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© 2001 American Society for Clinical Oncology Phase III Trial Comparing Two Dose Levels of Epirubicin Combined With Cyclophosphamide With Cyclophosphamide, Methotrexate, and Fluorouracil in Node-Positive Breast CancerFrom the Jules Bordet Institute, Belgian and Luxembourg Cooperative Centers, and Pharmacia-Upjohn, Brussels, Belgium. Address reprint requests to M.J. Piccart, MD, Chemotherapy Unit, Jules Bordet Institute, Boulevard de Waterloo 125, 1000 Brussels, Belgium; email: martine.piccart{at}bordet.be
PURPOSE: To compare a full-dose epirubicin-cyclophosphamide (HEC) regimen with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy and with a moderate-dose epirubicin-cyclophosphamide regimen (EC) in the adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: Node-positive breast cancer patients who were aged 70 years or younger were randomly allocated to one of the following treatments: CMF for six cycles (oral cyclophosphamide); EC for eight cycles (epirubicin 60 mg/m2, cyclophosphamide 500 mg/m2; day 1 every 3 weeks); and HEC for eight cycles (epirubicin 100 mg/m2, cyclophosphamide 830 mg/m2; day 1 every 3 weeks). RESULTS: Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively. Patient characteristics were well balanced among the three arms. One and three cases of congestive heart failure were reported in the EC and HEC arms, respectively. Three cases of acute myeloid leukemia were reported in the HEC arm. After 4 years of median follow-up, no statistically significant differences were observed between HEC and CMF (event-free survival [EFS]: hazards ratio [HR] = 0.96, 95% confidence interval [CI], 0.70 to 1.31, P = .80; distant-EFS: HR = 0.97, 95% CI, 0.70 to 1.34, P = .87; overall survival [OS]: HR = 0.97, 95% CI, 0.65 to 1.44, P = .87). HEC is more effective than EC (EFS: HR = 0.73, 95% CI, 0.54 to 0.99, P = .04; distant-EFS: HR = 0.75, 95% CI, 0.55 to 1.02, P = .06; OS HR = 0.69, 95% CI, 0.47 to 1.00, P = .05). CONCLUSION: This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer. Moreover, this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.
THE LAST 10 years have seen a growing number of phase III trials comparing an anthracycline-based regimen with a cyclophosphamide, methotrexate, and fluorouracil (CMF)–like regimen in the adjuvant therapy of node-positive breast cancer.1-9 Four of these trials have shown that the anthracycline-based regimen is more effective than the control treatment, consisting of CMF (intravenous [IV] or oral version) or melphalan-fluorouracil, in terms of both disease-free and overall survival.1-4 The advantage has been observed mainly in premenopausal patients.1-3 In this article, we report the 4-year results of a multicenter phase III trial started in 1988 that aimed to compare a full-dose epirubicin-cyclophosphamide treatment with classical CMF as adjuvant therapy in pre- and postmenopausal patients with stage II breast cancer. An additional purpose of this three-arm study was to compare the full-dose EC regimen with a moderate-dose version of the same regimen. The full-dose epirubicin-cyclophosphamide regimen (HEC) and the moderate-dose epirubicin-cyclophosphamide version (EC) were first evaluated in a pilot study run at the Jules Bordet Institute in Brussels, Belgium, in 1987. In the pilot study, different groups of patients with node-positive breast cancer aged 70 years or younger were subsequently treated with the following doses of epirubicin and cyclophosphamide: level 1, epirubicin 60 mg/m2, cyclophosphamide 500 mg/m2 (seven patients); level 2, epirubicin 80 mg/m2, cyclophosphamide 670 mg/m2 (five patients); level 3, epirubicin 90 mg/m2, cyclophosphamide 750 mg/m2 (eight patients); and level 4, epirubicin 100 mg/m2, cyclophosphamide 830 mg/m2 (nine patients). Because of the lack of life-threatening toxicity in the four different groups of patients, we estimated that each of the four evaluated dose levels was feasible in the adjuvant setting. Accordingly, we decided to test level 1 and level 4 in the context of the phase III trial, in which the control arm consisted of six cycles of CMF. The substantial differences in terms of planned dose-intensity and cumulative doses existing between level 1 and level 4 allowed us to explore the effect of decreasing or increasing dose-intensity and cumulative doses in a randomized study.
Patients aged 70 years or younger with radically resected, histologically confirmed breast carcinomas were eligible for study participation. At least one out of a minimum of 10 resected ipsilateral axillary nodes had to be infiltrated by the tumor at the pathology examination. Resection margins had to be free of tumor involvement, including lobular carcinoma-in-situ. Additional eligibility criteria were as follows: patient informed consent, performance status less than or equal to 1 on the Eastern Cooperative Oncology Group scale, left ventricular ejection fraction (LVEF) within normal limits, WBC count 4,000/m3 or higher, absolute neutrophil count 2,000/m3 or higher, platelet count 100,000/mm3 or higher, total bilirubin level 1.2 mg/dL or less, serum creatinine level 1.5 mg/dL or less, no distant metastases at the moment of study registration, no history of previous cancer except for carcinoma-in-situ of the cervix and basal-cell skin cancer, no other previous or concomitant diseases interfering with study participation, no previous medical or radiation therapy for breast cancer, interval elapsed between date of surgery and date of study randomization not exceeding 30 days, and adequate nonhormonal birth control measures implemented before study registration. The study protocol was reviewed and approved by the ethics committee of each participating institution.
Eligible patients were centrally randomized at the operational office of the chemotherapy unit of the Jules Bordet Institute. Treatment arm was allocated by the minimization method, accounting for the following stratification factors: participating institution, number of involved axillary nodes (one to three nodes or The study treatments were as follows: CMF for six cycles (ie, cyclophosphamide 100 mg/m2 by mouth on days 1 through 14, methotrexate 40 mg/m2 IV on days 1 and 8, fluorouracil 600 mg/m2 IV on days 1 and 8; cycles every 28 days); moderate-dose EC for eight cycles (ie, epirubicin 60 mg/m2 IV on day 1, cyclophosphamide 500 mg/m2 IV on day 1; cycles every 21 days); and HEC for eight cycles (ie, epirubicin 100 mg/m2 IV on day 1, cyclophosphamide 830 mg/m2 IV on day 1; cycles every 21 days). Treatment duration was 24 weeks in the three study arms. Tamoxifen, 40 mg daily for 5 years, was administered to postmenopausal patients with estrogen receptor (ER)–positive or unknown tumors. Hormone therapy was started after the last cycle of chemotherapy. Radiotherapy, which was mandatory in case of breast-conserving surgery and optional in case of previous mastectomy, was started after the end of chemotherapy. In the latter case, before participating in the study, each center specified the institutional guidelines with regard to eligibility criteria for radiotherapy after mastectomy. These guidelines had to be observed for all patients entered onto the study. Patients were treated with a 60cobalt. Two tangential photon fields were used for the chest wall or the breast, for a total International Commission on Radiological Unit dose of 50 Gy. The supraclavicular and internal mammary nodes were treated with a mixed beam (one third photons and two thirds electrons) for a total International Commission on Radiological Unit dose of 50 Gy. All fields were treated 5 days a week, 2 Gy per fraction, for 5 weeks. In the case of conservative treatment, a 10-Gy electron boost was added to the tumoral bed. Treatment delay was allowed in case of myelosuppression (ie, WBC count < 3,500/mm3 and/or platelet count < 100,000/mm3) persisting at the moment of next cycle administration. In case of myelosuppression persisting beyond 2 weeks from the supposed day of re-treatment, a 20% dose-reduction was implemented to allow treatment continuation. In case of myelosuppression at day 8 during CMF treatment, a 50% CMF dose-reduction was indicated if WBC count was 2,500 or higher and less than 3,500/mm3 and/or platelet count was 75,000 or higher and less than 100,000/mm3. In case of lower WBC and/or platelet counts, CMF day 8 was omitted. No use of colony-stimulating factors was allowed. A 20% dose reduction was recommended in case of any grade 3 to 4 nonhematologic toxicity. For patients receiving HEC or EC, in case of a LVEF absolute drop of at least 15%, or if LVEF fell 10% or more below the lower normal limit, epirubicin administration was interrupted for the next cycles of therapy. Initial staging consisted of medical history, physical examination, routine hematochemistry survey, bone scan, chest radiograph, liver ultrasound, and mammography. The follow-up evaluation consisted of the same work-up performed at the initial staging. The first evaluation was performed after the end of chemotherapy and once a year afterwards. A medical history and physical examination were scheduled once every 3 months for the first 2 years, and once every 6 months afterwards. Toxicity was graded according to the World Health Organization criteria and evaluated once every chemotherapy cycle administration. LVEF was assessed by myocardial scintigraphy scan or echocardiography at baseline, after course 4 and course 7, then 12 months after the randomization date. The primary hypothesis of the study was that HEC could have been associated with a 20% absolute increase of event-free survival (EFS) at 5 years over CMF, provided that the EFS rate at 5 years would have been 60% in the group of patients treated with CMF. According to this study hypothesis, and with an error type I level of 0.05 and an error type II level of 0.20, 86 patients per arm were required. In 1991, after the publication of the results from other trials exploring the same question and suggesting a lack of benefit for the anthracycline-based regimen over CMF,5,6 the study Steering Committee decided to modify the original hypothesis by reducing the expected absolute benefit associated with HEC to 12%. No efficacy data were available at the time of amending the statistical section of the study protocol. Accordingly, the sample size increased to 750 eligible patients (250 patients per arm). This sample size also allowed us to explore the hypothesis that HEC would have been associated with a 12% absolute increase of EFS at 5 years over EC, provided that the EFS rate for patients receiving EC would have been 60% at 5 years (error type I and type II levels of 0.05 and 0.20, respectively). From 1987 to 1988, when the study was designed, the Steering Committee judged that the third study comparison (CMF v EC) was less contributive to evaluating the value of anthracyclines in the adjuvant therapy of node-positive breast cancer. Accordingly, to avoid an increase in the study sample size, it was decided not to perform the CMF versus EC comparison. No correction for multiple testing was made because the EFS comparison HEC versus CMF was considered to be the primary study end point. All the other analyses have to be considered as exploratory, including the EC versus HEC comparison. EFS was defined as the interval elapsed between the date of randomization and the date of documented disease relapse, second primary, death, or date of last follow-up. Distant EFS was defined in the same way, but a documented locoregional recurrence was not considered to be an event. Local recurrence was defined as disease relapse, within the breast, after breast-sparing surgery, or within the chest wall, after mastectomy, in an area bounded superiorly by the clavicle, inferiorly by a horizontal line at the level of the xiphisternum, internally by the midline, and externally by the posterior axillary line. Regional recurrence was defined as disease relapse in the ipsilateral axillary, supraclavicular, or internal mammary lymph nodes. A breast carcinoma developing in the contralateral breast was viewed as a new primary tumor. Overall survival (OS) was defined as the interval elapsed between the date of randomization and the date of death for any reason, or the date of loss to follow-up. Follow-up duration was calculated in the subgroup of living patients as the time elapsed between the date of randomization and the date of the last observation. The efficacy analysis was carried out on all the eligible patients as well as on all the randomized patients. EFS and OS were described by Kaplan-Meier curves, and the comparisons among the three study arms were performed by log-rank tests. The log-rank test was also used to perform the EFS subgroup analysis. In addition, the hazards ratios (HRs) were estimated for the primary study comparison (HEC v CMF) as well as for the secondary comparison (HEC v EC) with the assumption that an HR of less than 1 corresponded to a benefit in favor of the HEC arm. The Cox proportional hazards model was used to adjust the estimated treatment effects for the influence of those factors with a prognostic impact in the univariate analyses. Model coefficients were obtained by the maximum likelihood method and their significance tested by likelihood ratios.
