While CAF is the standard adjuvant regimen of early breast cancer in the USA, FEC is an establisehd alternative and is used preferentially in Europe. In Europe, the second-generation anthracycline epirubicin (the 4′-epimer of doxorubicin) has been used in several countries preferentially as a component of chemotherapy regimens for the adjuvant treatment of early breast cancer. This trend was driven by a series of large phase III clinical trials comparing various anthracycline-containing regimens as well as CMF regimens in both node-positive and node-negative patients. For example, the International Collaborative Cancer Group (ICCG) conducted a large randomized trial comparing two different fluorouracil–epirubicin–cyclophosphamide (FEC) dosing regimens with two different CMF dosing regimens in node-positive premenopausal patients. That study found some evidence of longer OS (log-rank test, 5.66; p = .02) and RFS (log-rank test, 4.55; p = .03) with a six-cycle FEC regimen with a 50-mg/m2 epirubicin dose compared with a six-cycle CMF regimen.
French oncologists formed the French Adjuvant Study Group (FASG), which beginning in the 1990s conducted a series of clinical trials, each building on the results of previous trials. The FASG 05 trial of combination chemotherapy in node-positive breast cancer patients with hormone receptor–negative status compared epirubicin doses of 50 mg/m2 (FEC50) and 100 mg/m2 (FEC100). Both the 5- and 10-year follow-up analyses have shown significant advantages for the FEC100 regimen in DFS (66.3% versus 54.8%; p = .03) and OS (77.4% versus 65.3%; p = .007) . A 10-year follow-up revealed the superiority of six cycles of FEC100 in terms of DFS (45.3% in the FEC50 arm and 50.7% in the FEC100 arm), with a relative risk reduction of 24% (Wilcoxon p = .03), and in terms of OS, which similarly favored FEC100. The FASG 05 trial demonstrated a dose-response effect of epirubicin, as increasing the dose from 50 mg/m2 to 100 mg/m2 in the FEC regimen resulted in longer DFS and OS. In contrast, the Cancer and Leukemia Group B (CALGB) study of doxorubicin dosing of 60 mg/m2, 75 mg/m2, and 90 mg/m2 did not show better therapeutic efficacy with increasing doses of doxorubicin. In that randomized trial of 3,121 patients, increasing doxorubicin doses produced no significant reduction in the hazard of either cancer recurrence or death. The National Cancer Institute of Canada (NCIC) also evaluated both moderate-risk (1–3 positive nodes) and high-risk (>4 positive nodes) premenopausal women receiving either cyclophosphamide, epirubicin, 5-fluorouracil (CEF) or CMF. Patients fared better on the CEF regimen than on CMF; 63% of the CEF group remained relapse-free after 5 years, compared with 53% of the CMF group (p = .009), and OS rates for CEF and CMF were 77% and 70%, respectively (p = .03). Both the FASG 05 and the NCIC MA.5 trials showed the therapeutic benefit of optimal dosing of epirubicin as part of a combination chemotherapy regimen to achieve superior long-term 10-year survival in node-positive breast cancer patients at high risk for relapse.
Therapeutic benefit from epirubicin-containing chemotherapy has also been demonstrated in the setting of node-negative disease. In a planned pooled efficacy analysis of the National Epirubicin Adjuvant Trial and the Scottish Cancer Trials Breast Group BR9601 trials, 28% of the 2,391 patients enrolled in the two studies were node-negative. The trials compared the classic CMF regimen with 100 mg/m2 epirubicin followed by CMF (ECMF) and found that ECMF produced significantly better RFS (hazard ratio, 0.70; 95% confidence interval [CI], 0.58–0.85; p = .0003) and OS (hazard ratio, 0.64; 95% CI, 0.51–0.81; p = .0001), irrespective of nodal status. Those trials demonstrated that optimal dosing of epirubicin (100 mg/m2), when added to CMF combination chemotherapy in the adjuvant breast cancer setting, is required to achieve superior DFS and OS. The Danish Breast Cancer Group earlier obtained similar results. In their trial, 93% of the node-negative patients who received CEF (with 60 mg/m2 epirubicin) survived for 6 years, compared with 83% of those who received CMF (p < .01). Thus, extended follow-up has confirmed that higher-dose combination chemotherapy regimens containing epirubicin improve therapeutic efficacy for both node-positive and node-negative early breast cancer patients.
In regard to adding Taxotere after completing CEF, this was also studied in 1999 patients with the conclusion that, “Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive breast cancer patients and has a favorable safety profile.”
M. Colozza, E. de Azambuja, F. Cardoso, C. Bernard, and M. J. Piccart
Breast cancer: achievements in adjuvant systemic therapies in the pre-genomic era.
Oncologist, February 1, 2006; 11(2): 111 – 125
S. Gluck Adjuvant Chemotherapy for Early Breast Cancer: Optimal Use of Epirubicin
Oncologist, November 1, 2005; 10(10): 780 – 791.
C. Bonneterre, C. Bercez, M.-E. Bonneterre, X. Lenne, and B. Dervaux
Cost-effectiveness analysis of breast cancer adjuvant treatment: FEC 50 versus FEC 100 (FASG05 study) Ann. Onc., June 1, 2005; 16(6): 915 – 922.
Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial.J Clin Oncol. 2006 Dec 20;24(36):5664-71.
Gennari A, Sormani MP, Pronzato P, Puntoni M, Colozza M, Pfeffer U, Bruzzi P: HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. Journal of the National Cancer Institute 2008, 100:14-20.
Jun-Jie Li MD,Adjuvant Therapy of Breast Cancer with Pirarubicin Versus Epirubicin in Combination with Cyclophosphamide and 5-fluorouracil The Breast Journal Volume 17, Issue 6, pages 657–660, November/December 2011