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Journal of Clinical Oncology, Vol 23, No 22 (August 1), 2005: pp. 5166-5170 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.09.423 Randomized Trial Comparing Cyclophosphamide, Epirubicin, and Fluorouracil With Cyclophosphamide, Methotrexate, and Fluorouracil in Premenopausal Women With Node-Positive Breast Cancer: Update of National Cancer Institute of Canada Clinical Trials Group Trial MA5From the Departments of Clinical Epidemiology and Biostatistics and Medicine, McMaster University, Hamilton; University of Toronto, Toronto; Queen's University, Kingston, Ontario; and Department of Oncology, University of Calgary, Calgary, Alberta, Canada Address reprint requests to Mark Levine, MD, Clinical Trials Methodology Group, Henderson Research Centre, 711 Concession St, Hamilton, Ontario, Canada L8V 1C3; e-mail: mlevine{at}mcmaster.ca
PURPOSE: Certain anthracycline-containing adjuvant chemotherapy regimens are associated with improved relapse-free survival (RFS) and overall survival (OS) compared with the classic regimen of cyclophosphamide, methotrexate, and fluorouracil in women with early-stage breast cancer. PATIENTS AND METHODS: Between 1989 and 1993, 710 pre- and perimenopausal women with axillary node–positive breast cancer were randomly assigned to either cyclophosphamide 75 mg/m2 orally days 1 through 14, epirubicin 60 mg/m2 intravenously days 1 and 8, and fluorouracil 500 mg/m2 intravenously days 1 and 8 (CEF) or CMF (cyclophosphamide 100 mg/m2 orally days 1 through 14, methotrexate 40 mg/m2 intravenously days 1 and 8, and fluorouracil 600 mg/m2 intravenously days 1 and 8). On the basis of follow-up to May 1997 (median follow-up time, 59 months), there was a statistically significant improvement in RFS and OS for CEF compared with CMF. RESULTS: The trial results are now updated, with a median follow-up of 10 years for live patients. The 10-year RFS is 52% for patients who received CEF compared with 45% for CMF patients (hazard ratio [HR] for CMF v CEF = 1.31; stratified log-rank, P = .007). The 10-year OS for patients who received CEF and CMF are 62% and 58%, respectively (HR for CMF v CEF = 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure are slightly higher but acceptable (four patients [1.1%] in the CEF group v one patient [0.3%] in the CMF group). CONCLUSION: The previously demonstrated benefit of CEF compared with CMF adjuvant chemotherapy is maintained with longer follow-up in the MA5 trial.
Anthracyclines are currently an important component of adjuvant chemotherapy, but this was not always the case. In 1976, the combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) was first reported to be effective in women with axillary node–positive breast cancer and was soon widely used in clinical practice.1 In the 1980s, to improve on the results of CMF, a number of trials were conducted evaluating anthracycline-containing regimens, and the results were inconsistent.2-4 In a pilot study in women with node-positive and locally advanced breast cancer, we established the safety of an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil (CEF).5 The development of CEF was based on the concepts at that time that doxorubicin was one of the most active agents in advanced breast cancer, that epirubicin was less cardiotoxic than doxorubicin with no loss of antitumour efficacy, and that increasing the dose-intensity of chemotherapy improved outcome.6-10 The CEF regimen was then compared with CMF in pre- or perimenopausal women with axillary node–positive breast cancer in the MA5 trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). Recruitment to the trial occurred between 1989 and 1993. At a median follow-up of 59 months, there was a statistically significant improvement in relapse-free survival (RFS) and overall survival (OS) for CEF compared with CMF.11 There are few trials of adjuvant anthracycline chemotherapy that have reported long-term results of efficacy and safety. We now provide a 10-year update of the MA5 trial.
Patient Population Premenopausal or perimenopausal women with histologically confirmed axillary node–positive breast cancer who had undergone modified radical mastectomy or lumpectomy plus axillary dissection were studied. Menopausal status was defined according to the criteria described in our previous publication.11 Patients were excluded from the study if they had evidence of metastases, a documented history of cardiac disease or previous cancer except skin cancer, inadequate renal function, abnormal liver function tests, a serious underlying medical illness or psychiatric disorder, inflammatory or locally advanced breast cancer before surgery, microscopic evidence of residual tumor at the resection margin of the total mastectomy, gross tumor that remained in the axilla after surgery, or previous radiation therapy or chemotherapy for breast cancer; patients were also excluded if they were more than 10 weeks from initial surgery for breast cancer. Informed consent was obtained from eligible patients before assignment to treatment. The study protocol was approved by the institutional review board of each participating center.
