Special considerations in the design and implementation of pediatric otoprotection trials

Purpose Cisplatin-induced hearing loss (CIHL) is a common late effect after childhood cancer treatment having profound, lifelong consequences that lower quality of life. The recent identification of intravenous sodium thiosulfate (STS) as an effective agent for preventing pediatric CIHL represents a paradigm shift that has created new opportunities for expanding STS usage and developing additional otoprotectants. The purpose of this paper is to discuss key considerations and recommendations for the design and implementation of future pediatric otoprotection trials. Methods An approach synthesizing published data and collective experience was used. Results Key issues were identified in the categories of translational research, trial designs for systemic and intratympanic agents, measurement of ototoxicity, and biostatistical challenges. Conclusions Future pediatric otoprotection trials should emphasize (1) deep integration of preclinical and early-phase studies; (2) an embedded or free-standing design for systemic agents based on mechanistic considerations; (3) use of suitable audiologic testing batteries for children, SIOP grading criteria, and submission of raw audiologic data for central review; and (4) novel endpoints and innovative study designs that maximize trial efficiency for limited sample sizes. Additional recommendations include routine collection of DNA specimens for assessing modifying effects of genetic susceptibility and meaningful inclusion of patient/family advocates for informing trial development. Implications for Cancer Survivors Changing the historical paradigm from acceptance to prevention of pediatric CIHL through expanded research with existing and emerging otoprotectants will dramatically improve quality of life for future childhood cancer survivors exposed to cisplatin.