometabolic effect of hypothermia was found to be otoprotective as well. In a study by Spankovich et al, a reduction in Cisplatin-induced hearing loss after cold water irrigation of guinea pigs external auditory canal was demonstrated [24]. Moreover, hypothermia was effective also in preventing noise induced hearing loss as well as cochlear trauma induced by electrode insertion in cochlear implantation in animal models [25–28]. Hypothermia is not feasible as a treatment option for patients receiving cisplatin, however a pharmacologic agent that can induce hypometabolism of the cochlea has the potential to protect from its ototoxicity.
Clinical studies have failed to demonstrate the hearing-protective effects of aspirin shown in pre-clinical studies. In a phase 2, double-blind, randomised controlled trial in patients treated with cisplatin-based chemotherapy for multiple cancer types [15], short pre-treatment with aspirin did not protect from cisplatin-related ototoxicity.
At present, there are no approved treatments to prevent ototoxicity in patients undergoing cisplatin-based chemotherapy.
Our hypothesis was that in addition to its protective anti-inflammatory or anti-oxidative effect, high doses of aspirin may reduce cochlear activity, manifested as temporary threshold shift (TTS). Reduction in cochlear activity and metabolism may increase cochlear resilience to the damaging effects of cisplatin. We, therefore, explored in an animal model the protective effects of aspirin associated TTS against cisplatin induced ototoxicity, using auditory brainstem responses and scanning electron microscopy.