Cardiac assessment of early breast cancer patients 18 years after treatment with cyclophosphamide-, methotrexate-, fluorouracil- or epirubicin-based chemotherapy

Eur J Cancer. 2015 Nov;51(17):2517-24. doi: 10.1016/j.ejca.2015.08.011. Epub 2015 Aug 27.

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.

Trial registration: ClinicalTrials.gov NCT01554943.

Keywords: Adjuvant therapy; Late cardiac toxicity; Node-positive breast cancer.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / mortality
  • Chemotherapy, Adjuvant / methods
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Echocardiography
  • Epirubicin / administration & dosage
  • Epirubicin / adverse effects
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Follow-Up Studies
  • Heart Failure / chemically induced
  • Heart Failure / diagnostic imaging
  • Heart Failure / physiopathology
  • Humans
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects
  • Middle Aged
  • Neoplasm Recurrence, Local
  • Outcome Assessment, Health Care / methods
  • Outcome Assessment, Health Care / statistics & numerical data
  • Prognosis
  • Proportional Hazards Models
  • Survival Rate
  • Ventricular Dysfunction, Left / chemically induced
  • Ventricular Dysfunction, Left / diagnostic imaging
  • Ventricular Dysfunction, Left / physiopathology

Substances

  • Epirubicin
  • Cyclophosphamide
  • Fluorouracil
  • Methotrexate

Associated data

  • ClinicalTrials.gov/NCT01554943