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Prospective Evaluation of Early Cardiac Damage Induced by Epirubicin-Containing Adjuvant Chemotherapy and Locoregional Radiotherapy in Breast Cancer Patients

From the Departments of Medical Oncology, Cardiology, and Radiation Oncology, University Hospital, Groningen; and Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

Address reprint requests to W.T.A. van der Graaf, MD, PhD, Department of Medical Oncology, University Hospital, PO Box 30.001, 9700 RB Groningen, the Netherlands; email: w.t.a. van.der.graaf{at}int.azg.nl

PURPOSE: To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients.

PATIENTS AND METHODS: Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m²), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction.

RESULTS: No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P = .001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P < .01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P = .04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P < .01). No persistent alterations were found in diastolic function and HRV.

CONCLUSION: Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.

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