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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

Peter Schmid, Michael Untch, Valentin Kossé, Grigorij Bondar, Leonid Vassiljev, Valerie Tarutinov, Ute Lehmann, Lutz Maubach, Juergen Meurer, Diethelm Wallwiener, Kurt Possinger

From the Medizinische Klinik mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Mitte, Humboldt Universität zu Berlin; Frauenklinik, Helios Klinikum Berlin-Buch, Berlin; Institute of Oncology and Radiology, Kiew; Medical Academy, Dnepropetrowsk; Antitumor Centre, Donezk; Institute of Medical Radiology, Charkov, Ukraine; Takeda Pharma, Aachen; Omnicare CR, Cologne; Frauenklinik, Universitätsklinikum Tübingen, Eberhard-Karls-Universität Tübingen, Germany; and Charing Cross and Hammersmith Hospital, Imperial College London, London, United Kingdom

Address reprint requests to Peter Schmid, MD, PhD, Charing Cross and Hammersmith Hospital, Imperial College London, Fulham Palace Road, London, W6 8RF, United Kingdom; e-mail: p.schmid{at}imperial.ac.uk

	ABSTRACT

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Purpose Ovarian suppression with luteinizing hormone–releasing hormone (LHRH) agonists is an effective adjuvant treatment for premenopausal women with estrogen receptor (ER) –positive breast cancer. Whereas monthly LHRH agonist therapy has been well established, the value of every-3-months (3-monthly) formulations is unclear.

Patients and Methods This randomized phase III trial was performed to compare the 3-monthly depot LHRH agonist leuprorelin acetate (LAD-3M; n = 299) and chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF; n = 300) in pre- or perimenopausal patients with ER-positive, node-positive breast cancer.

Results With a median follow-up of 5.8 years, recurrence-free survival was similar for patients treated with LAD-3M or CMF (hazard ratio [HR], 1.19; 95% CI, 0.94 to 1.51; P = .15). There was no substantial heterogeneity in the relative treatment effect among subgroups defined by age, progesterone receptor (PR) status, nodal status, hormone levels, or menstrual recovery after treatment. Exploratory overall survival analysis favored LAD-3M (HR, 1.50; 95% CI, 1.13 to 1.99; P = .005). Chemotherapy-related adverse effects such as nausea, vomiting, and alopecia were more common with CMF, whereas symptoms of estrogen suppression such as hot flushes and sweating were initially more pronounced with LAD-3M.

Conclusion The 3-monthly depot LHRH-agonist leuprorelin acetate is an effective adjuvant treatment in premenopausal patients with hormone receptor–positive, node-positive breast cancer that is not inferior to CMF.

	INTRODUCTION

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Adjuvant chemotherapy and endocrine therapy have made a major impact on relapse-free and overall survival of pre- and postmenopausal women with early-stage breast cancer.¹ Current standard options for adjuvant treatment of premenopausal women include chemotherapy, antiestrogen therapy predominantly with tamoxifen, ovarian ablation by surgical oophorectomy or radiotherapy, and ovarian suppression by monthly luteinizing hormone–releasing hormone (LHRH) agonists. Therapeutic strategies are generally based on the endocrine responsiveness and the estimated risk of relapse defined by tumor size, axillary lymph node involvement, histologic and nuclear grade, lymphatic and/or vascular invasion, HER-2–overexpression, and age.²

In premenopausal women, approximately 60% of breast tumors express estrogen receptors (ERs) and/or progesterone receptors (PRs) and are considered hormone sensitive. These patients are therefore candidates for endocrine treatment. Ovarian ablation, the oldest form of systemic treatment for premenopausal women,³ has been shown to significantly improve long-term survival of premenopausal women, at least in the absence of chemotherapy.^1,4 During recent years, ovarian ablation has gradually been replaced by LHRH agonists, which produce reliable, specific suppression of ovarian estrogen production. A recent meta-analysis has shown that in women younger than 50 years of age, ovarian suppression or ablation increases 15-years relapse-free survival by 4.3%, translating into a 3.2% difference in overall survival at 15 years.¹

Because the amenorrhea induced by LHRH agonists is not permanent, they are an important pharmacologic group for the treatment of younger women who wish to maintain their fertility. Current formulations of LHRH agonists used in early breast cancer require monthly subcutaneous injections. Leuprorelin acetate is a specific LHRH agonist that is available as an every-3-months (3-monthly) depot⁵ and has shown activity in advanced breast cancer.^6-8

The Takeda Adjuvant Breast Cancer Study with Leuprorelin acetate (TABLE) trial was initiated to evaluate the efficacy and tolerability of the 3-monthly depot LHRH agonist leuprorelin acetate as adjuvant treatment of premenopausal, node-positive patients with early breast cancer. Patients were randomly assigned to receive 2 years of treatment with the 3-monthly depot LHRH-agonist leuprorelin acetate (LAD-3M) or six cycles of chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF).

	PATIENTS AND METHODS

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Study Design
This open-label, randomized phase III trial was conducted at 71 centers in Germany and the Ukraine. Enrollment began in September 1995 and ended in November 1998. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Harmonized Tripartite Guidelines for Good Clinical Practice, in compliance with local regulations, and with the institutional review boards of each participating center.

Patients were randomly assigned in a 1:1 ratio to one of the two treatment groups using a stratified random permuted block design (block size 4). Random assignment was performed centrally according to the order in which information on potential patients was received by fax. Patients were stratified by study center.

Objectives
The primary study objective was to compare relapse-free survival (RFS) between both treatment groups. Secondary end points included overall survival (OS), adverse events, estrogen suppression, menstrual status, and subjective state of health.

Patient Eligibility
Premenopausal women with histologically confirmed stage II or IIIA breast cancer were eligible for this study. Patients had to have between one and nine involved axillary lymph nodes, with at least 10 lymph nodes being examined. Initially, patients were required to have ER-positive tumors or tumors with unknown ER status. In March 1998, an amendment was issued, requesting positive ER status for enrollment (ie, patients with unknown ER status were ineligible thereafter).

Women with childbearing potential had to use adequate nonhormonal contraceptive measures during treatment. Written informed consent was required before admission to the study.

Patients were ineligible if they had received ovariectomy, radiomenolysis, adrenalectomy, or hypophysectomy. Further exclusion criteria included systemic treatment of cancer within 6 months before enrollment, intake of hormones (apart from contraceptives) within 2 weeks before entry, regular steroid therapy, endocrine abnormalities, severe concurrent medical conditions, and impaired renal function. Pregnant or lactating women were ineligible.

Treatment Plan
Within 6 weeks of definite surgery, patients were randomly assigned to receive LAD-3M (11.25 mg as subcutaneous injection every 3 months) for 2 years or six courses of CMF chemotherapy in 4-week intervals. A cycle of CMF consisted of cyclophosphamide (500 mg/m², intravenous [IV] infusion on days 1 and 8), methotrexate (40 mg/m² IV infusion on days 1 and 8), and fluorouracil (600 mg/m², IV infusion on days 1 and 8).

Patient Evaluation and Follow-Up
Before entry onto the study, all patients underwent staging work-up including a complete history and physical examination, CBC, chemistry profile, chest x-ray, abdominal ultrasound, bone scintigraphy, and further imaging studies as indicated.

A clinical, hematologic, and biochemical assessment was performed at 3-month intervals for the first 2 years and every 6 months thereafter. An extended search for relapse and metastases including mammography, chest x-ray, abdominal ultrasound, and bone scintigraphy was applied every 6 months during the first 2 years. Adverse events and toxicities were assessed at each visit during therapy. Every month, patients had to assess their subjective state of health by means of a questionnaire.

Luteinizing hormone, follicle-stimulating hormone, estradiol (E2), and leuprorelin acetate levels were measured in a central laboratory at baseline and after 3, 6, 12, 18, and 24 months. Hormone levels were measured before application of LAD-3M.

Evaluation Criteria
The primary end point was RFS, defined as the interval from the date of randomization to first evidence of local or distant recurrence, second primary cancer, or death without relapse. OS was defined as the interval from the date of random assignment to the date of death from any cause. Data on patients still alive or relapse free were censored at the time of last contact. Adverse events and toxicities were graded according to the National Cancer Institute Common Toxicity Criteria. Independent monitoring was performed to ensure eligibility of the patients, compliance with the protocol, and source data verification.

Statistical Analysis
The study was designed to test for one-sided equivalence (ie, noninferiority of LAD-3M and CMF) with a power of 80%, an alpha error of 5% and a maximal difference in 2-year RFS of 10%. Assuming a 2-year RFS of 75% and a drop-out rate of 30% the sample size was estimated at 300 patients per arm.

The primary efficacy analyses were based on a per-protocol (PP) population that included all randomly assigned patients without major protocol violations. Reasons for exclusion from the PP analyses were negative ER status, postmenopausal status, no lymph node involvement, delayed onset of study treatment, stage IIIB or IV disease, prior or concomitant systemic breast cancer therapy other than specified in the protocol, oophorectomy or radiotherapy of the ovaries, or premature withdrawal from study for reasons other than relapse or death.

The intention-to-treat (ITT) population included all randomly assigned patients who received at least one course of therapy. Patients who did not discontinue treatment prematurely for a reason other than relapse were assessed as "not relapse free." Safety analyses were performed on all patients who received at least one course of therapy. Adverse events with a definite, probable, possible, or unknown drug relationship were judged as adverse effects.

Early results of the trial have previously been presented.^9,10 This article reports data from an updated analysis with extended follow-up.

Standard descriptive methods were applied. All analyses were performed using SAS, version 8.2 (SAS Institute, Cary, NC). Differences at P .05 were considered statistically significant. RFS and OS were estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards models were fitted to estimate hazard ratios (HRs) and CIs.

	RESULTS

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Patient Characteristics
A total of 599 patients were randomly assigned to treatment with LAD-3M (n = 299) or CMF (n = 300). Five patients in each treatment group did not receive the allocated study medication and were excluded from ITT and safety analysis. Accordingly, the ITT population and the safety population included 589 patients. Another 63 patients (LAD-3M, n = 24; CMF, n = 39) were excluded from the primary efficacy population because of premature termination of study treatment or relevant protocol violations (Fig 1). Thus, the primary efficacy population consisted of 526 patients: 270 patients randomly assigned to LAD-3M and 256 to CMF.

View larger version (23K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Defined patient populations. LAD-3M, every-3-months administration of 3-monthly depot luteinizing hormone–releasing hormone agonist leuprorelin acetate; CMF, cyclophosphamide, methotrexate, fluorouracil; PP, per-protocol; ITT, intention to treat.

Efficacy
With a median follow-up of 5.8 years, there have been 269 recurrences and 197 deaths. Sites of recurrence and types of events are presented in Table 2. Figure 2 shows the Kaplan-Meier estimates for RFS. There was no significant difference in RFS between LAD-3M and CMF. The ITT 5-year RFS rates were 63.9% for LAD-3M and 63.4% for CMF (HR, 1.03; P = .83; Table A1, online only). Similar results were obtained for the PP analysis (HR, 1.02; P = .88)

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimate of (A) recurrence-free survival and (B) overall survival by treatment arm according to intention-to-treat analysis. LAD-3M, every-3-months administration of luteinizing hormone–releasing hormone agonist leuprorelin acetate; CMF, cyclophosphamide, methotrexate, fluorouracil.

Exploratory subgroup analyses were performed to investigate the influence of age, number of positive lymph nodes, tumor size, ER status, PR status, histologic grade, E2 levels, menstrual status, and study treatment on RFS (Tables A2 and A3, online only) and OS. The standard prognostic factors predicted recurrence as expected. None of these variables identified a subgroup of patients in which one of the two treatments was superior in terms of RFS, although subgroups were too small for definitive conclusions (Fig 3).

View larger version (30K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Analyses of (A) recurrence-free survival and (B) overall survival according to subgroup. The hazard ratios (with 95% CIs) are for the patients assigned to LAD-3M compared with those assigned to CMF, and were obtained from the unadjusted Cox model. The solid vertical line indicates a hazard ratio of 1.19, which is the value for all patients, and the dashed vertical line indicates a hazard ratio of 1.00, which is the null-hypothesis value. The size of the squares is proportional to the number of events in the subgroup. LAD-3M, every-3-months administration of luteinizing hormone–releasing hormone agonist leuprorelin acetate; CMF, cyclophosphamide, methotrexate, fluorouracil; ER, estrogen receptor; PR, progesterone receptor.

Hormone Data
As expected, median E2 and luteinizing hormone levels dropped significantly with LAD-3M, but returned to baseline within 6 months after stopping LAD-3M (Table A4, online only). In the CMF group, the E2 suppression was less pronounced during the first year but reached a similar degree as with LAD-3M after 2 years. However, the proportion of patients with E2 suppression to postmenopausal levels (ie, 30 pg/mL) was higher in the LAD-3M group compared with the CMF group (at 1 year: LAD-3M, 92.1%; CMF, 66.2%; P < .001; at 2 years: LAD-3M, 89.6%; CMF, 75.0%; P = .002).

Hormonal escape, defined as E2 levels more than 30 pg/mL at two consecutive measurements, was detected in 29 patients (10.4%) of the LAD-3M group. Thereof, in nine patients, increased E2 levels were present after 3 and 6 months but not subsequently, indicating delayed suppression. In only four patients, E2 levels escaped after initial suppression.

Effects of Treatment on Menstrual Function
Amenorrhea was reported in 88% of LAD-3M patients by 6 months and more than 95% during the remaining 2-year treatment period, compared with 43.9% of CMF patients after 6-months of chemotherapy and 62.1% at 2 years. The onset of amenorrhea was earlier in the LAD-3M group (mean, 22 ± 38 days) compared to the CMF group (mean, 110 ± 151 days).

Amenorrhea was reversible within 1 year of stopping LAD-3M in 45% of patients. In patients treated with CMF, the rate of amenorrhea steadily increased from 51.5% after 1 year to 62.1% after 2 years and 72.7% after 5 years. Further analysis by age showed that more than 90% of patients younger than 40 years at trial entry had normal menstrual function 1 year after the completion of therapy, compared with approximately 70% of patients between 40 and 45 years and 40% of patients older than 45 years.

Tolerability
Adverse effects were generally of low or moderate intensity (Table 3). As expected, symptoms of estrogen suppression such as hot flashes and increased sweating were more common in patients treated with LAD-3M, whereas acute adverse effects of chemotherapy such as nausea, vomiting, diarrhea, asthenia, and alopecia were reported more frequently in patients treated with CMF.

	DISCUSSION

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The TABLE study was the first trial to evaluate the 3-monthly application of an LHRH agonist in early breast cancer. The trial was designed to compare adjuvant LAD-3M treatment with CMF chemotherapy in premenopausal patients with node-positive, endocrine-responsive breast cancer. Results reported here showed no differences in RFS for patients treated with LAD-3M or CMF, with relative effects of LAD-3M and CMF being similar across subgroups defined by age and nodal status. OS analysis favored LAD-3M treatment over CMF, which was surprising considering that there were no differences in RFS and treatment-associated mortality. Further exploratory analyses indicated that the observed differences in OS might be related to a shorter survival time after relapse for patients in the CMF arm. Unfortunately, there is no information available on the treatment after relapse, and potential reasons for the findings remain unclear. Overall, the results of the survival analyses have to be interpreted with caution due to their exploratory nature.

A number of other trials have directly evaluated the efficacy of ovarian suppression with monthly applications of LHRH agonists versus CMF chemotherapy for premenopausal women and have showed that ovarian suppression gave similar results to CMF for women with ER-positive breast cancer, but CMF was superior for women with ER-negative breast cancer.^11-13 These results are in keeping with the findings for the 3-monthly administration in the TABLE study.

The TABLE study showed furthermore that the 3-monthly depot LAD-3M suppressed the ovarian function effectively in more than 95% of patients, which is similar to what has been described with monthly application of LHRH agonists.^11-13 As expected, ovarian suppression with LAD-3M was reversible, and approximately 45% of women reported normal menses after cessation of LAD-3M. Most of the LAD-3M–treated patients who did not return to normal menses were likely to have reached the natural menopause, which is reflected in the increasing incidence of persistent amenorrhea with age. These observations are in keeping with the results for other LHRH agonists, with which amenorrhea persisted in up to 60% of patients, depending on the age distribution.^11,12

The optimal duration of ovarian suppression is currently unclear. LHRH agonists are most commonly used for 2 to 5 years, but no trial has yet been conducted to directly compare different lengths of LHRH agonist therapy. In the TABLE study, LAD-3M was administered for 2 years, and ovarian function resumed in a substantial proportion of patients thereafter. Because there is controversy about the implications of whether amenorrhea is temporary or permanent, we performed an exploratory analysis between patients with menstrual recovery after LAD-3M and patients with persistent amenorrhea, which showed no relevant differences in RFS or OS. Although results have to be interpreted with caution because of the exploratory nature of this examination, these findings underline that temporary ovarian suppression for 2 years is an effective treatment. It will be subject to future studies to find out whether there is a group of patients who benefit from continuation of LHRH agonist treatment beyond 2 years.

There are a few caveats with respect to the design of the TABLE study. Firstly, the trial did not allow the use of tamoxifen. Although this is now considered standard, at the time when the trial was designed there was still some controversy about the use of tamoxifen for premenopausal patients. However, several randomized trials and meta-analyses have demonstrated a clear benefit for the addition of tamoxifen to chemotherapy irrespective of age and/or menopausal status.^1,14 It is therefore possible that the addition of tamoxifen could have shown a benefit for CMF and tamoxifen compared with endocrine therapy. The optimal endocrine regimen is also currently unclear. Several studies evaluated the combination of tamoxifen and ovarian suppression and showed that total endocrine blockade is as good as or even better than chemotherapy for premenopausal women with early-stage, hormone-responsive disease.^15-17 A direct comparison between tamoxifen plus LHRH agonists and tamoxifen or LHRH agonists alone would be required to clearly define the role of combined endocrine therapy, but respective trials are still ongoing. A second concern about the TABLE study is that different types and schedules of CMF (particularly the classic CMF regimen with oral cyclophosphamide), newer chemotherapy regimens such as anthracycline-taxane combinations, or dose-dense regimens may give different results from those of the CMF regimen used in this trial, limiting our ability to extrapolate findings from this trial to current adjuvant chemotherapy regimens. Furthermore, this study is underpowered to show a small but potentially clinically relevant benefit for chemotherapy because it was designed only to rule out a difference of 10% in RFS. Finally, no prospective quality-of-life assessment was undertaken.

To our knowledge, the TABLE study was the first trial to evaluate 3-monthly application of an LHRH agonist in the adjuvant setting, and results reported here show that LAD-3M is effective and well tolerated. The results with LAD-3M are in keeping with the outcome reported for monthly LHRH agonist therapy, but LAD-3M provides the advantage of requiring less frequent injections and patient visits. Overall, the TABLE study provides further support for the value of adjuvant endocrine treatment for selected node-positive patients with endocrine-responsive disease.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Ute Lehmann, Takeda Pharma; Lutz Maubach, Takeda Pharma Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Peter Schmid, Takeda Pharma Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Peter Schmid, Michael Untch, Diethelm Wallwiener, Kurt Possinger

Administrative support: Ute Lehmann, Lutz Maubach

Provision of study materials or patients: Peter Schmid, Michael Untch, Valentin Kossé, Grigorij Bondar, Leonid Vassiljev, Valerie Tarutinov, Diethelm Wallwiener, Kurt Possinger

Collection and assembly of data: Peter Schmid, Juergen Meurer

Data analysis and interpretation: Peter Schmid, Juergen Meurer, Kurt Possinger

Manuscript writing: Peter Schmid

Final approval of manuscript: Peter Schmid, Michael Untch, Valentin Kossé, Grigorij Bondar, Leonid Vassiljev, Valerie Tarutinov, Juergen Meurer, Diethelm Wallwiener, Kurt Possinger

	Appendix

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	NOTES

 
Supported by Takeda Pharma (Aachen, Germany).

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002; the San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003; the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and the San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004.

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 AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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2. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005. Ann Oncol 16:1569-1583, 2005[Abstract/Free Full Text]

3. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment. Lancet 2:104-107, 1896

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5. Boccardo F, Rubagotti A, Amoroso D, et al: Endocrinological and clinical evaluation of two depot formulations of leuprolide acetate in pre- and perimenopausal breast cancer patients. Cancer Chemother Pharmacol 43:461-466, 1999[CrossRef][Medline]

6. Taguchi T, Koyama H, Yayoi K, et al: Long-term clinical study on TAP-144-SR, an LH-RH agonist depot formulation, in premenopausal patients with advanced or recurrent breast cancer: TAP-144-SR Breast Cancer Study Group. Gan To Kagaku Ryoho 22:495-508, 1995[Medline]

7. Taguchi T, Koyama H, Yayoi K, et al: A dose-comparative study on TAP-144-SR, an LH-RH agonist depot formulation, in premenopausal patients with advanced or recurrent breast cancer: TAP-144-SR Breast Cancer Study Group. Gan To Kagaku Ryoho 22:477-494, 1995[Medline]

8. Dowsett M, Mettah P, Mansi J, et al: Dose comparative endocrine clinical study of leuprorelin in pre-menopausal breast cancer patients. Br J Cancer 62:834-837, 1990[Medline]

9. Untch M, Kahlert S, Kosse V, et al: LHRH-analogue therapy with leuprorelin-acetate threee months depot offers similar efficacy to conventional adjuvant CMF chemotherapy in receptor positive, node positive breast cancer patients. Breast Cancer Res Treat 82, 2003 (suppl 1; abstr 40)

10. Schmid P, Possinger K, Kassjanenko I, et al: Leuprorelinacetate 3 month-depot versus cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant treatment in premenopausal patients with node–positive breast cancer: 5-year results of the TABLE-Study. Breast Cancer Res Treat 88, 2004 (suppl 1; abstr 414)

11. Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate, and 5-fluorouracil as adjuvant therapy in pre-menopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Res Association Study. J Clin Oncol 20:4628-4635, 2002[Abstract/Free Full Text]

12. Ejlertsen B, Dombernowsky P, Mouridsen HT, et al: Comparable effect of ovarian ablation (OA) and CMF chemotherapy in premenopausal hormone receptor positive breast cancer patients (PRP). Proc Am Soc Clin Oncol 18:66a, 1999 (abstr 248)

13. 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]

14. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998[CrossRef][Medline]

15. 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 18:2718-2727, 2000[Abstract/Free Full Text]

16. 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 20:4621-4627, 2002[Abstract/Free Full Text]

17. Roche H, Kerbrat P, Bonneterre J, et al: 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. Ann Oncol 17:1221-1227, 2006[Abstract/Free Full Text]

Submitted September 8, 2006; accepted February 13, 2007.

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