To assess whether the three treatment arms were well balanced for main patient and tumor characteristics, The relative dose-intensity for each study drug was calculated on the basis of the ratio of the dose actually delivered in the actual time over the expected dose in the planned time. The planned time corresponded to the interval elapsing between day 1 of the chemotherapy cycle and day 1 of the next cycle. For the last chemotherapy cycle, the planned time was 21 days for the HEC and EC arms and 28 days for the CMF arm. The relative dose-intensity for each study regimen was calculated as an arithmetic mean between the relative dose-intensities of the two or three drugs belonging to the study regimen.
Patient Characteristics Eight hundred four patients were randomized between March 1988 and December 1996. Twenty-seven patients were considered ineligible for the following reasons: inadequate disease stage (14 patients; CMF = 7, EC = 2, HEC = 5), inadequate cardiac or bone marrow function (three patients; CMF = 1, EC = 1, HEC = 1), violation of other eligibility criteria (five patients; CMF = 2, EC = 1, HEC = 2), and withdrawal of consent before treatment was begun (five patients; CMF = 2, EC = 1, HEC = 2). Main patient and tumor characteristics corresponding to the 777 eligible patients are reported in Table 1. No statistically significant differences in the distribution of main characteristics were observed among the three treatment arms. Between 41% and 44% of patients were postmenopausal when they were randomized.
The study median follow-up was as follows: 58 (range, 5 to 119), 52 (range, 7 to 116), and 56 (range, 1 to 120) months for CMF, EC, and HEC arms, respectively. One, nine, and 13 patients were lost to follow-up in the CMF, EC, and HEC arms, respectively; this difference in follow-up loss is statistically significant (P = .007). The median time to loss of follow-up was 32.3 months, suggesting that the increase in follow-up loss, reported in the anthracycline-based arms, was unlikely to be due to an increased acute toxicity. At the time of the present analysis, 253 relapses (CMF, 81 events; HEC, 74 events; EC, 98 events) and 164 deaths (CMF, 52 events; HEC, 47 events; EC, 65 events) have been reported.
Chemotherapy Administration
The originally planned chemotherapy program was ended for 229 (90%), 225 (84%), and 181 (71%) patients in the CMF, EC, and HEC arms, respectively. The main toxicity reasons leading to early treatment discontinuation were digestive intolerance (six patients) and persistent myelotoxicity (five patients) for patients receiving CMF, and drop of LVEF for patients receiving the epirubicin-based treatment (21 and 33 patients in the EC and HEC arms, respectively).
Radiotherapy and Tamoxifen Treatment
Side Effects
In two of the three cases of acute myeloid leukemia reported in the HEC arm, chromosome analysis was performed and disclosed a translocation 9q11 in one patient, and multiple genomic anomalies were present in the second patient. The time elapsed between the date of randomization and the date of documented acute myeloid leukemia was 21, 32, and 57 months.
Treatment Activity
HEC versus EC comparison. Figure 2 summarizes the results regarding the head-to-head comparison between the two EC regimens delivered at different dose-intensities. The analysis was adjusted by the surgery type and the number of positive ipsilateral axillary nodes. A statistically significant difference in favor of HEC over EC was observed in terms of EFS and OS, whereas the distant EFS analysis approached statistical significance without showing a formal difference between the two arms (EFS, HR = 0.73, 95% CI, 0.54 to 0.99, P = .04; distant EFS, HR = 0.75, 95% CI, 0.55 to 1.02, P = .06; OS, HR = 0.69, 95% CI, 0.47 to 1.00, P = .05). The results were not different when the ineligible patients (27 patients) were included in the analysis.
