Cisplatin, a platinum-containing chemotherapy drug, is an effective treatment for various types of cancers. Cisplatin has become a cornerstone in chemotherapeutic regimens for medulloblastoma (a type of brain cancer) and also for other types of cancers in pediatric oncology. In the last few years, there have been several breakthroughs in the development of advanced treatment for medulloblastoma. Efficient therapeutic approaches, such as radiation therapy and the use of adjuvant chemotherapy containing cisplatin, have improved survival rates over time. However, these therapeutic approaches are associated with short-term and long-term side effects and have negatively impacted the quality of life in long-term cancer survivors [1].
How does cisplatin therapy cause hearing loss?
One of the common and debilitating toxicities of cisplatin use is cisplatin-induced hearing loss, predominantly impacting children, adolescents, and young adults. It is caused by the death of the cochlear outer hair cells and it is progressive, irreversible, and frequently accompanied by tinnitus (buzzing noise in the ear). This side effect is dose-dependent and can be temporary or permanent. The long-term effects of hearing loss are more severe in children whose developmental milestones are still in their initial stages. The effects of hearing loss are detrimental throughout life and vary from person to person. It has been demonstrated that in children hearing loss specifically affects:
Learning outcomes
Behavioral and cognitive development and
Psychosocial development
In adults, hearing loss has an impact on social isolation, anxiety, sadness, and depression. Thus, the identification of safe and effective preventive measures for cisplatin-induced ototoxicity is crucial, particularly in children since hearing loss can impede speech and spoken language development [2], [3].
How is cisplatin-induced hearing loss prevented?
Historically, the only treatment for cisplatin-induced hearing loss has been dose reduction, deletion, and delay in the administration of cisplatin. According to studies, the frequency of ototoxicity (pharmacological adverse reaction affecting the inner ear) following cisplatin therapy depends on the:
Doses given
Patient's age
Amount of cranial radiation
It also depends on other elements like noise exposure and hearing level before treatment. The outer hair cells in the organ of Corti are damaged by reactive oxygen species that develop in the cochlea as a result of cisplatin administration. The cytotoxic effects of cisplatin can be counteracted by sulfur-containing antioxidants such as sodium thiosulfate, which could prevent cisplatin-induced ototoxicity [2], [3].
How does sodium thiosulfate prevent cisplatin-induced hearing loss in mb patients?
Several agents have been investigated in animal models to develop preventive medicines that selectively protect against cisplatin's ototoxic side effects, without interfering with its antitumoral efficacy. Only a few treatments have demonstrated positive effects in the clinic, even though many have been successful in preclinical research. Sodium thiosulfate has revealed promising results as an otoprotective agent. Sodium thiosulfate is a thiol-containing antioxidant that has been shown to protect against cisplatin-induced hearing loss in preclinical trials without impairing anti-tumor effectiveness when given at the appropriate period after cisplatin. The US Food and Drug Administration (FDA) has approved sodium thiosulfate as an antidote for cyanide and nitroprusside toxicity as well as for calciphylaxis. Several studies have shown that sodium thiosulfate was effective in preventing or reducing the incidence and severity of cisplatin-induced hearing loss in children treated with cisplatin for medulloblastoma. The exact mechanism by which sodium thiosulfate protects against cisplatin-induced hearing loss is not known. However, it is thought to work by scavenging the harmful reactive oxygen species and platinum-containing molecules that are responsible for the toxic effect on the inner ear, and it preserves the activity of antioxidant enzymes. Sodium thiosulfate is a safe and well-tolerated drug. The most common side effect is mild gastrointestinal upset. More studies are needed to confirm the efficacy of sodium thiosulfate in preventing cisplatin-induced hearing loss in children [1], [4].
Current scenario
The results of clinical trials appear to mark the beginning of a new era, one in which more optimistic options have replaced the historical acceptance of cisplatin-induced hearing loss as an unavoidable side effect of curative cancer treatment. Together, previous studies showed that sodium thiosulfate lowers the risk of cisplatin-induced hearing loss without causing any serious adverse events. It raises the possibility that patients with medulloblastoma and likely those with other confined malignancies can safely utilize sodium thiosulfate. However, further research is necessary to effectively utilize sodium thiosulfate as a part of the otoprotection strategy, due to the possibility of adverse effects on survival.
References
T. Harao, A. Yamada, M. Kinoshita, S. Kamimura, and H. Moritake, “Prevention of cisplatin-induced hearing-loss by sodium thiosulfate in medulloblastoma,” Pediatr Int, vol. 62, no. 10, pp. 1204–1206, Oct. 2020, DOI: 10.1111/ped.14271.
R. A. Hazlitt, J. Min, and J. Zuo, “Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss,” J. Med. Chem., vol. 61, no. 13, pp. 5512–5524, Jul. 2018, doi: 10.1021/acs.jmedchem.7b01653.
D. Yu, J. Gu, Y. Chen, W. Kang, X. Wang, and H. Wu, “Current Strategies to Combat Cisplatin-Induced Ototoxicity,” Frontiers in Pharmacology, vol. 11, 2020, DOI: 10.3389/fphar.2020.00999
H. H, S. Z, H. H, F. Y, B. Hf, and N. S, “Drug Repurposing in Medulloblastoma: Challenges and Recommendations,” Current treatment options in oncology, vol. 22, no. 1, Nov. 2020, DOI: 10.1007/s11864-020-00805-0.
