Abstract
In the Netherlands, approximately 600 children are diagnosed with cancer each year. Advances in treatment and supportive care have increased the five-year survival rate to 75%, but this also means more children experience both short- and long-term toxicities, including ototoxicity. This can manifest as hearing loss, tinnitus, and vertigo. Ototoxicity
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in children with cancer is multifactorial, caused by antineoplastic therapies such as platinum-based agents, cranial irradiation, and brain surgery. Supportive care medications, including aminoglycosides, glycopeptides, and loop diuretics, also contribute. This thesis investigates the frequency and determinants of ototoxicity and the (pre)clinical efficacy of sodium thiosulfate (STS) in preventing cisplatin-induced hearing loss. Previous research has linked prolonged antibiotic use to hearing loss, but the specific impact of aminoglycosides and glycopeptides in children remains unclear. Chapter 2 presents a systematic literature review of 30 studies, showing wide variations in hearing loss prevalence: 0–57% in aminoglycoside-treated children and 54–55% in those treated with glycopeptides. Aminoglycosides were often co-administered with cisplatin and other ototoxic agents. Chapter 3 examines the impact of radiotherapy (photon, proton, and brachytherapy) on hearing loss in survivors of head and neck rhabdomyosarcoma. Audiological assessments conducted at least two years post-treatment revealed that up to 19% experienced significant hearing loss. A unique low-to-middle-frequency hearing loss pattern was observed in some patients, while higher frequencies remained better preserved. Higher cochlear irradiation doses were significantly associated with hearing loss. Since 2015, pediatric oncology care in the Netherlands has been centralized at the Princess Máxima Center, enabling standardized audiological monitoring. Chapter 4 analyzes data from 2015–2020 on children with solid tumors. Audiological monitoring was performed in 62.6% of patients before treatment, 79.0% during, and 82.1% post-treatment. By the end of treatment, 51.2% (Muenster classification) and 36.5% (SIOP classification) had hearing loss of grade ≥2. Risk factors included cisplatin treatment and dosage, age at diagnosis, vincristine treatment, and male sex. This retrospective analysis serves as the foundation for the ongoing SOUND study, a prospective investigation into ototoxicity prevalence and determinants (Chapter 5). Chapter 6 explores genetic susceptibility to ototoxicity. A Genome-Wide Association Study (GWAS) identified an intronic variant (rs893507) in the TCERG1L gene, associated with a 3.11-fold increased risk of hearing loss. Validation in independent cohorts and in vitro experiments suggest TCERG1L plays a role in cisplatin-induced damage. The final chapters (7 and 8) evaluate STS as an otoprotective agent. A review of 31 studies confirms STS effectively reduces hearing loss in both preclinical and clinical settings. Clinical trials show systemic STS administration is safe for children with localized non-metastatic disease, and efforts are ongoing to implement STS in pediatric oncology. This thesis enhances our understanding of ototoxicity prevalence and risk factors in pediatric oncology patients and assesses STS’s efficacy. The Onco-Ototoxicity Consortium, a collaboration between the Princess Máxima Center and UMC Utrecht, is committed to early identification and prevention of ototoxicity. Continued collaborative research will be essential to reducing ototoxicity in children with cancer.
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