FEMALE SEX AND HIGHER DRUG DOSE AS RISK-FACTORS FOR LATE CARDIOTOXIC EFFECTS OF DOXORUBICIN THERAPY FOR CHILDHOOD-CANCER

Background. 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 obje ctive was to identify risk factors for late cardiotoxicity. Methods. W e examined echocardiograms from 120 children and adults who had receiv ed cumulative doses of 244 to 550 mg of doxorubicin per square meter o f body-surface area for the treatment of acute lymphoblastic leukemia or osteogenic sarcoma in childhood, a mean of 8.1 years earlier. Measu rements 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. Results. All echocardiographic measur ements were abnormal at follow-up a minimum of two years after the end of therapy, with more frequent and severe abnormalities in female pat ients. In a multivariate analysis, female sex and a higher cumulative dose of doxorubicin were associated with depressed contractility (P le ss than or equal to 0.001), and there was an interaction between these two variables. independent and significant associations were found be tween a higher rate of administration of doxorubicin and increased aft erload (P less than or equal to 0.001), left ventricular dilatation, a nd depressed left ventricular function; between a higher cumulative do se and depressed left ventricular function (P less than or equal to 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-vent ricular-wall thickness and increased afterload (P less than or equal t o 0.001). Conclusions. 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.