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© 2003 American Society for Clinical Oncology 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
From the Centre René Gauducheau, Nantes; Centre Eugéne Marquis, Rennes; Centre Hospitalier de Lyon Sud; Centre Léon Bérard, Lyon; Centre Georges-François Leclerc, Dijon; Centre Antoine Lacassagne, Nice; Centre Hospitalier Jean Minjoz, Besançon; Centre Hospitalier de Bretagne Sud, Lorient; Institut Claudius Régaud, Toulouse; Centre Hopsitalier André Boulloche, Montbéliard; Centre Hospitalier Universitaire Dupuytren, Limoges; Clinique Sainte-Catherine, Avignon; Institut Jean Godinot, Reims; Hôpital Nord; Clinique Radiologique et Orthopédique, Saint-Etienne; Hôpital Notre-Dame de Bon Secours, Metz; Centre Hospitalier Jean Monnet, Epinal; Institut Gustave Roussy, Villejuif; Centre Hospitalier Général, Troyes; Centre Hospitalier, Annecy; Clinique le Méridien, Cannes; Centre Hospitalier Général, Montélimar; Centre Jean Perrin, Clermont-Ferrand; Centre Hositalier Général, Belfort; and Centre Hospitalier Général, Tarbes, France. Address reprint requests to Pierre Fumoleau, MD, Département d’Oncologie Médicale, Centre René Gauducheau, Boulevard Jacques Monod, 44805 Nantes Saint-Herblain, France; email: fumoleau{at}gauducheau-nantes.fnclcc.fr.
Purpose: To evaluate the duration and dose intensity of epirubicin-based regimens in premenopausal patients with lymph node-positive breast cancer. Patients and Methods: Between 1986 and 1990, 621 patients with operable breast cancer were randomly assigned to receive fluorouracil (Roche SA, Basel, Switzerland) 500 mg/m2, epirubicin (Pharmacia SA, Milan, Italy) 50 mg/m2, and cyclophosphamide (Asta Medica AG, Frankfurt, Germany) 500 mg/m2 every 21 days (FEC 50) for six cycles (6 FEC 50); FEC 50 for three cycles (3 FEC 50); or the same regimen with epirubicin 75 mg/m2 (FEC 75) for three cycles (3 FEC 75). All patients in the three arms received chest wall irradiation at the end of the third cycle. Results: After a 131-month median follow-up, the 10-year disease-free survival (DFS) was 53.4%, 42.5%, and 43.6% (P = .05) in the three arms, respectively. Pairwise comparisons demonstrate that 6 FEC 50 was superior both to 3 FEC 50 (P = .02) and to 3 FEC 75 (P = .05). The 10-year overall survival (OS) for the 6 FEC 50 arm was 64.3%, for the 3 FEC 50 arm it was 56.6%, and for the 3 FEC 75 arm, it was 59.7% (P = .25), respectively. Pairwise comparisons demonstrate that 6 FEC 50 was more effective than 3 FEC 50 (P = .10). Cox regression analysis demonstrates that OS was significantly better in the 6 FEC 50 than in the 3 FEC 50 arm (P = .046). No severe infections (grade 3 to 4), acute cardiac toxicity, or deaths from toxicity have been observed. Only five patients developed delayed cardiac dysfunctions, and three patients developed acute myeloblastic leukemia. Conclusion: After a long-term follow-up in an adjuvant setting, the benefit of six cycles of FEC 50 compared with three cycles, whatever the dose, is highly significant in terms of DFS. As regards OS, the group receiving six cycles of FEC 50 has significantly better results than the group receiving three cycles of FEC 50.
ADJUVANT SYSTEMIC chemotherapy can prolong disease-free survival (DFS) and overall survival (OS) among patients with breast cancer and axillary lymph node involvement. In 1986, when the trial was initiated, randomized trials of adjuvant combination chemotherapy conducted by Bonadonna et al1 and the National Surgical Adjuvant Breast and Bowel Project (NSABP)2 provided the first evidence of efficacy in patients with positive lymph nodes, particularly in premenopausal women. These results were confirmed by the first Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of all breast cancer trials.3 Adjuvant therapy significantly reduced the yearly odds of recurrence (36% ± 5%) and death (24% ± 5%) in patients younger than 50 years of age. Anthracyclines are among the most active drugs for treatment of advanced breast cancer.4 In women with advanced disease, three of four major trials demonstrated that regimens containing anthracyclines are superior to similar combinations of cyclophosphamide, methotrexate, and fluorouracil (CMF) with regard to the response rate, time to progression, and survival.5 The French Epirubicin Study Group demonstrated that epirubicin was as effective as and less toxic than doxorubicin when administered at equimolar doses to patients with advanced breast cancer.6 Anthracyclines have been used in adjuvant chemotherapy in the OncoFrance trial (premenopausal patients),7 the NSABP B-118 and B-159 trials (patients unresponsive to tamoxifen), and the Milan trial10 (patients with more than three axillary nodes involved). The second trial of adjuvant treatment with CMF indicated that the optimal duration of adjuvant chemotherapy was 6 months.11 However, the NSABP B-15 trial favored four cycles of doxorubicin plus cyclophosphamide administered in 63 days.9 Intensive chemotherapy regimens have been tested as adjuvant treatment for early breast cancer in two published trials since 1986 (Cancer and Leukemia Group B [CALGB] and NSABP B-22).12,13 This trial, conducted by the French Adjuvant Study Group (FASG 01), was designed to investigate the concept of optimal duration and the dose intensity of adjuvant chemotherapy in premenopausal patients with lymph node-positive, resectable breast cancer.
Patient Population Between July 1986 and July 1990, 621 women with operable breast cancer, recruited from 25 institutions in France, were enrolled on the study. The women had all undergone modified radical mastectomy or lumpectomy plus axillary dissection. The study recruited premenopausal women younger than 50 years of age, with last menses occurring less than 1 year ago, and with histologically proven axillary lymph node involvement (at least five axillary lymph nodes resected). The main eligibility criteria were World Health Organization (WHO) performance status  2; normal hematologic (granulocyte count  2,000/mm3, platelet count 100,000/mm3), hepatic (bilirubin 35µmol/L), and renal (serum creatinine level 130 µmol/L) functions; and no cardiac dysfunction (baseline left ventricular ejection fraction [LVEF] 50%). LVEF was measured at rest by radioisotopic or ultrasonographic methods. Patients were excluded from the study if they had evidence of metastases, a documented history of cardiac disease or previous cancer (except treated basal cell and squamous cell carcinoma of the skin or cancer of the uterine cervix), a serious underlying medical illness or psychiatric disorder, inflammatory or locally advanced breast cancer before surgery, previous radiation therapy, or hormonotherapy or chemotherapy for breast cancer, or if treatment start exceeded 42 days from initial surgery for breast cancer. Potentially eligible patients also underwent bone scan, chest radiograph, abdominal ultrasound or computed tomographic scan, and contralateral mammography. Written informed consent was obtained from each patient in a standard procedure at each participating institution according to the French "loi Huriet."
Treatment Regimens Adjuvant hormonotherapy, preventive use of colony-stimulating factors, and antibiotics were prohibited. Antiemetic treatment was prescribed routinely before each cycle. A cooling cap could be used, according to the usual practice of each institution. The allocated treatment was started within 42 days after initial surgery. An absolute granulocyte count less than 2,000/mm3 or a platelet count less than 100,000/mm3 on day 21 led to a treatment interruption of at least 1 week. 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. Locoregional radiotherapy was delivered within 15 days after the third chemotherapy cycle, and patients in arm A (6 FEC 50) received the fourth chemotherapy cycle within 15 days after completing radiotherapy. After mastectomy, radiation to the chest wall, supraclavicular area, internal mammary chain, and, in case of pN1 tumor, to the axillary area was delivered and consisted of 50 Gy in 25 fractions for each target. Patients who underwent lumpectomy received local radiation to the breast that consisted of 55 Gy in 27 fractions plus a complementary breast irradiation of 10 to 15 Gy and local radiation to the supraclavicular area, internal mammary chain, and axillary area (in case of pN1 tumor) consisting of 50 Gy in 25 fractions for each target. The tolerability of chemotherapy was evaluated before each cycle: an ECG and an absolute blood count 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 every 6 months during the 5-year follow-up period, and yearly thereafter.
