Beneficial and harmful effects of anthracyclines in the treatment of childhood acute lymphoblastic leukaemia: a systematic review and meta-analysis

Abstract

Anthracyclines are used to treat childhood acute lymphoblastic leukaemia (ALL) but non-randomized studies suggest that cardiotoxicity may be a problem. Individual patient data from trials in childhood ALL that randomized anthracyclines or methods of reducing cardiotoxicity were analysed by standard meta-analysis methods. Results were grouped and combined according to: addition of an anthracycline to standard therapy, type of anthracycline, mode of administration, and the use of a cardioprotectant. Data from 958 patients in 4 trials, recruiting between 1972 and 1984, showed that addition of an anthracycline reduced bone marrow relapse and, non-significantly, non-bone marrow relapse, resulting in an increased relapse-free interval. However there was a non-significant increase in induction failures, and in deaths in first remission. Event-free survival at 5 years was 56.7% with anthracycline versus 52.8% without (Odds Ratio = 0.91; 95% Confidence Interval = 0.76-1.10; P = 0.3). There were no significant differences found in other treatment comparisons. The limited data from trials did not demonstrate differences in clinically evident cardiotoxicity. Anthracyclines are effective against bone marrow relapse but have not been shown to significantly increase event free survival in childhood ALL. The evidence on type of anthracycline, method of administration or use of cardioprotectant was insufficient to be able to rule out important differences.

Figure 1

Effect of the addition of an anthracycline on overall event rate. O.R. = Odds ratio. CI = confidence interval. The result for each trial and its 99% confidence interval is represented by a black square, whose size is proportional to the amount of information available, and a horizontal line. Overall results for each subgroup and overall are represented by diamonds whose widths indicate 95% confidence intervals. Total numbers of events and patients are adjusted for trials contributing more than one comparison so that patients are only counted once.

Figure 2

Descriptive curve showing the effect of the addition of an anthracycline on (a) event free survival and (b) overall survival.

Figure 3

Effect of the method of anthracycline administration on overall event rate. Abbreviations and symbols as in figure 1.

Figure 4

Effect of cardioprotectant on overall event rate. Abbreviations and symbols as in figure 1.