Abstract: 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. 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.

Plain-language summary: This systematic review focused on randomised studies evaluating the antitumour effects of anthracycline therapy. The authors found that at the moment no high quality evidence is available which shows that the use of anthracyclines has an increased antitumour effect in acute lymphoblastic leukaemia (ALL) as compared to treatment without anthracyclines, but there was some suggestion that this might be the case. Further high quality studies are needed to provide a definitive conclusion. For Wilms' tumour, rhabdomyosarcoma and undifferentiated sarcoma, Ewing's sarcoma, non-Hodgkin lymphoma, hepatoblastoma and acute myeloid leukaemia (AML) the review authors found only limited data and were unable to draw conclusions. Also, there were no data for other childhood cancers. More high quality research is needed. At the moment there are five ongoing or unpublished randomised studies evaluating the use of anthracyclines in the following types of childhood cancer, hepatoblastoma, ALL (two studies), rhabdomyosarcoma, and Wilms' tumour.