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

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 do...

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Published in:	Pediatrics (Evanston) Vol. 130; no. 6; pp. 1003 - 1011
Main Authors:	LIPSHULTZ, Steven E, MILLER, Tracie L, ASSELIN, Barbara L, CLAVELL, Luis A, ATHALE, Uma, MICHON, Bruno, LAVERDIERE, Caroline, SCHORIN, Marshall A, LARSEN, Eric, USMANI, Naheed, SALLAN, Stephen E, LIPSITZ, Stuart R, NEUBERG, Donna S, DAHLBERG, Suzanne E, COLAN, Steven D, SILVERMAN, Lewis B, HENKEL, Jacqueline M, FRANCO, Vivian I, CUSHMAN, Laura L
Format:	Journal Article
Language:	English
Published:	Elk Grove Village, IL American Academy of Pediatrics 01-12-2012
Subjects:	Acute lymphocytic leukemia Adolescent Antibiotics, Antineoplastic - administration & dosage Antibiotics, Antineoplastic - toxicity Biological and medical sciences Cancer Care Facilities Cardiomyopathies - chemically induced Cardiotoxins - administration & dosage Cardiotoxins - toxicity Child Child, Preschool Clinical outcomes Clinical trials Demographic aspects Disease-Free Survival Dosage and administration Dose-Response Relationship, Drug Doxorubicin Doxorubicin - administration & dosage Doxorubicin - toxicity Drug Administration Schedule Drug therapy Echocardiography - drug effects Female Follow-Up Studies General aspects Heart Ventricles - drug effects Hematologic and hematopoietic diseases Humans Infusion therapy Infusions, Intravenous Leukemia Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Male Medical sciences Methods Patient outcomes Pediatrics Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality Risk Factors Survival analysis United States Ventricular Function, Left - drug effects United States Antineoplastic agent Heart Pediatrics Continuous Toxicity Leukemia Cardiovascular disease Doxorubicin Isomerases Evolution Child Human DNA topoisomerase (ATP-hydrolysing) Enzyme Enzyme inhibitor Malignant hemopathy Topoisomerase II inhibitor Long term Antibiotic cardiotoxicity Bolus injection anthracycline Perfusion Anthracyclins Circulatory system Comparative study Cancer
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Summary:	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). 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. 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). 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.
ISSN:	0031-4005 1098-4275
DOI:	10.1542/peds.2012-0727