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Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer (BIG 1-98)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00004205
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : December 12, 2017
Sponsor:
Collaborators:
UNICANCER
Danish Breast Cancer Cooperative Group
Information provided by (Responsible Party):
ETOP IBCSG Partners Foundation

Study Description
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Brief Summary:

RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by reducing the production of estrogen. Hormone therapy using tamoxifen may fight breast cancer by blocking the uptake of estrogen by the tumor cells. If is not yet known which treatment regimen is most effective for breast cancer.

PURPOSE: Randomized double-blind phase III trial to compare the effectiveness of letrozole with that of tamoxifen in treating postmenopausal women who have breast cancer that has been surgically removed.


Condition or disease Intervention/treatment Phase
Breast Cancer Drug: letrozole Drug: tamoxifen citrate Phase 3

Detailed Description:

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.

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.

PROJECTED ACCRUAL: A total of 5,180 patients (1,295 per treatment arm) will be accrued for this study within 6 years.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8028 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III Study to Evaluate Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women With Receptor (ER and/or PgR) Positive Tumors
Study Start Date : March 1998
Actual Primary Completion Date : December 2008
Actual Study Completion Date : June 30, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Tamoxifen
Tamoxifen for 5 years after randomization.
 Drug: tamoxifen citrate
Tamoxifen 20 mg daily oral administration.
Experimental: Letrozole
Letrozole for 5 years after randomization.
 Drug: letrozole
Letrozole 2.5 mg daily oral administration.
Experimental: Tamoxifen, then letrozole
Tamoxifen for 2 years after randomization, then letrozole for the next 3 years.
 Drug: letrozole
Letrozole 2.5 mg daily oral administration.

Drug: tamoxifen citrate
Tamoxifen 20 mg daily oral administration.
Experimental: Letrozole, then tamoxifen
Letrozole for 2 years after randomization, then tamoxifen for the next 3 years.
 Drug: letrozole
Letrozole 2.5 mg daily oral administration.

Drug: tamoxifen citrate
Tamoxifen 20 mg daily oral administration.


Outcome Measures
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Primary Outcome Measures :
  1. Disease free survival. [ Time Frame: Up to end of year 2015 ]
    Time from randomization to recurrence (including recurrence restricted to the breast after breast conserving treatment), metastasis, appearance of a second primary tumor, or death from any cause, whichever occurs first, assessed up to end of year 2015, for a maximum of 17 years


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Up to end of year 2015 ]
    Time from randomization to death from any cause, assessed up to end of year 2015, for a maximum of 17 years

  2. Safety [ Time Frame: 5 years after randomization. ]
    Morbidity information will be recorded using the Adverse Event Form (AE).

  3. Systemic relapse [ Time Frame: Up to end of year 2015 ]
    Time from randomization to appearance of any recurrent or metastatic disease in sites other than the local mastectomy scar, the ipsilateral breast in case of breast conservation, or the contralateral breast, assessed up to end of year 2015, for a maximum of 17 years


Eligibility Criteria
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Ages Eligible for Study:   30 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
      • Not postmenopausal at the start of adjuvant chemotherapy AND 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 45 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

PATIENT CHARACTERISTICS:

Age:

  • 30 and over

Sex:

  • Female

Menopausal status:

  • Postmenopausal

Performance status:

  • Not specified

Life expectancy:

  • Not specified

Hematopoietic:

  • WBC greater than 3,000/mm^3
  • Platelet count at least 100,000/mm^3
  • 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:

  • No lung embolism

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

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00004205


Locations
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Denmark
Rigshospitalet
Copenhagen, Denmark, 2100
France
Institut Bergonie
Bordeaux, France, 33076
Switzerland
Kantonsspital - St. Gallen
St. Gallen, Switzerland, CH-9007
Sponsors and Collaborators
ETOP IBCSG Partners Foundation
UNICANCER
Danish Breast Cancer Cooperative Group
Investigators
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Study Chair: Beat Thurlimann, MD Cantonal Hospital of St. Gallen
Study Chair: Louis Mauriac, MD Institut Bergonié
Study Chair: Henning T. Mouridsen, MD, PhD Rigshospitalet, Denmark
More Information
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Publications of Results:
De Censi A, Sun Z, Thurlimann BJK, et al.: Bone mineral density (BMD) in participants (pts) of trial BIG 1-98 comparing adjuvant letrozole (L) versus tamoxifen (T) or their sequence. [Abstract] J Clin Oncol 29 (Suppl 15): A-516, 2011.
Huober JB, Cole BF, Wu J, et al.: Symptoms of endocrine treatment and outcome: A retrospective analysis of the monotherapy arms of the BIG 1-98 trial. [Abstract] J Clin Oncol 29 (Suppl 15): A-522, 2011.
Ribi K, Aldridge J, Phillips K, et al.: Changes in cognitive function in postmenopausal women 1 year after completing adjuvant letrozole or tamoxifen in the Breast International Group (BIG) 1-98 trial. [Abstract] J Clin Oncol 28 (Suppl 15): A-527, 2010.
Regan MM, Colleoni M M, Giobbie-Hurder A, et al.: Adjusting for selective crossover in analyses of letrozole (Let) versus tamoxifen (Tam) in the BIG 1-98 trial. [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, Texas. A-16, 2009.
Ribi KE, Phillips KA, Sun Z, et al.: Cognitive function in postmenopausal women receiving adjuvant letrozole or tamoxifen in the Breast International Group (BIG) 1-98 trial. [Abstract] J Clin Oncol 27 (Suppl 15): A-510, 2009.
Viale G, Regan MM, Dell'Orto P, et al.: Central review of ER, PgR and HER2 in BIG 1-98 evaluating letrozole vs. letrozole followed by tamoxifen vs. tamoxifen followed by letrozole as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, Texas. A-76, 2009.
Zaman K, Thürlimann B, Huober J, et al.: Modelling bone mineral density in Swiss breast cancer patients treated with letrozole, tamoxifen and sequences of letrozole and tamoxifen in the BIG 1-98 study (SAKK 21/07). [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, Texas. A-5037, 2009.
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.
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.
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.

Other Publications:
Skedgel C, Rayson D, Younis T, et al.: Direct and indirect economic evaluation of upfront and sequential adjuvant treatment in postmenopausal women with breast cancer based on the BIG 1-98 trial. [Abstract] J Clin Oncol 27 (Suppl 15): A-6594, 2009.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: ETOP IBCSG Partners Foundation
ClinicalTrials.gov Identifier: NCT00004205    
Other Study ID Numbers: CDR0000067451
IBCSG-18-98
DAN-DBCG-IBCSG-1-98
FRE-FNCLCC-IBCSG-1-98
EU-99022
NOVARTIS-2026703019
BIG-1-98
First Posted: January 27, 2003    Key Record Dates
Last Update Posted: December 12, 2017
Last Verified: December 2017
Keywords provided by ETOP IBCSG Partners Foundation:
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
breast cancer in situ
 recurrent breast cancer
ductal breast carcinoma
lobular breast carcinoma in situ
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Tamoxifen
Letrozole
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Aromatase Inhibitors
 Steroid Synthesis Inhibitors
Enzyme Inhibitors
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents