Phase III Randomized Study of Adjuvant Letrozole Versus Tamoxifen in Postmenopausal Women With Operable, Hormone Receptor-Positive Breast Cancer
Last Modified: 1/7/2009  First Published: 1/1/2000
Alternate Title Basic Trial Information Objectives Entry Criteria Expected Enrollment Outline Published Results Related Publications Trial Contact Information Registry Information
Alternate Title
Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer
Basic Trial Information
Phase | Type | Status | Age | Protocol IDs |
---|
Phase III | Treatment | Closed | 30 and over | IBCSG-1-98 DAN-DBCG-IBCSG-1-98, FRE-FNCLCC-IBCSG-1-98, EU-99022, IBCSG-18-98, NOVARTIS-2026703019, NCT00004205, BIG-I-98 |
Objectives - Compare adjuvant letrozole vs tamoxifen administered for 5 years in postmenopausal women with operable, hormone receptor-positive breast cancer.
- Compare these treatment regimens given sequentially vs continuously in this patient population.
- Compare these treatment regimens in terms of overall survival, disease-free and systemic-free survival, safety, and tolerability in this patient population.
Entry Criteria Disease Characteristics:
- Histologically confirmed resectable adenocarcinoma of the breast
- pT1, pT2, pT3, or minimal dermal involvement on
pathology only
- pN0, pN1, pN2, or M0
- Negative nodal status
- At least 8 nodes are negative
- Unknown nodal status
- Less than 8 nodes examined and no pathological
finding
- Positive nodal status
- Any positive finding independent of the number of
nodes examined
- Negative sentinel node or no prior nodal dissection
allowed if all other
criteria met
- Must have had total mastectomy, lumpectomy, or quadrantectomy
- Should have prior chest wall radiotherapy after
segmental mastectomy or
histopathologic T4 dermal involvement
- Stage I, II, or IIIa allowed if the tumor is completely removed
macroscopically and margins of the resected tumor are microscopically
free of tumor
- Must undergo chest wall radiotherapy or second
resection if microscopic
disease at the mastectomy margins
- No bilateral disease except in situ disease, either ductal or lobular of
the contralateral breast
- Postmenopausal
- Regardless of prior hormonal replacement therapy
(HRT) or hysterectomy:
- Bilateral oophorectomy and any age
- Radiologic castration and amenorrheic for at least 3
months and any age
- Nonpostmenopausal prior to adjuvant chemotherapy and
completed at least 6 courses of prior cyclophosphamide, methotrexate,
and fluorouracil (CMF) or
at least 4 courses of prior
anthracycline-cyclophosphamide continuation
therapy and at least age 40 with follicle stimulating
hormone (FSH),
luteinizing hormone (LH), and estradiol (E2)
postmenopausal levels
- No prior HRT:
- Prior hysterectomy and less than age 55 with
FSH/LH/E2
postmenopausal levels
- Prior hysterectomy and at least age 55
- No prior HRT or hysterectomy:
- Amenorrhea more than 1 year and less than age 50
- Amenorrhea more than 6 months and at least age 50
- Prior HRT regardless of hysterectomy:
- At least 1 month since prior HRT and less than age
55 with FSH/LH/E2 postmenopausal levels
- At least 1 month since prior HRT and at least age 55
- FSH/LH/E2 postmenopausal levels and uncategorized
- No distant metastases, including bone scans showing hot spots
unconfirmed as benign disease or skeletal pain of unknown cause
- At least 10% hormone receptor-positive tumor cells
- Hormone receptor status:
- Estrogen receptor positive
AND/OR - Progesterone receptor positive
Prior/Concurrent Therapy:
Biologic therapy: - Prior immunotherapy or biological response modifiers (e.g.,
interferon) allowed
Chemotherapy: - See Disease Characteristics
- Prior adjuvant or neoadjuvant chemotherapy allowed
- Concurrent adjuvant chemotherapy allowed
Endocrine therapy: - See Disease Characteristics
- Prior neoadjuvant hormonal therapy allowed (e.g.,
antiestrogens, progestins, or aromatase inhibitors) if no more than 4 months duration
and no disease progression
- Prior corticosteroids allowed
- At least 4 weeks since prior HRT
- Prior adjuvant antiestrogen therapy allowed if less than 1
month duration and immediately after surgery, radiotherapy, and/or
chemotherapy
- Prior antiestrogens for chemoprevention allowed if at least 18
months between completion of chemoprevention and diagnosis
- No other concurrent antiestrogens or aromatase
inhibitors
- No concurrent raloxifene
- No concurrent systemic HRT with or without progestins of more
than 3 months duration
Radiotherapy: - See Disease Characteristics
- Concurrent radiotherapy allowed
Surgery: - See Disease Characteristics
Other: - At least 30 days since prior systemic investigational
drugs
- At least 7 days since prior topical investigational
drugs
- Concurrent bisphosphonates allowed
Patient Characteristics:
Age: Sex: Menopausal status: Performance status: Life expectancy: Hematopoietic: - WBC greater than 3,000/mm3
- Platelet count at least 100,000/mm3
- Hemoglobin greater than 10 g/dL
Hepatic: - Bilirubin less than 3.0 mg/dL
- SGOT or SGPT less than 1.5 times upper limit of
normal
- No hepatic disease that would preclude study
Renal: - Creatinine less than 1.8 mg/dL
- No renal disease that would preclude study
Cardiovascular: - No cardiovascular disease that would preclude study
- Prior deep vein thrombosis allowed if medically
stable
Pulmonary: Other: - No other prior or concurrent malignancy within the past 5
years except adequately treated basal or squamous cell skin cancer or
carcinoma in situ of the cervix
- No prior noncompliance to medical regimens
- No other nonmalignant systemic diseases that would preclude
follow-up
- HIV negative
Expected Enrollment A total of 5,180 patients (1,295 per treatment arm) will be accrued for this
study within 6 years. Outline This is a randomized, double-blind, multicenter study. Patients are
stratified according to adjuvant chemotherapy (prior therapy vs no prior or
concurrent therapy vs concurrent therapy), prior surgery (modified radical
mastectomy vs a lesser surgical procedure), and participating center. Patients
are randomized to one of four treatment arms. - Arm I: Patients receive adjuvant oral tamoxifen daily for 5 years.
- Arm II: Patients receive adjuvant oral letrozole daily for 5
years.
- Arm III: Patients receive adjuvant oral tamoxifen daily for 2 years
followed by adjuvant oral letrozole daily for 3 years.
- Arm IV: Patients receive adjuvant oral letrozole daily for 2 years
followed by adjuvant oral tamoxifen daily for 3 years.
Patients may receive concurrent radiotherapy. Some patients receive
concurrent adjuvant chemotherapy beginning within 8 weeks after surgery and
continuing for no more than 6 months. Patients are followed annually. Published ResultsCrivellari D, Sun Z, Coates AS, et al.: Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol 26 (12): 1972-9, 2008.[PUBMED Abstract] Doughty JC: A review of the BIG results: the Breast International Group 1-98 trial analyses. Breast 17 (Suppl 1): S9-S14, 2008.[PUBMED Abstract] Mouridsen HT, Giobbie-Hurder A, Mauriac L, et al.: BIG 1-98: a randomized double-blind phase III study evaluating letrozole and tamoxifen given in sequence as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. [Abstract] 31st Annual San Antonio Breast Cancer Symposium, December 10-14, 2008, San Antonio, Texas. A-13, 2008. Rasmussen BB, Regan MM, Lykkesfeldt AE, et al.: Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol 9 (1): 23-8, 2008.[PUBMED Abstract] Viale G, Giobbie-Hurder A, Regan MM, et al.: Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 26 (34): 5569-75, 2008.[PUBMED Abstract] Wardley AM: Understanding the BIG results: Insights from the BIG 1-98 trial analyses. Adv Ther 25 (12): 1257-75, 2008.[PUBMED Abstract] Coates AS, Keshaviah A, Thürlimann B, et al.: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 25 (5): 486-92, 2007.