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, Steven E.; Miller, Tracie L.; Lipsitz, Stuart R.; Neuberg, Donna S.; Dahlberg, Suzanne E.; Colan, Steven D.; Silverman, Lewis B.; Henkel, Jacqueline M.; Franco, Vivian L.; Cushman, Laura L.; Asselin, Barbara L.; Clavell, Luis A.; Athale, Uma; Michon, Bruno; Laverdiere, Caroline; Schorin, Marshall A.; Larsen, Eric; Usmani, G. Naheed; and Sallan, Stephen E., "Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes" (2012). Pediatric Publications and Presentations. 27.