Statistical Analysis
Patient Characteristics Six hundred and twenty-one patients were enrolled onto the study. Of these, nine (1.4%) were ineligible because of metastatic disease, and 10 (1.6%) were lost to follow-up after random allocation (Table 1  ). These patients were excluded from the efficacy analysis (n = 602). The safety and compliance analysis involved all treated patients (n = 603; Table 1). All protocol violations were well balanced among the three arms, as were baseline characteristics (Table 2). Major protocol violations were included in the analysis and were as follows: age 50 years (n = 26, upper range = 50 years), neutrophil count greater than 2,000/mm3 at baseline (n = 7), LVEF less than 50% (n = 14), fewer than five axillary nodes resected (n = 2), interval between surgery and treatment onset exceeding 42 days (n = 11), adjuvant tamoxifen prescribed (n = 12), and wrong treatment arm allocation (n = 10). At the cutoff date for analysis (June 2001), the median follow-up period was 131 months (range, 1 to 178 months).
Treatment Among the 603 treated patients (6 FEC 50 = 207, 3 FEC 50 = 200, 3 FEC 75 = 196), the mean number of cycles administered was 5.8 with 6 FEC 50 and three with 3 FEC 50 and 3 FEC 75. Twenty-two patients (17 with 6 FEC 50, four with 3 FEC 50, and one with 3 FEC 75) stopped treatment prematurely. The main reasons were the patient’s refusal (n = 7), nonhematologic toxicity (n = 6), hematologic toxicity (n = 4), disease progression (n = 2), late discovery of initial metastatic disease (n = 2), and lost to follow-up (n = 1). The mean epirubicin dose received was 298.8 mg/m2 (intended dose, 300 mg/m2) in the 6 FEC 50 arm, 149.2 mg/m2 (intended dose, 150 mg/m2) in the 3 FEC 50 arm, and 221.6 mg/m2 (intended dose, 225 mg/m2) in the 3 FEC 75 arm. The mean epirubicin relative dose intensity was 15 mg/m2/wk (90.2%) in the 6 FEC 50 arm, 15.3 mg/m2/wk (92.0%) in the 3 FEC 50 arm, and 22.5 mg/m2/wk (90.2%) in the 3 FEC 75 arm.
Disease-Free Survival
Overall Survival There were 237 deaths involving 76 (36.2%) of the 210 patients in the 6 FEC 50 arm, 85 (43.1%) of the 197 patients in the 3 FEC 50 arm, and 76 (39.0%) of the 195 patients in the 3 FEC 75 arm. Nine deaths (4.3%) in the 6 FEC 50 arm were unrelated to disease progression: second cancer (two patients, one pancreatic carcinoma and one pleural mesothelioma), alcoholism (two patients), traffic accident (one patient), and unknown reason (four patients). Four deaths (2.0%) in the 3 FEC 50 arm were unrelated to disease progression: meningitis (one patient, 5 months after treatment completion), Mallory-Weiss syndrome (one patient), acute leukemia (one patient), and cirrhosis (one patient). Three deaths (1.5%) in the 3 FEC 75 arm were unrelated to disease progression: congestive heart failure (one patient, after receiving mitoxantrone), acute leukemia (one patient), and unknown reason (one patient). The 10-year OS rates were 64.3% (95% CI, 57.8% to 70.8%) with 6 FEC 50, 56.6% (95% CI, 49.7% to 63.5%) with 3 FEC 50, and 59.7% (95% CI, 52.8% to 66.6%) with 3 FEC 75 (P = .25; Fig 2 ). The pairwise comparisons show a trend in favor of 6 FEC 50 compared with 3 FEC 50 (P = .10; HR = 0.77; 95% CI, 0.61 to 0.93; Table 3 ). There was no difference between 6 FEC 50 and 3 FEC 75 (P = .59); and between 3 FEC 50 and 3 FEC 75 (P = .28) (Table 3). The power of differences that could be detected was 62%. When a Cox proportional hazards model was performed, age and number of positive nodes were independent prognostic factors for death (P = .0002 and P < 10-3, respectively) (Table 3). In this model, the overall comparison of treatment does not demonstrate a difference among the three groups (P = .11), but the pairwise comparisons show the significant superiority of 6 FEC 50 over 3 FEC 50 (P = .046; HR = 0.73; 95% CI, 0.57 to 0.89; Table 3).
