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© 2001 American Society for Clinical Oncology 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 TrialCollaborators and their affiliations are listed in Appendix. Address reprint requests to Jacques Bonneterre, MD, PhD, Département de Sénologie et Cancérologie Gynécologique, Centre Oscar Lambret, 3 Rue Frédéric Combemale, 59020 Lille, Cedex, France; email: j-bonneterre{at}o-lambret.fr
PURPOSE: To determine the influence of the epirubicin dose in operable node-positive breast cancer patients with factors of poor prognosis.
PATIENTS AND METHODS: Between April 1990 and July 1993, 565 operable breast cancer patients with either more than three positive nodes or between one and three positive nodes with Scarff Bloom Richardson grade RESULTS: The median follow-up was 67 months. The 5-year disease-free survival (DFS) was 54.8% with FEC 50 and 66.3% with FEC 100 (P = .03). The 5-year overall survival (OS) was 65.3% and 77.4%, respectively (P = .007). The mean relative dose-intensity was similar in the two groups (90.3% and 86.1%, respectively). Neutropenia and anemia were significantly more frequent in FEC 100 (P < 10-3), as were nausea-vomiting (P = .008) and stomatitis and alopecia (P < 10-3). Nine cases of grade 3 infection occurred only with FEC 100, and no toxic deaths occurred. Three cases of acute cardiac toxicity were observed (FEC50 = 1, FEC100 = 2) and 10 patients (FEC50 = 6, FEC100 = 4) presented delayed cardiac dysfunctions. Two cases of secondary leukemia were observed (acute lymphatic leukemia with FEC 50 and acute myelogenous leukemia with FEC 100). CONCLUSION: After 5 years of follow-up, the increased epirubicin dose led to a significant benefit in terms of DFS and OS, with a high survival rate among patients with poor-prognosis breast cancer.
THE USE OF ADJUVANT chemotherapy in axillary node-positive breast cancer is well established. Its efficacy has been demonstrated on both disease-free survival (DFS) and overall survival (OS) in this setting. In an overview of the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials, the benefit in terms of survival and DFS was only observed among patients younger than 50 years and with fewer than three involved lymph nodes.1 Then, two meta-analyses have been published. The first pooled results from different groups using various therapeutic regimens and compared them with those of a natural-history database from three centers.2,3 The second was the first meta-analysis published by the Early Breast Cancer Trialists’ Collaborative Group.4 The conclusions of these two studies were similar: the benefit of chemotherapy was observed both in patients with fewer than three involved lymph nodes and in patients with more extensive lymph node involvement. Anthracyclines are among the most active drugs in advanced breast cancer5-8 and in the adjuvant setting.9-12 In advanced breast cancer, results of randomized trials had shown higher response rates with fluorouracil, doxorubicin, and cyclophosphamide (FAC) compared with the regimen of cyclophosphamide, methotrexate, and fluorouracil (CMF).6-8 Then, several studies comparing an anthracycline-containing regimen and CMF in adjuvant setting were initiated.13-16 The French Epirubicin Study Group demonstrated that epirubicin was as effective as and less toxic than doxorubicin when administered at equimolar doses (50 mg/m2) to patients with advanced breast cancer.17 These results were confirmed by the Italian Multicentre Breast Study comparing the same regimens.18 In 1986, the French Adjuvant Study Group (FASG) initiated a phase III study, FASG 01, involving 602 premenopausal patients with node-positive operable breast cancer to determine the optimal dose and duration of epirubicin-based adjuvant chemotherapy, comparing fluorouracil 500 mg/m2, epirubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days for six cycles (6 FEC 50) with FEC 50 and FEC 75 for three cycles each (3 FEC 50 and 3 FEC 75, respectively). After 8 years of follow-up, 6 FEC 50 significantly improved the DFS compared with 3 FEC 50 (P = .018) or 3 FEC 75 (P = .04), and OS was also significantly better in the group receiving 6 FEC 50 than in those receiving 3 FEC 50 (67.4% v 60.8%; P = .04).19 These results, both in the metastatic and the adjuvant setting, led us to consider 6 FEC 50 as our adjuvant standard treatment in node-positive breast cancer patients. The dose-response relationship of epirubicin-based chemotherapy for advanced breast cancer has been examined in two randomized phase III trials comparing FEC 50 with this same regimen except with epirubicin dose of 100 mg/m2 (FEC 100), with a significant improvement in the response rate, response duration, and time to progression in favor of FEC 100.20,21 In the adjuvant setting, the dose-intensity studies conducted by Hryniuk et al22 established a correlation between the mean dose-intensity and the 3-year DFS rate. At the beginning of the 1990s, four different groups initiated trials in the adjuvant setting to test intensive chemotherapy regimens; they comprised the Cancer and Leukemia Group B trial (CALGB 8,541),23 the NSABP B-22 trial,24 the National Cancer Institute of Canada (NCIC) trial designed to compare a high dose of epirubicin in the FEC regimen (120 mg/m2 every 4 weeks ie, 30mg/m2/wk) with a classic CMF in premenopausal patients with node-positive operable breast cancer,14 and our study (FASG 05).
The FASG 05 study compared 6 FEC 50 with 6 FEC 100 every 3 weeks (16.7 mg/m2/wk v 33.3 mg/m2/wk) to determine the effect of epirubicin dose and dose-intensity on DFS and OS in patients with poor prognostic factors, ie, extensive lymph node involvement (N > 3) or one to three positive nodes with Scarff Bloom Richardson (SBR) grade
Patient Population Between April 1990 and July 1993, 565 women, recruited from 20 institutions in France, with operable breast cancer who had undergone modified radical mastectomy or lumpectomy plus axillary dissection were enrolled onto the study. Premenopausal and postmenopausal women with histologically proven axillary lymph node involvement (at least five axillary nodes resected) with more than three positive nodes or between one and three positive nodes with SBR grade  2 and hormone receptor negativity (both estrogen and progesterone) were studied. Postmenopausal status was defined as an amenorrhea for at least 1 year. The main eligibility criteria were age between 18 and 64 years, World Health Organization (WHO) performance status  2, normal hematologic (granulocyte count 2,000/mm3, platelet count 100,000/mm3), hepatic (bilirubin 35 µmol/L) and renal (serum creatinine level 130 µmol/L) functions, 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, hormonotherapy or chemotherapy for breast cancer, or were more than 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 or oral informed consent was obtained from each patient in a standard procedure at each participating institution. The study protocol was approved by the ethical committee of the coordinating center according to the French loi Huriet.
Treatment Regimens Preventive use of colony-stimulating factors (CSF) and antibiotics was prohibited. Antiemetic treatment was prescribed routinely before each cycle. A cooling cap could be used, according to the usual practices of each institution. The allocated treatment was started within 42 days after initial surgery. An absolute granulocyte count less than 2,000/mm3 and/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. In postmenopausal patients, tamoxifen 30 mg/d was prescribed at the first chemotherapy cycle, for 3 years. In case of hormone receptor negativity, tamoxifen administration was left to the discretion of the investigators, but the policy had to be similar for both arms in a given center. Locoregional radiotherapy was delivered within 30 days after the last chemotherapy cycle according to standard procedures. 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 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
DFS was defined as the time from randomization until first relapse (local, regional, and distant). A contralateral breast cancer was considered a new primary malignancy. OS was defined as the time from randomization until death, related or not to breast cancer. All survival and DFS rates were computed according to the Kaplan-Meier method, and survival curves were compared with the log-rank test or the stratified log-rank test as appropriate.28,29 The prevalence of the following classic prognostic factors was analyzed: menopausal status (pre- v postmenopausal), surgery (conservative v radical), number of involved lymph nodes (one to three v > three), tumor size ( < 20 mm v
Patient Characteristics Five hundred sixty-five patients were enrolled onto the study. Of these, 20 (3.7%) were ineligible (because of advanced or metastatic disease, n = 18, or no breast cancer, n = 2), and eight (1.4%) were lost to follow-up after randomization ( Table 1): these patients were excluded from the efficacy analysis (n = 537). The safety and compliance analysis involved all the treated patients (n = 546) (Table 1). All the protocol violations were well balanced between the two arms, as were baseline characteristics ( Table 2). Major protocol violations were included in the analysis and were as follows: age 65 years (n = 9), less than four positive nodes and hormone receptor positivity (n = 14), neutrophil count less than 2,000/mm3 at baseline (n = 6), LVEF less than 50% (n = 11), ECG abnormalities (n = 4), interval between surgery and treatment outset exceeding 42 days (n = 19), and wrong treatment arm allocation (n = 6). As regards hormone therapy, the protocol violations were as follows: concomitant luteotropin-releasing hormone agonist (n = 10), postmenopausal patients not treated with tamoxifen (n = 19), and premenopausal patients treated with tamoxifen (n = 24). In hormone receptor–negative postmenopausal patients (n = 94), 70 (74.5%) received tamoxifen with no difference between the two arms. At the cutoff date for analysis (October 1998), the median follow-up period was 67 months (range, 2 to 96 months).
