N-acetylcysteine
Three randomized placebo-controlled trials have explored if N-acetylcysteine can avert CiO administered intratympanic(Riga et al., 2013, Yoo et al., 2014) or orally (Yıldırım et al., 2010). A RCT used intratympanic N-acetylcysteine at 10% in 20 patients with different types of tumors. They found that treated ears with N-acetylcysteine had no significant changes in auditory thresholds while the control ears had a significant decrease in auditory thresholds at the 8000 Hz frequency band (P = 0.008) with cisplatin (Riga et al., 2013). Another RCT assessed the effectiveness of intratympanic N-acetylcysteine at 2% to prevent hearing and tinnitus due to cisplatin in 11 patients with head and neck cancer receiving concomitant radiotherapy. No benefit in hearing preservation or tinnitus incidence was found (Yoo et al. 2014). The concentration difference of N-acetylcysteine may have influenced the disparity of the results as the occurrence of side effects. For instance, the highest concentration of N-acetylcysteine was associated with pain application among almost all patients (Riga et al., 2013), while the trial with a lower concentration of N-acetylcysteine did not report adverse reactions (Yoo et al., 2014). The third RCT compared the protective hearing effect of placebo, oral N-acetylcysteine, and salicylate in 54 patients with solid organ tumors receiving cisplatin. Audiometry and auditory brainstem parameters showed no significant difference between placebo and salicylate. On the other hand, the N-acetylcysteine group did have a reduction in cisplatin hearing ototoxicity at 10,000 and 12,000 Hz (p<0.005) compared to placebo. Nonetheless, safety outcomes between study interventions were not reported (Yıldırım et al., 2010).