Toxicity Toxicity was evaluated in the 603 treated patients according to WHO criteria. Table 4 shows the adverse events per patient. Neutropenia and nausea-vomiting were significantly less frequent in the 3 FEC 50 arm (P = .007 and P = .012, respectively). The occurrence of alopecia was significantly higher with 3 FEC 75 (P < 10-3). Among the three groups, there was no grade 3 to 4 infection, no neutropenic fever, and no deaths from toxicity. Only seven grade 1 transient cardiac abnormalities were diagnosed during the chemotherapy, and none of them necessitated treatment interruption.
Five cases of delayed cardiac toxicity were reported (6 FEC 50, n = 1; 3 FEC 50, n = 1; 3 FEC 75, n = 3), and all patients had undergone regional radiation on the left side. Only one of these patients received only adjuvant therapy: She presented clinical signs of congestive heart failure (CHF) 7 years after a cumulative epirubicin dose of 221 mg/m2; these signs were not found thereafter. Four patients developed delayed cardiac side effects after chemotherapy for metastatic disease: Three patients had received mitoxantrone (one LVEF decrease from 50% to 38%, one CHF, and one death from CHF), and one patient who had received epirubicin presented with obstructive cardiomyopathy.
Second Malignancies Three cases of acute myeloblastic leukemia (AML) occurred (3 FEC 50, n = 2; 3 FEC 75, n = 1). In the 3 FEC 50 arm, one patient presented with AML French-American-British (FAB) 4 59 months after random assignment and after a cumulative epirubicin dose of 154 mg/m2; she died of AML 3 months after its diagnosis. The other patient in the 3 FEC 50 arm presented with AML FAB 2 125 months after random allocation and was still alive 1 year after the diagnosis. In the 3 FEC 75 arm, the patient presented with AML FAB 2 with t(9;22) translocation and 46XX 49 months after randomization and after a cumulative epirubicin dose of 225 mg/m2; she died of AML 24 months after its diagnosis. The remaining 11 cases of secondary malignancy (6 FEC 50, n = 5; 3 FEC 50, n = 4; 3 FEC 75, n = 2) were as follows: colorectal carcinoma occurred in three patients, pancreatic carcinoma occurred in two patients, and ovarian carcinoma, basocellular carcinoma, thyroid carcinoma, malignant melanoma, pleural mesothelioma, and soft tissue sarcoma each occurred in one patient.
This study was designed to evaluate the optimal duration of an epirubicin-based adjuvant chemotherapy (six or three cycles) and the role of the epirubicin dose intensity (50 or 75 mg/m2) in premenopausal lymph node-positive patients. After 10 years of follow-up, our results demonstrate a significant advantage of the six-cycle regimen over the three-cycle regimens in terms of DFS (P = .004 and P = 0.05, respectively). As regards 10-year OS, at equimolar doses of 50 mg/m2, six cycles were significantly superior to three cycles (P = .046), but the 3 FEC 75 was not different from the 6 FEC 50 or 3 FEC 50. Compliance, with more than 90% of scheduled epirubicin dose delivered, and toxicity profile were classical with these regimens when they were administered without hematopoietic support or anti-HT3 prophylaxis. The long-term cardiac toxicity was mild: only one patient presented with transient CHF signs after adjuvant treatment, and four patients developed cardiac side effects after retreatment for metastatic disease (three after mitoxantrone, one after epirubicin). Three cases of AML occurred: two FAB 2 and one FAB 4. The 10-year results support the superiority of six cycles of FEC 50 compared with three cycles and are in accordance with other trials. Numerous studies previously tried to better define the optimal duration of adjuvant chemotherapy using CMF or anthracycline-based regimens or more recently, using taxanes in a sequential manner after anthracyclines. Bonadonna et al11 showed that the optimal duration of adjuvant CMF was 6 months rather than 12 months. The Ludwig V trial results20 proved the inadequacy of one perioperative cycle of chemotherapy for lymph node-positive patients. In 1990, the ECOG trial21 comparing 12 cycles to four cycles of CMF, both combined with prednisone and tamoxifen, failed to demonstrate any benefit in favor of the 12-cycle regimen. The first report of Schumacher et al, 22 published in 1994 after a 5-year follow-up, showed that six courses of CMF were not superior to three courses, but only with respect to recurrence-free survival. These results were confirmed after a 10-year follow-up.23 In 1996, the International Breast Cancer Study Group reported the results of a trial designed to determine the optimal duration and timing of adjuvant chemotherapy for lymph node-positive, premenopausal breast cancer patients.24 Patients who received three cycles of CMF without reintroduction had a 5-year DFS rate of 53%, compared with 58% in the other groups (P = .04). The authors concluded that three courses of adjuvant CMF were inferior to