Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it. In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin and compromising language and cognitive development. Candidate gene studies have previously reported associations of cisplatin ototoxicity with genetic variants in the genes encoding glutathione S-transferases and megalin. We report association analyses for 220 drug-metabolism genes in genetic susceptibility to cisplatin-induced hearing loss in children. We genotyped 1,949 SNPs in these candidate genes in an initial cohort of 54 children treated in pediatric oncology units, with replication in a second cohort of 112 children recruited through a national surveillance network for adverse drug reactions in Canada. We identified genetic variants in TPMT (rs12201199, P value = 0.00022, OR = 17.0, 95% CI 2.3-125.9) and COMT (rs9332377, P value = 0.00018, OR = 5.5, 95% CI 1.9-15.9) associated with cisplatin-induced hearing loss in children.

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.

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This study has identified a novel association between protein-coding variation in SLC16A5 and cisplatin-induced ototoxic effects. These findings have provided insight into the molecular mechanisms of this adverse drug reaction in adult patients with germ cell testicular cancer. Given that previous studies have shown that cimetidine, an SLC16A5-inhibitor, prevents murine cisplatin-induced ototoxic effects, the findings from this study have important implications for otoprotectant strategies in humans.

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Adverse drug reactions such as ototoxicity, which occurs in approximately one-fifth of adult patients who receive cisplatin treatment, can incur large socioeconomic burdens on patients with testicular cancer who develop this cancer during early adulthood. Recent genome-wide association studies have identified genetic variants in and that are associated with cisplatin-induced ototoxicity. We sought to explore the role of these genetic susceptibility factors to cisplatin-induced ototoxicity in patients with testicular cancer. Extensive clinical and demographic data were collected for 229 patients with testicular cancer treated with cisplatin. Patients were genotyped for two variants, rs1872328 and rs62283056, that have previously been associated with hearing loss in cisplatin-treated patients. Analyses were performed to investigate the association of these variants with ototoxicity in this cohort of adult patients with testicular cancer. Pharmacogenomic analyses revealed that rs1872328 was significantly associated with cisplatin-induced ototoxicity [ = 2.83 × 10, OR (95% CI):14.7 (2.6-84.2)]. rs62283056 was not significantly associated with ototoxicity caused by cisplatin ( = 0.39); however, this variant was associated with hearing loss attributable to any cause [ = 5.67 × 10, OR (95% CI): 3.2 (1.4-7.7)]. This study has provided the first evidence for the role of rs1872328 in cisplatin-induced ototoxicity in patients with testicular cancer. These results support the use of this information to guide the development of strategies to prevent cisplatin-induced ototoxicity across cancers. Further, this study has highlighted the importance of phenotypic differences in replication studies and has provided further evidence for the role of rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment. .

Hearing loss has important consequences for the survivors of childhood cancer including communication, learning, cognition and quality of life. Due to the presentation and configuration of ototoxic hearing loss, the test frequencies that are prioritised and the sequence of testing may differ from standard paediatric hearing evaluations. Hearing should be monitored during treatment and after completion of therapy.

Background Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin‐induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL. Methods Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan‐Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy. Results In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%‐84%), with a rapid increase observed to 27% (95% CI, 21%‐35%) at 3 months and to 61% (95% CI, 53%‐69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%‐62%; P < .001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m2 increase: hazard ratio [HR], 1.20; 95% CI, 1.01‐1.41) vincristine (HR, 2.87; 95% CI, 1.89‐4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17‐2.95) further influenced CIHL development over time. Conclusions In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co‐)medication. These results highlight the need for audiological monitoring at each cisplatin cycle.