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Journal of Clinical Oncology, Vol 23, No 12 (April 20), 2005: pp. 2686-2693 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.059 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 TrialFrom the Centre Oscar Lambret, Lille; Institut Claudius Régaud, Toulouse; Centre Eugène Marquis, Rennes; Centre Léon Bérard, Lyon; Centre René Gauducheau, Nantes; Centre Antoine Lacassagne, Nice; Centre Hospitalier de Bretagne Sud, Lorient; Centre Paul Strauss, Strasbourg; Centre Georges-François Leclercq, Dijon; Pfizer, Saint-Quentin en Yvelines, France Address reprint requests to Jacques Bonneterre, MD, Département d'Oncologie Médicale, Centre Oscar Lambret, 3 rue Frédéric Combemale, 59020 Lille Cedex, France; e-mail: j-bonneterre{at}o-lambret.fr
PURPOSE: The French Adjuvant Study Group 05 (FASG-05) showed that fluorouracil 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 100 mg/m2 (FEC 100) was superior to the same regimen with epirubicin 50 mg/m2 (FEC 50) in terms of disease-free survival (DFS) and overall survival (OS) in adjuvant treatment of early breast cancer. We report 10-year data on efficacy, and long-term side effects for FASG-05. PATIENTS AND METHODS: We randomly assigned 565 patients to treatment with FEC 50 or FEC 100 after surgery. Postmenopausal patients also received tamoxifen for 3 years, and almost all patients (96%) also received radiotherapy. RESULTS: Median follow-up was 110 months. The 10-year DFS was 45.3% (95% CI, 41.9% to 48.7%) with FEC 50 and 50.7% (95% CI, 47.3% to 54.1%) with FEC 100 (Wilcoxon P = .036; log-rank P = .08). The 10-year OS was 50.0% (95% CI, 46.7% to 53.3%) with FEC 50 and 54.8% (95% CI, 51.3% to 58.3%) with FEC 100 (Wilcoxon P = .038; log-rank P = .05). Delayed cardiac toxicity (before relapse) occurred in four patients (1.5%) in the FEC 50 arm and three patients (1.1%) in the FEC 100 arm. Cardiac toxicity after relapse occurred in six (4.3%) and five (4.1%) patients treated with FEC 50 and FEC 100, respectively. CONCLUSION: Treatment with adjuvant FEC 100 demonstrated superior DFS and OS versus FEC 50 at 10 years of follow-up. This survival advantage was not offset by long-term complications such as cardiac toxicity and second malignancy. Given the risk-benefit ratio, FEC 100 is a more optimal regimen for long-term survival in patients with poor prognosis.
It is well established that adjuvant chemotherapy prolongs disease-free survival (DFS) and overall survival (OS) in women with axillary node–positive breast cancer. Appropriate chemotherapy can reduce the risk of death by up to 27%.1 Anthracyclines are among the most active cytotoxic agents against breast cancer, and anthracycline-based regimens have been shown to be superior to non–anthracycline-based regimens.1,2
The anthracyclines doxorubicin and epirubicin have been extensively studied in the treatment of breast cancer. Epirubicin at a dose of 50 mg/m2 per course has similar efficacy to the same dose of doxorubicin but is significantly better tolerated.3,4 This low toxicity suggests that higher doses of epirubicin may produce more optimal clinical outcomes. Escalation of doxorubicin dose does not seem to improve survival (in one study,5 doses from 60 mg/m2 to 90 mg/m2 administered as adjuvant therapy to women with node-positive primary disease had nearly identical 5-year rates of DFS), but a significant survival benefit was associated with epirubicin dose escalation in the French Adjuvant Study Group 05 (FASG-05) randomized trial. FASG-05 was designed to determine the effect of epirubicin dose and dose intensity in women with node-positive, poor-prognosis, early breast cancer. Poor-prognosis factors were defined as extensive lymph node involvement (N > 3) or one to three positive nodes with Scarff Bloom Richardson (SBR) grade
Detailed descriptions of the patients and methods have previously been reported.6
Patients
The main eligibility criteria were age between 18 and 64 years; WHO performance status
Treatment Regimens The allocated treatment was started within 42 days after initial surgery. Treatment was interrupted for at least 1 week if an absolute granulocyte count was less than 2,000/mm3 and/or a platelet count was less than 100,000/mm3 on day 21. Treatment was stopped if hematologic recovery took more than 3 weeks. The epirubicin dose was reduced by 50% if serum bilirubin levels were 35 to 50 µmol/L, and treatment was stopped if bilirubin levels exceeded 50 µmol/L. Postmenopausal women were prescribed tamoxifen 30 mg/d for 3 years unless hormone receptors were negative, in which case tamoxifen was prescribed at the discretion of investigators. Each institution's policy regarding tamoxifen use was similar for both treatment arms. Locoregional radiotherapy was delivered within 30 days after the last chemotherapy cycle according to standard procedures. After mastectomy, radiation (50 Gy in 25 fractions for each target) was delivered to the chest wall, supraclavicular area, and internal mammary chain, and to the axillary area in case of pN1 tumor. Patients who underwent lumpectomy received local radiation to the breast (55 Gy in 27 fractions plus a complementary breast irradiation of 10 to 15 Gy), and to the supraclavicular area, internal mammary chain, and axillary area in case of pN1 tumor (50 Gy in 25 fractions for each target). Nearly all patients (96%) also received radiotherapy. The tolerability of chemotherapy was evaluated before each successive cycle. An ECG and CBC were performed on day 21, and nonhematologic toxicity was evaluated during the period between each cycle according to WHO criteria. LVEF was assessed at the end of chemotherapy. Subjects underwent clinical, biochemical, and radiologic assessments (bilateral mammography, abdominal ultrasound or computed tomographic scan, and bone scan) every 6 months during the 5-year follow-up period, and yearly thereafter.
