Abstract
BACKGROUND: One of the most important adverse effects of anthracyclines is cardiotoxicity. A well-informed decision on the use of anthracyclines in the treatment of childhood cancers should be based on evidence regarding both antitumour efficacy and cardiotoxicity. This review is the second update of a previously published Cochrane review. OBJECTIVES: To compare antitumour efficacy (survival and tumour response) and cardiotoxicity of treatment including or not including anthracyclines in children with childhood cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 6), MEDLINE (1966 to July 2013) and EMBASE (1980 to July 2013). In addition, we searched reference lists of relevant articles and conference proceedings, the International Society for Paediatric Oncology (SIOP) (from 2002 to 2012) and American Society of Clinical Oncology (ASCO) (from 2002 to 2013). We have searched for ongoing trials in the ISRCTN register and the National Institute of Health register (both screened August 2013) (http://www.controlled-trials.com). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing treatment of any type of childhood cancer with and without anthracyclines and reporting outcomes concerning antitumour efficacy or cardiotoxicity. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment and data extraction. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified RCTs for seven types of tumour, acute lymphoblastic leukaemia (ALL) (three trials; 912 children), Wilms' tumour (one trial; 316 children), rhabdomyosarcoma and undifferentiated sarcoma (one trial; 413 children), Ewing's sarcoma (one trial; 94 children), non-Hodgkin lymphoma (one trial; 284 children), hepatoblastoma (one trial; 255 children) and acute myeloid leukaemia (AML) (one trial; 394 children). All studies had methodological limitations. For ALL no evidence of a significant difference in antitumour efficacy was identified in the meta-analyses, but in most individual studies there was a suggestion of better antitumour efficacy in patients treated with anthracyclines. For both Wilms' tumour and Ewing's sarcoma a significant difference in event-free and overall survival in favour of treatment with anthracyclines was identified, although for Wilms' tumour the significant difference in overall survival disappeared with long-term follow-up. For rhabdomyosarcoma and undifferentiated sarcoma, non-Hodgkin lymphoma and hepatoblastoma no difference in antitumour efficacy between the treatment groups was identified. The same was true for AML, with the exception of overall survival in a post hoc analysis in a subgroup of patients with relapsed core binding factor (CBF)-AML in which patients treated with anthracyclines did better. Clinical cardiotoxicity was evaluated in four RCTs; no significant difference between the treatment groups was identified, but in all individual studies there was a suggestion of a lower rate of clinical cardiotoxicity in patients who did not receive anthracyclines. None of the studies evaluated asymptomatic cardiac dysfunction. No RCTs were identified for other childhood cancers. AUTHORS' CONCLUSIONS: At the moment no evidence from RCTs is available which underscores the use of anthracyclines in ALL. However, 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For Wilms' tumour, rhabdomyosarcoma and undifferentiated sarcoma, Ewing's sarcoma, non-Hodgkin lymphoma, hepatoblastoma and AML only one RCT was available for each type and, therefore, no definitive conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours. For other childhood cancers no RCTs were identified and therefore no conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours.