Annals of Oncology Advance Access originally published online on May 26, 2006
Annals of Oncology 2006 17(8):1221-1227; doi:10.1093/annonc/mdl107
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 European Society for Medical Oncology
Complete hormonal blockade versus epirubicin-based chemotherapy in premenopausal, one to three node-positive, and hormone-receptor positive, early breast cancer patients: 7-year follow-up results of French Adjuvant Study Group 06 randomised trial
1 Institut Claudius Régaud, Toulouse; 2 Centre Eugène Marquis, Rennes; 3 Centre Oscar Lambret, Lille; 4 Centre Georges-François Leclerc, Dijon; 5 Centre Hospitalier André Boulloche, Montbéliard; 6 Centre Hospitalier Universitaire Dupuytren, Limoges; 7 Centre Hospitalier de Bretagne Sud, Lorient; 8 Centre Jean Perrin, Clermont-Ferrand; 9 Centre Léon Bérard, Lyon; 10 Institut Sainte-Catherine, Avignon, France
* Correspondence to: Prof. H. Roché, Département d'Oncologie Médicale, Institut Claudius Régaud, 20–24 rue du Pont Saint-Pierre, 31052 Toulouse Cedex, France. Tel: +33-5-61-42-41-29; Fax: +33-5-61-42-46-23; E-mail: roche{at}icr.fnclcc.fr
 |
Abstract |
|---|
 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
|---|
Background: The purpose of this study was to determine optimal adjuvant therapy between complete hormonal blockade in premenopausal patients with hormone receptor positive breast cancer and one to three positive nodes.
Patients and methods: We randomised 333 patients to receive either LHRH agonist (triptorelin 3.75 mg i.m., monthly) plus tamoxifen 30 mg/day for 3 years (TAM-LHRHa, n = 164), or fluorouracil 500 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days for six cycles, without any hormonal treatment (FEC50, n = 169).
Results: The 7-year disease-free survival (DFS) was 76% with TAM-LHRHa, and 72% with FEC50 (P = 0.13). The 7-year overall survival (OS) was 91% and 88%, respectively (P = 0.20). The multivariate analysis confirmed that both treatments were not different for DFS and OS (P = 0.83 and P = 0.41, respectively). Amenorrhoea occurred in 64% of patients treated with FEC50; it was temporary in 58% of cases after hormonotherapy and in 31% after chemotherapy.
Conclusion: In intermediate-risk breast cancer, complete hormonal blockade and chemotherapy provided similar outcomes. Hormonal treatment is an alternative to chemotherapy in hormone-sensitive patients, considering the preference of patients in terms of quality of life.
Key words: breast cancer, epirubicin, hormonal blockade, hormone-receptor positive, node-positive, premenopausal
|
introduction |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
In the 1990s, the standard adjuvant treatment for premenopausal women with node-positive, early breast cancer was chemotherapy. Randomized trials of adjuvant chemotherapy conducted by Bonadonna et al. and the National Surgical Adjuvant Breast and Bowel Project (NSABP) provided the first evidence of efficacy in patients with positive nodes, particularly in premenopausal women [1
, 2]. These results were confirmed by the first Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis of all breast cancer trials and in the OncoFrance trial [3, 4]. The French Adjuvant Study Group (FASG) demonstrated that the optimal epirubicin-based chemotherapy in premenopausal, node-positive breast cancer patients was six cycles of FEC50 rather than three cycles [5].
In 1985, the benefit of adjuvant tamoxifen was demonstrated by the Nolvadex Adjuvant Trial Organisation (NATO) study [6]. Later, the EBCTCG meta-analysis showed the advantage of ovarian ablation in early breast cancer [7]. The combination of luteinising hormone-releasing hormone agonist (LHRHa) with tamoxifen demonstrated an advantage over LHRHa alone or tamoxifen alone in premenopausal advanced breast cancer [8–10]. In the adjuvant setting, trials comparing CMF (cyclophosphamide, methotrexate and fluorouracil) with hormonal blockade in premenopausal, hormone-responsive patients demonstrated that chemotherapy was equivalent to ovarian ablation, tamoxifen alone and LHRHa alone [11–14], but was significantly less effective than tamoxifen plus LHRHa [15].
The present trial was designed to investigate the optimal adjuvant treatment in intermediate-risk, one to three involved nodes, hormone-receptor positive (HR+), premenopausal patients. We decided to compare our standard epirubicin-based chemotherapy at the same time as a hormonal treatment combining tamoxifen and LHRHa for 3 years.
|
patients and methods |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
study population
Premenopausal women younger than 50 years with operable breast cancer who had undergone surgery (i.e., modified mastectomy, tumorectomy or lumpectomy) plus axillary dissection (one to three involved nodes; at least five axillary lymph nodes removed), and estrogen and/or progesterone receptors positivity (defined as a value
10 fmol/mg proteins) were eligible for the study. Premenopausal status was defined as last menses occurring less than 1 year ago and no previous hysterectomy. The main eligibility criteria were World Health Organization (WHO) performance status 
2; normal haematologic (granulocyte count 2.109/l, platelet count 100.109/l), hepatic (bilirubin 35 µmol/l) and renal (serum creatinine level 130 µmol/l) functions; and no cardiac dysfunction [baseline left ventricular ejection fraction (LVEF) 50%]. 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 if treatment start exceeded 42 days from initial surgery for breast cancer. Potentially eligible patients underwent bone scan, chest radiograph, abdominal ultrasound or computed tomographic scan, and contralateral mammography. Written informed consent was obtained from each patient before randomisation. The protocol was reviewed and approved by the Ethics Committee/Institutional Review Board according to French law.
treatment regimens
Patients were randomised to receive triptorelin 3.75 mg/month intramuscularly (i.m.) plus tamoxifen 30 mg/day orally for 3 years (TAM-LHRHa) or fluorouracil 500 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 intravenously (i.v.) every 21 days for six cycles (FEC50), without hormonal treatment. The allocated treatment was started within 42 days after initial surgery.
Locoregional radiotherapy commenced within 6 weeks after initial surgery in the TAM-LHRHa group, and within 30 days after the last chemotherapy cycle in the FEC50 group. After mastectomy, radiation to the chest wall, supraclavicular area, internal mammary chain and to the axillary area (according to the practices of each institution) was delivered and consisted of 50 Gy in 25 fractions for each target. Patients who underwent breast-conserving surgery received an additional boost of 10–15 Gy.
For chemotherapy, preventive use of granulocyte-colony stimulating factor (G-CSF) and antibiotics was prohibited. Antiemetic treatment was prescribed routinely before each cycle. An absolute granulocyte count less than 2 x 109/l or a platelet count less than 100 x 109/l 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; treatment was stopped if bilirubin levels exceeded 50 µmol/l. The tolerability of chemotherapy was evaluated before each cycle: an electrocardiogram and an absolute blood count were performed on day 21; non-haematologic toxicity was evaluated between each cycle according to WHO criteria. It was recommended to assess LVEF within 3–4 weeks after the last chemotherapy cycle.
The occurrence of amenorrhoea was recorded and classified according to the following criteria [16]: treatment-related amenorrhoea (TRA) was 6 months without menstrual periods in a patient who was premenopausal at diagnosis; early TRA began within 1 year of starting treatment and late TRA began more than 1 year after starting treatment if a woman was less than 50 years when TRA occurred; temporary TRA was the reappearance of regular menstruation after TRA occurrence.
Patients underwent clinical and biochemical assessments every 6 months during a 5-year follow-up period and yearly thereafter. A radiological assessment was performed yearly during a 5-year follow-up period and every 2 years thereafter. Patients were followed until death.
randomization and statistical analyses
This was a randomised, multicenter, open-label phase III study. Randomization procedures were centralised and well balanced per block. The randomisation was stratified by centre. The primary end point was the 5-year disease-free survival (DFS) defined as the time from random allocation until first relapse (local, regional and distant). A contralateral breast cancer was considered a new primary malignancy. This trial was designed to detect a 10% difference in DFS with an 80% power and accept a two-sided type I error of 10%. This hypothesis required 553 patients. Patients were entered onto an intention-to-treat analysis using SPSS software (SPSS, Inc., Chicago, IL). The secondary end point was overall survival (OS) defined as the time from random assignment until death, regardless of its cause.
The chi-square test was used to compare categorical variables [17]. Continuous variables were compared using analysis of variance [18]. DFS and OS rates were computed and compared according to the Kaplan–Meier method [19]. The per-year incidence of relapse was calculated according to the number of patients in each group who were at risk at each diagnosis time. The multivariate analysis (Cox regression model) was adjusted for age, surgery, Scarff-Bloom and Richardson (SBR) grade, pathological tumour size and amenorrhoea [20]. Statistical analysis has been performed in a double-blind fashion both by Pfizer, France and by an independent biostatistician.
|
results |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
patient characteristics
Between 1990 and 1998, 333 patients were enrolled from 14 French centres. Of these, two were lost to follow-up after random allocation and were excluded from the efficacy analysis (Table 1). The safety and compliance analysis involved all treated patients (Table 1). Baseline characteristics were well balanced between both arms, except for SBR grade: there were significantly more grade 1 tumours in the TAM-LHRHa group (18.9%) than in the FEC50 group (9.5%) (Table 2). Major protocol violations were included in the analysis and were as follows: age
50 years (n = 9), fewer than five axillary nodes resected (n = 2), more than three axillary nodes involved (n = 1), HR negative (n = 2) or not determined (n = 4), neutrophil count lower than 2.109/l (n = 2), LVEF <50% (n = 5) and wrong treatment arm allocation (n = 2).
|
|
treatment and acute toxicity
Among treated patients, 160 received TAM-LHRHa and 164 received FEC50. The median duration of tamoxifen was 36 months (range 5–53) and that of triptorelin was 36 months (range 2–51). Hormonotherapy was prolonged over 36 months in 37 patients (23%) for tamoxifen (range 37–53) and in 27 patients (17%) for triptorelin (range 37–51). The tamoxifen dose was reduced (20 mg/day) in three patients; the triptorelin dose was retained in the whole population. Temporary interruption of hormonotherapy occurred in one patient for tamoxifen (patient's refusal) and in three patients for triptorelin (mistake). Twenty-seven patients (17%) stopped hormonal treatment prematurely: 17 patients stopped completely the hormonal treatment (relapse in 12, contralateral breast cancer in three, hot flushes in one, endometrial abnormalities in one); and 10 patients stopped triptorelin alone (intolerance in four, weight gain in three, endometrial abnormalities in two, mistake in one).
Among the patients who received FEC50, 98% received six cycles. Three patients stopped chemotherapy prematurely: one after the second cycle presented with a phlebitis due to a catheter, and two after the fifth cycle refused to continue the treatment. The mean cumulative epirubicin dose received was 297 mg/m2 (intended dose 300 mg/m2). The mean epirubicin relative dose intensity was 15 mg/m2/week (91% of the intended dose). Acute toxicity was classical of those observed with FEC50 [5]. Grade 3–4 neutropenia occurred in 10% of the patients without preventive use of G-CSF, no case of grade 3–4 anaemia occurred, grade 1–2 anaemia were observed in 12% and no case of thrombocytopenia was observed. The other severe side-effects were: grade 3–4 nausea-vomiting in 32% of patients, one case of grade 3 stomatitis and grade 3 alopecia in 10%. Two patients presented with a transient grade 1 tachycardia during chemotherapy. No grade 3–4 infections or toxic death occurred.
amenorrhoea
Irrespective of age at the beginning of adjuvant treatment, amenorrhoea occurred in all patients receiving TAM-LHRHa and in 104 patients (64%) receiving FEC50. In the FEC50 arm, amenorrhoea occurred in 38% of patients younger than 40 years and 73% of those 40 years (P < 0.0001). Early amenorrhoea occurred in all patients receiving TAM-LHRHa and in 84% of those receiving FEC50. The distribution of amenorrhoea appearance according to time is described in Figure 1.
|
Irrespective of age at the occurrence of last menses, the amenorrhoea was temporary in 58% of patients receiving TAM-LHRHa and in 31% of those receiving FEC50. Irrespective of the adjuvant treatment received, the amenorrhoea was temporary in 68% of patients younger than 40 years at last menses and in 43% of those who were
40 years (P = 0.005).
disease-free and overall survival
The median follow-up was 83 months (range 4–135). Recurrence was evaluated in 331 patients: 32 relapsed (20%) in the TAM-LHRHa arm and 45 (27%) in the FEC50 arm. The 7-year DFS rates were 76% [95% confidence interval (CI) 68–84] with TAM-LHRHa and 72% (95% CI 65–80) with FEC50 (P = 0.13, Figure 2). Patients treated with FEC50 relapsed earlier than those treated with TAM-LHRHa (37 versus 52 months, P = 0.08). Relapses occurred mainly after the end of TAM-LHRHa treatment. In the FEC50 group, this incidence was higher between the first and fourth year after random allocation, then decreased regularly during the follow-up (Figure 3). No significant difference was detected in the pattern of recurrences between treatment groups (Table 3). Patients who received FEC50 developed significantly less multiple-site recurrences than those who received TAM-LHRHa (P = 0.02, Table 3). When a Cox proportional hazards model was performed, age was an independent prognostic factor of relapse (Table 4). In this model, the comparison of treatment did not show any difference between groups (Table 4).
