Prevention of cisplatin-induced hearing loss in children: Informing the design of future clinical trials.

Lori M Minasian,Lillian Sung,Brad H Pollock,David R Freyer,Ann O'Mara,Mark Krailo,A Lindsay Frazier,Kay W Chang,Joseph Kelaghan,Gregory Reaman

doi:10.1002/cam4.1563

Abstract

Cisplatin is an essential chemotherapeutic agent in the treatment of many pediatric cancers. Unfortunately, cisplatin‐induced hearing loss (CIHL) is a common, clinically significant side effect with life‐long ramifications, particularly for young children. ACCL05C1 and ACCL0431 are two recently completed Children’s Oncology Group studies focused on the measurement and prevention of CIHL. The purpose of this paper was to gain insights from ACCL05C1 and ACCL0431, the first published cooperative group studies dedicated solely to CIHL, to inform the design of future pediatric otoprotection trials. Use of otoprotective agents is an attractive strategy for preventing CIHL, but their successful development must overcome a unique constellation of methodological challenges related to translating preclinical research into clinical trials that are feasible, evaluate practical interventions, and limit risk. Issues particularly important for children include use of appropriate methods for hearing assessment and CIHL severity grading, and use of trial designs that are well‐informed by preclinical models and suitable for relatively small sample sizes. Increasing interest has made available new funding opportunities for expanding this urgently needed research.

Highlights

Cisplatin is an essential chemotherapeutic agent in the treatment of neuroblastoma, osteosarcoma, hepatoblastoma, germ cell tumors, medulloblastoma, and other pediatric cancers.[1]
With ACCL0431 providing proof-o f-p rinciple that Cisplatin-induced hearing loss (CIHL) can be prevented, interest in preventing CIHL is growing and new otoprotection agents are in early stages of development
What major insights from ACCL05C1 and ACCL0431 can inform optimal design of future otoprotection trials? From ACCL05C1, we recommend: (1) use of uniform, internationally accepted ototoxicity criteria that are optimal for children; and (2) use of central review of raw audiologic data to improve accuracy, reduce bias, and allow use of multiple ototoxicity criteria for comparison between randomized groups

Summary

Introduction

Cisplatin is an essential chemotherapeutic agent in the treatment of neuroblastoma, osteosarcoma, hepatoblastoma, germ cell tumors, medulloblastoma, and other pediatric cancers.[1]. In children, especially very young children, it is debilitating because hearing loss leads to impaired language acquisition, difficulty with learning and psychological development, and subsequent reduction in social functioning that will affect them for the remainder of their lives.[3,4] Long-term studies of pediatric cancer survivors demonstrate that CIHL results in lower educational performance, increased need for special education services, higher unemployment and nonindependent living, and poorer child- reported quality of life compared with controls.[5,6,7] Depending on the cumulative dose and the dosing schedule, as many as 75% of children with CIHL qualify for hearing aids or hearing assistance.[3,4,8] survivors with hearing aids still experience abnormal hearing, tinnitus, poor speech discrimination in noisy environments, social hardships, and substantial expense.[9,10]

Objectives

Methods

Findings

Conclusion