Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes
Department of Pediatrics
Adolescent; Antibiotics, Antineoplastic; Cancer Care Facilities; Cardiomyopathies; Cardiotoxins; Child; Child, Preschool; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Echocardiography; Female; Follow-Up Studies; Heart Ventricles; Humans; Infusions, Intravenous; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; United States; Ventricular Function, Left
Cardiology | Hemic and Lymphatic Diseases | Oncology | Pediatrics
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.
DOI of Published Version
Pediatrics. 2012 Dec;130(6):1003-11. doi: 10.1542/peds.2012-0727. Link to article on publisher's site
Lipshultz SE, Miller TL, Lipsitz SR, Neuberg DS, Dahlberg SE, Colan SD, Silverman LB, Henkel JM, Franco VL, Cushman LL, Asselin BL, Clavell LA, Athale U, Michon B, Laverdiere C, Schorin MA, Larsen E, Usmani GN, Sallan SE. (2012). Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes. Pediatric Publications. https://doi.org/10.1542/peds.2012-0727. Retrieved from https://escholarship.umassmed.edu/peds_pp/27