title: Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer.
abstract: BACKGROUND
  Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. This review is an update of a previously published Cochrane review.
  
  
  OBJECTIVE
  To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions, or no treatment.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 8), MEDLINE/PubMed (1949 to September 2015), and EMBASE/Ovid (1980 to September 2015) for potentially relevant articles. In addition, we searched reference lists of relevant articles, conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, and the European Symposium on Late Complications from Childhood Cancer (from 2005 to 2015), and ongoing trial databases (the ISRCTN Register, the National Institutes of Health (NIH) Register, and the trials register of the World Health Organization (WHO); all searched in September 2015).
  
  
  METHODS
  Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions, or no treatment.
  
  
  METHODS
  Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments, which another review author checked. We performed analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions.
  
  
  RESULTS
  In the original version of the review we identified two RCTs; in this update we identified no additional studies. One trial (135 participants) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline-induced cardiac dysfunction. The other trial (68 participants) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, adenosine triphosphate, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no statistically significant differences in overall survival, mortality due to heart failure, development of clinical heart failure, and quality of life between treatment and control groups. A post-hoc analysis showed a decrease (that is improvement) in one measure of cardiac function (left ventricular end-systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Participants treated with enalapril had a higher risk of dizziness or hypotension (risk ratio 7.17, 95% confidence interval 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function, and adverse events between treatment and control groups.
  
  
  CONCLUSIONS
  Only one trial evaluated the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.Only one trial evaluated the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatments on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.
authors.forename: Daniel K L
authors.initials: DK
authors.lastname: Cheuk
authors.forename: Elske
authors.initials: E
authors.lastname: Sieswerda
authors.forename: Elvira C
authors.initials: EC
authors.lastname: van Dalen
authors.forename: Aleida
authors.initials: A
authors.lastname: Postma
authors.forename: Leontien C M
authors.initials: LC
authors.lastname: Kremer
mesh_terms: D000328:Adult; D000069586:Adult Survivors of Child Adverse Events; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D018943:Anthracyclines / Q000008:administration & dosage* / Q000009:adverse effects; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002648:Child; D004656:Enalapril / Q000009:adverse effects / Q000627:therapeutic use*; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D010725:Phosphocreatine / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D010725:Phosphocreatine; D004656:Enalapril