Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy

BACKGROUND: The use of anthracycline chemotherapy is limited by the occurrence of cardiotoxicity. In an effort to prevent this cardiotoxicity, different anthracycline dosage schedules (i.e. peak doses and infusion durations) have been studied. OBJECTIVES: The primary objective was to determine the occurrence of cardiotoxicity with the use of different anthracycline dosage schedules in cancer patients. SEARCH STRATEGY: We searched the databases of The Cochrane Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 2, 2004), MEDLINE (1966 to June 2004) and EMBASE (1980 to June 2004). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which different anthracycline dosage schedules were compared in cancer patients (children and adults). DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection, quality assessment and data-extraction including adverse effects. MAIN RESULTS: We identified six RCTs of varying quality addressing different anthracycline infusion durations (625 patients). The meta-analysis showed a statistically significant lower rate of clinical heart failure with an infusion duration of 6 hours or longer as compared to a shorter infusion duration, i.e. maximal duration of 1 hour (RR = 0.27; 95% confidence interval (CI) 0.09 to 0.81; 5 studies; 557 patients). In individual studies the infusion duration of 6 hours or longer also seemed to reduce the risk of subclinical cardiac damage. No statistically significant difference in response rate was found (RR = 0.83; 95% CI 0.45 to 1.54; 2 studies; 292 patients). No statistically significant difference in overall survival was found (HR = 1,42; 95% CI 0.61 to 3.30; 2 studies; 322 patients), but there was unexplained heterogeneity (I(2)=75%). No conclusions can be made regarding adverse effects. It should be emphasised that the majority of patients included in these studies were adults with different solid tumours. Children with leukaemia could not be included in the performed meta-analyses, but they were included in the descriptive results of non-pooled studies. No RCTs addressing different anthracycline peak doses with the same cumulative anthracycline dose in both treatment groups were identified. AUTHORS' 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. There is no evidence which suggests a difference in response rate and survival between both treatment groups. Since there is only a small amount of data for children and also because data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children. For different anthracycline peak doses no high quality evidence was available and therefore, no definitive conclusions can be made about the occurrence of cardiotoxicity in patients treated with different anthracycline peak doses.