Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes

Abstract

Background and objectives: Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL).

Methods: The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m(2) of doxorubicin in 30 mg/m(2) doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function.

Results: A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with ≥1 echocardiogram ≥3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24).

Conclusions: In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion.

FIGURE 1

Summary of the DFCI Childhood ALL Consortium Protocol 91-01 randomized controlled trial for long-term cardiotoxicity of doxorubicin in children with high-risk acute lymphoblastic leukemia.

FIGURE 2

Changes in estimated mean z scores among 92 children with high-risk acute lymphoblastic leukemia receiving continuous or bolus infusions of doxorubicin as a cardioprotectant strategy. Years indicates time from date of diagnosis expressed in years. A, LV fractional shortening; B, LV end-diastolic posterior wall thickness; C, LV mass; D, LV end-systolic dimension; and E, LV end-diastolic dimension. Bars represent 95% confidence intervals; * indicates the P value for the difference between treatment arms; † indicates that there is a P < .05 for the difference between baseline and the follow-up time-point; ‡ indicates that there is a P < .01 for the difference between baseline and the follow-up time-point.