Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer.
Late cardiotoxic effects of doxorubicin are increasingly a problem for patients who survive childhood cancer. Cardiotoxicity is often progressive, and some patients have disabling symptoms. Our objective was to identify risk factors for late cardiotoxicity.



We examined echocardiograms from 120 children and adults who had received cumulative doses of 244 to 550 mg of doxorubicin per square meter of body-surface area for the treatment of acute lymphoblastic leukemia or osteogenic sarcoma in childhood, a mean of 8.1 years earlier. Measurements of blood pressure and left ventricular function, contractility (measured as the stress-velocity index), end-diastolic posterior-wall thickness, end-diastolic dimension, mass, and afterload (measured as end-systolic wall stress) were compared with sex-specific values from a cohort of 296 normal subjects.



All echocardiographic measurements were abnormal at follow-up a minimum of two years after the end of therapy, with more frequent and severe abnormalities in female patients. In a multivariate analysis, female sex and a higher cumulative dose of doxorubicin were associated with depressed contractility (P < or = 0.001), and there was an interaction between these two variables. Independent and significant associations were found between a higher rate of administration of doxorubicin and increased afterload (P < or = 0.001), left ventricular dilatation, and depressed left ventricular function; between a higher cumulative dose and depressed left ventricular function (P < or = 0.001); between a younger age at diagnosis and reduced left-ventricular-wall thickness and mass and increased afterload; and between a longer time since the completion of doxorubicin therapy and reduced left-ventricular-wall thickness and increased afterload (P < or = 0.001).



Female sex and a higher rate of administration of doxorubicin were independent risk factors for cardiac abnormalities after treatment with doxorubicin for childhood cancer; the prevalence and severity of abnormalities increased with longer follow-up.
Lipshultz
S E
SE
Department of Cardiology, Children's Hospital, Boston, MA 02115, USA.
Lipsitz
S R
SR
Mone
S M
SM
Goorin
A M
AM
Sallan
S E
SE
Sanders
S P
SP
Orav
E J
EJ
Gelber
R D
RD
Colan
S D
SD
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000704:Analysis of Variance; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging; D006801:Humans; D007223:Infant; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D012307:Risk Factors; D012737:Sex Factors; D017741:Survivors; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects
D004317:Doxorubicin