|
|
|
|
There were 35 deaths involving 13 patients (8%) in the TAM-LHRHa arm and 22 (13%) in the FEC50 arm. All deaths were related to the progression of breast cancer. The 7-year OS rates were 91% (95% CI 85–96) with TAM-LHRHa and 88% (95% CI 83–93) with FEC50 (P = 0.20, Figure 4). When a Cox proportional hazards model was performed, initial surgery was an independent prognostic factor of death. In this model, the comparison of treatment did not show any difference between groups (Table 4).
|
delayed cardiac toxicity and second malignancies
Three delayed cardiac toxicities were reported (two in TAM-LHRHa; one in FEC50). During TAM-LHRHa treatment, one patient presented with an echographic LVEF of 33%, which was not comparable to the baseline value performed with another method. After a cumulative epirubicin dose of 293 mg/m2, one patient presented with radioisotopic LVEF of 42% (baseline value 69%). One patient, treated with TAM-LHRHa, presented with a decrease in LVEF from 74% to 54% after an epirubicin-based chemotherapy for metastatic disease (cumulative epirubicin dose 150 mg/m2). In all patients, the decrease in LVEF was transient, without any further cardiac disorders.
Twenty-three patients developed contralateral breast cancer: 13 (6%) in the TAM-LHRHa arm and 10 (5%) in the FEC50 arm. There was no difference between treatment groups. Second malignancies occurred in six patients (one in TAM-LHRHa; five in FEC50). Seven years after initiation of TAM-LHRHa therapy, one patient developed an endometrial cancer. Two years after FEC50, one patient presented with an acute myeloblastic leukemia (AML) French–American–British (FAB) 3. To date, this patient is still in remission for both AML and breast cancer. The remaining four cases in the FEC50 arm were: chronic myeloid leukemia, malignant melanoma, basal cell carcinoma of the skin, and head and neck carcinoma.
|
discussion |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
This study was designed to determine the optimal adjuvant treatment in intermediate-risk, premenopausal breast cancer patients. As in other trials investigating endocrine therapy versus chemotherapy, our recruitment was slow. During the last 2 years of inclusion, the rhythm of enrolment decreased to one patient/month. We therefore decided to stop the recruitment before the completion of the required number of patients. The small sample size led to underpowered results at a value of 61% instead of the 80% scheduled power. After a 7-year follow-up, our results failed to demonstrate any significant advantage for one of these strategies. Compliance to chemotherapy and toxicity profile were typical of six cycles of FEC50. The safety of hormonal treatment was good. Nevertheless, treatment interruption was more frequent with TAM-LHRHa (17%) than with FEC50 (2%). In the adjuvant trials comparing CMF-based chemotherapy with hormonal blockade, hormonotherapy was stopped prematurely in 13% of patients treated with LHRHa alone [14
] and in 14% of those treated with tamoxifen plus LHRHa [15]. In these trials, CMF was stopped prematurely in 7% and 17%, respectively [14, 15].
The contribution of chemotherapy in premenopausal node-positive breast cancer patients was described with non-anthracyline-based regimens [1, 2]. The EBCTCG meta-analysis clearly demonstrated the superiority of an anthracyline-based chemotherapy over CMF regimens [21]. In the adjuvant setting, the FASG initially defined the FEC50 regimen as the reference treatment. Our first adjuvant trial (FASG 01) conducted in premenopausal, node-positive breast cancer patients showed that six cycles of FEC50 were significantly better than three cycles of FEC50 or FEC75 in terms of 10-year disease-free survival [5]. The study comparing six cycles of FEC50 to six cycles of FEC100 (FASG 05), in poor prognosis node-positive breast cancer patients, demonstrated the superiority of FEC100 in terms of 10-year DFS and OS, irrespective of the menopausal status [22]. The FEC100 regimen should be considered one of the standard adjuvant chemotherapy for node-positive, early breast cancer patients.