Statistical Analysis
Patient Characteristics A total of 565 women were enrolled on the study, which began in April 1990; enrollments were ended in July 1993. Of these 565 women, 537 were eligible for efficacy analysis, and 546, for safety analysis (Table 1). Baseline characteristics were well balanced between arms (Table 2). Major protocol violations were included in the analysis and were outlined in a previous publication that gave the details of the 5-year follow-up.6 At the cutoff date for this analysis (June 2002), the median follow-up period was 110 months (range, 4 to 143 months).
Treatment Among the 546 treated patients (FEC 50, 278 patients; FEC 100, 268 patients), the mean number of cycles administered was 5.92 for FEC 50 and 5.85 for FEC 100. Women in the FEC 50 arm received 95.7% of planned cycles versus 94.0% in the FEC 100 arm. Reasons for stopping treatment prematurely are outlined in the previous publication.6 The median intercycle delay was 21 days in each arm. The median cumulative epirubicin dose was 300 mg/m2 (range, 98 to 357 mg/m2) in the FEC 50 arm (intended dose, 300 mg/m2) and 600 mg/m2 (range, 91 to 625 mg/m2) in the FEC 100 arm (intended dose, 600 mg/m2). The median epirubicin dose intensity was 16 mg/m2/wk (range, 7 to 18 mg/m2/wk) in the FEC 50 arm and 30 mg/m2/wk (range, 14 to 34 mg/m2/wk) in the FEC 100 arm. The relative dose intensity was 94% in the FEC 50 arm and 91% in the FEC 100 arm. The median dose-intensity for fluorouracil and cyclophosphamide (which were administered on the same schedule) was slightly but significantly lower in the FEC 100 arm (Table 3).
Nearly half of enrolled women received concurrent hormonal therapy (FEC 50, 47.5%; FEC 100, 48.5%); most of those receiving hormonal therapy were postmenopausal. The mean duration of hormonal therapy was 33.8 months (standard deviation [SD], ± 16.9) in the FEC 50 arm and 37.9 months (SD, ± 17.1) in the FEC 100 arm (P = .06). Radiation therapy was administered to 96% of women in both arms of the study.
DFS
The Cox proportional hazards model showed that modified mastectomy and more than three positive axillary lymph nodes were independent prognostic factors of relapse. In this model, the comparison of treatments demonstrates improvement in DFS with FEC 100 relative to FEC 50 (P = .08; hazard ratio [HR] = 1.24; 95% CI, 0.97 to 1.59).
OS
The Cox proportional hazards model showed that the same prognostic factors as for relapse were independently involved in the occurrence of death. In this model, the comparison of treatment shows a significant improvement with the FEC 100 regimen (P = .04; HR = 1.31; 95% CI, 1.18 to 1.44).
Acute Toxicity
Delayed Cardiac Toxicity
Cardiac Toxicity After Relapse Cardiac toxicity after relapse (occurrence of a cardiac event with associated clinical manifestations after the occurrence of relapse) was reported in six of 139 patients (4.3%) who received FEC 50 and five of 123 (4.1%) who received FEC 100 (P = .92). Five and three patients had left ventricular dysfunction in the FEC 50 and FEC 100 groups, respectively (3.6% and 2.4%; P = .59). Toxicity consisted of left ventricular dysfunction with or without CHF (n = 8), rhythm disturbances (n = 2), and cardiovascular collapse (n = 1). In all but two cases (both in the FEC 100 group), patients received additional treatment for metastatic disease that might have contributed to the cardiac toxicity.
