title: Different dosage schedules for reducing cardiotoxicity in people with cancer receiving anthracycline chemotherapy.
abstract: BACKGROUND
  This review update has been managed by both the Childhood Cancer and Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Groups.The use of anthracycline chemotherapy is limited by the occurrence of cardiotoxicity. To prevent this cardiotoxicity, different anthracycline dosage schedules have been studied.
  
  
  OBJECTIVE
  To determine the occurrence of cardiotoxicity with the use of different anthracycline dosage schedules (that is peak doses and infusion durations) in people with cancer.
  
  
  METHODS
  We searched the databases of the Cochrane Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 11, 2015), MEDLINE (1966 to December 2015), and EMBASE (1980 to December 2015). We also searched reference lists of relevant articles, conference proceedings, experts in the field, and ongoing trials databases.
  
  
  METHODS
  Randomised controlled trials (RCTs) in which different anthracycline dosage schedules were compared in people with cancer (children and adults).
  
  
  METHODS
  Two review authors independently performed the study selection, the 'Risk of bias' assessment, and data extraction. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
  
  
  RESULTS
  We identified 11 studies: 7 evaluated different infusion durations (803 participants), and 4 evaluated different peak doses (5280 participants). Seven studies were RCTs addressing different anthracycline infusion durations; we identified long-term follow-up data for one of the trials in this update. The meta-analysis showed a statistically significant lower rate of clinical heart failure with an infusion duration of six hours or longer as compared to a shorter infusion duration (risk ratio (RR) 0.27; 95% confidence interval 0.09 to 0.81; 5 studies; 557 participants). The majority of participants included in these studies were adults with different solid tumours. For different anthracycline peak doses, we identified two RCTs addressing a doxorubicin peak dose of less than 60 mg/m(2) versus 60 mg/m(2) or more, one RCT addressing a liposomal doxorubicin peak dose of 25 mg/m(2) versus 50 mg/m(2), and one RCT addressing an epirubicin peak dose of 83 mg/m(2) versus 110 mg/m(2). A significant difference in the occurrence of clinical heart failure was identified in none of the studies. The participants included in these studies were adults with different solid tumours. High or unclear 'Risk of bias' issues were present in all studies.
  
  
  CONCLUSIONS
  An anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure, and it seems to reduce the risk of subclinical cardiac damage. Since there is only a small amount of data for children and data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children.We identified no significant difference in the occurrence of clinical heart failure in participants treated with a doxorubicin peak dose of less than 60 mg/m(2) or 60 mg/m(2) or more. Only one RCT was available for the other identified peak doses, so we can make no definitive conclusions about the occurrence of cardiotoxicity. More high-quality research is needed, both in children and adults and in leukaemias and solid tumours.
authors.affiliation: Department of Paediatric Oncology, Emma Children's Hospital/Academic Medical Center, PO Box 22660 (room TKsO-247), Amsterdam, Netherlands, 1100 DD.
authors.forename: Elvira C
authors.initials: EC
authors.lastname: van Dalen
authors.forename: Helena J H
authors.initials: HJ
authors.lastname: van der Pal
authors.forename: Leontien C M
authors.initials: LC
authors.lastname: Kremer
mesh_terms: D000328:Adult; D018943:Anthracyclines / Q000008:administration & dosage* / Q000009:adverse effects; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D002303:Cardiac Output, Low / Q000139:chemically induced / Q000517:prevention & control; D002648:Child; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic