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Doxorubicin Administration by Continuous Infusion Is Not Cardioprotective: The Dana-Farber 91-01 Acute Lymphoblastic Leukemia Protocol

From the Divisions of Pediatric Cardiology and Pediatric Hematology/Oncology, Strong Children’s Hospital and University of Rochester Medical Center, James P. Wilmot Cancer Center, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY; Departments of Pediatric Oncology and Biostatistical Science, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Department of Cardiology, Children’s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, SC; Department of Pediatrics, McMaster University, Hamilton, Ontario, Hospital Ste Justine, Montreal, and Le Centre Hospitalier de L’Universite, Laval, Quebec, Canada; San Jorge Children’s Hospital, Puerto Rico; Maine Children’s Cancer Program, The Barbara Bush Children’s Hospital at Maine Medical Center, Portland, ME; and Department of Pediatrics, Oschsner Institutions, New Orleans, LA.

Address reprint requests to Steven E. Lipshultz, MD, Division of Pediatric Cardiology, University of Rochester Medical Center, 601 Elmwood Ave, Box 631, Rochester, NY 14642; email: steve_lipshultz@ urmc.rochester.edu.

PURPOSE: 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.

PATIENTS AND METHODS: In a randomized study, children with high-risk acute lymphoblastic leukemia received doxorubicin 360 mg/m² in 30-mg/m² 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.

CONCLUSION: 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.

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