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.