In premenopausal women with advanced breast cancer, it has been demonstrated that the optimal hormonal treatment was the combination of castration (surgical or medical) with tamoxifen [8–10]. Three major trials have been conducted using CMF-based chemotherapy [15, 23, 24]. Two of them (GROCTA 2, IBCSG trial VIII) failed to reach a significant difference between CMF and ovarian blockade in estrogen receptor-positive (ER+), node-positive or node-negative patients [23, 24]. The ABCSG 5 trial compared CMF with tamoxifen plus goserelin in HR+ patients of whom 50% were node-negative. The DFS was significantly better with endocrine blockade [15]. One trial compared tamoxifen plus ovarian suppression to an anthracycline-based chemotherapy in ER+, node-positive patients [25]. The hormonal blockade was significantly better than FAC50 in terms of DFS, with no difference in OS. In our trial in which 50 mg/m2 of epirubicin replaced 50 mg/m2 of adriamycin and LHRHa replaced ovarian ablation, no significant difference was found. Finally, an Intergroup trial compared CAF regimen alone, or followed by LHRHa, or by tamoxifen plus LHRHa, in HR+, premenopausal, node-positive patients [26]. Chemo-endocrine therapy improved DFS significantly, with no difference in OS.
In premenopausal breast cancer patients, amenorrhoea has been shown to be one of the actions of chemotherapy. A significant improvement in relapse and survival was described in women who develop amenorrhoea compared with those whose menses persist after chemotherapy [27, 28]. According to chemotherapy regimens, the incidence of chemo-induced amenorrhoea is different. Comparison of the available data is difficult because of differences in trial design and definition of the variables. Cyclophosphamide is the most commonly implicated drug, the antimetabolites do not seem to cause significant gonadal dysfunction and the role of anthracyclines is not clear [16]. There is no evidence that duration of treatment, dose intensity, schedule or administration route are independent variables [16]. The incidence of chemo-induced amenorrhoea with CMF regimens was 59% in the ZEBRA trial [14], 68% in the GROCTA 2 trial [23] and 77% in the ABCSG 5 trial [15], which is very close to the incidence observed in our study (64%). In a multivariate model, the effect of amenorrhoea was reduced and age lower than 40 years remained the main significant risk factor. The role of amenorrhoea duration is not fully elucidated. In a retrospective analysis of IBCSG, DFS was similar in patients whose menses returned after brief amenorrhoea and those whose menses ceased and did not recover [29]. However, the optimal duration of LHRHa remains an issue. In our trial, as in those using LHRHa for 2 or 3 years, no difference compared with chemotherapy was observed [14, 23, 24]. Trials demonstrating a superiority of hormonal blockade combined either LHRHa for 3 years plus tamoxifen for 5 years, or tamoxifen with ovarian ablation [15, 25]. In our trial, we observed an increased risk of relapse at the end of hormonal treatment.
When optimal treatments were used, results were not strongly different between regimens. Hormonal blockade could, therefore, be a legitimate alternative to chemotherapy in HR+, node-positive patients. However, most of the trials lacked power to conclude clearly the superiority of one therapeutic approach. Additional trials could be helpful to define better the optimal adjuvant therapy in HR+, premenopausal women. Moreover, the optimal duration of LHRHa therapy remains unsolved. None of these well-conducted trials has published quality of life data. We have to take into account side-effects related to a premature menopause, such as osteoporosis and cardiovascular diseases.
|
Acknowledgements |
|---|
This work was supported by grants from Ipsen Biotech, France and 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.
Presented at the American Society of Clinical Oncology 36th Annual Meeting, New Orleans, Louisiana, 20–23 May 2000.
Received for publication December 28, 2005. Revision received April 1, 2006. Accepted for publication April 4, 2006.
|
References |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
1. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer, the results of 20 years of follow-up. N Engl J Med 1995; 332: 901–906.
2. Fisher B, Cardone P, Economou SG et al. 1-phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med 1975; 292: 117–122.[Abstract]
3. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992; 339: 1–15.[ISI][Medline]
4. 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 1996; 14: 1136–1145.
5. 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.
