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Journal of Clinical Oncology, Vol 24, No 31 (November 1), 2006: pp. 4956-4962
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.05.1235
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Similar Efficacy for Ovarian Ablation Compared With Cyclophosphamide, Methotrexate, and Fluorouracil: From a Randomized Comparison of Premenopausal Patients With Node-Positive, Hormone Receptor–Positive Breast Cancer

Bent Ejlertsen, Henning T. Mouridsen, Maj-Britt Jensen, Nils-Olof Bengtsson, Jonas Bergh, Soren Cold, Per Edlund, Marianne Ewertz, Peter W. de Graaf, Claus Kamby, Dorte L. Nielsen

From the Department of Oncology, Rigshospitalet, Copenhagen University Hospital; Danish Breast Cancer Cooperative Group Registry, Copenhagen; Department of Oncology, Odense University Hospital, Odense; Department of Oncology, Aalborg Hospital, Aarhus University, Aarhus; Department of Oncology, Herlev University Hospital, Herlev, Denmark; Department of Oncology, Umeaa County Hospital, Umeaa; Radiumhemmet, Stockholm Oncology, Karolinska Institute and University Hospital, Stockholm; Department of Oncology, Gaavle County Hospital, Gaavle, Sweden; and the Department of Surgery and Traumatology, Reinier de Graaf Groep, Delft, the Netherlands

Address reprint requests to Bent Ejlertsen, MD, PhD, Department of Oncology, Bldg 5012 Rigshospitalet, 9. Blegdamsvej, DK-2100 Copenhagen, Denmark; e-mail: ejlertsen{at}rh.dk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Purpose To compare the efficacy of ovarian ablation versus chemotherapy in early breast cancer patients with hormone receptor–positive disease.

Patients and Methods We conducted an open, randomized, multicenter trial including premenopausal breast cancer patients with hormone receptor–positive tumors and either axillary lymph node metastases or tumors with a size of 5 cm or more. Patients were randomly assigned to ovarian ablation by irradiation or to nine courses of chemotherapy with intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) administered every 3 weeks.

Results Between 1990 and May 1998, 762 patients were randomly assigned, and the present analysis is based on 358 first events. After a median follow-up time of 8.5 years, the unadjusted hazard ratio for disease-free survival in the ovarian ablation group compared with the CMF group was 0.99 (95% CI, 0.81 to 1.22). After a median follow-up time of 10.5 years, overall survival (OS) was similar in the two groups, with a hazard ratio of 1.11 (95% CI, 0.88 to 1.42) for the ovarian ablation group compared with the CMF group.

Conclusion In this study, ablation of ovarian function in premenopausal women with hormone receptor–positive breast cancer had a similar effect to CMF on disease-free and OS. No significant interactions were demonstrated between treatment modality and hormone receptor content, age, or any of the well-known prognostic factors.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
The overview published by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) in 1996 clearly established that ovarian ablation by surgery or ovarian irradiation significantly improves disease-free and long-term survival in premenopausal women with early breast cancer.1 In addition, the most recent EBCTCG overview showed that a similar effect could be obtained by ovarian suppression with a luteinizing hormone–releasing hormone inhibitor.2 Ovarian ablation by surgery or pelvic irradiation was assessed directly against polychemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) by the Scottish Cancer Trials Breast Group and the Imperial Cancer Research Fund Breast Unit at Guy's Hospital in a small trial of 332 premenopausal patients, and they detected no significant overall differences in event-free or overall survival (OS).3 In addition, three trials have compared 2 years of ovarian suppression with goserelin or leuprorelin acetate directly with CMF-based chemotherapy in premenopausal breast cancer patients. In the Zoladex Early Breast Cancer Research Association trial, 1,640 patients with node-positive breast cancer were randomly assigned to goserelin compared with CMF.4 The International Breast Cancer Study Group trial VIII included patients with node-negative breast cancer and randomly assigned 346 patients to goserelin, 361 patients to CMF, and 358 patients to CMF followed by goserelin.5 Finally, results from an interim analysis have been published including 227 patients with node-positive disease from the Takeda Adjuvant Breast Cancer Study with leuprorelin acetate.6 Patients included in the three fully reported trials were unselected regarding hormone receptor status. Subset analyses of the Zoladex Early Breast Cancer Research Association and International Breast Cancer Study Group VIII trials demonstrated equivalence between ovarian suppression and CMF in patients with estrogen receptor (ER) –positive disease, whereas superiority of ovarian ablation compared with CMF was established in the Scottish trial. In contrast, CMF was consistently superior to ovarian ablation or suppression in ER-negative patients.7

Our trial was designed to compare the effects of ovarian ablation and CMF on disease-free survival (DFS) and OS in premenopausal women with hormone receptor–positive breast cancer. We report the results of the preplanned analysis conducted 5 years after closure of recruitment.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
This study was a randomized, phase III, multicenter, open trial recruiting patients from centers in Denmark, two health care regions in Sweden, and one region in the Netherlands. The Danish Breast Cancer Cooperative Group (DBCG) prepared the original protocol (DBCG Trial 89B), and minor regional modifications were later added in the subprotocols of the other health care regions. The study included women who had a completely resected unilateral invasive carcinoma of the breast and no signs of distant metastasis as determined by physical examination and chest radiography. Bone scintigraphy (if positive, to be confirmed by radiography) or bone radiography was performed in the case of bone pain or bone resorption markers (alkaline phosphatase and ionized calcium) above the reference interval. Lower axillary clearance (level I and part of level II) in combination with breast-conserving surgery or mastectomy was required before random assignment. Patients were premenopausal (normal menstrual period within 2 months, normal menstrual period within 12 months, and follicle-stimulating hormone in the premenopausal range, or age 50 years or younger with at least one ovary preserved at hysterectomy), had hormone receptor–positive tumors (ER and/or progesterone receptor [PgR] positive), and were at high risk of relapse, defined as metastasis to at least one lymph node or a tumor exceeding 5 cm. The pathologic procedure included classification of histologic type according to regional guidelines (eg, WHO or Ackerman), examination of tumor margins, invasion into skin or deep fascia, measurement of gross tumor size, and number of metastatic and total number of lymph nodes identified. All invasive ductal carcinomas was graded for malignancy.8,9 ER and PgR were analyzed using dextran-coated charcoal assays in frozen tissue or immunohistochemical assays.10 According to the standard practice in several centers, PgR was only analyzed if ER was negative. Tumors were considered to be receptor positive in the quality controlled and validated biochemical ligand-binding assay as defined by the laboratories in each region. After immunohistochemical staining, tumors were considered receptor positive if the percentage of ER- or PgR-positive epithelial cells was 10% or greater.

This trial was conducted according to the Helsinki Declaration and was approved by ethical committees with jurisdiction for the participating institutions. Informed consent was obtained before random assignment, after oral and written information. Patients were randomly assigned by the data center of each participating group, and data from each cooperative group were collected by the group's data center and accumulated centrally by the DBCG Registry. The DBCG Data Center undertook central review, querying, and analysis of data.

Adjuvant Therapy
By random assignment, patients were allocated to ovarian ablation or CMF. Ovarian ablation was performed by irradiation, and the requested limits of the pelvic portals used were from the inferior border of the fifth lumbar vertebra to the lowermost aspect of obturator foramen and 1 to 2 cm lateral of the inner pelvic sidewalls. The field arrangement involved the use of anterior and posterior fields against the minor pelvic region. The intended dose was a median absorbed dose in the target volume of 15 Gy administered in 5 fractions over a 1-week period using a linear accelerator. Locoregional radiotherapy was carried out according to regional guidelines.

Patients in the CMF group who were not assigned to locoregional radiotherapy received nine cycles of cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 (CMF) administered intravenously on day 1 of every third week, whereas patients assigned to radiotherapy received one or two cycles of CMF before radiotherapy and one or two cycles of single-agent cyclophosphamide (850 mg/m2) concomitant with radiotherapy followed by CMF to a total of nine cycles of chemotherapy. The doses were adjusted according to WBC and platelet counts on day 1 of the scheduled cycle as follows: platelets ≥ 100 x 109/L and WBC ≥ 3 x 109/L, 100% of all three drugs; platelets of 75 to 99 x 109/L or WBC of 2.0 to 2.9 x 109/L, 50% of all three drugs. If platelets were less than 75 x 109/L or WBC were less than 2.0 x 109/L, then treatment was delayed for 1 week.

Follow-Up
Symptoms, adverse effects including amenorrhea, and findings on clinical examination were recorded every 12 weeks during the first year, every 6 months during the second through the fifth year, and thereafter annually to a total of 10 years. A complete follow-up on vital status was obtained in Denmark through linkage to the civic registration. Hemoglobin, WBC count, and platelet count were examined on day 1 of each CMF cycle. Additional biochemical tests and imaging examinations were performed when indicated by symptoms or signs.

Statistical Analysis
On the basis of DBCG protocols 77B and 82B, it was expected that 150 patients per year could be entered onto the protocol and that the 5-year recurrence-free rate would be 65%. The preplanned sample size was 750 patients in 5 years, with an additional 5-year follow-up. A relative 25% decrease in DFS was considered clinically unacceptable. A 20% type II error and a 5% type I error were accepted in a two-sided design. Random assignment was stratified according to center; the patients were allocated to treatment by the minimization method, with a random component of 20%. The DBCG Registry performed data collection, validation, and analysis. Follow-up time was quantified in terms of a Kaplan-Meier estimate of potential follow-up.11 OS was calculated as the time elapsed from random assignment until death, irrespective of cause of death. DFS was defined as the duration of survival without locoregional recurrence, distant metastases, contralateral breast cancer, or death irrespective of cause. OS and DFS were analyzed unadjusted by the intent-to-treat principle using a log-rank test stratified by center. For multivariate analysis, the Cox proportional hazards regression model was applied to assess the per-protocol adjusted relative risk of treatment regimen and to explore interactions. Factors included in the multivariate analyses were age (≤ 40, 41 to 45, or ≥ 46 years), tumor size (≤ 20 mm, > 20 mm, or unknown), nodal status (< 10 lymph nodes or unknown number examined or ≥ 10 lymph nodes examined, as well as zero to three, four to five, six to 10, or ≥ 11 positive lymph nodes), histologic type and grade (ductal grade 1, ductal grade 2 or unknown grade, ductal grade 3, lobular, or histologic type other than ductal and lobular), hormone receptor status (both ER and PgR positive, one positive and the other negative, or one or both unknown), center, and treatment regimen. Interactions between treatment and the covariates of age, positive lymph node status, tumor size, and hormone receptor status were investigated in separate models. The assumptions of proportional hazards were assessed by log(–log) S plots and Schoenfeld residuals and by including in the model a time-dependent component for each covariate. The hazard rate of tumor type and grade were not proportional, and therefore, stratification was used. Associations between regimen and other characteristics were analyzed using {chi}2 tests. P values are two tailed. Statistical analyses were performed with the SAS 8.2 program package (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
From January 1990 to May 1998, we recruited 762 patients from 22 centers in Denmark, Sweden, and the Netherlands. Recruitment was closed immediately after the publication of the EBCTCG overviews in 1998 demonstrating a substantial effect of tamoxifen in younger women with breast cancer and superiority of anthracycline-containing chemotherapy regimens compared with regimens without anthracyclines.12,13 Thirty-three patients withdrew their consent, 13 patients were ineligible, and one patient was lost to follow-up for DFS (Fig 1). All patients were included in the unadjusted analysis according to the intent-to-treat principle. The two groups were well balanced, with no significant differences between the two groups (Table 1).


Figure 1
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  		Fig 1. Trial profile. CMF, cyclophosphamide, methotrexate, and fluorouracil; OA, ovarian ablation; OS, overall survival; RFS, recurrence-free survival.

 

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  		Table 1. Baseline Characteristics of the Intent-to-Treat Population

 
Study Outcome
This analysis was conducted 5 years after closure of recruitment as preplanned. Median estimated potential follow-up time was 8.5 years for DFS and 10.5 years for OS. A total of 358 first events were observed, 182 in the ovarian ablation group and 176 in the CMF group (Table 2). Figure 2A shows the Kaplan-Meier curves for DFS. The unadjusted hazard ratio for DFS in the ovarian ablation group compared with the CMF group was 0.99 (95% CI, 0.81 to 1.22; P = .95 by the log-rank test). Median DFS time was 130 months in the ovarian ablation group compared with 122 months in the CMF group. Causes of death are listed in Table 2, and the unadjusted hazard ratio for OS in the ovarian ablation group compared with the CMF group was 1.11 (95% CI, 0.88 to 1.42; P = .38 by the log-rank test). The Kaplan-Meier curves for OS are shown in Figure 2B; median survival has hitherto not been reached.


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  		Table 2. End Point Events

 

Figure 2
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  		Fig 2. Kaplan-Meier estimates of (A) disease-free survival and (B) overall survival. CMF, cyclophosphamide, methotrexate, and fluorouracil; OA, ovarian ablation.

 
A supportive and unplanned multivariate analysis of DFS and OS did not reveal any effect on the per-protocol relative risk when adjusting for prognostic factors including age, nodal status, tumor size, ER status, PgR status, histologic type, and grade. Type of surgery had no significant impact and was excluded (data not shown). The adjusted per-protocol hazard ratio for DFS in the ovarian ablation group compared with the CMF group was 1.04 (95% CI, 0.83 to 1.30; P = .72), and the corresponding hazard ratio for OS was 1.19 (95% CI, 0.92 to 1.54; P = .18). Patients were considered to be hormone receptor positive if their tumors were either ER or PgR positive, and explorative retrospective subgroup analyses were performed according to ER and PgR status. In the subgroup of patients with ER-negative or PgR-negative tumors, treatment with CMF resulted in a significant increase in DFS and OS (Fig 3). The treatment effect of both modalities seemed to be similar irrespective of age, nodal status, tumor size, histologic type, and grade, and there was little difference between CMF and ovarian ablation in any of the subgroups (Fig 3).


Figure 3
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  		Fig 3. Forest plots illustrating proportional hazard models for (A) disease-free survival and (B) overall survival. Hazard ratios (HRs) refer to estimates obtained in the multivariate analysis. HR, hazard ratio; CMF, cyclophosphamide, methotrexate, and fluorouracil; OA, ovarian ablation; ER, estrogen receptor; PgR, progesterone receptor.

 
Toxicity
Treatment-related deaths were not reported. Among patients randomly assigned to CMF, dose-limiting toxicities were rare (Table 3), but depression of bone marrow function (WBC ≤ 3.0 x 109/L) was observed at least once in 200 patients (57%). The relative cumulative dose (actual/planned mg/m2) of CMF was 0.97, and the relative dose-intensity (actual/planned mg/m2 per time unit) of CMF was 0.91. Despite prophylactic antiemetics, which as a standard did not include 5-hydroxytryptamine-3 antagonists at that time, 114 patients (33%) in the CMF group had moderate or severe nausea and vomiting, whereas moderate or complete alopecia only was reported in 18 patients (5%).


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  		Table 3. Toxicity in the CMF Group

 
In the ovarian ablation group, a permanent cessation of menses was not attained in eight patients despite pelvic irradiation. One patient continued regular menses, four patients continued to have irregular menstrual periods, and three patients resumed menses after a suspension of at least 1 year. In the CMF group, 240 patients had regular menses at random assignment, and 89 of these patients (37%) either continued regular menses (63 patients) or resumed regular menses (26 patients). A permanent cessation of menses was registered in 93 patients (39%) in the CMF group, whereas the consequences were unclear in 58 patients (24%).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
This trial shows a similar effect of the intravenous, every-3-week CMF regimen and ovarian ablation in high-risk, premenopausal, node-positive breast cancer patients with tumors expressing hormone receptors. However, although the number of events is not sufficient to claim equivalence, our results are consistent with previously published trials and with the indirect comparisons from the EBCTCG overview.

The EBCTCG 1998 overview demonstrated a significant reduction in risk of recurrence and death with anthracycline-containing regimens compared with regimens without anthracyclines.9 Early findings in another trial, which was part of a joint program with the current trial, suggested that the substitution of methotrexate in CMF with epirubicin would lead to a further 25% to 30% proportional reduction in mortality.14 Therefore, the relative role of ovarian ablation and chemotherapy will change after further improvements in the efficacy of adjuvant chemotherapy, including the addition of taxanes and trastuzumab in the treatment of patients with human epidermal growth factor receptor 2–positive breast cancers.15 Despite the differences observed in group-wise comparisons, the improvements observed with every single cytotoxic drug might be restricted to small patient groups. TOP2A copy number changes in the primary tumor seem promising as a predictive factor for the use of anthracyclines,16,17 and the use of such factors could re-establish selection criteria for the use of ovarian ablation.

It has been hypothesized that the effect of CMF in premenopausal patients is mediated partly through chemocastration and partly through a cytotoxic effect.18 A significant interaction was not observed between age and treatment modality, but given the limited number of events, the present results neither support nor refute our previous suggestion. Only one patient continued regular menses after pelvic irradiation, and the field arrangement used in the current study was proven to be both safe and efficient. Localization of the ovaries by ultrasound or other methods19 before initiation of radiotherapy does not seem to be necessary unless smaller field sizes, for some reason, are preferred. The incidence of contralateral breast cancer was only 3% in both groups.

Although there was no significant interaction in the multivariate analysis between hormone receptor status and treatment modality, retrospective explanatory analyses suggest that CMF was superior to ovarian ablation with respect to both DFS and OS in patients with tumors discordant for hormone receptors (eg, either ER- or PgR-negative tumors). These retrospective analyses were based on the small subgroups of patients and should be interpreted with caution. The predictive value of PgR is uncertain for ovarian ablation in early breast cancer, but the presence of PgR may reflect a functional ER pathway,20 providing a biologic explanation for a less beneficial effect of ovarian ablation in patients with PgR-negative tumors irrespective of ER status. The possible predictive value of PgR positivity has not been reported in other trials comparing ovarian ablation and chemotherapy. A retrospective analysis of the randomized Swedish trial comparing 2 versus 5 years of postoperative tamoxifen showed a significantly better DFS and OS in patients with PgR-positive tumors compared with patients with PgR-negative tumors.21 The positive predictive value of PgR positivity was confirmed in the combined analysis from two large databases, using identical assays for ER and PgR.22 However, the improvement of DFS and OS with tamoxifen in patients with ER-positive tumors was similar in the EBCTCG meta-analysis irrespective of PgR status,8 but large differences could obviously be anticipated in the assays used in the different trials included in the meta-analysis. Hormone receptor status was examined in the current trial before random assignment according to the practice of regional laboratories, and cutoff levels for dextran-coated charcoal and the different immunohistochemical assays used were only defined for receptor positivity. Symptoms of menopause are distressing to many women and include hot flushes, night sweats, vaginal dryness, and dyspareunia. The moderate toxicity observed from CMF provides especially younger women with a possibility to preserve ovarian function and to avoid premature menopausal symptoms as well as the long-term consequences of hormone deprivation including osteoporosis and increased risk of cardiovascular disease. We suggest that premenopausal patients with hormone receptor–positive and node-positive breast cancer should be recommended ovarian ablation as a secondary option if chemotherapy is unacceptable.

The EBCTCG meta-analysis published in 1992 and the National Surgical Adjuvant Breast and Bowel Project B09 study suggested that concurrently administered chemotherapy and tamoxifen might be antagonistic, particularly in premenopausal patients.23,24 Therefore, tamoxifen was not allowed in the current trial, and recruitment was discontinued after the publication of the EBCTCG meta-analysis in 1998.12 Overall, this updated and large-scale EBCTCG meta-analysis showed an improvement in DFS and OS from 5 years of tamoxifen, which seemed to be independent of age older than or younger than 50 years and the presence or absence of chemotherapy, but this study did not have sufficient power to allow subgroup analysis with respect to both age groups and absence or presence of chemotherapy. The relative effect of tamoxifen after ovarian ablation and chemotherapy has not been analyzed directly in randomized trials or indirectly in a meta-analysis. Unfortunately, the possible influence of tamoxifen on the results of the current trial remains speculative.


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
The following institutions and people participated in the study: Danish Breast Cancer Cooperative Group (DBCG) Registry, Copenhagen, Denmark: Susanne Möller, MSc; Katrín Gunnarsdóttir, MSc; Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark: Marianne Ewertz, MD; Aarhus University Hospital, Aarhus, Denmark: Jorn Andersen, MD; Meander Medical Center, Amersfoort, Netherlands: Cees J. Rodenburg, MD; Rigshospitalet, Copenhagen, Denmark: Henning T. Mouridsen, MD; Reinier de Graaf Groep, Delft, the Netherlands: Peter W. de Graaf; Esbjerg County Hospital, Esbjerg, Denmark: Erik Sandberg, MD; Eskilstuna County Hospital, Eskilstuna, Sweden: Brita Stenstam, MD; Gävle County Hospital, Gävle, Sweden: Johan Ahlgren, MD; Herlev University Hospital, Herlev, Denmark: Claus Kamby, MD; Herning County Hospital, Herning, Denmark: Knud Aage Moller, MD; Karlstad County Hospital, Karlstad, Sweden: Martin Söderberg; Leiden University Hospital, Leiden, the Netherlands: Johan W. Nortier, MD; Naestved County Hospital, Naestved, Denmark: Preben Philip, MD; St. Antonius Hospital, Nieuwegein, the Netherlands: Peter H. Slee, MD; Odense University Hospital, Odense, Denmark: Soren Cold, MD; Örebro University Hospital, Örebro, Sweden: Lars Andreassen, MD; Roskilde County Hospital, Roskilde, Denmark: Peter Grundtvig, MD; Sonderborg County Hospital, Sonderborg, Denmark: Ebbe Lindegaard-Madsen, MD; Vejle County Hospital, Vejle, Denmark: Erik H. Jakobsen, MD; Umeaa County Hospital, Umeaa, Sweden: Nils-Olof Bengtsson, MD; Uppsala University Hospital, Uppsala, Sweden: Jonas Bergh, MD; IKMN Trial Bureau, Integraal Kankercentrum Midden Nederland, Utrecht, the Netherlands: Irma van Beuningen, MSc; Oudenrijn Hospital, Utrecht, the Netherlands: Sytze G. van der Vegt, MD; Västeraas County Hospital, Västeraas, Sweden: Jorgen Hansen; and Viborg County Hospital, Viborg, Denmark: Vera Haahr, MD.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
Author Contributions
 REFERENCES
 
