title: Cardiac assessment of early breast cancer patients 18 years after treatment with cyclophosphamide-, methotrexate-, fluorouracil- or epirubicin-based chemotherapy.
abstract: BACKGROUND
  Epirubicin-based chemotherapy improves the outcome of early breast cancer (BC) patients. However, cardiotoxicity remains an important side effect.
  
  
  METHODS
  We re-consented node-positive BC patients enrolled in a phase III trial between 1988 and 1996 which compared six cycles of oral cyclophosphamide, methotrexate, fluorouracil (CMF) versus two epirubicin-cyclophosphamide regimens differing by the anthracycline cumulative dose [standard-dose epirubicin and cyclophosphamide (SDE) (8 × 60 mg/m(2)) and higher-dose epirubicin and cyclophosphamide (HDE) (8 × 100 mg/m(2))]. Eligible patients were those who were alive and free of disease and had no contra-indications to the proposed tests (cardiac evaluation). Cardiotoxicity was defined as asymptomatic systolic dysfunction (left ventricular ejection fraction (LVEF)< 50%, New York Heart Association (NYHA) Class I) or symptomatic heart failure (NYHA Class II-IV). Differences in cardiotoxicity between CMF and SDE/HDE were assessed using chi-square and Fisher Exact tests for binary variables and t-test and Wilcoxon test for continuous variables.
  
  
  RESULTS
  Among the 777 patients, 20 cases of CHF were reported (CMF = 1, SDE = 5, HDE = 14; p < 0.001). Between September 2010 and June 2013, 82 patients (30%) out of 269 eligible patients accepted to participate in this substudy. Median follow-up was 18 years (range 15-24). Epirubicin-treated patients had significantly higher heart rate, more abnormal echocardiograms and LVEF by magnetic resonance imaging (MRI) compared to CMF-treated ones. A trend towards higher BNP was also observed in the SDE/HDE group (P = 0.08). No differences were observed in LVEF assessed by echocardiogram or troponin T levels.
  
  
  CONCLUSIONS
  Participation rate in this substudy was lower than expected highlighting the complexity of re-calling patients several years after the initial BC diagnosis. After 18 years, epirubicin-treated patients had a lower LVEF by MRI, more abnormal echocardiograms, higher heart rates compared to patients treated with CMF. However, no major delayed cardiotoxicity was observed.
authors: Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: evandro.azambuja@bordet.be.
authors: Evandro
authors: E
authors: de Azambuja
authors: Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors: Lieveke
authors: L
authors: Ameye
authors: Department of Oncology, Hôpital Ambroise Pare, Mons, Belgium.
authors: Marie
authors: M
authors: Diaz
authors: Neuropsychologue CHIREC, Brussels, Belgium.
authors: Sandrine
authors: S
authors: Vandenbossche
authors: Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors: Philippe
authors: P
authors: Aftimos
authors: Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors: Sara
authors: S
authors: Bejarano Hernández
authors: Department of Radiology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors: Chao
authors: C
authors: Shih-Li
authors: Cardiology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors: François
authors: F
authors: Delhaye
authors: Department of Oncology, CHC-Clinique Saint-Joseph, Liege, Belgium.
authors: Christian
authors: C
authors: Focan
authors: Department of Oncology, CHU Tivoli - GOHH, La Louviere, Belgium.
authors: Nathalie
authors: N
authors: Cornez
authors: Clinique Ste-Elisabeth, Namur, Belgium.
authors: Anita
authors: A
authors: Vindevoghel
authors: Department of Oncology, Hôpital de Jolimont, Haine St Paul, Belgium.
authors: Marc
authors: M
authors: Beauduin
authors: Department of Radiology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors: Marc
authors: M
authors: Lemort
authors: Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors: Marianne
authors: M
authors: Paesmans
authors: Swiss Cardiovascular Center, Inselspital, Bern University Hospital, Bern, Switzerland.
authors: Thomas
authors: T
authors: Suter
authors: Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors: Martine
authors: M
authors: Piccart-Gebhart
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005500:Follow-Up Studies; D006333:Heart Failure / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology
chemical_list: D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate
keywords: Adjuvant therapy; Late cardiac toxicity; Node-positive breast cancer