Treatment Among the 546 treated patients (FEC 50 = 278, FEC 100 = 268), the mean number of cycles administered was 5.9 with FEC 50 and 5.85 with FEC 100. Twenty-eight patients (12 with FEC 50 and 16 with FEC 100) stopped treatment prematurely. The main reasons were the patient’s refusal (n = 7), nonhematologic toxicity (n = 7), cardiac toxicity (n = 4), persistent neutropenia (n = 1), disease progression (n = 1), late discovery of initial metastatic disease (n = 1), death (n = 2; stroke and pleural involvement), catheter obstruction (n = 1), traffic accident (n = 1), and unknown (n = 3). The mean epirubicin dose received was 298.2 mg/m2 (intended dose, 300 mg/m2) in FEC 50 and 589.8 mg/m2 (intended dose, 600 mg/m2) in FEC 100. The mean epirubicin relative dose-intensity was 15.1 mg/m2/wk, ie, 90.3% (± 10.2) in FEC 50 and 28.7 mg/m2/wk ie, 86.1% (± 11.8) in FEC 100 with no significant difference between the two regimens.
DFS
Survival There were 171 deaths, involving 101 (37.3%) of the 271 patients in FEC 50 and 70 (26.3%) of the 266 patients in FEC 100. Nine (3.3%) of the FEC 50 patients died before recurrence because of the following: second cancer (four patients: two colorectal carcinomas, one gastric carcinoma, and one nasal fossa cylindroma), acute leukemia (one patient), myocardial infarct (one patient), stroke (one patient), and unknown reason (two patients). Six (2.3%) of the FEC 100 patients died, the causes of death being as follows: pancreatic carcinoma (one patient), acute leukemia (one patient), stroke (one patient), suicide (two patients), cardiovascular collapse (one patient included with an anteroseptal necrosis on ECG). The 5-year OS rates were 65.3% (CI95, 59.6% to 71.0%) with 6 FEC 50 and 77.4% (CI95, 72.4% to 82.4%) with 6 FEC 100, with a highly significant difference in favor of 6 FEC 100 (P = .007, Fig 2). The 5-year OS rates for the subgroups of patients with one to three and more than three positive nodes are listed in Table 3. For OS, the hazards ratios for FEC 50 compared with FEC 100 were 0.81 (P = .63; CI95, 0.34 to 1.91) for the one-to-three node group, with only 21 events in 98 patients, and 1.71 (P = .001; CI95, 1.23 to 2.38) for the more than three node group. In the Cox model, the RR for death with FEC 50 compared with FEC 100 was 1.55 (P = .005; CI95, 1.14 to 2.10). In this analysis, the number of positive nodes was an independent prognostic factor for death, with an RR of 0.60 (P = .03; CI95, 0.38 to 0.94) for patients with one to three involved nodes compared with patients with more than three involved nodes.
Acute Toxicity Toxicity was evaluated in 546 patients according to WHO criteria. Table 4 shows the adverse events per patient. Neutropenia and anemia were significantly less frequent in FEC 50 (P < 10-3). Nine cases of grade 3 infection occurred (FEC 50, n = 0; FEC 100, n = 9) and comprised neutropenic fever (n = 7), vaginitis (n = 1), and an undocumented infection (n = 1). Two of these patients received CSF during subsequent cycles. Patients in FEC 50 were also significantly less likely to have severe nausea/vomiting (P = .008), stomatitis (P < 10-3), and alopecia (P < 10-3). Other grades 3 to 4 clinical side effects occurred in six patients (FEC 50, n = 2; FEC 100, n = 4), with grade 3 asthenia (n = 3) and grades 3 (n = 2) and 4 (n = 1) injection site injuries related to extravasation. No toxic deaths occurred.
Thirteen cardiac abnormalities were diagnosed during chemotherapy (FEC 50, n = 6; FEC 100, n = 7). These included three grade 2 conditions requiring treatment interruption (one case of left ventricular hypertrophy on the ECG in FEC 50, one LVEF decrease from 68% at baseline to 41% without clinical signs in FEC 100, and one left ventricular insufficiency on the ECG plus LVEF = 45% with no baseline measurement in FEC 100).
Delayed Cardiac Toxicity
Second Malignancies Second malignancies occurred in 37 patients. Twenty-one patients developed contralateral breast cancer (14 in FEC 50, seven in FEC 100) after a median period of 24 months (range, 10 to 79 months) in FEC 50 and 45 months (range, 23 to 89 months) in FEC 100. Two cases of acute leukemia occurred. One woman in FEC 50 developed acute lymphoblastic leukemia with the t(9;22) translocation, 55 months after randomization and after a cumulative epirubicin dose of 300 mg/m2; she died of acute lymphoblastic leukemia 1 year after its diagnosis. One woman in FEC 100 developed acute myeloblastic leukemia (AML) French American British 4 with t(8;16) and del(17q21), 9 months after randomization and after a cumulative epirubicin dose of 600 gm/m2; she died of AML 1 month after its diagnosis with disseminated intravascular coagulation. Fourteen patients developed second malignancies (seven in FEC 50, seven in FEC 100) after a median period of 44 months (range, 23 to 77 months) in FEC 50 and 33 months (range, 18 to 67 months) in FEC 100. These cases were as follows: endometrial carcinomas occurred in three patients treated with tamoxifen (one of whom also developed concomitant basocellular carcinoma), colorectal carcinomas in three, pancreatic carcinoma in one, stomach carcinoma in one, lung carcinoma in one, bladder carcinomas in two, basocellular carcinoma in one, nasal fossa cylindroma in one, and cheek histiocytoma in one.
We observed a significant improvement in 5-year DFS (66.3% v 54.8%, P = .03) and OS (77.4% v 65.3%, P = .007) with FEC 100 regimen relative to FEC 50. These results are noteworthy, even in the patients treated with FEC 50, because all the patients had factors of poor prognosis and one half were premenopausal. Even if this study was not powered for a subset analysis, it is worth noting that the difference was significant only in patients with more than three positive nodes. Moreover, the mean epirubicin relative dose-intensity was excellent with both regimens (90.3% and 86.1% for FEC 50 and FEC 100, respectively) and better than the results obtained with FEC 120 days1 to 8, every 4 weeks, in the study by Levine, in which the mean epirubicin relative dose-intensity was only 77%.18 As regards safety, FEC 100 was more toxic than FEC 50, but these adverse events were acceptable and no toxic deaths occurred. The place of anthracyclines in adjuvant treatment of breast cancer is well established. The latest results of the Early Breast Cancer Trialists’ Collaborative Group demonstrate the advantage of anthracycline-containing regimens over CMF in 11 randomized trials, with a 5-year absolute benefit in terms of DFS (3.2%, 2P = .006) and OS (2.7%, 2P = .02).31 The reduction in the annual risk with anthracycline-containing regimens is 12% ± 4% (2P = .006) for relapse and 11% ± 5% (2P = .02) for death. The use of FEC is supported by the results of several studies comparing FEC and CMF. In 1996, Coombes et al13 used two alternative schedules of FEC versus CMF according to the participating centers, and no significant benefit for the anthracycline-containing regimen was observed. FEC1 (fluorouracil 600 mg/m2 d1 intravenously [IV], epirubicin 50 mg/m2 d1 IV, cyclophosphamide 600 mg/m2 d1 IV, eight cycles every 3 weeks) and CMF1 (cyclophosphamide 100 mg/m2 d1 to d14 orally, methotrexate 40 mg/m2 d1 and d8 IV, fluorouracil d1 and d8 IV, six cycles every 4 weeks) were of similar efficacy. However, FEC2 (fluorouracil 600 mg/m2 d1 and d8 IV, epirubicin 50 mg/m2 d1 IV, cyclophosphamide d1 and d8 IV, six cycles every 4 weeks) improved DFS and OS compared with CMF2 (cyclophosphamide 600 mg/m2 d1 and d8 IV, methotrexate d1 and d8 IV, fluorouracil 600 mg/m2 d1 and d8 IV, six cycles every 4 weeks). Recently, Mouridsen et al15 compared IV CMF to FEC 60 in premenopausal node-negative and node-positive patients and observed a significant improvement in 6-year OS with FEC 60 compared with CMF (76% v 69%, P = .01). Di Leo et al16 compared a classic oral CMF regimen with EC 60 and high-dose EC (epirubicin 100 mg/m2, cyclophosphamide 830 mg/m2) in 777 node-positive breast cancer patients: no difference was observed among the three treatment groups after a median follow-up of 50 months, but longer follow-up and a larger number of patients are required to confirm these results. Finally, Levine et al14 compared FEC 120 every 4 weeks with a classic CMF regimen and showed the superiority of FEC over CMF in terms of both 5-year DFS (63% v 53%, P = .009) and OS (77% v 70%, P = .03) in premenopausal women with axillary node-positive breast cancer. In this study, the epirubicin dose-intensity was higher than in the other trials (30 mg/m2/wk). Given the clear advantage of an anthracycline-containing adjuvant regimen, the benefit of dose intensification has been studied. Recently, Hryniuk et al32 and Frei et al33 tried to construct a scale using the concept of summation dose-intensity (SDI), ie, integrating the contributions of the individual agents within a combination regimen. They defined the unit dose-intensity as the dose of each drug required to produce a 30% objective response rate. In the single-agent trials, dose-response relationships were linear when the studies covered a range of dose-intensities. In randomized trials testing dose-intensity in metastatic disease, response rates and median survival correlated linearly with the SDI of the treatment arms. The results in metastatic disease were negative if the difference between the arms was less than 0.54 SDI units. Adjuvant trials testing a difference in dose-intensity of less than 0.65 SDI units were also negative. In our study, the increment of 0.65 SDI units was calculated by the authors with 1.16 and 1.82 SDI units for FEC 50 and FEC 100, respectively.32 In comparison, the commonly used AC regimen has a total of 1.91 SDI units, the 4-week FAC regimen using 2 weeks of daily oral cyclophosphamide has 2.10 units, and the FEC regimen used by Levine et al has 1.96 SDI units. Furthermore, these regimens contain amounts of anthracycline similar to those in FEC 100. In the adjuvant setting, three major teams initiated intensive chemotherapy studies during the same period as our own study. The NCIC study compared six cycles of FEC 120 days1 to 8, every 4 weeks, to six cycles of classic CMF in premenopausal node-positive patients.14 The FEC regimen had a comparable intended epirubicin dose-intensity to that of our FEC 100 regimen every 21 days (30 v 33 mg/m2/wk, ie, a 10% difference), but the actual doses delivered were 23.1 and 28.7 mg/m2/wk, with an increase of 24% in our study. This could explain why both FEC regimens gave similar results for both 5-year DFS (63% v 66.3%) and OS (77% v 77.4%), despite the fact that more than 60% of patients had one to three involved axillary nodes in the NCIC trial, whereas 80% of our patients had at least four positive nodes. The CALGB 8,541 study examined three different doses of cyclophosphamide, doxorubicin, and fluorouracil in node-positive breast cancer patients: after long-term follow-up, this trial showed the greatest benefit with the most dose-intense adjuvant therapy, but the standard treatment (cyclophosphamide 300 mg/m2, doxorubicin 30 mg/m2, fluorouracil 300 mg/m2 x 2, for four cycles) was probably underdosed.34 The subsequent CALGB trial (CALGB 9,344) studied doxorubicin dose intensification (60, 75, and 90 mg/m2) plus cyclophosphamide 600 mg/m2, with or without paclitaxel consolidation. After 18 months of follow-up, there was no benefit of dose intensification,35 but this follow-up period was short. Indeed, after 3 years of follow-up, we observed an advantage in favor of FEC 100 in terms of DFS (P = .02) but no difference as regards OS.36 The NSABP B-22 and B-25 trials showed no significant benefit of a cyclophosphamide dose intensification from 600 to 2,400 mg/m2.37,38 The results of our study and of these dose intensification studies demonstrate a potential value of higher anthracycline doses but fail to show an advantage of increasing the cyclophosphamide dose-intensity. Moreover, in several retrospective studies, the efficacy of anthracycline-containing regimens has been correlated with the overexpression of the c-erbB-2 oncogene.39-41 Moreover, the CALGB found a dose-effect of doxorubicin for relapse-free survival.39 Also, the FASG initiated a retrospective study to determine the correlation between the c-erbB-2 status and the epirubicin dose in terms of DFS and OS. Regarding, hematologic toxicity, FEC 100 is more toxic than FEC 50. The incidence of neutropenic fever was low (2.7%) with FEC 100, without CSF support or antibiotic prophylaxis, compared with 8.5% with FEC 120 days1 to 8 and antibiotic prophylaxis in Levine’s study.14 We conclude that our days 1 to 21 schedule is better than days 1 to 8 every 4 weeks in terms of hematologic safety and that it allows a better relative dose-intensity. On the other hand, nonhematologic toxicity was similar to that observed in Levine’s study.14 The risk of cardiac toxicity was low, with only two cases (0.4%) occurring after adjuvant treatment and eight (1.4%) cases after anthracycline or anthracenedione-containing chemotherapy for advanced disease. Three recent studies of cardiac toxicity after doxorubicin and epirubicin in the adjuvant setting have been published. The study by Shapiro et al42 compared the incidence of cardiac events after five and 10 cycles of AC (cumulative doxorubicin dose, 225 or 450 mg/m2). After a median follow-up of 6 years, six events (4.3%) had occurred after 5 AC, compared with 16 (11.8%) after 10 AC (RR = 3.6, P < .0003), mainly in patients who had received locoregional radiotherapy. In the study by Basser et al43 of long-term cardiac effects after high-dose chemotherapy with epirubicin-cyclophosphamide (200 mg/m2 + 4 g/m2 for three cycles, with CSF support), there were four cases (4%) of cardiac toxicity. Finally, Gianni et al44 studied cardiac sequelae in operable breast cancer patients after CMF with or without doxorubicin (75 mg/m2, four cycles): after 12 years, the incidence of systolic dysfunction was significantly higher in patients who received doxorubicin (7.9% v 0.7% with CMF, P < .01). It is now well established that epirubicin has better cardiac safety than doxorubicin,17,18,45 but cardiac outcome in long-term survivors remains controversial. For this reason, we have initiated a prospective study of long-term cardiac function involving the patients treated in the present study. An increased incidence of AML after chemotherapy with alkylating agents and/or topoisomerase II inhibitors has been described in a number of studies. The secondary AML arising in patients treated with alkylators is generally of the M1-M2 French American British subtype, whereas secondary AML arising in patients treated with topoisomerase II inhibitors is generally of the M4-M5 subtypes. In the present study, one case (0.2%) of AML 4 with t(8;16) and del 17q21 occurred a short time after treatment completion, and the case of acute lymphoblastic leukemia is not strongly related to the chemotherapy. In Levine’s study, after 5 years of follow-up, four cases of AML had occurred in 351 patients treated with FEC (1.1%).14 A 10-year follow-up review of the M.D. Anderson experience in six adjuvant or neoadjuvant trials with the FAC regimen gave an estimated leukemia rate of 1.5%, which increased to 2.5% when radiotherapy was added.46 After a short follow-up period in the study by the Scandinavian Breast Cancer Study Group, there were seven cases of AML/myelodysplastic syndrome in patients receiving the tailored FEC regimen.47 On the other hand, there were no cases of secondary AML in the OncoFrance trial after 13 years of follow-up among patients treated with the AVCF regimen as adjuvant therapy.48 The NSABP B-22 and B-25 studies showed a high rate of secondary leukemias correlating with the cumulative dose of cyclophosphamide, with six cases (0.26%) in 2,305 patients at 5 years and 16 cases (0.63%) in 2,548 patients at 4 years, respectively.37,49 Acute leukemia is rare in patients treated with CMF. Valagussa et al50 reported a 0.23% cumulative rate of acute leukemia over 15 years in 2,465 patients who received CMF. 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. The dose-response relationship of epirubicin-based chemotherapy for advanced breast cancer has been examined previously in two randomized trials comparing FEC 50 with FEC 100, with a significant improvement in the response rate, response duration, and time to progression.20,21 Our study is the first to demonstrate a strong benefit in terms of DFS and OS when the epirubicin dose is increased from 50 mg/m2 to 100 mg/m2, and confirms the epirubicin dose-effect in the adjuvant setting, as previously observed in advanced disease. We conclude that women with operable breast cancer benefit more from FEC 100 than from FEC 50. At this epirubicin of dose 100 mg/m2, the safety profile is acceptable, without CSF or antibiotic prophylaxis, when administered every 3 weeks for six cycles.
FASG organizations and trialists, in order of institutional accruals: Centre Oscar Lambret, Lille (A. Adenis, J. Bonneterre, M.E. Bonneterre, J.M. Pion, L. Vanlemmens); Institut Claudius Régaud, Toulouse (L. Gladieff, B. de Lafontan, P. Martel, J. Mihura, H. Roché); Centre Eugène Marquis, Rennes (D. Gédouin, P. Kerbrat, T Lesimple); Centre Léon Bérard, Lyon (A. Brémond, Y. Devaux); Centre René Gauducheau, Nantes (V. Delecroix, P. Fumoleau, C. Maugard-Louboutin); Centre Antoine Lacassagne, Nice (M. Namer); Centre Hospitalier de Bretagne Sud, Lorient (M.J. Goudier, F. Morice); Hospitalier Jean Minjoz, Besançon (P. Montcuquet, S. Schraub); Centre Georges-Franqois Leclerc, Dijon (B. Coudert, P. Fargeot, C. de Gislain, F. Mayer); Centre Henri Becquerel, Rouen (P. Bastit, B. Chevallier); Centre Hospitalier André Boulloche, Montbéliard (A. Grandgirard, A. Monnier, X. Sun); Centre Hospitalier Universitaire Dupuytren, Limoges (P. Clavère, J.P. Ollivier, B. Rhein, B. Roullet); Centre Hospitalier, Annecy (J. Datchary); Centre Hospitalier Louis Pasteur, Colmar (B. Audhuy, J.C. Barats, F. Kohser); Clinique le Méridien, Cannes (S. Dides, R. Ramos); Institut Jean Godinot, Reims (A. Cattan, J.C. Eymard, C. Pourny, B. Weber); Clinique Radiologique et Orthopédique, Saint-Etienne (G. de Laroche, A. Pichon); Hôpital Nord, Saint-Etienne (P. Seffert); Institut Gustave Roussy, Villejuif (M. Hayat, E. Zambon); Centre Jean Perrin, Clermont-Ferrand (P. Chollet, I. Van Praagh).
Supported by grants from Pharmacia & Upjohn, Saint-Quentin en Yvelines, France. We are indebted to Elisabeth Luporsi (Centre Alexis Vautrin, Nancy, France) for her statistical contribution.
1. Wolmark N, Fisher B: Adjuvant chemotherapy in stage II breast cancer, an overview of the NSABP clinical trials. Breast Cancer Res Treat 3: 19-26, 1983 2. Jones SE, Moon TE, Bonadonna G, et al: Comparison of different trials of adjuvant chemotherapy in stage II breast cancer using a natural history data base. Am J Clin Oncol 10: 387-395, 1987[Medline] 3. Moon TE, Jones SE, Bonadonna G, et al: Development and use of a natural history data base of breast cancer study. Am J Clin Oncol 10: 396-403, 1987[Medline] 4. Early Breast Cancer Trialist’s Collaborative Group: Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. N Engl J Med 319:1681-1692, 1988 5. Tormey DC: Adriamycin in breast cancer: An overview of studies. Cancer Chemother Rep 6: 319-327, 1975 6. Bull J, Tormey D, Li SH, et al: A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer 41: 1649-1657, 1978[Medline]
7.
Aisner J, Weinberg V, Perloff M, et al: Chemotherapy versus chemoimmunotherapy (CAF v CAFP v CMF each ± MER) for metastatic breast carcinoma of the breast. J Clin Oncol 5: 1523-1533, 1987 8. Perloff M, Norton L, Korzun A, et al: Advantage of an adriamycin plus halotestin after initial cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone for adjuvant therapy of node positive stage II breast cancer. Proc Am Soc Clin Oncol 5: 70a, 1986 (abstr 273)
9.
Misset JL, Di Palma M, Delgado M, et al: Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: Final report after a 16-year median follow-up duration. J Clin Oncol 14: 1136-1145, 1996 10. Fisher B, Redmond C, Wicherham DL, et al: Doxorubicin-containing regimens for the treatment of stage II breast cancer. The NSABP experience. J Clin Oncol 7: 572-582, 1989[Abstract] 11. 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 non responsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8: 1483-1496, 1990[Abstract] 12. Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. JAMA 273: 542-547, 1995[Abstract] 13. 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] 14. 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. J Clin Oncol 16: 2651-2658, 1998[Abstract] 15. Mouridsen HT, 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) 16. Di Leo A, Larsimont D, Beauduin M, et al: CMF or anthracycline-based adjuvant chemotherapy for node-positive breast cancer patients: 4 year results of a Belgian randomised clinical trial with predictive markers analysis. Proc Am Soc Clin Oncol 18: 69a, 1999 (abstr 258) 17. 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 18. 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 19. Fumoleau P, Brémond A, Kerbrat P, et al: Better outcome of premenopausal node-positive breast cancer patients treated with 6 cycles vs 3 cycles of adjuvant chemotherapy: Eight year follow-up results of FASG 01. Proc Am Soc Clin Oncol 18: 67a, 1999 (abstr 252)
20.