The authors indicated no potential conflicts of interest.


   Author Contributions
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
REFERENCES
 

Conception and design: Bent Ejlertsen, Henning T. Mouridsen

Administrative support: Bent Ejlertsen, Henning T. Mouridsen

Provision of study materials or patients: Bent Ejlertsen, Henning T. Mouridsen, Nils-Olof Bengtsson, Jonas Bergh, Soren Cold, Per Edlund, Marianne Ewertz, Peter W. de Graaf, Claus Kamby, Dorte L. Nielsen

Collection and assembly of data: Bent Ejlertsen, Henning T. Mouridsen, Maj-Britt Jensen, Nils-Olof Bengtsson, Jonas Bergh, Soren Cold, Per Edlund, Marianne Ewertz, Peter W. de Graaf, Claus Kamby, Dorte L. Nielsen

Data analysis and interpretation: Bent Ejlertsen, Henning T. Mouridsen, Maj-Britt Jensen, Jonas Bergh

Manuscript writing: Bent Ejlertsen, Henning T. Mouridsen, Maj-Britt Jensen, Jonas Bergh, Soren Cold, Marianne Ewertz, Claus Kamby, Dorte L. Nielsen

Final approval of manuscript: Bent Ejlertsen, Henning T. Mouridsen, Maj-Britt Jensen, Nils-Olof Bengtsson, Jonas Bergh, Soren Cold, Per Edlund, Marianne Ewertz, Peter W. de Graaf, Claus Kamby, Dorte L. Nielsen

 


   NOTES
 
Presented in part at the 35th Annual Meeting of the American Society of Clinical Oncology, May 15-18, 1999, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
1. Early Breast Cancer Trialists' Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet 348:1189-1196, 1996[CrossRef][Medline]

2. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline]

3. 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 341:1293-1298, 1993[Medline]

4. 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 20:4628-4635, 2002[Abstract/Free Full Text]

5. 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 95:1833-1846, 2003[Abstract/Free Full Text]

6. Schmid P, Untch M, Wallwiener D, et al: Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node-positive, premenopausal breast cancer patients: Preliminary results of the TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate). Anticancer Res 22:2325-2332, 2002[Medline]

7. Dellapasqua S, Colleoni M, Gelber RD, et al: Adjuvant endocrine therapy for premenopausal women with early breast cancer. J Clin Oncol 23:1736-1750, 2005[Free Full Text]

8. Bloom J, Richardson WW: Histological grading and prognosis in breast cancer: A study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11:359-377, 1957[Medline]

9. Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology 19:403-410, 1991[Medline]

10. Andersen J, Thorpe SM, King WJ, et al: The prognostic value of immunohistochemical estrogen receptor analysis in paraffin-embedded and frozen sections versus that of steroid-binding assays. Eur J Cancer 26:442-449, 1990[Medline]

11. Schemper M, Smith TL: A note on quantifying follow-up in studies of failure time. Control Clin Trials 17:343-346, 1996[CrossRef][Medline]

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13. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[CrossRef][Medline]

14. 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 Oncol 18:68a, 1999 (abstr 254)

15. Nowak AK, Wilcken NR, Stockler MR, et al: Systematic review of taxane-containing versus non-taxane-containing regimens for adjuvant and neoadjuvant treatment of early breast cancer. Lancet Oncol 5:372-380, 2004[CrossRef][Medline]

16. Di Leo A, Gancberg D, Larsimont D, et al: HER-2 amplification and topoisomerase II alpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 8:1107-1116, 2002[Abstract/Free Full Text]

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Submitted November 28, 2005; accepted June 15, 2006.


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