title: Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33101. slipshultz@med.miami.edu
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
authors.forename: Tracie L
authors.initials: TL
authors.lastname: Miller
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Lipsitz
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.forename: Steven D
authors.initials: SD
authors.lastname: Colan
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Henkel
authors.forename: Vivian I
authors.initials: VI
authors.lastname: Franco
authors.forename: Laura L
authors.initials: LL
authors.lastname: Cushman
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Asselin
authors.forename: Luis A
authors.initials: LA
authors.lastname: Clavell
authors.forename: Uma
authors.initials: U
authors.lastname: Athale
authors.forename: Bruno
authors.initials: B
authors.lastname: Michon
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdière
authors.forename: Marshall A
authors.initials: MA
authors.lastname: Schorin
authors.forename: Eric
authors.initials: E
authors.lastname: Larsen
authors.forename: Naheed
authors.initials: N
authors.lastname: Usmani
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
mesh_terms: D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000633:toxicity*; D002173:Cancer Care Facilities; D009202:Cardiomyopathies / Q000139:chemically induced*; D054715:Cardiotoxins / Q000008:administration & dosage* / Q000633:toxicity*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000633:toxicity*; D004334:Drug Administration Schedule; D004452:Echocardiography / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality; D012307:Risk Factors; D014481:United States; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D054715:Cardiotoxins; D004317:Doxorubicin