longer CMF regimens, especially in younger women and for those with estrogen receptor-negative primary tumors. The introduction of anthracyclines in the adjuvant setting led to the study of their contribution compared with CMF. The NSABP B-15 trial9 concluded that six cycles of CMF were comparable to four cycles of anthracyclines both for efficacy and toxicity. The shorter duration of the anthracycline regimen (2 months) led to its wide use in the United States. Thereafter, the results of EBCTCG meta-analyses in 1992 and 19983,25 reinforced clearly the contribution of anthracycline-based adjuvant chemotherapy, especially in premenopausal patients with lymph node-positive tumors. However, the optimal duration of anthracycline-based chemotherapy was not clearly established. Recent consensus conferences (National Institutes of Health, St-Gallen, Switzerland)26,27 recommended four to six cycles of anthracycline, which corresponds to 3 to 6 months of treatment. Our study, initiated in 1986, anticipated the contribution of anthracycline using epirubicin because of its efficacy and better safety profile. At present, it is the only study that compares directly the duration of two anthracycline-chemotherapy regimens and demonstrates the superiority of a six-cycle regimen. The question of the optimal anthracycline dose in an adjuvant setting remains controversial. Our results did not indicate that 3 FEC 75 was different from 3 FEC 50, both for DFS and OS, but that probably three cycles were insufficient in such a population, whatever the dose. Actually, in the adjuvant setting, both epirubicin and doxorubicin demonstrated a dose effect. With doxorubicin, the CALGB 8541 study12 showed the greatest benefit with the most dose-intense adjuvant therapy. In contrast, the subsequent CALGB trial (CALGB 9344)28 studied doxorubicin dose intensification (60, 75, and 90 mg/m2) without demonstrating any benefit. With epirubicin, a dose effect between FEC 50 and FEC 100 has been clearly demonstrated in the FASG-05 trial29 in lymph node-positive patients with a poor prognosis. A significant improvement of both 5-year DFS (66.3% v 54.8%; P = .03) and 5-year OS (77.4% v 65.3%; P = .007) was observed in favor of the FEC 100 regimen without increasing dramatically acute and delayed toxic effects. The FEC 100 regimen should be considered now as the standard adjuvant chemotherapy for patients with lymph node-positive, early breast cancer. Both the immediate and delayed tolerability profiles of the FEC regimens used in this study are classical and well known. At a dose of 50 or 75 mg/m2 without hematopoietic support, there was no grade 3 to 4 infection, febrile neutropenia, or death from toxicity. The frequency of grade 3 to 4 nausea and vomiting was superior with 3 FEC 75 and 6 FEC 50 without anti-HT3 prophylaxis because of the period during which this study was conducted (1986 to 1990). The occurrence of delayed cardiac events was extremely low. Only one patient presented with transient cardiac abnormalities after adjuvant chemotherapy, which did not require treatment. The five cases of cardiac toxicity that occurred during the treatment of metastatic disease were related to mitoxantrone retreatment for four patients and to epirubicin for one patient. These results are consistent with our experience of the long-term cardiac toxicity of epirubicin.29,30 It is now well established that epirubicin has a better cardiac tolerability than doxorubicin.6,31–33 An increased incidence of AML following chemotherapy with alkylating agents and/or topoisomerase II inhibitors has been described in a number of studies.13,34–38 Secondary AML arising in patients treated with alkylators usually exhibits the M1-M2 FAB subtype, whereas secondary AML arising in patients treated with topoisomerase II inhibitors usually exhibits the M4-M5 subtypes. In our study, three cases of secondary AML were diagnosed: one FAB 4, and two FAB 2. The causality of adjuvant chemotherapy was doubtful in one case, which occurred more than 10 years after treatment completion. In our study, FEC was associated with a low risk of secondary leukemia, and the benefits of this regimen greatly outweighed the risk of treatment-related leukemia. In conclusion, after a 10-year follow-up, our study demonstrates a significant benefit in favor of six cycles over three cycles of the FEC regimen in premenopausal patients with lymph node-positive breast cancer. These results are in accordance with published data and coincide with the most recent recommendations issued from meta-analysis and consensus conferences, which favored four to six cycles of anthracycline-based adjuvant chemotherapy. Our collaborative group, FASG, had considered 6 FEC 50 as the standard treatment until the recent results of the FASG-05 trial, which clearly demonstrates the advantage of FEC 100. These results led us to change our reference adjuvant chemotherapy to six cycles of FEC 100.