Treatment Regimens All patients who underwent lumpectomy received local radiation that consisted of 50 Gy in 25 fractions to the breast after completion of chemotherapy. Radiation to the chest wall after total mastectomy and radiation to the regional nodes were not permitted. Patients in both arms were not to receive tamoxifen, long-term prednisone therapy, or other hormones.
Outcomes
Statistical Analysis
The hazard ratios (HRs) between CMF and CEF for recurrence and mortality and 95% CIs were obtained using the Cox proportional hazards model with a single treatment covariate. An adjusted HR was also calculated by including additional covariates, such as age (< 50 years and
The database for the current analysis was locked in April 2002. All patients on the trial who were alive were observed for a minimum of 9 years and a median of 10 years. Seven hundred sixteen women underwent random assignment; six patients (one on CMF and five on CEF) were ineligible and, therefore, excluded. Seven hundred ten eligible patients (351 on CEF and 359 on CMF) were included in the analysis. The treatment groups were reasonably balanced for baseline characteristics, including age, axillary nodes, hormone receptor status, and type of surgery (Table 1). There was no statistically significant difference in any of the baseline characteristics between groups.
Two hundred one CMF patients have developed breast cancer recurrence compared with 162 CEF patients. The 10-year RFS for CMF patients was 45% compared with 52% for CEF patients (HR = 1.31; 95% CI, 1.06 to 1.61; stratified log-rank, P = .007; stratified Wilcoxon, P = .005; Fig 1). The disease-free survival rates for nodal subgroups and subgroups based on ER status are listed in Table 2. When a Cox model was performed, which adjusted for age, tumor size, nodal status, and ER level, the HR for recurrence was 1.31 (95% CI, 1.06 to 1.61).
One hundred fifty-three CMF patients have died compared with 131 CEF patients. The 10-year survival rate for CMF was 58% compared with 62% for CEF (HR = 1.18; 95% CI, 0.94 to 1.49; stratified log-rank, P = .085; stratified Wilcoxon, P = .047; Fig 2). The corresponding survival data for nodal and ER status subgroups are listed in Table 2. In the Cox model, the adjusted HR for mortality was 1.16 (95% CI, 0.91 to 1.46).
As a sensitivity analysis, we performed a failure-free survival analysis that included recurrence, second primary cancer, or death as an event. The HR was 1.25 (95% CI, 1.02 to 1.52; stratified log-rank, P = .015; stratified Wilcoxon, P = .012). At the time of the trial publication in 1998, five patients in the CEF group experienced acute leukemia. One patient experienced congestive heart failure in the CMF group. There have been no further cases of leukemia in the CEF group, but one patient in the CMF group experienced leukemia. There have been four cases of congestive heart failure in CEF patients but no additional cases in CMF patients; these cases occurred between 16 and 58 months after study entry. One of these patients with congestive heart failure received doxorubicin for metastases to the chest wall.
