Genetic polymorphisms contributing to hearing loss in children treated with platinum agents: a systematic review and meta-analysis protocol

Abstract

Introduction: The improved survival rates of children with cancer have heightened concerns about treatment-related chronic health conditions, including platinum-induced hearing loss (PIHL). Cisplatin and carboplatin, widely used in paediatric cancer therapies, frequently cause irreversible sensorineural hearing loss. PIHL affects 1.7-90.1% of patients exposed to these drugs, yet known risk factors-including age, cisplatin dosage, cranial radiation and co-treatment with ototoxic drugs-fail to fully explain interindividual variability. Genetic factors likely play a role in susceptibility to PIHL. Since genetic susceptibility in children may differ from adults, and given the critical window of auditory development, a focused investigation of paediatric genetic factors using quantitative methods is warranted to detect small to moderate effects and understand the polygenic nature of PIHL.

Methods and analysis: In this study, we will systematically review and conduct a meta-analysis of genetic polymorphisms associated with PIHL in individuals diagnosed before the age of 21 years. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, the review will include randomised controlled trials, cohort, case-control and cross-sectional studies that analyse the genetic influence on PIHL in paediatric populations treated with cisplatin and carboplatin. A comprehensive search of PubMed, EMBASE and Cochrane databases will be conducted, supplemented by backward citation searching. Data will be extracted on study design, treatment details, hearing loss assessment methods, genetic findings and covariates. We will use forest plots to present the results, and both Mantel-Haenszel fixed-effects model and random-effects model will be used for meta-analysis. Heterogeneity will be assessed with the I² index. The study will address potential heterogeneity, individual study quality, proportion of missing data and meta-analysis bias. The quality of the evidence of the meta-analysis will be assessed using the Grading quality of evidence and strength of Recommendations (GRADE) approach.

Discussion: This systematic review will enhance our understanding of the genetic contribution to PIHL in children and serve as a basis for further research for improvement of personalised treatment strategies for paediatric cancer care.

Prospero registration number: CRD42024532664.

Ethics and dissemination: All the included patient's data are already published with an ethics approval for each study, respectively. No original data will be collected.

Keywords: CHEMOTHERAPY; GENETICS; Hearing; Ototoxicity; PAEDIATRICS; Paediatric oncology.