Discussion
This systematic review is a comprehensive synthesis of all the interventions that have been used in adult patients to mitigate cisplatin-induced ototoxicity. Previous systematic reviews have described the evidence on potential therapeutic targets based on animal models (Mukherjea et al., 2020), have noted the effectiveness of a particular intervention (Duval et al., 2012), or have focused on the pediatric population (Freyer et al., 2020). This is the first systematic review in the adult population with CiO that broadly recopilates the evidence on pharmacological and non-pharmacological interventions. Our study approach allowed us to search for ototoxicity caused by other types of platinum and chemotherapy agents, albeit the retrieved studies only focused on cisplatin ototoxicity. In total eleven interventions (nine pharmacological and two non-pharmacological) for CiO in adults were identified. Based on the authors’ information, this review analyzes the most interventions to date. All of the interventions have been tested as a preemptively otoprotective strategy and only one (corticosteroids) has been assessed in one study as a treatment strategy once the hearing deficit is established due to cisplatin administration (Nasr et al., 2018). This finding may be relevant to explain the ineffective results of some interventions. The action of free radical oxygen species may take time to occur as cisplatin accumulates in the cochlea, meantime the prophylactic effect of the otoprotective intervention may be lost, not coinciding with the nadir damage on the ear function(Breglio et al., 2017, Tang et al., 2021).
We encounter four pharmacological and two non-pharmacological interventions with positive results that merit future investigation. Of the pharmacological interventions, sodium thiosulfate, corticoids, sertraline, and statins showed a preserving hearing effect. Nevertheless, the current evidence on these interventions has limiting aspects to consider. A considerable number and severity of side effects were reported in the intratympanic corticoids trial, a single trial has been conducted with sertraline and statins, and the statins trial had a heterogeneous intervention which limits the confidence of the results. Although the studies showed a partial benefit, sodium thiosulfate appears as the most promising intervention to prevent CiO in adults undergoing cisplatin therapy. These results are similar to what has been found in high-quality RCT in the pediatric population, where sodium thiosulfate reduced the incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival (Brock et al., 2018). A recent systematic review and meta-analysis, based on four studies with mixed pediatric and adult populations, confirms the otoprotective effect of sodium thiosulfate (Chen et al., 2021). On the other hand, the two non-pharmacological interventions that showed positive results were multivitamins and D-methionine. As with the pharmacological interventions, this too has limiting considerations. The multivitamins regimens tested vary widely among the studies, and the evidence regarding D-methionine consists of a unique pilot trial. None of the studies testing non-pharmacological interventions had a good quality rating. However, the safety profile of these dietary supplements seems to be superior and could make them a good option depending on future trials. Moreover, the low number of participants reduces the chances of detecting significant adverse events and increases the likelihood of Type II errors. (Faber et al., 2014).
Additionally, our results highlighted the focus and gaps of CiO research. Even though tinnitus and vertigo are symptoms that may considerably affect patients’ quality of life, even more than the mild hearing loss that occurs above the frequency range of human speech (0.25 – 8 kHz) that may go undetected (Chauhan et al., 2011), few studies in our review documented them. Moreover, none showed that any kind of intervention could prevent or palliate these symptoms. It is not clear why the studies did not take the whole spectrum of CiO symptoms into account, given that cisplatin-induced tinnitus is reported to be prevalent with high cumulative cisplatin doses(p=0.007) and in older populations (p=0.007)(Frisina et al., 2016 ). Investigators have also found cisplatin-induced tinnitus is significantly correlated with reduced hearing per frequency (0.25-12 kHz, p< 0.0001) and vertigo (OR = 6.47; p< 0.0001)(El Charif et al., 2019), which means it is uncommon for patients to experience hearing loss without tinnitus and vertigo. This suggests that these symptoms are likely underdiagnosed or overlooked in oncology, hematology, or palliative care consultations. Currently, four clinical trials in adult patients with CiO risk are underway to evaluate sodium thiosulfate and mannitol, rosuvastatin, and intratympanic N-acetylcysteine (Dizon et al., Kasem et al., Sajeniouk et al., Cavelier et al.). Only one of them considers the apparition of tinnitus in their outcomes. Therefore, future high-quality randomized clinical trials should consider the shortcomings and successes of existing evidence to improve their internal validity.