The results of the MA5 trial published in 1998 demonstrated the superiority of CEF compared with classical CMF.11 The 5-year RFS for CEF was 63% compared with 53% for CMF (HR = 1.3; 95% CI, 1.04 to 1.65). The 5-year OS for CEF and CMF were 77% and 70%, respectively (HR = 1.22; 95% CI, 0.91 to 1.64). The updated analysis shows that the previously demonstrated benefit of CEF over CMF is maintained. The CMF to CEF HRs for both RFS and OS at 5 years and 10 years are consistent with each other. Our trial was not powered for comparison of treatment regimens in subgroups based on nodes or hormone receptor status. However, the HRs favored CEF in patients with one to three nodes and four or more nodes. This was also observed at the 5-year analysis. In our earlier publication, the results of the comparison of treatments based on ER status subgroups were not presented. In the current analysis, the HRs favored CEF in patients with ER-positive and -negative tumors. Currently, patients with hormone receptor–positive tumors often receive endocrine therapy. The results of the MA5 trial may not be readily extrapolated to today's practice because of the absence of endocrine therapy in the trial. Serious adverse experiences, such as leukemia and heart failure, are of concern with intensive anthracycline regimens. Since the previous publication, there have been no further cases of leukemia in CEF patients. The cases previously reported occurred between 15 and 41 months after randomization. Since the previous analysis, there have been four cases of heart failure in the CEF group. All of these cases occurred before 5 years of follow-up. In fact, these cases actually occurred during the follow-up period of our 1998 publication, but data came in after the database was closed. Currently, all patients on the trial who are alive have been observed for a minimum of 9 years. Hence, it is reassuring that there seems to be no late cardiotoxicity. There has been only one other adjuvant trial of an anthracycline regimen compared with classic CMF, and this trial has a much shorter follow-up than our trial.12 Although anthracycline-containing regimens are now commonly used as adjuvant therapy, there are relatively few publications concerning long-term efficacy and safety results of trials that evaluated such agents a number of years ago.13,14 Currently, taxanes are often incorporated into anthracycline regimens.15,16 It is unknown how CEF compares with an anthracycline/taxane regimen. Presently, CEF is being compared with doxorubicin and cyclophosphamide followed by paclitaxel and with dose-dense high-dose epirubicin and cyclophosphamide followed by paclitaxel in a large multicenter trial conducted by the NCIC CTG with the participation of the US Intergroup. Recently the combination of docetaxel, doxorubicin, and fluorouracil has been reported to have better RFS and OS but increased febrile neutropenia compared with fluorouracil, doxorubicin, and cyclophosphamide.17 There are limitations in comparing fluorouracil, doxorubicin, and cyclophosphamide with CEF because the regiments contain different anthracyclines and are administered through different schedules. In conclusion, the long-term superiority of CEF compared with CMF in the MA5 trial is maintained. It is reassuring that no further late toxicity has occurred. This provides important information that serves as a foundation as current research in adjuvant therapy is evaluating incorporating new potentially cardiotoxic agents into anthracycline regimens.
Althoguh all authors have completed the disclosure declaration, the following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported in part by a grant-in-aid from Pharmacia Inc (now Pfizer). Presented in part at the 25th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 10-14, 2002. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294: 405-410, 1976[Abstract] 2. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8: 1483-1496, 1990[Abstract] 3. Moliterni A, Bonadonna G, Valagussa P, et al: 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: 1124-1130, 1991[Abstract] 4. Carpenter JT, Velez-Garcia E, Aron BS, et al: Five year results of a randomized comparison of cyclophosphamide, doxorubicin (Adriamycin), and fluorouracil (CAF) versus cyclophosphamide, methotrexate, and fluorouracil (CMF) for node positive breast cancer: A Southeastern Cancer Study Group Study. Proc Am Soc Clin Oncol 13:66, 1994 (abstr 68) 5. Levine MN, Bramwell V, Pritchard K, et al: A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer. Eur J Cancer 29A: 37-43, 1992
6. Torti FM, Bristow MM, Lum BL, et al: Cardiotoxicity of epirubicin and doxorubicin: Assessment by endomyocardial biopsy. Cancer Res 46: 3722-3727, 1986
7. Jain KK, Casper ES, Geller NL, et al: A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 3: 818-826, 1985 8. Italian Multicentre Breast Study with Epirubicin: Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide versus fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: An Italian multicentre trial—Italian Multicentre Breast Study with Epirubicin. J Clin Oncol 6:976-982, 1988 9. French Epirubicin Study Group: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin: French Epirubicin Study Group. J Clin Oncol 6: 679-688, 1988[Abstract]
10. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4: 1162-1170, 1986 11. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16: 2651-2658, 1998[Abstract] 12. Hutchins L, Green S, Ravdin P, et al: CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: First results of Intergroup Trial INT 0102. Proc Am Soc Clin Oncol 17:1a, 1998 (abstr 2) 13. Bonneterre J, Roche H, Kerbrat P, et al: Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 23:2686-2693, 2005
14. Bonadonna G, Zambetti M, Moliterni A, et al: Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate, and fluorouracil in operable breast cancer. J Clin Oncol 22: 1614-1620, 2004
15. Henderson IC, Berry DA, Demetri G, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node positive primary breast cancer. J Clin Oncol 21: 976-983, 2003
16. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21: 1431-1439, 2003 17. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302-2313, 2005 Submitted December 15, 2004; accepted March 24, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 years), tumor size (T1, T2, and T3), nodal status (one to three and 