[PUBMED Abstract] Coates AS, Mouridsen H, Sun Z, et al.: Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: updated safety analysis of trial BIG 1-98. [Abstract] J Clin Oncol 25 (Suppl 18): A-521, 2007. Crivellari D, Sun Z, Coates AS, et al.: Aromatase inhibitors (AI) for elderly patients: efficacy, compliance and safety according to patient age in the BIG 1-98 trial. [Abstract] J Clin Oncol 25 (Suppl 18): A-9033, 501s, 2007. Koeberle D, Thuerlimann B: Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98. Breast Cancer Res Treat 105 (Suppl 1): 55-66, 2007.[PUBMED Abstract] Mauriac L, Keshaviah A, Debled M, et al.: Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial. Ann Oncol 18 (5): 859-67, 2007.[PUBMED Abstract] Monnier AM: The Breast International Group 1-98 trial: big results for women with hormone-sensitive early breast cancer. Expert Rev Anticancer Ther 7 (5): 627-34, 2007.[PUBMED Abstract] Mouridsen H, Keshaviah A, Coates AS, et al.: Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1-98 trial. J Clin Oncol 25 (36): 5715-22, 2007.[PUBMED Abstract] Rasmussen BB, Regan MM, Lykkesfeldt AE, et al.: Central assessment of ER, PgR and HER2 in BIG 1-98 evaluating letrozole (L) compared to tamoxifen (T) as initial adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. [Abstract] J Clin Oncol 25 (18 Suppl 20): A-538, 2007. Viale G, Regan MM, Maiorano E, et al.: Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1-98. J Clin Oncol 25 (25): 3846-52, 2007.[PUBMED Abstract] Forbes JF: The use of early adjuvant aromatase inhibitor therapy: contributions from the BIG 1-98 letrozole trial. Semin Oncol 33 (2 Suppl 7): S2-7, 2006.[PUBMED Abstract] Thürlimann B, Keshaviah A, Coates AS, et al.: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353 (26): 2747-57, 2005.[PUBMED Abstract] Related PublicationsDelea TE, El-Ouagari K, Karnon J, et al.: Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in postmenopausal women with hormone-receptor positive early breast cancer from a Canadian perspective. Breast Cancer Res Treat 108 (3): 375-87, 2008.[PUBMED Abstract] Delea TE, Karnon J, Sofrygin O, et al.: Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in hormone receptor-positive postmenopausal women with early-stage breast cancer. Clin Breast Cancer 7 (8): 608-18, 2007.[PUBMED Abstract] Buzdar A, Chlebowski R, Cuzick J, et al.: Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer. Curr Med Res Opin 22 (8): 1575-85, 2006.[PUBMED Abstract] Scott LJ, Keam SJ: Letrozole : in postmenopausal hormone-responsive early-stage breast cancer. Drugs 66 (3): 353-62, 2006.[PUBMED Abstract] Wardley AM: Emerging data on optimal adjuvant endocrine therapy: Breast International Group trial 1-98/MA.17. Clin Breast Cancer 6 (Suppl 2): S45-50, 2006.[PUBMED Abstract]
Trial Contact Information
Trial Lead Organizations International Breast Cancer Study Group ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | Beat Thurlimann, MD, Protocol chair | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) |
Federation Nationale des Centres de Lutte Contre le Cancer ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | Louis Mauriac, MD, Protocol chair | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) |
Danish Breast Cancer Cooperative Group ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | Henning Mouridsen, MD, PhD, Protocol chair | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) |
Registry Information | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | Official Title | | A Phase III Study to Evaluate Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women with Receptor (ER and/or PgR) Positive Tumors | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | Trial Start Date | | 1998-03-18 | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | Registered in ClinicalTrials.gov | | NCT00004205 1 | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | Date Submitted to PDQ | | 1999-12-02 | ![](https://webarchive.library.unt.edu/eot2008/20090511110730im_/http://www.cancer.gov/images/spacer.gif) | Information Last Verified | | 2001-03-14 |
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.
Table of Links
1 | http://clinicaltrials.gov/ct/show/NCT00004205 |
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