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Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer

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Poole, Christopher J., Earl, Helena M., Hiller, Louise, Dunn, Janet A., Bathers, Sarah, Grieve, Robert J., Spooner, David A., Agrawal, Rajiv K., Brunt, A. Murray, O’Reilly, Susan M. et al.

. (2006) Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. New England Journal of Medicine, Vol.355 (No.18). pp. 1851-1862. ISSN 0028-4793

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Official URL: http://dx.doi.org/10.1056/NEJMoa052084

Abstract

Background
The National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer.

Methods
In NEAT, we compared four cycles of epirubicin followed by four cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) with six cycles of CMF alone. In the BR9601 trial, we compared four cycles of epirubicin followed by four cycles of CMF, with eight cycles of CMF alone every 3 weeks. The primary end points were relapsefree
and overall survival. The secondary end points were adverse effects, dose intensity, and quality of life.

Results
The two trials included 2391 women with early breast cancer; the median follow-up was 48 months. Relapse-free and overall survival rates were significantly higher in the epirubicin–CMF groups than in the CMF-alone groups (2-year relapse-free survival, 91% vs. 85%; 5-year relapse-free survival, 76% vs. 69%; 2-year overall survival, 95% vs. 92%; 5-year overall survival, 82% vs. 75%; P<0.001 by the log-rank test for all comparisons). Hazard ratios for relapse (or death without relapse) (0.69; 95% confidence interval [CI], 0.58 to 0.82; P<0.001) and death from any cause (0.67; 95% CI, 0.55 to
0.82; P<0.001) favored epirubicin plus CMF over CMF alone. Independent prognostic factors were nodal status, tumor grade, tumor size, and estrogen-receptor status (P<0.001 for all four factors) and the presence or absence of vascular or lymphatic
invasion (P = 0.01). These factors did not significantly interact with the effect of epirubicin plus CMF. The overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone but did not significantly affect the delivered-dose intensity or the quality of life.

Conclusions
Epirubicin plus CMF is superior to CMF alone as adjuvant treatment for early breast cancer.
(ClinicalTrials.gov number, NCT00003577.)

Item Type:

Journal Article

Subjects:

R Medicine > R Medicine (General)
R Medicine > RS Pharmacy and materia medica

Divisions:

Faculty of Medicine > Warwick Medical School

Library of Congress Subject Headings (LCSH):

Anthrcyclines -- Testing, Breast cancer, Drugs testing

Journal or Publication Title:

New England Journal of Medicine

Publisher:

Massachusetts Medical Society Publisher

ISSN:

0028-4793

Official Date:

2 November 2006

Dates:

Date	Event
2 November 2006	Published

Volume:

Vol.355

Number:

No.18

Page Range:

pp. 1851-1862

Identification Number:

10.1056/NEJMoa052084

Status:

Peer Reviewed

Access rights to Published version:

Open Access

Description:

Final version (as published).

Funder:

Cancer Research UK (CRUK), Pfizer Inc.

Related URLs:

Other

References:

