Clinical and genetic determinants of ototoxicity after childhood cancer

Approximately 550–600 children are diagnosed with cancer every year in the Netherlands. Improvements in treatment protocols brought a large increase in survival for many childhood cancers with a current overall long-term survival of ~80%. With the expansion of the childhood cancer survivor population, side-effects of treatment have become more prevalent and have drawn our attention. One of these side-effects is hearing impairment, induced by platinum treatment. The primary aim of this thesis was to investigate determinants of ototoxicity which occur during and after platinum treatment for childhood cancer. To compare five commonly used ototoxicity grading systems, we evaluated the concordance among the Brock, Chang, International Society of Pediatric Oncology (SIOP) Boston, U.S. National Cancer Institute Common Technology Criteria for Adverse Events (CTCAE) version 4.03, and Muenster ototoxicity grading scales using Kappa values. The results showed that the concordance among Muenster and Chang criteria was lowest (ĸ:0.636) and was highest among Chang and Brock criteria (ĸ:0.975). We then evaluated the time to detection of hearing loss. In general, Muenster detected hearing loss the earliest in time, followed by Chang, SIOP and Brock. We subsequently analyzed the frequency and determinants of ototoxicity in a cross-sectional multicenter study. Ototoxicity seems to be influenced by the type of platinum and dose of cisplatin. For patients treated with a cumulative cisplatin dose of 300 mg/m2 or more, a 5-fold higher risk of ototoxicity was observed, compared with patients treated with a lower cumulative cisplatin dose. Furthermore, young age at diagnosis, concomitant carboplatin use and furosemide co-treatment increased the risk for hearing impairment in childhood cancer patients treated with platinum agents, but not treated with cranial irradiation. While many factors influence hearing impairment during and after platinum treatment, genetic factors have been suggested to play a role in ototoxicity as well. Evidence from previous studies looking for associations between genetic variation and ototoxicity was largely insufficient or inconclusive, due to failure of independent replication or the small sample size, limiting statistical power. Our candidate gene approach could not replicate the evidence for the single nucleotide polymorphisms in ACYP2, LRP2, NFE2L2, OTOS, TPMT, SOD2, SLC22A2, GSTP1, ABCC3 and SLC16A5 genes being associated with ototoxicity. However, meta-analysis of all available literature showed that rs1872328 in ACYP2 could possibly be related to platinum ototoxicity in childhood cancer patients and survivors. As platinum-treated or cranial irradiated childhood cancer survivors have an increased risk of developing ototoxicity, clinical practice guidelines are necessary to promote early detection. Clinical practice guidelines for long-term follow-up of childhood cancer survivors have been developed by groups in North America and Europe, but recommendations vary among existing guidelines. This results in duplication of work and uncertainty for both survivor and health care providers which guideline to follow. The International Late Effects of Childhood Cancer Guideline Harmonization Group has been initiated to harmonize clinical practice guidelines for childhood cancer survivors. We described the overall methods of our worldwide collaborative effort to harmonize the recommendations for surveillance of ototoxicity after treatment for childhood and young adult cancer