Published by Oxford University Press 2005
Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials
1 Centre Antoine Lacassagne, Nice; 2 Centre Georges-François Leclerc, Dijon; 3 Institut Claudius Régaud, Toulouse; 4 Centre René Gauducheau, Nantes; 5 Centre Eugène Marquis, Rennes; 6 Centre Hospitalier Jules Courmont, Lyon; 7 Centre Hospitalier André Boulloche, Montbéliard; 8 Centre Alexis Vautrin, Nancy; 9 Clinique St-Vincent, Besançon; 10 Centre Oscar Lambret, Lille, France
* Correspondence to: Prof. M. Namer, Département d'Oncologie Médicale, 33 rue de Valombrose, 06186 Nice Cedex 2, France. Tel: +33-6-12-21-00-01; E-mail: moise.namer{at}wanadoo.fr
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Abstract |
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Background: The purpose was to compare disease-free survival (DFS) between epirubicin-based chemoendocrine therapy and tamoxifen alone in one to three node-positive (N1–3), estrogen-receptor-positive (ER+), postmenopausal early breast cancer (EBC) patients.
Patients and methods: We analyzed, retrospectively, 457 patients randomized in FASG 02 and 07 trials who received: tamoxifen alone (30 mg/day, 3 years); or FEC50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2, cyclophosphamide 500 mg/m2, six cycles every 21 days) plus tamoxifen started concurrently. Radiotherapy was delivered after the third cycle in FASG 02 trial, and after the sixth in FASG 07 trial.
Results: The 9-year DFS rates were 72% with tamoxifen and 84% with FEC50-tamoxifen (P = 0.008). The multivariate analysis showed that pathological tumor size >2 cm was an independent prognostic factor (P = 0.002), and treatment effects remained significantly in favor of chemoendocrine therapy (P = 0.0008). The 9-year overall survival rates were 78% and 86%, respectively (P = 0.11). In the multivariate model, there was a trend in favor of chemoendocrine therapy (P = 0.07).
Conclusion: The addition of FEC50 adjuvant chemotherapy to tamoxifen significantly improves long-term DFS in N1–3, ER+ and postmenopausal women. Chemoendocrine therapy seems to be more effective than tamoxifen in terms of long-term survival.
Key words: adjuvant therapy, breast cancer, epirubicin, estrogen-receptor positive, node-positive, tamoxifen
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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From 1970 to 1985, several teams investigated the value of adjuvant treatment in postmenopausal breast cancer. Five well-designed randomized trials compared a chemotherapy regimen with a control arm, but none showed an improvement in survival [1
–5]. The chemotherapy regimen was usually cyclophosphamide, methotrexate and fluorouracil (CMF), or melphalan monotherapy. In 1985, only one of eight adjuvant tamoxifen therapy randomized trials showed a survival advantage [6–13].
Combined chemotherapy and hormonotherapy showed promise, but only one of five randomized trials showed a slight benefit for poor-risk, hormone-receptor-positive (HR+) postmenopausal patients [7, 14–17]. This was the only trial to include an anthracycline in the chemotherapy regimen [14]. By 1986, four major trials involving more than 150 patients with advanced disease had demonstrated the superiority of regimens containing adriamycin over the CMF regimen in terms of the response rate, time to progression and survival [18].
At the same period, the French Adjuvant Study Group (FASG) demonstrated that the optimal epirubicin-based chemotherapy in premenopausal, node-positive breast cancer patients was six cycles of FEC 50 [19]. We started simultaneously a prospective randomized trial, FASG 02, involving node-positive postmenopausal breast cancer patients, to investigate the impact of tamoxifen, an epirubicin-containing chemotherapy regimen, and a combination of these two treatments on disease-free (DFS) and overall survival (OS), in comparison with a control group not receiving adjuvant therapy [20]. In 1991, we initiated a second trial, FASG 07, in postmenopausal women to compare tamoxifen with chemoendocrine therapy in patients with one to three positive nodes (N1–3) and HR+ tumor [21]. We present here individual data of each trial and pooled data of both studies in N1–3, estrogen-receptor-positive (ER+) patients comparing tamoxifen with chemoendocrine therapy.
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patients and methods |
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study population
Between 1986 and 1990, 776 node-positive women with operable breast cancer were randomized in the FASG 02 trial, irrespective of hormone receptors status. The FASG 07 was initiated in 1991 and ended in 1998, enrolling 335 one to three node-positive (N1–3), hormone-receptor-positive (HR+) patients. The distribution of patients is described in Table 1. Both studies recruited postmenopausal women aged from 50 to 65 years, with last menses occurring more than 1 year previously. Estrogen and/or progesterone receptors positivity was defined as an upper value of 10 fmol/mg proteins. The women had all undergone modified radical mastectomy or lumpectomy plus axillary dissection (at least five axillary lymph nodes resected). The main eligibility criteria were World Health Organization (WHO) performance status
2, normal hematologic (granulocyte count 
2000/mm3, platelet count 100 000/mm3), hepatic (bilirubin 35 µmol/l) and renal (serum creatinine level 130 µmol/l) functions, and no cardiac dysfunction (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.
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treatment regimens
In the FASG 02 trial, patients were randomized to receive: tamoxifen 30 mg/day for 3 years (Tam); FEC50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2, cyclophosphamide 500 mg/m2, six cycles every 21 days); FEC50 and Tam initiated simultaneously (FEC50-Tam); or no systemic treatment (control). In the FASG 07 trial, patients were randomized to receive either Tam or FEC50-Tam. The allocated treatment was started within 42 days after initial surgery (Table 1).
Locoregional radiotherapy was delivered within 6 weeks after initial surgery in Tam or control groups. In the FASG 02 trial, it was delivered within 15 days after the third chemotherapy cycle, and then patients received the fourth chemotherapy cycle within 15 days after completing radiotherapy. Radiotherapy was delivered within 30 days after the last chemotherapy cycle in the FASG 07 trial. After mastectomy, radiation to the chest wall, supraclavicular area, internal mammary chain and, in the 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, which consisted of 55 Gy in 27 fractions plus a complementary breast irradiation of 10–15 Gy and local radiation to the supraclavicular area, internal mammary chain and axillary area (in the case of pN1 tumor) consisting of 50 Gy in 25 fractions for each target.
For chemotherapy, preventive use of granulocyte-colony stimulating factor (G-CSF) and antibiotics were prohibited. An absolute granulocyte count of less than 2000/mm3 or a platelet count of 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 35–50 µmol/l and treatment was stopped if bilirubin levels exceeded 50 µmol/l. The tolerability of chemotherapy was evaluated before each cycle: an ECG and a complete blood count were performed on day 21, and nonhematologic toxicity was evaluated during the period between each cycle, according to WHO criteria. Subjects underwent clinical and biochemical assessments every 6 months during the 5-year follow-up period and yearly thereafter. A radiological assessment was performed every year during the 5-year follow-up period and every 2 years thereafter.
statistical analysis
Individual data of each trial were analyzed separately. All assessable patients were entered onto an intention-to-treat analysis using SPSS software (SPSS Inc., Chicago, IL). The FASG 02 trial was designed as a 2 x 2 factorial plan in order to compare hormonotherapy and chemotherapy.
Taking into account differences in inclusion criteria and study design between both trials, the pooled survival analysis involved N1–3, ER+ patients, and compared Tam arms with FEC50-Tam arms (Table 1). The safety analysis involved all the patients who received Tam or FEC50-Tam, irrespective of baseline characteristics (Table 1). The 
2 test was used to compare baseline categorical variables and the incidence of adverse events in both groups [22]. Continuous variables were compared using analysis of variance [23]. DFS and local-DFS were defined as the time from random allocation until first relapse (local, regional and distant) or first ipsilateral relapse, respectively. A contralateral breast cancer was considered a new primary malignancy. Overall survival (OS) was defined as the time from random assignment until death, whether or not it was related to breast cancer. DFS, local-DFS and OS rates were computed according to the Kaplan–Meier method, and survival curves were compared with the log-rank test or log-rank test stratified on the study for the pooled analysis [24, 25]. The Cox regression analysis was stratified on the study and adjusted for adjuvant treatment, age, surgical procedure, Scarff-Bloom and Richardson (SBR) grade, pathologic tumor size (pT) and progesterone receptors (PR) [26]. Statistical analysis has been performed in a double-blind fashion both by Pfizer, France and by an independent biostatistician.
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results |
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patient and treatment characteristics
In each study, baseline characteristics were well balanced among treatment arms. When clinical and pathologic characteristics were compared between both studies, they were significantly different for all variables (Table 2). Noteworthy, in the FASG 07 trial, it was mandatory to have estrogen and/or progesterone positive receptors. In this study, 99% of the patients were ER-positive and one patient had unknown PgR. In the FASG 02 trial, as hormone receptor status was not a screening criteria, more than 20% of the patients had no assessment of HR and the same rate had ER-negative tumor. In N1–3, ER+ patients assessable for pooled efficacy analysis, these characteristics were comparable among Tam and FEC50-Tam arms (Table 2). This allowed comparison of treatment arms in this population.
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Treatment characteristics and compliance to adjuvant therapy are described in Table 3. Patients received locoregional radiotherapy in 94% of the cases. Radiotherapy modalities were similar in both studies regarding sites irradiated and doses delivered. In 517 patients receiving chemotherapy, 361 (70%) received radiotherapy between the third and the fourth cycle.
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survival analysis
FASG 02. The median follow-up was 134 months (range 4–202). The incidence of relapse, local relapse and death, as well as 11-year DFS, local-DFS and OS rates are shown in Table 4 (Figures 1A, 2A). Per study design, the 2 x 2 factorial plan showed a significant benefit of hormonotherapy compared with the absence of hormonotherapy for both 11-year DFS and OS (62% versus 46%, P < 0.0001; 65% versus 54%, P = 0.002, respectively). There was no advantage of chemotherapy (54% versus 52%, P = 0.35; 61% versus 59%, P = 0.14, respectively). The Cox regression model demonstrated that independent prognostic factors of relapse were pT [hazard ratio (HR) = 0.68; 95% confidence interval (CI) 0.39–0.97; P = 0.01], and axillary lymph nodes involvement (HR = 0.54, 95% CI 0.25–0.83, P <0.0001). In this model, the absence of hormonotherapy remained significantly deleterious (HR = 2.25, 95% CI 1.85–2.65, P = 0.0001), as the absence of chemotherapy did not modify disease outcome (HR = 1.39, 95% CI 0.97–1.81, P = 0.12). There was no interaction between hormonotherapy and chemotherapy (P = 0.76), and hence the model can be considered additive.
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FASG 07. The median follow-up was 89 months (range 28–140). The incidence of relapse, local relapse and death, as well as 8-year DFS, local-DFS and OS rates, are shown in Table 4 (Figures 1B, 2B). In terms of relapse, the advantage of chemoendocrine therapy over hormonotherapy remained significant in the multivariate model (HR = 0.44, 95% CI 0.00–0.99, P = 0.004) and pT was the only independent prognostic factor (HR = 0.30, 95% CI 0.00–0.88, P = 0.0001).
Pooled analysis. The median follow-up was 113 months (range 4–202). The incidence of relapse, local relapse and death, as well as 9-year DFS, local-DFS and OS rates, are shown in Table 4 (Figures 1C, 2C). In terms of relapse, the advantage of chemoendocrine therapy over hormonotherapy remained significant in the multivariate analysis (P = 0.0008) and pT was the only independent prognostic factors (P = 0.002) (Table 5). As regards death, no prognostic factor was statistically significant. There was a trend for improvement in survival in favor of chemoendocrine therapy (P = 0.07).
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acute toxicity
Chemotherapy acute toxicity was evaluated according to WHO criteria and was typical of those observed with six cycles of FEC 50 [19
, 27]. This toxicity was not different between both trials and was similar in patients who received no concurrent Tam. Hormonotherapy was stopped prematurely in 119 (17%) patients. The main reasons for Tam interruption were: relapse (n = 91), toxicity (n = 14), gynecologic disturbances (n = 5), endometrial carcinoma (n = 1), patient's refusal (n = 2), protocol violation (n = 1), second malignancy (n = 5), Guillain–Barre syndrome (n = 1) and death (n = 5: suicide, cirrhosis, traffic accident, and unknown reasons in 2). Fifty-nine (11%) patients did not receive the complete schedule of chemotherapy for the following reasons: patient's refusal (n = 17), digestive toxicity (n = 7), hematologic toxicity (n = 5), cardiac toxicity (n = 6), infection (n = 3), radiotherapy injury (n = 3), venous injury (n = 3), late discovery of initial metastatic breast cancer (n = 4), relapse (n = 2), protocol violation (n = 2), lost to follow-up (n = 3) and unknown reason (n = 4). As regards hematologic toxicity, grade 3–4 neutropenia occurred in 13% of the patients without preventive use of G-CSF; three cases (0.6%) of grade 3 infection were reported; no case of grade 3–4 anemia occurred and grade 1–2 anemia was observed in 19%; a thrombocytopenia was observed in 1% of patients. The other severe side-effects observed were: grade 3–4 nausea-vomiting in 24% of patients without anti 5-HT3 prophylaxis, five cases (1%) of grade 3 stomatitis, and grade 3 alopecia in 23%. No toxic death was registered. Four patients presented with a left ventricular dysfunction: LVEF was <50% in two (no baseline value available in both cases), a reduction in LVEF of 18% in one, and worsening of a pre-existing left ventricular hypertrophia in one. In 11 patients, conduction or rhythm disturbances were diagnosed. None of these 15 patients presented with subsequent cardiac clinical symptoms.
delayed cardiac events
Cardiac events occurring during the follow-up period are described in Table 6. Overall, a severe cardiac event was reported in six patients who did not receive adjuvant chemotherapy (1.1%), and in six patients who received epirubicin-based adjuvant chemotherapy (1.1%).
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In patients who were free of anthracycline either in the adjuvant setting or in the metastatic setting, two CHF occurred of whom one patient died as a result of the CHF, one patient developed a left ventricular hypertrophia, one had a transient decrease in LVEF and one had a myocardial infarct. One patient who received Tam in the adjuvant setting, then 400 mg/m2 of epirubicin for her metastatic disease had a non-complicated LVEF decrease.
In patients who received FEC50 or FEC50-Tam, one died of CHF (0.2%), one died of myocardial infarct (previous myocardial infarct before randomization), one died of a cardiogenic shock related to an anemia after receiving mitoxantrone-based first-line chemotherapy, and three had non-complicated decrease in LVEF.
second malignancies
Overall, 38 patients (3.5%) developed a contralateral breast cancer: 28 cases (3.7%) in the FASG 02 trial and 10 cases (3.1%) in the FASG 07 trial. The median onset was 60 months (range 4–149 months). There was no difference between studies and treatment groups for incidence and onset period.
Second malignancies occurred in 58 patients (5.4%): seven in the control arm (3.8%), 16 in Tam arms (4.5%), 10 in the FEC50 arm (5.4%) and 25 in FEC50-Tam arms (7.2%). Fifteen patients developed an endometrial cancer: three in patients who did not receive Tam (0.8%) and 12 in those who received Tam (1.7%). Five years after FEC50 plus adjuvant tamoxifen, one patient presented with an acute lymphoblastic leukemia (ALL) and subsequently died. One case of acute myeloblastic leukemia (AML) French American British (FAB) 4 occurred in a patient who received tamoxifen alone as adjuvant therapy, then received for relapse a first-line chemotherapy with epirubicin (cumulative dose 300 mg/m2), and a second-line with mitoxantrone (cumulative dose 108 mg/m2). This case was probably related to mitoxantrone (18 months after initiation of mitoxantrone). The remaining 41 cases were: lymphoma (1), myeloma (1), ovarian carcinoma (7), cervical neoplasia (4), digestive tract carcinoma (15), lung carcinoma (1), head and neck carcinoma (1), thyroid carcinoma (3), kidney carcinoma (2), basocellular carcinoma (5) and sarcoma (1).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The FASG 02 trial was not designed to compare tamoxifen and chemoendocrine therapy directly but to evaluate the respective contribution of hormonotherapy and chemotherapy in node-positive postmenopausal patients. If the role of tamoxifen was clear, we failed to demonstrate the contribution of chemotherapy. The results of chemotherapy were probably decreased by the arm containing only chemotherapy without tamoxifen, which was clearly a wrong approach in this subset of patients. The FEC50-Tam arm was superior for DFS, local-DFS and OS. As no interaction was found between hormonotherapy and chemotherapy, the model can be considered additive. The FASG 07 trial compared tamoxifen and chemoendocrine therapy directly and we showed a significant advantage of FEC50-Tam over Tam in terms of DFS in a favorable subset of node-positive, postmenopausal women. As regards OS, the low number of events did not demonstrate a difference between treatment arms. The pooled analysis of both trials reinforced and confirmed the results obtained in the FASG 07 trial. This analysis allowed us to demonstrate an improvement in local-DFS and a trend in a better OS with chemoendocrine therapy in spite of a relatively modest number of deaths. However, our results have the limitation of a retrospective and pooled analysis. Patient population of the two studies is not similar: in the FASG 02 trial, patients were treated irrespective of hormone receptor status (42% of ER negative/unknown) and 38% of them presented with nodes involvement superior than three nodes.
The contribution of chemotherapy in postmenopausal women remains controversial. In 1995, the Oxford meta-analysis concluded that, in patients older than 50 years and ER+, the reduction in risks of relapse and death was superior with tamoxifen than with chemotherapy [28]. However, benefits obtained with both treatments could be considered additive. Recently, the International Breast Cancer Study Group (IBCSG) trial compared tamoxifen alone with tamoxifen combined with three cycles of CMF in 608 node-positive, postmenopausal women [29]. The 5-year DFS was significantly better with chemoendocrine therapy (P = 0.03), whereas no difference was observed in terms of OS. In the Oxford meta-analysis, anthracycline-based chemotherapy showed a significant improvement in DFS and OS over CMF, irrespective of age, ER and nodal status [28]. The Southwest Oncology Group (SWOG) compared CAF regimen plus tamoxifen (concurrent or sequential) to tamoxifen alone. Chemotherapy added a significant 10-year DFS and OS benefit to tamoxifen in postmenopausal, node-positive, HR+ patients [30]. Using epirubicin single-agent combined with tamoxifen, two studies demonstrated the advantage of the association in postmenopausal, node-positive patients after 5–6 years of follow-up [31, 32]. Among these patients, 27% and 100% of patients were older than 65 years, respectively. The contribution of chemotherapy in node-positive, postmenopausal patients has recently been presented with taxanes. Surprisingly, the addition of three cycles of docetaxel after three cycles of FEC 100 significantly improved 5-year DFS compared with six cycles of FEC 100, whereas no advantage was found in premenopausal women [33]. Overall, our study confirmed the advantage of an anthracycline-based chemotherapy combined with tamoxifen in HR+, postmenopausal patients. We found that this benefit was also true in the case of intermediate-risk disease, such as one to three axillary lymph nodes involvement. This could be evaluated for node-negative breast cancer women.
The timing of hormonal treatment was also addressed. The recent observations made by SWOG strongly suggested that a sequential administration of tamoxifen after chemotherapy improved DFS and OS [30]. Taking this hypothesis into account, our results could be improved if tamoxifen and chemotherapy have been used sequentially. On the other hand, a Spanish study failed to show an advantage of concomitant or sequential use of tamoxifen after 5 years of follow-up in postmenopausal, node-positive women who received four adjuvant cycles of epirubicin-cyclophosphamide [34]. To date, concurrent or sequential administrations of hormonal treatment have to be tested with aromatase inhibitors in order to confirm results obtained with tamoxifen.
We conclude that epirubicin-based adjuvant chemotherapy combined with tamoxifen significantly improves long-term DFS in a good prognostic subset of node-positive patients. The benefit/risk ratio remains in favor of chemoendocrine therapy as few cardiac events or secondary leukemia occurred. When both trials were initiated, no quality-of-life assessment was foreseen. Given the differences of tolerability between endocrine and chemoendocrine treatments, this topic has to be evaluated and the patient's preference has to be taken into account. Probably, the use of aromatase inhibitors and taxanes has to be explored to improve the outcome of postmenopausal and elderly breast cancer patients.
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Acknowledgements |
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This work was supported by grants from Pfizer, France. We are indebted to Dr Elisabeth Luporsi (Centre Alexis Vautrin, Nancy, France) for her statistical contribution. Isabelle Chapelle-Marcillac provided editorial assistance in the preparation of the manuscript.
Received for publication March 24, 2005. Revision received August 18, 2005. Accepted for publication August 19, 2005.
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References |
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1. Bonadonna G, Valagussa P, Rossi A et al. Ten year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat 1985; 5: 95–115.[CrossRef][Web of Science][Medline]
2. Crowther D. Controlled adjuvant chemotherapy trials for breast cancer in the United Kingdom. In Jones SE, Salmon E (eds): Adjuvant Therapy of Cancer, 2nd edition. New York, NY: Grune and Stratton 1979; 237–244.
3. Rubens RD, Hayward JL, Knight RK et al. Controlled trial of adjuvant chemotherapy with melphalan for breast cancer. Lancet 1983; 1: 839–843.[CrossRef][Medline]
4. Senn HJ, Jungi WF, Amgwerd R. Chemo (immuno) therapy with CMF + BCG in node-negative and node-positive breast cancer. In Jones SE, Salmon E (eds): Adjuvant Therapy of Cancer, 3rd edition. New York, NY: Grune and Stratton 1981; 331–337.
5. Wolmark N, Fisher B. Adjuvant chemotherapy in stage II breast cancer: a brief overview of the NSABP clinical trials. World J Surg 1985; 9: 699–706.[Medline]
6. Nolvadex Adjuvant Trial Organisation. Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer. Analysis at six years by Nolvadex Adjuvant Trial Organisation. Lancet 1985; 1: 836–840.[Web of Science][Medline]
7. Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet 1984; 1: 1256–1260.[CrossRef][Medline]
8. Rose C, Thorpe SM, Andersen KW et al. Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values. Lancet 1985; 1: 16–19.[CrossRef][Web of Science][Medline]
9. Palshof T, Mouridsen HT, Daehnfeldt JL. Adjuvant endocrine therapy of primary operable breast cancer. Report on the Copenhagen breast cancer trials. Eur J Cancer 1980; Suppl 1: 183–187.
10. Pritchard KI, Meakin JW, Boyd NF et al. A randomized trial of adjuvant tamoxifen in postmenopausal women with axillary node-positive breast cancer. In Jones SE, Salmon E (eds): Adjuvant Therapy of Cancer, 4th edition. New York, NY: Grune and Stratton 1984; 339–347.
11. Ribeiro G, Swindell R. The Christie Hospital tamoxifen (Nolvadex) adjuvant trial for operable breast carcinoma – 7-yr results. Eur J Cancer Clin Oncol 1985; 21: 897–900.[Medline]
12. Rose C, Thorpe SM, Mouridsen HT et al. Antiestrogen treatment of postmenopausal women with primary high risk breast cancer. Breast Cancer Res Treat 1983; 3: 77–84.[Medline]
13. Wallgren A, Baral E, Cartensen J et al. Should adjuvant tamoxifen be given for several years in breast cancer ? In Jones SE, Salmon E (eds): Adjuvant Therapy of Cancer, 4th edition. New York, NY: Grune and Stratton 1984; 331–337.