Overall comparison. Kaplan-Meier plots for EFS and OS are reported in Fig 3. The 3-year EFS and corresponding 95% CIs for the three study arms are as follows: CMF = 78% (95% CI, 73% to 83%), HEC = 80% (95% CI, 74% to 86%), and EC = 72% (95% CI, 66% to 78%). The 3-year OS and corresponding 95% CIs are as follows: CMF = 91% (95% CI, 87% to 95%), HEC = 92% (95% CI, 89% to 96%), and EC = 89% (95% CI, 85% to 93%).
An exploratory subgroup analysis was performed with regard to EFS. The following parameters were investigated: age (< 50 or  50 years), number of positive ipsilateral axillary nodes (one to three or 4), tumor size (pT1 or > pT1), ER and progesterone receptor status (positive or negative), and histologic grade (1, 2, or 3). None of these variables identified a subgroup of patients in which one of the three arms was superior to the other two in terms of 5-year EFS (95% CI) according to nodal status: for one to three nodes: CMF 75% (67% to 83%), HEC 77% (69% to 85%), EC 70% (61% to 79%); four nodes or more: CMF 54% (44% to 74%), HEC 61% (50% to 72%), EC 47% (36% to 58%). Five-year EFS (95% CI) according to age was as follows: younger than 50 years old: CMF 63% (53% to 73%), HEC 68% (59% to 77%), EC 61% (51% to 71%); 50 years of age or older: CMF 70% (60% to 80%), HEC 73% (63% to 83%), EC 59% (49% to 69%). Five-year EFS (95% CI) according to ER status was as follows: ER positive: CMF 70% (62% to 78%), HEC 73% (65% to 81%), EC 62% (53% to 71%); ER negative: CMF 56% (39% to 73%), HEC 60% (46% to 74%), EC 58% (45% to 71%). The overall incidence of local failure as first site of disease recurrence (local only, locoregional, and local plus distant) was as follows: 5%, 6%, and 5% for CMF, EC and HEC, respectively.
In this study, we report the 4-year results of a multicenter phase III trial comparing a full-dose EC regimen (HEC) with classical CMF and with a moderate-dose EC regimen in the adjuvant therapy of patients with node-positive breast cancer. Our results suggest that the full-dose epirubicin-based regimen is as effective as CMF and more active than the moderate-dose regimen with regard to EFS, distant EFS, and OS. Different reasons may explain the lack of benefit of HEC over CMF. First, the sample size of the present study was calculated by assuming that HEC would have been associated with a 12% absolute increase in EFS over CMF. On the basis of this hypothesis, 250 patients per arm were recruited. It is possible that by increasing the study sample size, smaller differences in EFS between HEC and CMF might have been found. In addition, a longer study follow-up, obviously associated with an increased number of events, might disclose a difference between the anthracycline-based and the CMF arms. With the exception of the French study,1 the other three trials demonstrating the superiority of the anthracycline-based regimen over CMF or CMF-like regimens2-4 had larger samples sizes than the present study and detected differences in the 5-year EFS ranging between 7% and 10%. Another potential explanation is that the control arm (CMF) and the anthracycline-based arm (HEC) did not differ except for the epirubicin variable. There were three other factors that might have conferred an advantage to the CMF arm, namely, (1) cyclophosphamide was administered by the oral route for 14 consecutive days in the CMF arm, whereas the same drug was administered by the IV route on day 1 in patients receiving HEC. It has been hypothesized that orally administered cyclophosphamide would be an important component of the CMF regimen, which might at least partially explain the demonstrated superiority of the orally administered CMF over the IV route delivered once every 3 weeks in patients with metastatic breast cancer.10,11 (2) There was a different dose-density in the two study arms because CMF was administered according to a day 1 to day 8 schedule once every 4 weeks, whereas HEC was administered on one single day every 3 weeks. (3) Patients receiving HEC did not benefit from the administration of fluorouracil. It is noteworthy that in three of the four positive trials,2-4 the two treatment arms differed mainly in the anthracycline variable, whereas the route of cyclophosphamide administration, the number of nonanthracycline drugs, and the treatment schedule were comparable. A third possible explanation for the reported results is that the present study recruited both pre- and postmenopausal patients. The latter group represented between 41% and 44% of the whole study population. In three of the four positive studies,1-3 the superiority of the