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.[ISI][Medline]
7. Early Breast Cancer Trialists' Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996; 348: 1189–1196.[CrossRef][ISI][Medline]
8. Klijn JG, Blamey RW, Boccardo F et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19: 343–353.
9. Klijn JG, Beex LV, Mauriac L et al. Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 2000; 92: 903–911.
10. Jonat W, Kaufmann M, Blamey RW et al. A randomised study to compare the effect of the luteinising hormone releasing hormone (LHRH) analogue goserelin with or without tamoxifen in pre- and perimenopausal patients with advanced breast cancer. Eur J Cancer 1995; 31A: 137–142.
11. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy's Hospital, London. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Lancet 1993; 341: 1293–1298.[ISI][Medline]
12. Ejlertsen B, Dombernowsky P, Mouridsen HT et al. Comparable effect of ovarian ablation and CMF chemotherapy in premenopausal hormone receptor positive breast cancer patients. Proc Am Soc Clin Oncol 1999; 18: 248 (Abstr).
13. Boccardo F, Rubagotti A, Amoroso D et al. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, oestrogen-receptor positive breast cancer patients. An update at 7 years of the 1st GROCTA (Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group) trial. Eur J Cancer 1992; 28: 673–680.[CrossRef][Medline]
14. Jonat W, Kaufmann M, Sauerbrei W et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 2002; 20: 4628–4635.
15. Jakesz R, Hausmaninger H, Kubista E et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group trial 5. J Clin Oncol 2002; 20: 4621–4627.
16. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996; 14: 1718–1729.
17. Snedecor GW, Cochran WG. Statistical Methods, 7th edition. Ames: Iowa State University Press 1980.
18. Duncan DB. P-tests and intervals for comparison suggested by the data. Biometrics 1975; 31: 339–359.[CrossRef][ISI]
19. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[CrossRef][ISI]
20. Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972; 34: 187–202.
21. Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–942.[CrossRef][ISI][Medline]
22. Bonneterre J, Roche H, Kerbrat P et al. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2005; 23: 2686–2693.
23. Boccardo F, Rubagotti A, Amoroso D et al. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. J Clin Oncol 2000; 18: 2718–2727.
24. Castiglione-Gertsch M, O'Neill A, Price KN et al. Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 2003; 95: 1833–1846.
25. Roche H, Mihura J, de Lafontan B et al. Castration and tamoxifen versus chemotherapy (FAC) for premenopausal, node and receptor positive breast cancer patients: a randomized trial with a 7 years median follow-up. Proc Am Soc Clin Oncol 1996; 15: 117 (Abstr).
26. Davidson N, O'Neill A, Vukov A et al. Effect of chemohormonal therapy in premenopausal, node (+), receptor (+) breast cancer: an Eastern Cooperative Oncology Group phase III Intergroup trial (E5188, INT-0101). Proc Am Soc Clin Oncol 1999; 18: 249 (Abstr).
27. Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients: the International Breast Cancer Study Group. Ann Oncol 1990; 1: 183–188.
28. Bianco AR, Del Mastro L, Gallo C et al. Prognostic role of amenorrhoea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer 1991; 63: 799–803.[ISI][Medline]
29. Pagani O, O'Neill A, Castiglione M et al. Prognostic impact of amenorrhoea 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 1998; 34: 632–640.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Schmid, M. Untch, V. Kosse, G. Bondar, L. Vassiljev, V. Tarutinov, U. Lehmann, L. Maubach, J. Meurer, D. Wallwiener, et al. Leuprorelin Acetate Every-3-Months Depot Versus Cyclophosphamide, Methotrexate, and Fluorouracil As Adjuvant Treatment in Premenopausal Patients With Node-Positive Breast Cancer: The TABLE Study J. Clin. Oncol., June 20, 2007; 25(18): 2509 - 2515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Walshe, N. Denduluri, and S. M. Swain Amenorrhea in Premenopausal Women After Adjuvant Chemotherapy for Breast Cancer J. Clin. Oncol., December 20, 2006; 24(36): 5769 - 5779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Wolff and N. E. Davidson Still Waiting After 110 Years: The Optimal Use of Ovarian Ablation As Adjuvant Therapy for Breast Cancer J. Clin. Oncol., November 1, 2006; 24(31): 4949 - 4951. [Full Text] [PDF]
|
|
E-letters:
Read all E-letters
- Comments on "Complete Hormonal Blockade ..." by H. Roché et. al.
- Orhan Sencan, et al.
- Annals of Oncology, 11 Aug 2006 [Full text]
- Correspondence
- Henri Roché, et al.
- Annals of Oncology, 29 Aug 2006 [Full text]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||