Second Malignancies Other second malignancies occurred in 23 patients, including 10 (3.7%) treated with FEC 50 and 13 (4.9%) treated with FEC 100. The mean time to appearance of these malignancies was 64.5 (SD, ± 31.8) months with FEC 50 and 60.7 (SD, ± 36.6) months with FEC 100. One woman in each group developed leukemia within the first 5 years, which was described in the previous publication.6 No new cases of leukemia were reported. The most common second malignancy was endometrial cancer, reported in four women treated with FEC 100 and in none treated with FEC 50. The most common second cancer in women treated with FEC 50 was colorectal cancer, reported in two women treated with FEC 50 and in one woman treated with FEC 100. Other cancer types (lymphoma, ovarian, stomach, pancreas, esophagus, lung, bladder, thyroid, basal cell, head and neck, and histiocytoma) were not reported in more than one patient in each arm.
This study shows that when epirubicin is administered at a dose of 100 mg/m2 per cycle rather than 50 mg/m2 per cycle, significantly improved 10-year survival benefits are observed in this poor-prognosis breast cancer patient population. The significant improvement seen at 5 years for FEC 100 versus FEC 50 in DFS (66.3% v 54.8%, P = .03) and OS (77.4% v 65.3%, P = .007)6 was maintained at the 10-year follow-up (DFS, 50.7% v 45.3%; Wilcoxon P = .036; OS, 54.8% v 50.0%; Wilcoxon P = .038). These survival rates are particularly impressive as all patients, both premenopausal and postmenopausal, had poor prognoses. It is noteworthy that there were slight discrepancies in P values between log-rank and Wilcoxon tests, especially in DFS. The number of patients at risk is lower after 10 years of follow-up. The Wilcoxon test is more powerful and sensitive, as it gives more weight on early event times and takes into account the longer elapsed time. Thus, we considered that the comparison between treatment arms was more accurate using the Wilcoxon test, which gives more weight to early events corresponding to early survival benefits. Independent prognostic factors of relapse were a high number of axillary lymph nodes involved and modified mastectomy, which was associated with large tumor size, multifocal tumor, and lobular carcinoma. The Cox regression model demonstrates that FEC 100 remains superior to FEC 50 independently of prognostic factors. Surprisingly, the rate of contralateral breast cancer (CBC) was lower with FEC 100. Classically, it has been described that hormone therapy decreases the risk of CBC.13 On the other hand, we have recently presented results from the overall FASG database showing that the main prognostic factor to develop a CBC was negative progesterone receptors (PR).14 In the present trial, the rate of PR-negative patients was higher than in the usual breast cancer population because of the inclusion criteria. These results could be explained by the fact that FEC 100 reduced the risk of CBC, even in PR-negative tumors. The long-term safety of the FEC regimen that was demonstrated at 5 years was maintained at the 10-year analysis. No additional cases of acute myelogenous leukemia were identified between the 5-year and 10-year follow-up. Cases of CHF were well controlled with symptomatic treatment, and there were no deaths from this cause. Delayed cardiac toxicity occurred no more often in the FEC 100 group than in the FEC 50 group. In FEC 50 patients, there was no case of left ventricular dysfunction (LVD), three cardiac events were mild, and death due to myocardial infarction was not related to chemotherapy per investigator determinations. This has been previously reported in the study of long-term cardiac function in FASG-05 patients who were free of disease.15 Left ventricular dysfunction was a characteristic finding in FEC 100–treated patients who developed delayed cardiotoxicity. Cardiac toxicity after relapse was reported in 4% of FEC 50–and FEC 100–treated patients; however, all but two patients were at risk for cardiotoxicity because of subsequent treatment for metastatic disease that included an anthracycline or anthracenedione. Although acute toxicity was more common in the FEC 100 group (as described in the 5-year analysis), these adverse events were deemed acceptable, and no toxicity-related deaths occurred.6 It should also be noted that chemotherapy was administered without the use of hematopoietic growth factors, antibiotics, or current antiemetic therapies, which are more effective