anthracycline-containing arm was confined to premenopausal patients. Indeed, the Canadian study recruited only premenopausal patients,2 the Danish trial found a benefit only in the groups of node-negative and node-positive premenopausal patients,3 and the French study failed to show an advantage in the postmenopausal subgroup.1 Nevertheless, it remains unclear why the anthracycline-based therapy should be less effective in postmenopausal women. It has been hypothesized that the increased incidence of amenorrhea reported with the anthracycline-containing treatments might explain its improved activity in premenopausal patients.2,3 Whether chemotherapy-induced amenorrhea represents a favorable prognostic factor in patients receiving adjuvant therapy still represents a controversial issue.12 Data from the International Breast Cancer Study Group based on 1,196 premenopausal patients with early breast cancer suggest that a significantly prolonged disease-free survival is observed in patients with permanent CMF-induced amenorrhea, particularly in the subgroup of ER-positive tumors.13 Independent of our tentative explanations for the observed results, it has already been reported that the benefit deriving from the use of anthracyclines in the adjuvant therapy of breast cancer is modest and may be associated with an increased risk of acute myeloid leukemia, although the benefit definitely outweighs this risk.2,14 In recent years, it has been hypothesized on the basis of some retrospective studies that larger differences in activity between an anthracycline-based therapy and a CMF-like regimen might exist according to the overexpression of HER-2.15-17 HER-2–positive patients might derive larger benefits when receiving anthracyclines, whereas in HER-2–negative patients, no significant differences in outcome would be detected between the two adjuvant regimens. However, given that the results of these studies are limited by their retrospective design and the lack of standardization of HER-2 evaluation, we are still lacking a validated predictive marker that allows us to select the most appropriate adjuvant chemotherapy regimen. The secondary end point of this study was to explore the worth of a full-dose EC regimen (HEC) over the moderate-dose version (EC). Our results suggest that HEC is more effective than EC in terms of EFS, distant EFS, and OS. These data confirm the previously reported results from the Cancer and Leukemia Group B, demonstrating that a low-dose cyclophosphamide, doxorubicin, and fluorouracil regimen is associated with a worse outcome when compared with an intermediate- and full-dose cyclophosphamide, doxorubicin, and fluorouracil in the adjuvant therapy of stage II breast cancer.18 The results of a French trial exploring the worth of a full-dose anthracycline-based regimen over an intermediate-dose version in patients with node-positive breast cancer have been recently updated.19 The full-dose regimen, consisting of the combination of fluorouracil, epirubicin, and cyclophosphamide, was shown to be more effective than the intermediate dose in terms of disease-free survival and OS. The Cancer and Leukemia Group B and the French trial, as well as our study, provide us with evidence-based justifications not to reduce the planned dose-intensity of adjuvant chemotherapy, unless properly justified by concomitant medical reasons. These trials do not support dose intensification beyond the standard dose-intensity. Indeed, trials exploring the question of increasing the dose-intensity of doxorubicin or cyclophosphamide in patients with node-positive breast cancer have failed to show additional benefit for the intensified over the conventionally dosed regimen.20,21 In conclusion, this three-arm study did not demonstrate a superiority of the full-dose epirubicin-based regimen over classical CMF in a population of 800 pre- and postmenopausal patients with node-positive breast cancer. The full dose was more effective than the moderate-dose epirubicin-based regimen with regard to EFS, distant EFS, and OS. Because of the lack of superiority of HEC over CMF, and because of a slightly increased toxicity observed with this regimen in comparison with CMF, we do not recommend the use of the HEC regimen in the standard clinical practice. A companion study, the preliminary results of which have been presented elsewhere,22,23 is now ongoing to evaluate the value of HER-2 and topoisomerase II alpha as possible predictive markers, thus identifying distinct subgroups of patients where the epirubicin-based regimens would be more effective than CMF.
