Journal of the National Cancer Institute Advance Access published online on July 29, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn206
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© The Author 2008. Published by Oxford University Press.
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New Insight Into Epirubicin Cardiac Toxicity: Competing Risks Analysis of 1097 Breast Cancer Patients
Affiliations of authors: Department of Oncology, Herlev Hospital (MR, DN, TS), Department of Cardiology, Hvidovre Hospital (GN), and Department of Biostatistics, Institute of Public Health (PKA), University of Copenhagen, Denmark; Department of Statistical Sciences, University of Padova, Italy (GC)
Correspondence to: Marianne Ryberg, MD, Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark (e-mail: mary{at}heh.regionh.dk).
Background: Current recommendations that cancer patients receive a maximum cumulative dose of 900 mg/m2 epirubicin are based on the risk of epirubicin-mediated cardiotoxicity and do not take into account the competing risk of death from cancer. Here, we identify risk factors for cardiotoxicity and overall mortality and determine the cumulative dose of epirubicin that yields a 5% risk for cardiotoxicity for cancer patients from different risk backgrounds.
Methods: Data were collected from 1097 consecutive anthracycline-naive patients treated for metastatic breast cancer with epirubicin. Patients who developed congestive heart failure classified as New York Heart Association class 2 or higher were recorded as having cardiotoxicity. Independent Cox multiple regression analyses for cardiotoxicity and for overall mortality were followed by competing risks analysis, with cardiotoxicity as the primary event and death from all other causes as the competing event. All statistical tests were two-sided.
Results: A total of 11.4% of patients developed cardiotoxicity. Risk factors for cardiotoxicity included increased cumulative dose of epirubicin (hazard ratio per every 100 mg/m2 administered = 1.40, 95% confidence interval = 1.21 to 1.61), patient age, predisposition to cardiac disease, history of mediastinal irradiation, or antihormonal treatment for metastatic disease. Risk factors for death from all other causes (including breast cancer) included lesser dosages of epirubicin, increased tumor burden, prior use of adjuvant chemotherapy, and patient age. The cumulative dosage of epirubicin that carries a 5% risk of cardiotoxicity was lower than previously assumed and was dependent on risks of both cardiotoxicity and overall mortality.
Conclusion: Maximum cumulative dosages of epirubicin are presented that confer a 5% risk of cardiotoxicity for patients with different sets of risk factors.
| CONTEXT AND CAVEATS Prior knowledge The use of anthracyclines, such as doxorubicin and epirubicin, for cancer treatment has been limited by their association with cardiomyopathy and congestive heart failure. Current guidelines that patients be given a cumulative dose of no more than 900 mg/m2 of epirubicin are based on simple estimates of the risk of epirubicin-mediated cardiotoxicity without regard to risk of death from other causes. Study design Data were collected from 1097 Danish women with no previous history of treatment with anthracyclines who were being treated for metastatic breast cancer with several epirubicin-based regimens. Risk factors for cardiotoxicity and for death from all other causes (including cancer) were assessed, and hazard ratios for both outcomes were used to calculate recommended maximum cumulative dosages for epirubicin. Contribution Patient age, predisposition to cardiac disease, and history of mediastinal irradiation or of antihormonal cancer treatment were risk factors for epirubicin-mediated cardiotoxicity. Smaller total epirubicin dose, increased tumor burden, prior use of adjuvant chemotherapy, and patient age contributed to risk of death from other causes. Implications Recommended cumulative maximal dosages of epirubicin have generally been revised downward and are presented here for patients with different risk backgrounds. Limitations As a retrospective study, this analysis carries some possibility that some patients could have been misclassified or could have provided incomplete risk histories. From the Editors
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Manuscript received October 31, 2007; revised May 14, 2008; accepted May 21, 2008.
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J Natl Cancer Inst 2008 100: 1046-1047.
J Natl Cancer Inst 2008 100: 1045.
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