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Anthracycline-induced cardiotoxicity in patients with early-stage breast cancer: the Canadian Cancer Trials Group (CCTG) MA.21 experience

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Abstract

Purpose

Anthracyclines are frequently used in adjuvant treatment for early-stage breast cancer (ESBC). The purpose of this study was to evaluate cardiotoxic effects in the first five years after treatment with different anthracycline-based regimens.

Methods

CCTG MA.21 (NCT000142) was a phase III trial in ESBC that compared cyclophosphamide (75 mg/m2) orally for 14 days, epirubicin (60 mg/m2) and fluorouracil, IV days one and eight (CEF) for six cycles; dose-dense epirubicin (120 mg/m2) and cyclophosphamide, IV every 2 weeks for six cycles with concurrent G-CSF then paclitaxel every 2 weeks for four cycles (ddEC/T); doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for four cycles then four cycles q3 weekly paclitaxel (175 mg/m2) (AC/T). Endpoints: LVEF decline; LV function changes (heart failure), or Grade 3–4 cardiac ischemia/infarction. A competing risk analysis was performed with endpoints of cardiotoxicity or recurrence in first 5 years after completion of chemotherapy.

Results

2104 women were randomized. Compliance with cardiac LVEF assessments was 70% at 5 years in all arms. The 5-year cumulative risks of any cardiac event for CEF, ddECT, and AC/T were 22.3% (95%CI 18.9 to 25.7), 14.2% (95%CI 11.0 to 17.3), and 8.1% (95%CI 5.8 to 10.4), respectively, p < 0.0001. At 5 years, women in the ddEC/T and AC/T group had significantly lower risk of cardiotoxicity than those given CEF (HR 0.599 and 0.371, respectively). Most events were asymptomatic drop in LVEF.

Conclusions

Asymptomatic changes in LVEF accounted for most of the cardiotoxicity. The majority of cardiac events occurred in year one although occurrence of cardiotoxicity over time highlights the need for improved risk stratification to guide cardiac surveillance strategies.

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Acknowledgements

We would to thank all of the women who participated in this trial and the many clinical trials staff that helped to compile these data.

Funding

This work was funded by the Canadian Society Cancer Research Institute (CSCRI), Canadian Institute for Health Research (CIHR), and the National Cancer Institute-US.

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Duke Cancer Institute, 10 Brian Searle Drive, Seeley G Mudd Bldg Room 455, Durham, NC, 27710, USA

    S. F. Dent

  2. Division of Medical Oncology, University of Ottawa, Ottawa, ON, Canada

    J. Botros & M. Rushton

  3. Division of Medical Oncology, Thunder Bay Regional Health Sciences, Thunder Bay, ON, Canada

    O. Aseyev

  4. Department of Oncology, McMaster University, Hamilton, ON, Canada

    M. N. Levine

  5. Canadian Cancer Trials Group (CCTG), Queens University, Kingston, ON, Canada

    W. R. Parulekar, P. O’Brien, B. E. Chen & L. E. Shepherd

  6. Department of Oncology, Saint John Regional Hospital, Saint John, New Brunswick, Canada

    M. Burnell

  7. Division of Medical Oncology/Hematology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada

    K. I. Pritchard

Authors
  1. S. F. Dent
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  2. J. Botros
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  7. P. O’Brien
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  10. B. E. Chen
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  11. L. E. Shepherd
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Corresponding author

Correspondence to S. F. Dent.

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Conflict of interest

Susan Dent—advisory board/consulting, honoraria: Pfizer, Novartis, Eli Lilly; research funding Novartis Kathleen I. Pritchard—Advisory board/consulting, honoraria: Pfizer, Roche, Amgen, Novartis, Eisai, Genomic Health Inc., Myriad Genetic Laboratories.

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Dent, S.F., Botros, J., Rushton, M. et al. Anthracycline-induced cardiotoxicity in patients with early-stage breast cancer: the Canadian Cancer Trials Group (CCTG) MA.21 experience. Breast Cancer Res Treat 184, 733–741 (2020). https://doi.org/10.1007/s10549-020-05887-w

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  • DOI: https://doi.org/10.1007/s10549-020-05887-w

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