Early Breast Cancer Trialists' Collaborative Group. (1992). Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet, 339, pp. 71-85.
Habeshaw, T. Paul, J. Jones, R. et al. (1991). Epirubicin at 2 dose levels with prednisolone as treatment for advanced breast-cancer: the results of a randomized trial. J Clin Oncol,9, pp.295-304.
Buzzoni, R. Bonadonna,G., Valagussa, P. Zambetti, M. (1991). Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than 3 positive axillary nodes. J Clin Oncol, 9, pp. 2134-2140.
Bonadonna, G. Zambetti, M. Moliterni, A. Gianni, L. Valagussa, P. (2004). Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate, and fluorouracil in operable breast cancer. J Clin Oncol, 22, pp.1614-1620.
Bonadonna, G. Zambetti, M. Valagussa, P. (1995). Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA, 273, pp.542-547.
Moliterni, A. Bonadonna, G. Valagussa, P. Ferrari, L. Zambetti, M. (1991). Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast-cancer with one to three positive axillary nodes. J Clin Oncol, 9, pp.1124-1130.
Norton, L. Day, R. (1991). Potential innovations in scheduling in cancer chemotherapy. In: DeVita, V.T. Jr. Hellman, S. Rosenberg, S.A. eds. Important advances in oncology. Philadelphia: J.B. Lippincott, pp. 57-72.
Day, R.S. (1986). Treatment sequencing, asymmetry, and uncertainty: protocol strategies for combination chemotherapy. Cancer Res, 46, pp.3876-3885.
Goldie, J.H. Coldman, A.J. (1979). A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep, 63, pp. 1727-1733.
Goldie, J.H. Coldman, A.J. Gudauskas, G.A. (1982). Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep, 66, pp. 439-449.
Earl, H. Iddawela, M. (2004) Epirubicin as adjuvant therapy in breast cancer. Expert Rev Anticancer Ther, 4, pp. 189-195.
Goldhirsch, A. Colleoni, M. Coates, A.S. Castiglione-Gertsch, M. Gelber, R.D. (1998). Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? Ann Oncol, 9, pp.489-493.
Engelsman, E. Klijn, J.C. Rubens, R.D. et al. (1991). "Classical CMF" versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: an EORTC Breast Cancer Co-operative Group Phase III Trial (10808). Eur J Cancer, 27, pp. 966-970.
Bonadonna, G. Valagussa, P. ( 1981). Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med, 304, pp. 0-15.
Kaplan, E.L. Meier, P. (1958). Nonparametric estimation from incomplete observations. J Am Stat Assoc, 53, pp. 457-481.
Cox, D.R. (1972). Regression models and life-tables. J R Stat Soc [B], 34, pp.187-220.
Early Breast Cancer Trialists' Collaborative Group. (1990). Treatment of early breast cancer. Worldwide evidence 1985-1990. Oxford, England: Oxford University Press. Vol 1.
Aaronson, N.K. Ahmedzai, S. Bergman, B. et al. (1993). The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst, 85, pp. 365-376.
Sprangers, M.A.G. Groenvold, M. Arraras, J.I. et al. (1996). The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol, 14, pp. 2756-2768.
Hunter, M.S. (1992). The Women's Health Questionnaire: a measure of mid-aged women's perceptions of their emotional and physical health. Psychol Health, 7, pp. 45-54.
Qian, W. Parmar, M.K.B. Sambrook, R.J. Fayers, P.M. Girling, D.J. Stephens, R.J. (2000). Analysis of messy longitudinal data from a randomised clinical trial. Stat Med, 19, pp. 2657-2674.
O'Brien, P.C. (1984). Procedures for comparing samples with multiple endpoints. Biometrics, 40, pp.1079-1087.
Levine, M.N. Bramwell,,V.H. Pritchard, K.I. et al. (1998). Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol,16, pp. 2651-2658.
French Adjuvant Study Group. (2001). Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol, 19, pp. 602-611.
Early Breast Cancer Trialists' Collaborative Group. (1998). Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet, 352, pp. 930-942.
Coombes, R.C. Bliss, J.M. Wils. J. et al. (1996). Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol, 14, pp. 35-45
Crump, M. Tu, D.S. Shepherd, L. Levine, M. Bramwell, V. Pritchard, K. (2003). Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 21, pp. 3066-3071.
Praga, C. Bergh, J. Bliss, J. et al. (2005). Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol, 23, pp. 4179-4191
Pulsoni, A. Pagano, L. Lo Coco, F. et al. (2002). Clinicobiological features and outcome of acute promyelocytic leukemia occurring as a second tumor: the GIMEMA experience. Blood, 100, pp. 1972-1976.
Detourmignies, L. Castaigne, S. Stoppa, A.M. et al. (1992). Therapy-related acute promyelocytic leukemia: a report on 16 cases. J Clin Oncol,10, pp. 1430-1435.
Leonard, R.C. Lind, M. Twelves, C. et al. ( 2004). Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. J Natl Cancer Inst, 96, pp. 1076-1083.
Gianni, L. Baselga, J. Eiermann,W. et al. (2005). European Cooperative Trial in Operable Breast Cancer (ECTO): improved freedom from progression (FFP) from adding paclitaxel (T) to doxorubicin (A) followed by cyclophosphamide methotrexate and fluorouracil (CMF). J Clin Oncol, 23: Suppl. 7S-7S.
Hopwood, P. Ellis, P. Barrett-Lee, P. et al. (2005). Impact on quality of life (QL) during chemotherapy (CT) of FEC-T compared to FEC or E-CMF: results from the UKNCRI Taxotere as Adjuvant Chemotherapy Trial (TACT). J Clin Oncol, 23: Suppl. 43S-43S.
Piccart-Gebhart, M.J. Proctor, M. Leyland-Jones, B. et al. (2005). Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med, 353, pp. 1659-1672.
Buzdar, A.U. Ibrahim, N.K. Francis, D. et al. (2005). Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol, 23, pp. 3676-3685.