Abstract: We identified 13 eligible cohort studies including 2837 participants with a hearing test after treatment with a platinum analogue for different types of childhood cancers. All studies had methodological limitations, with regard to both internal (risk of bias) and external validity. Participants were treated with cisplatin, carboplatin or both, in varying doses. The reported prevalence of hearing loss varied considerably between 0% and 90.1%; none of the studies provided data on tinnitus. Three studies reported a prevalence of 0%, but none of these studies provided a definition for hearing loss and there might be substantial or even complete overlap in included participants between these three studies. When only studies that did provide a definition for hearing loss were included, the prevalence of hearing loss still varied widely between 1.7% and 90.1%. All studies were very heterogeneous with regard to, for example, definitions of hearing loss, used diagnostic tests, participant characteristics, (prior) anti-tumour treatment, other ototoxic drugs and length of follow-up. Therefore, pooling of results was not possible. Only two studies included a control group of people who had not received platinum treatment. In one study, the prevalence of hearing loss was 67.1% (95% confidence interval (CI) 59.3% to 74.1%) in platinum-treated participants, while in the control participants it was 7.4% (95% CI 6.2% to 8.8%). However, hearing loss was detected by screening in survivors treated with platinum analogues and by clinical presentation in control participants. It is uncertain what the effect of this difference in follow-up/diagnostic testing was. In the other study, the prevalence of hearing loss was 20.1% (95% CI 17.4% to 23.2%) in platinum-treated participants and 0.4% (95% CI 0.12% to 1.6%) in control participants. As neither study was a randomized controlled trial or controlled clinical trial, the calculation of a risk ratio was not feasible as it is very likely that both groups differed more than only the platinum treatment. Only two studies evaluated possible risk factors using multivariable analysis. One study identified a significantly higher risk of hearing loss in people treated with cisplatin 400 mg/m2 plus carboplatin 1700 mg/m2 as compared to treatment with cisplatin 400 mg/m2 or less, irrespective of the definition of hearing loss. They also identified a significantly higher risk of hearing loss in people treated with non-anthracycline aminoglycosides antibiotics (using a surrogate marker) as compared to people not treated with them, for three out of four definitions of hearing loss. The other study reported that age at treatment (odds ratio less than 1 for each single-unit increase) and single maximum cisplatin dose (odds ratio greater than 1 for each single-unit increase) were significant predictors for hearing loss, while gender was not. This systematic review shows that children treated with platinum analogues are at risk for developing hearing loss, but the exact prevalence and risk factors remain unclear. There were no data available for tinnitus. Based on the currently available evidence we can only advise that children treated with platinum analogues are screened for ototoxicity in order to make it possible to diagnose hearing loss early and to take appropriate measures. However, we are unable to give recommendations for specific follow-up protocols including frequency of testing. Counselling regarding the prevention of noise pollution can be considered, such as the use of noise-limiting equipment, avoiding careers with excess noise and ototoxic medication. Before definitive conclusions on the prevalence and associated risk factors of platinum-induced ototoxicity can be made, more high-quality research is needed. Accurate and transparent reporting of findings will make it possible for readers to appraise the results of these studies critically.

Plain-language summary: The evidence is current to September 2015. We found 13 studies including 2837 participants with a hearing test after platinum-based therapy for different types of childhood cancers. Participants were treated with cisplatin, carboplatin or both, in varying doses. All studies were very different with regard to definitions of hearing loss, used diagnostic tests, participant characteristics, (prior) anti-cancer treatment, other ototoxic drugs and length of follow-up. The reported frequency of hearing loss varied between 0% and 90.1%; none of the studies provided data on tinnitus (that is, ringing in the ears). Three studies reported a frequency of 0%, but none of these studies provided a definition for hearing loss and there might be substantial or even complete overlap in included participants between these three studies. When only studies that did provide a definition for hearing loss were included, the frequency of hearing loss still varied between 1.7% and 90.1%. Only two studies included people who had not received platinum treatment (called control group). In one study, the frequency of hearing loss was 67.1% in people treated with platinum, while in the control group it was 7.4%. In the other study, the frequency of hearing loss was 20.1% in people treated with platinum and 0.44% in the control group. But due to methodological problems of these studies, it is unclear how reliable these results are. Only two studies evaluated possible risk factors. One study found a higher risk of hearing loss in people treated with cisplatin 400 mg/m2 plus carboplatin 1700 mg/m2 compared to treatment with cisplatin 400 mg/m2 or less, irrespective of the definition of hearing loss. They also found a higher risk of hearing loss in people treated with non-anthracycline aminoglycosides antibiotics (that is, a certain type of antibiotics) as compared to people not treated with these antibiotics, for three out of four definitions of hearing loss. The other study reported that age at treatment (lower risk in older children) and single maximum cisplatin dose (higher risk with an increasing dose) were significant predictors for hearing loss, while gender was not. Based on the currently available evidence, we can only advise that children treated with platinum analogues are screened for ototoxicity in order to make it possible to diagnose hearing loss early and to take appropriate measures. However, we are unable to give recommendations for specific follow-up methods including how often hearing is tested. Counselling regarding the prevention of noise pollution can be considered, like the use of noise-limiting equipment, avoiding careers with excess noise and ototoxic medicines. Before definitive conclusions on how often hearing loss happens (called prevalence) and associated risk factors of platinum-induced ototoxicity can be made, more high-quality research is needed. All studies had problems relating to quality of the evidence.