Role of Cisplatin Dose Intensity and TPMT Variation in the Development of Hearing Loss in Children

Abstract

Background: Cisplatin, widely used in the treatment of solid tumors, causes permanent hearing loss in more than 60% of treated children. Previous studies have implicated several clinical factors in the development of ototoxicity, including cumulative cisplatin dose. However, the role of cisplatin dose intensity in the development of hearing loss in children remains unclear. Pharmacogenetic studies have also identified genetic variants in TPMT that increase the risk of cisplatin-induced hearing loss. This study aims to determine whether cisplatin dose intensity contributes to the risk of hearing loss in children and whether genetic variations in TPMT further modifies the risk of cisplatin-induced hearing loss. Methods: The authors genotyped 371 cisplatin-treated children for the presence of any 3 TPMT-risk variants. Patients were categorized into high-, moderate-, and low-intensity cisplatin dosing groups according to the cisplatin dose administered per unit time. Kaplan–Meier curves were plotted to compare the cumulative incidence of hearing loss between the genotype and dose intensity groups. Results: Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity than those receiving cisplatin at low dose intensity (P = 9 × 10−7). Further stratification by TPMT genotype revealed that carriers of ≥1 TPMT variants receiving high-intensity cisplatin developed ototoxicity sooner and more often than their wild-type counterparts (93.8% vs. 56.6% at 12 months; P = 5 × 10−5) and noncarriers receiving low-intensity cisplatin (21.2% at 12 months). Conclusions: Cisplatin dose intensity is strongly associated with ototoxicity development in children, and this risk is further increased by the presence of TPMT-risk alleles.