14. Kaufmann F, Maas H, Kubli F et al. Risk adapted adjuvant chemo-hormone therapy in operable nodal positive breast cancer. In Jones SE, Salmon E (eds): Adjuvant Therapy of Cancer, 4th edition. New York, NY: Grune and Stratton 1984; 369–378.
15. Pearson OH, Hubay CA, Marshall JS et al. Adjuvant endocrine therapy, cytotoxic chemotherapy and immunotherapy in stage II breast cancer: five-year results. Breast Cancer Res Treat 1983; 3 (Suppl): S61–S68.
16. Taylor SG 4th, Kalish LA, Olson JE et al. Adjuvant CMFP versus CMFP plus tamoxifen versus observation alone in postmenopausal, node-positive breast cancer patients: three-year results of an Eastern Cooperative Oncology Group study. J Clin Oncol 1985; 3: 144–154.[Abstract]
17. Wolmark N, Fisher B. Adjuvant tamoxifen and chemotherapy in stage II breast cancer: interim findings from NSABP protocol B-09. World J Surg 1985; 9: 750–755.[Medline]
18. Mouridsen HT. Anthracyclines in the treatment of early breast cancer. Drugs 1993; 45 (Suppl 2): 1–3.[Web of Science][Medline]
19. Fumoleau P, Kerbrat P, Romestaing P et al. Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol 2003; 21: 298–305.
20. Namer M, Fumoleau P, Devaux E et al. Node-positive postmenopausal breast cancer patients: six-year follow-up results of a randomized trial testing the role of hormonotherapy (HT), chemotherapy (CT), or combination. Proc Am Soc Clin Oncol 1996; 16: 78 (Abstr).
21. Fargeot P, Roche H, Kerbrat P et al. Disease-free survival advantage of chemoendocrine therapy vs tamoxifen alone in node-positive (N+), positive hormone-receptors (Hr+) operable postmenopausal breast cancer patients (Pts): results of FASG-07 randomized trial. Proc Am Soc Clin Oncol 2000; 19: 332 (Abstr).
22. Snedecor GW, Cochran WG. Statistical Methods, 7th edition. Ames: Iowa State University Press 1980.
23. Duncan DB. P-tests and intervals for comparison suggested by the data. Biometrics 1975; 31: 339–359.[CrossRef]
24. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[CrossRef][Web of Science]
25. Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc [A] 1972; 135: 185–198.
26. Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972; 34: 187–202.
27. 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 2001; 19: 602–611.
28. Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–942.[CrossRef][Web of Science][Medline]
29. Crivellari D, Bonetti M, Castiglione-Gertsch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breats cancer: the International Breast Cancer Study Group trial VII. J Clin Oncol 2000; 18: 1412–1422.
30. Albain K, Barlow W, O'Malley F et al. Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). San Antonio Breast Cancer Symposium 2004: 37 (Abstr).
31. Wils JA, Bliss JM, Coombes MG et al. Epirubicin plus tamoxifen versus tamoxifen alone in node-positive post menopausal patients with breast cancer: a randomized trial of the International Collaborative Cancer Group. J Clin Oncol 1999; 17: 1988–1998.
32. Fargeot P, Bonneterre J, Roche H et al. Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of the French adjuvant study group 08 trial. J Clin Oncol 2004; 22: 4622–4630.[Medline]
33. Roché H, Fumoleau P, Spielmann M et al. Five years analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) for the adjuvant treatment of node positive breast cancer. San Antonio Breast Cancer Symposium 2004: 27 (Abstr).
34. Pico C, Martin M, Jara C et al. Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study. Ann Oncol 2004; 15: 79–87.
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