Continuous versus bolus infusion of doxorubicin in children with ALL: Long-term cardiac outcomes

Steven E. Lipshultz, Tracie L. Miller, Stuart R. Lipsitz, Donna S. Neuberg, Suzanne E. Dahlberg, Steven D. Colan, Lewis B. Silverman, Jacqueline M. Henkel, Vivian I. Franco, Laura L. Cushman, Barbara L. Asselin, Luis A. Clavell, Uma Athale, Bruno Michon, Caroline Laverdière, Marshall A. Schorin, Eric Larsen, Naheed Usmani, Stephen E. Sallan

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

BACKGROUND AND OBJECTIVES: Doxorubicin, effective against manymalignancies, 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/m2 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 (continuousinfusion, 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.

Original languageEnglish (US)
Pages (from-to)1003-1011
Number of pages9
JournalPediatrics
Volume130
Issue number6
DOIs
StatePublished - Dec 2012

Keywords

  • Anthracycline
  • Cardiotoxicity
  • Doxorubicin
  • Leukemia
  • Pediatrics

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Arts and Humanities (miscellaneous)

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