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Special considerations in the design and implementation of pediatric otoprotection trials

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Abstract

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.

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Data Availability

All data cited in this review article are available in the public domain.

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Funding

Partial funding for this work is reported by EO (1K23DC014291 from NIH/NIDCD).

Author information

Authors and Affiliations

  1. Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    David R. Freyer & Etan Orgel

  2. Departments of Pediatrics, Medicine, and Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    David R. Freyer

  3. Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Etan Orgel

  4. Department of Audiology, Doernbecher Children’s Hospital, Portland, OR, USA

    Kristin Knight

  5. Oregon Health and Science University, Portland, OR, USA

    Kristin Knight

  6. Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA

    Mark Krailo

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Contributions

The manuscript was conceptualized by DRF. The original draft manuscript was written by DRF with sections contributed by EO (translational considerations) and KK (measurement of ototoxicity). Critical review and editing of the manuscript was done by all authors.

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Correspondence to David R. Freyer.

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Freyer, D.R., Orgel, E., Knight, K. et al. Special considerations in the design and implementation of pediatric otoprotection trials. J Cancer Surviv 17, 4–16 (2023). https://doi.org/10.1007/s11764-022-01312-x

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