than those available at the time of the study. Polychemotherapy using an anthracycline-containing regimen has been the cornerstone of treatment for women without preexisting heart disease who require adjuvant chemotherapy for breast cancer.1,2,16,17 In the adjuvant setting, the FASG initially defined the FEC 50 regimen as a reference treatment. Our first adjuvant trial (FASG-01), conducted in premenopausal, node-positive breast cancer patients, showed that six cycles of FEC 50 were significantly better than three cycles of FEC 50 or FEC 75 in terms of 10-year DFS.18 The FEC regimen is widely accepted in Europe, while four cycles of the AC regimen (doxorubicin and cyclophosphamide) is commonly used in the US based on the NSABP B-15 trial showing results similar to those obtained using six cycles of CMF (cyclophosphamide, methotrexate, and fluorouracil).19 On the other hand, when FEC regimens were compared with six cycles of CMF, the results were significantly in favor of FEC, irrespective of epirubicin dose (50, 60, or 120 mg/m2).20-23 There are no phase III studies comparing epirubicin with doxorubicin as adjuvant therapy at optimal doses of each anthracycline. However, phase III comparisons of FEC and fluorouracil, adriamycin, and cyclophosphamide (FAC) at the same doses in metastatic disease confirm similar efficacy, but consistently demonstrate improved safety for epirubicin.3,4,24 Investigations of adjuvant taxanes continue, and additional studies are exploring the potential benefit of adding a taxane to an anthracycline-based adjuvant regimen such as AC or FEC.25-28 In general, higher doses of adjuvant epirubicin up to 100 mg/m2 have been associated with improved response.29 In addition, the National Cancer Institute of Canada–Clinical Trials Group (NCIC-CTG) MA.5 trial tested six cycles of adjuvant CEF 120 (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) against six cycles of conventional CMF. The CEF 120 regimen was superior in both OS and DFS, with acceptable toxicity.22 The 10-year follow-up showed continued superiority in terms of DFS and OS of CEF 120 compared with CMF.23 To date, few other anthracycline-containing adjuvant regimens have 10-year follow-up data available. Results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-15 trial showed only similar survival outcomes between four cycles of the AC regimen (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 every 21 days) compared with six cycles of conventional CMF at 10 year's follow-up.30 The 10-year follow-up survival data reported here further highlight the long-term benefit of an epirubicin-containing adjuvant regimen. The best disease-free and overall survival was seen with epirubicin 100 mg/m2 per cycle; dosing at this level is possible because of the drug's long-term safety profile. Epirubicin 100 mg/m2 per cycle dose is accepted as optimal by many oncologists, but its use is by no means universal; the 50 mg/m2 dose is still administered in clinical practice. Our data suggest that in node-positive poor-prognosis breast cancer patients, there appears to be a survival advantage when epirubicin is administered at 100 mg/m2 per cycle as part of a polychemotherapy regimen in the adjuvant setting. The significant benefits in DFS and OS for FEC 100 over FEC 50 are confirmed after 10 years of follow-up. This advantage is not offset by long-term toxicity, as FEC 100 is associated with an acceptably low risk of long-term cardiac toxicity and second malignancy.
The following authors 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. Consultant: Isabelle Chapelle-Marcillac, Pfizer. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Organisations : The French participating centers are, in order of institutional accruals: Centre Oscar Lambret, Lille; Institut Claudius Régaud, Toulouse; Centre Eugène Marquis, Rennes; Centre Léon Bérard, Lyon; Centre René Gauducheau, Nantes; Centre Antoine Lacassagne, Nice; Centre Hospitalier de Bretagne Sud, Lorient; Centre Hospitalier Jean Minjoz, Besançon; Centre Georges-François Leclerc, Dijon; Centre Henri Becquerel, Rouen; Centre Hospitalier André Boulloche, Montbéliard; Centre Hospitalier Universitaire Dupuytren, Limoges; Centre Hospitalier, Annecy; Centre Hospitalier Louis Pasteur, Colmar; Clinique le Méridien, Cannes; Institut Jean Godinot, Reims; Clinique Radiologique et Orthopédique, Saint-Etienne; Hôpital Nord, Saint-Etienne; Institut Gustave Roussy, Villejuif; Centre Jean Perrin, Clermont-Ferrand.
