Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer

N Engl J Med. 1995 Jun 29;332(26):1738-43. doi: 10.1056/NEJM199506293322602.


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 objective was to identify risk factors for late cardiotoxicity.

Methods: 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.

Results: 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).

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Analysis of Variance
  • Child
  • Child, Preschool
  • Doxorubicin / administration & dosage
  • Doxorubicin / adverse effects*
  • Female
  • Follow-Up Studies
  • Heart Diseases / chemically induced*
  • Heart Diseases / diagnostic imaging
  • Humans
  • Infant
  • Male
  • Myocardial Contraction / drug effects
  • Osteosarcoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Risk Factors
  • Sex Factors
  • Survivors
  • Ultrasonography
  • Ventricular Function, Left / drug effects


  • Doxorubicin