The French participating centers are, in order of institutional accruals: Centre René Gauducheau, Nantes; Centre Hospitalier de Lyon Sud, Lyon; Centre Eugène Marquis, Rennes; Centre Georges-François Leclerc, Dijon; Centre Antoine Lacassagne, Nice; Centre Hospitalier Jean Minjoz, Besançon; Centre Hospitalier de Bretagne Sud, Lorient; Institut Claudius Régaud, Toulouse; Centre Hospitalier André Boulloche, Montbéliard; Centre Hospitalier Universitaire Dupuytren, Limoges; Clinique Sainte-Catherine, Avignon; Institut Jean Godinot, Reims; Hôpital Nord, St-Etienne; Hôpital Notre-Dame de Bon Secours, Metz; Clinique Radiologique et Orthopédique, Saint-Etienne; Centre Hospitalier Jean Monnet, Epinal; Institut Gustave Roussy, Villejuif; Centre Hospitalier Général, Troyes; Centre Hospitalier, Annecy; Centre Hospitalier Général, Montélimar; Centre Jean Perrin, Clermont-Ferrand; Clinique le Méridien, Cannes; Centre Hospitalier Général, Belfort; and Centre Hospitalier Général, Tarbes.
Supported by grants from Pharmacia and Upjohn, Saint-Quentin en Yvelines, France.
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16. 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 17. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 18. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc A 135:185–198, 1972[CrossRef] 19. Cox DR: Regression models and life-tables. J R Stat Soc B 34:187–202, 1972 20. Goldhirsch A, Gelber RD: Randomized perioperative therapy in operable breast cancer: The Ludwig trial V. Recent Results Cancer Res 115:43, 1989[Medline] 21. Falkson HC, Gray R, Wolberg WH, et al: Adjuvant trial of 12 cycles of CMFPT followed by observation or continuous tamoxifen versus four cycles of CMFPT in postmenopausal women with breast cancer: An Eastern Cooperative Oncology Group phase III study. J Clin Oncol 8:599–607, 1990[Abstract]
22. Schumacher M, Bastert G, Bojar H, et al: Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients. J Clin Oncol 12:2086–2093, 1994
23. Sauerbrei W, Bastert G, Bojar H, et al: Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients: An update based on 10 years’ follow-up. German Breast Cancer Study Group. J Clin Oncol 18:94–101, 2000
24. The International Breast Cancer Study Group: Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol 14:1185–1194, 1996 25. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930–942, 1998[CrossRef][Medline]
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29. 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 30. Bonneterre J, Roché H, Kerbrat P, et al: Long-term cardiac follow-up in free of disease patients after receiving 6 FEC 50 vs 6 FEC 100 (FASG-05 trial) as adjuvant chemotherapy for node-positive breast cancer. Proc Am Soc Clin Oncol 21:154, 2002 (abstr) 31. Shapiro CL, Hardenbergh P, Gelman R, et al: Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol 16:3493–3501, 1998[Abstract]
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35. Diamandidou E, Buzdar AU, Smith TL, et al: Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: The University of Texas M. D. Anderson Cancer Center experience J Clin Oncol 14:2722–2730, 1996 36. The Scandinavian Breast Cancer Study Group 9401: Results from a randomized adjuvant breast cancer study with high dose chemotherapy with CTCb supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy. Proc Am Soc Clin Oncol 18:3, 1999 (abstr) 37. Delaloge S, Di M, Guérin S, et al: Adjuvant doxorubicin, vincristine, cyclophosphamide, fluorouracil (AVCF), for breast cancer: No treatment-related leukemia at 13-year follow-up. Proc Am Soc Clin Oncol 17:449, 1998 (abstr) 38. Decillis A, Anderson S, Bryant J, et al: Acute myeloid leukemia and myelodysplastic syndrome on NSABP B-25: an update. Proc Am Soc Clin Oncol 16:459, 1997 (abstr) Submitted April 19, 2002; accepted September 23, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to compare baseline categorical variables and the incidence of adverse events in the three groups.