Supported by grants from Pfizer, France. We are indebted to Dr Elisabeth Luporsi (Centre Alexis Vautrin, Nancy, France) for her statistical contribution. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003 and St Gallen Breast Cancer Conference, St Gallen, Switzerland, March 12-15, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[CrossRef][Medline] 2. Carlson RW, Anderson BO, Bensinger W, et al: NCCN practice guidelines for breast cancer. Oncology 14:33-49, 2000 3. French Epirubicin Study Group: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 6:679-688, 1988[Abstract]
4. The Italian Multicentre Breast Study with Epirubicin: Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: An Italian Multicentre Trial. J Clin Oncol 6:976-982, 1988
5. Henderson IC, Berry DA, Demetri GD, 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
6. French Adjuvant Study Group: 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 19:602-611, 2001 7. Snedecor GW, Cochran WG: Statistical Methods (ed 7). Ames, IA, Iowa State University Press, 1980 8. Duncan DB: P-tests and intervals for comparison suggested by the data. Biometrics 31:339-359, 1975[CrossRef]
9. Meyer RM, Browman GP, Samosh ML, et al: Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma. J Clin Oncol 13:2386-2393, 1995 10. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 11. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc [A] 135:185-198, 1972 12. Cox DR: Regression models and life-tables. J R Stat Soc [B] 34:187-202, 1972
13. Chen Y, Thompson W, Semenciw R, et al: Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev 8:855-861, 1999 14. Simon H, Monnier A, Namer M, et al: Prognostic factors of contralateral breast cancer in 3,653 early breast cancer patients: 9-year follow-up results of French Adjuvant Study Group trials. Proc Am Soc Clin Oncol 23:14, 2004 (abstr 551)
15. Bonneterre J, Roché H, Kerbrat P, et al: Long-term cardiac follow-up in relapse-free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French adjuvant study group. J Clin Oncol 22:3070-3079, 2004 16. National Institutes of Health Consensus Development Panel: Conference Statement: Adjuvant Therapy for Breast Cancer. J Natl Cancer Inst 93:979-989, 2000
17. Goldhirsch A, Wood WC, Gelber RD, et al: Meeting highlights: Updated International Expert Consensus of the primary therapy of early breast cancer. J Clin Oncol 21:3357-3365, 2003
18. Fumoleau P, Kerbrat P, Romestaing P, et al: Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol 21:298-305, 2003 19. 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] 20. Coombes RC, Bliss JM, Wils J, et al: 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 14:35-45, 1996[Abstract] 21. Mouridsen H, Andersen J, Andersson M, et al: Adjuvant anthracycline in breast cancer. Improved outcome in premenopausal patients following substitution of methotrexate in the CMF combination with epirubicin. Proc Am Soc Clin Oncol 18:68a, 1999 (abstr 254) 22. 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] 23. Pritchard KI, Levine MN, Bramwell VHC, et al: A randomized trial comparing CEF to CMF in premenopausal women with node positive breast cancer: Update of NCIC CTG MA. 5. Breast Cancer Res Treat 76:S33, 2002 (suppl 1, abstr) 24. Lopez M, Papaldo P, DiLauro L, et al: 5-Fluorouracil, adriamycin, cyclophosphamide (FAC) vs. 5-fluorouracil, epirubicin, cyclophosphamide (FEC) in metastatic breast cancer. Oncology 46:1-5, 1989[Medline]
25. Citron ML, Berry DA, Cirrincione CT, 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 26. Mamounas EP, Bryant J, Lembersky BC, et al: Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. Proc Am Soc Clin Oncol 22:4, 2003 (abstr 12)
27. Fumoleau P, Bonneterre J, Luporsi E: Adjuvant chemotherapy for node-positive breast cancer patients: Which is the reference today? J Clin Oncol 21:1190-1192, 2003 28. Fumoleau P, Roché H, Asselain B, et al: Evaluation of early cardiotoxicity in breast cancer patients treated with epirubicin (E)-based adjuvant chemotherapy: Results from the PACs 01 study. Proc Am Soc Clin Oncol 20:28a, 2001 (abstr 107)
29. Levine MN, Eisen A: Anthracycline adjuvant chemotherapy: How much is enough? J Clin Oncol 19:599-601, 2001 30. 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 Classic Papers and Current Comments, Breast Cancer 5:656-657, 2002 Submitted May 11, 2004; accepted January 4, 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
2 and hormone receptor negativity (both estrogen and progesterone). At the 5-year follow-up of FASG-05, DFS and OS were significantly improved with epirubicin 100 mg/m2 per cycle compared with 50 mg/m2 per cycle as part of the fluorouracil, epirubicin, cyclophosphamide (FEC) regimen.
2; normal hematologic, hepatic, and renal function; no cardiac dysfunction (baseline left ventricular ejection fraction [LVEF] 
2 test was used to compare baseline categorical variables and the incidence of adverse events in the FEC 100 and FEC 50 groups.
