Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol.
OBJECTIVE
Acute doxorubicin-induced cardiotoxicity can be prevented in adults by continuous infusion of the drug, but mechanisms of cardiotoxicity are different in children. We compared cardiac outcomes in children receiving bolus or continuous infusion of doxorubicin.


METHODS
In a randomized study, children with high-risk acute lymphoblastic leukemia received doxorubicin 360 mg/m(2) in 30-mg/m(2) doses every 3 weeks either by bolus (within 1 hour, n = 57) or by continuous infusion (over 48 hours, n = 64). Echocardiograms obtained before doxorubicin and at longest follow-up times were centrally remeasured, and z scores of cardiac measurements were calculated based on a healthy population.


RESULTS
The groups were similar in age, sex distribution, doxorubicin dose, and duration of follow-up. Before treatment, measures of left ventricular (LV) structure and function did not reveal dilated cardiomyopathy and were not statistically different between bolus and continuous-infusion groups. The follow-up echocardiograms demonstrated no significant difference between the two groups for any cardiac characteristic, but both groups showed significant abnormalities of LV structure and function compared with normal and with baseline. For example, the mean LV fractional shortening fell by approximately two SD in both groups between the two echocardiograms. LV contractility was depressed in both groups (for bolus patients, median z score = -0.70 SD, P =.006; for continuous-infusion patients, median z score = -0.765, P =.005). Dilated cardiomyopathy and inadequate LV hypertrophy were noted in both groups. Clinical cardiac manifestations and event-free survival did not differ.


CONCLUSIONS
Continuous doxorubicin infusion over 48 hours for childhood leukemia did not offer a cardioprotective advantage over bolus infusion. Both regimens were associated with progressive subclinical cardiotoxicity. Other cardioprotective strategies should be explored.
Lipshultz
Steven E
SE
Division of Pediatric Cardiology, Strong Children's Hospital and University of Rochester Medical Center, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. steve_lipschultz@urmc.rochester.edu
Giantris
Amy L
AL
Lipsitz
Stuart R
SR
Kimball Dalton
Virginia
V
Asselin
Barbara L
BL
Barr
Ronald D
RD
Clavell
Luis A
LA
Hurwitz
Craig A
CA
Moghrabi
Albert
A
Samson
Yvan
Y
Schorin
Marshall A
MA
Gelber
Richard D
RD
Sallan
Stephen E
SE
Colan
Steven D
SD
D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D004334:Drug Administration Schedule; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D012307:Risk Factors; D018709:Statistics, Nonparametric
D000970:Antineoplastic Agents; D004317:Doxorubicin