Female Sex and Higher Drug Dose as Risk Factors for Late Cardiotoxic Effects of Doxorubicin Therapy for Childhood Cancer
Steven E. Lipshultz, M.D., Stuart R. Lipsitz, D.Sc., Suzanne M. Mone, M.S., Allen M. Goorin, M.D., Stephen E. Sallan, M.D., Stephen P. Sanders, M.D., E. John Orav, Ph.D., Richard D. Gelber, Ph.D., and Steven D. Colan, M.D.
Background Late cardiotoxic effects of doxorubicin are increasinglya problem for patients who survive childhood cancer. Cardiotoxicityis often progressive, and some patients have disabling symptoms.Our objective was to identify risk factors for late cardiotoxicity.
Methods We examined echocardiograms from 120 children and adultswho had received cumulative doses of 244 to 550 mg of doxorubicinper square meter of body-surface area for the treatment of acutelymphoblastic leukemia or osteogenic sarcoma in childhood, amean of 8.1 years earlier. Measurements of blood pressure andleft ventricular function, contractility (measured as the stress–velocityindex), end-diastolic posterior-wall thickness, end-diastolicdimension, mass, and afterload (measured as end-systolic wallstress) were compared with sex-specific values from a cohortof 296 normal subjects.
Results All echocardiographic measurements were abnormal atfollow-up a minimum of two years after the end of therapy, withmore frequent and severe abnormalities in female patients. Ina multivariate analysis, female sex and a higher cumulativedose of doxorubicin were associated with depressed contractility(P<0.001), and there was an interaction between these twovariables. Independent and significant associations were foundbetween a higher rate of administration of doxorubicin and increasedafterload (P<0.001), left ventricular dilatation, and depressedleft ventricular function; between a higher cumulative doseand depressed left ventricular function (P<0.001); betweena younger age at diagnosis and reduced left-ventricular-wallthickness and mass and increased afterload; and between a longertime since the completion of doxorubicin therapy and reducedleft-ventricular-wall thickness and increased afterload (P<0.001).
Conclusions Female sex and a higher rate of administration ofdoxorubicin were independent risk factors for cardiac abnormalitiesafter treatment with doxorubicin for childhood cancer; the prevalenceand severity of abnormalities increased with longer follow-up.
Source Information
From the Department of Cardiology (S.E.L., S.M.M., S.P.S., S.D.C.) and the Division of Hematology–Oncology (A.M.G., S.E.S.), Children's Hospital; the Department of Pediatrics, Harvard Medical School (S.E.L., A.M.G., S.E.S., S.P.S., R.D.G., S.D.C.); the Department of Pediatric Oncology (A.M.G., S.E.S.) and the Division of Biostatistics (S.R.L., R.D.G.), Dana–Farber Cancer Institute; the Department of Biostatistics, Harvard School of Public Health (S.R.L., E.J.O., R.D.G.); and the Department of Medicine, Brigham and Women's Hospital (E.J.O.) — all in Boston.
Address reprint requests to Dr. Lipshultz at the Department of Cardiology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
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