title: Medical interventions for the prevention of platinum-induced hearing loss in children with cancer.
abstract: BACKGROUND
  Platinum-based therapy, including cisplatin, carboplatin and/or oxaliplatin, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different otoprotective medical interventions have been studied.
  
  
  OBJECTIVE
  The primary objective was to assess the efficacy of different otoprotective medical interventions in preventing hearing loss in children with cancer treated with platinum-based therapy. Secondary objectives were to determine possible effects of these interventions on anti-tumour efficacy, toxicities other than hearing loss and quality of life.
  
  
  METHODS
  We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE (PubMed) (1945 to 22 December 2011) and EMBASE (Ovid) (1980 to 22 December 2011). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2006 to 2011), the American Society of Pediatric Hematology/Oncology (2007 to 2011) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010). We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register and the National Institute of Health Register for ongoing trials (www.controlled-trials.com) (searched on 20 December 2011).
  
  
  METHODS
  Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) evaluating platinum-based therapy together with an otoprotective medical intervention versus platinum-based therapy with placebo, no additional treatment or another protective medical intervention in children with cancer.
  
  
  METHODS
  Two review authors independently performed the study selection, risk of bias assessment of included studies and data extraction, including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
  
  
  RESULTS
  We identified two RCTs and one CCT (total number of patients 149) evaluating the use of amifostine versus no additional treatment. Two studies included children with osteosarcoma, the other study included children with hepatoblastoma. Patients received cisplatin only or a combination of cisplatin and carboplatin, either administered intra-arterially or intravenously. All studies had methodological limitations. Unfortunately, pooling of the results of included studies was not possible. However, in all individual studies no significant difference was identified in symptomatic ototoxicity only (that is grade 2 or higher) and combined asymptomatic and symptomatic ototoxicity (that is grade 1 or higher) between children treated with or without amifostine. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided information on tumour response, defined as the number of patients with a good or partial remission. The 'available data' analysis (data were missing for one patient), 'best case scenario' analysis and 'worst case scenario' analysis all showed a difference in favour of amifostine, but this difference was significant only in the 'worst case scenario' analysis (P = 0.04). No information on survival was available for any of the included study populations. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided data on the number of patients with adverse effects other than ototoxicity grade 3 or higher. There was a significant difference in favour of the control group in the occurrence of vomiting grade 3 or 4 (RR 9.04; 95% CI 1.99 to 41.12; P = 0.004). No significant difference was identified between treatment groups for cardiotoxicity and renal toxicity grade 3 or 4. None of the studies evaluated quality of life. No eligible studies were found for possible otoprotective medical interventions other than amifostine and other types of malignancies.
  
  
  CONCLUSIONS
  At the moment there is no evidence from individual studies in children with osteosarcoma and hepatoblastoma treated with different platinum analogues and dosage schedules which underscores the use of amifostine as an otoprotective intervention as compared to no additional treatment. Since pooling of results was not possible and all studies had serious methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. Based on the currently available evidence, we are not able to give recommendations for clinical practice. For other possible otoprotective medical interventions and other types of malignancies no eligible studies were identified, so no conclusions can be made about their efficacy in preventing ototoxicity in children treated with platinum-based therapy. More high quality research is needed.
authors.affiliation: Cochrane Childhood Cancer Group, Emma Children’s Hospital / Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Jorrit W
authors.initials: JW
authors.lastname: van As
authors.forename: Henk
authors.initials: H
authors.lastname: van den Berg
authors.forename: Elvira C
authors.initials: EC
authors.lastname: van Dalen
mesh_terms: D000293:Adolescent; D004999:Amifostine / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001859:Bone Neoplasms / Q000188:drug therapy; D016190:Carboplatin / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000009:adverse effects*; D018849:Controlled Clinical Trials as Topic; D034381:Hearing Loss / Q000139:chemically induced / Q000517:prevention & control*; D018197:Hepatoblastoma / Q000188:drug therapy; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008113:Liver Neoplasms / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D012516:Osteosarcoma / Q000188:drug therapy; D020011:Protective Agents / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D020011:Protective Agents; D016190:Carboplatin; D004999:Amifostine; D002945:Cisplatin