Focan C, Andrien JM, Closon MT, et al: Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: A prospective randomized trial. J Clin Oncol 11: 1253-1263, 1993
21.
Brufman G, Colajori E, Ghilezan N, et al: Doubling epirubicin dose intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rates. An international randomised phase III study in metastatic breast cancer. The Epirubicin High Dose (HEPI 010) Study Group. Ann Oncol 8: 155-162, 1997 22. Hryniuk NM, Levine MN, Levine L: Analysis of dose intensity for chemotherapy in early (stage II) and advanced breast cancer. J Natl Cancer Inst Monogr 1: 87-94, 1986
23.
Wood W, Budman D, Korzun AN, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330: 1253-1259, 1994 24. Dimitrov N, Anderson S, Fisher B, et al: Dose intensification and increased total dose of adjuvant chemotherapy for breast cancer: Findings from NSABP B-22. Proc Am Soc Clin Oncol 13: 64a, 1994 (abstr) 25. Snedecor GW, Cochran WG: Statistical Methods ( ed 7 ). Ames, IA, Iowa State University Press, 1980 26. Duncan DB: P-tests and intervals for comparison suggested by the data. Biometrics 31: 339-359, 1975
27.
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 28. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 29. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc A 135: 185-198, 1972 30. Cox DR: Regression models and life-tables. J R Stat Soc B 34: 187-202, 1972 31. Early Breast Cancer Trialist’s Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998
32.
Hryniuk W, Frei E III, Wright FA: A single scale for comparing dose-intensity of all chemotherapy regimens in breast cancer: Summation dose-intensity. J Clin Oncol 16: 3137-3147, 1998 33. Frei E III, Elias A, Wheeler C, et al: The relationship between high-dose treatment and combination chemotherapy: The concept of summation dose intensity. Clin Cancer Res 4: 2027-2037, 1998[Abstract]
34.
Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst 90: 1205-1211, 1998 35. Henderson IC, Berry DA, Demetri G, et al: Improved disease-free survival and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer. Proc Am Soc Clin Oncol 17: 101a, 1998 (abstr 390A) 36. Bonneterre J, Roché H, Brémond A, et al: A randomized trial of adjuvant chemotherapy with FEC 50 vs FEC 100 for node-positive operable breast cancer early report. Proc Am Soc Clin Oncol 15: 82a, 1996 (abstr 104)
37.
Fisher B, Anderson S, Wickerham D, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15: 1858-1869, 1997 38. Wolmark N, Fisher B, Anderson S: The effect of increasing dose intensity and cumulative dose of adjuvant cyclophosphamide in node positive breast cancer: Results of NSABP B-25. Breast Cancer Res Treat 46: 16, 1997 (abstr) 39. Thor AD, Budman DR, Berry DA, et al: Selecting patients for higher dose adjuvant CAF: c-erbB-2, p53, dose and dose intensity in stage II, node + breast cancer (CALGB 8869 and 8541). Proc Am Soc Clin Oncol 16: 128a, 1997 (abstr 452) 40. Ravdin PM, Green S, Albain KS, et al: Initial report of the SWOG biological correlative study of c-erbB-2 expression as a predictor of outcome in a trial comparing CAF T and tamoxifen alone. Proc Am Soc Clin Oncol 17: 97a, 1998 (abstr 374)
41.
Paik S, Bryant J, Park C, et al: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90: 1361-1370, 1998 42. 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]
43.
Basser RL, Abraham R, Bik To L, et al: Cardiac effects of high-dose epirubicin and cyclophosphamide in women with poor prognosis breast cancer. Ann Oncol 10: 53-58, 1999 44. Gianni L, Zambetti M, Moliterni A, et al: Cardiac sequelae in operable breast cancer after CMF ± doxorubicin (A) ± irradiation. Proc Am Soc Clin Oncol 18: 68a, 1999 (abstr 255)
45.
Torti FM, Bristow MM, Lum BL, et al: Cardiotoxicity of epirubicin and doxorubicin: Assessment by endomyocardial biopsy. Cancer Res 46: 3722-3727, 1986
46.
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 47. 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 18:2a, 1999 (abstr 3) 48. 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: 117a, 1998 (abstr 449) 49. 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: 130a, 1997 (abstr 459)
50.
Valagussa P, Moliterni A, Terenziani M, et al: Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer. Ann Oncol 5: 803-808, 1994 Submitted September 21, 1999; accepted September 18, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 test was used to compare baseline categorical variables and the incidence of adverse events in the two groups.