Supported in part by Pharmacia-Upjohn Belgium.
1. 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 2. Levine M, Bramwell VH, Pritchard KI, et al: Randomised 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] 3. 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) 4. Fisher B, Redmond C, Wickerham DL, et al: Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 7: 572-582, 1989[Abstract] 5. 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] 6. Moliterni A, Bonadonna G, Valagussa P, et al: Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes. J Clin Oncol 9: 1124-1130, 1991[Abstract] 7. 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] 8. Carpenter JT, Velez-Garcia E, Aron BS, et al: Five-year results of a randomized comparison of cyclophosphamide, doxorubicin and fluorouracil for node positive breast cancer: A Southeastern Cancer Study Group study. Proc Am Soc Clin Oncol 13: 66, 1994 (abstr 68) 9. Budd TG, Green S, O’Bryan RM, et al: Short-course FAC-M versus 1 year of CMFVP in node-positive, hormone receptor-negative breast cancer: An intergroup study. J Clin Oncol 13: 831-839, 1995[Abstract]
10.
Goldhirsch A, Coates AS, Colleoni M, et al: Adjuvant chemoendocrine therapy in postmenopausal breast cancer: Cyclophosphamide, methotrexate, and fluorouracil dose and schedule may make a difference. J Clin Oncol 16: 1358-1362, 1998 11. Engelsman E, Klijn JC, Rubens RD, et al: "Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: An EORTC Breast Cancer Cooperative Group phase III trial. Eur J Cancer 27: 966-970, 1991 12. Del Mastro L, Venturini M, Sertoli MR, et al: Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: Prognostic role and clinical implications. Breast Cancer Res Treat 43: 183-190, 1997[Medline] 13. Pagani O, O’Neill A, Castiglione M, et al: Prognostic impact of amenorrhea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: Results of the International Breast Cancer Study Group (IBCSG) trial VI. Eur J Cancer 34: 632-640, 1998 14. Early Breast Cancer Trialist’s Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352: 930-942, 1998[Medline]
15.
Thor AD, Berry DA, Budman DR, et al: erb B-2, p-53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90: 1346-1360, 1998
16.
Paik S, Bryant J, Park C, et al: erb B-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 17. Paik S, Bryant J, Wolmark N: ERB-B2 overexpression and response to chemotherapy: NSABP studies. Proc 21st Ann San Antonio Breast Cancer Symp. 1998, p 231 (abstr 18)
18.
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 19. Bonneterre J, Roché H, Bremond A, et al: Results of a randomised trial of adjuvant chemotherapy with FEC 50 vs FEC 100 in high risk node-positive breast cancer patients. Proc Am Soc Clin Oncol 17: 124a, 1998 (abstr 473)
20.
Fisher B, Anderson S, Wickerham DL, 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 21. Henderson IC, Berry D, Demetri G, et al: Improved disease-free 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) 22. 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 randomized clinical trial with predictive markers analysis. Proc Am Soc Clin Oncol 18: 69a, 1999 (abstr 258) 23. Di Leo A, Larsimont D, Beauduin M, et al: Her 2 and topoisomerase II alpha as predictive markers for node-positive breast cancer patients randomized to adjuvant CMF or epirubicin-cyclophosphamide. Eur J Cancer 35: S205, 1999 (abstr 802) Submitted May 12, 2000; accepted March 16, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 and Kruskal-Wallis tests were used. The Kruskal-Wallis test was performed to compare the distributions of age and pathologic tumor size. All reported P values were two-tailed. 
