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Breast CancerPhase 3BIG 1-98NCT00004205

Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer

A Phase 3 study testing letrozole and tamoxifen citrate in people with Breast Cancer, run by ETOP IBCSG Partners Foundation at 3 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 30 to 120 years, women only
Conditions the study is for
Breast Cancer
What is being tested?
letrozole and tamoxifen citrate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
8,028 participants
Where
3 sitesin 3 countries
Study dates
Mar 1998to 30 Jun 2016
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 to 120 years
  • Women only
  • No healthy volunteers
  • Adult, Older adult

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

Trial locations and contacts

3 sites in 3 countries.

3 sites in 3 countries

Denmark1 site

  • Rigshospitalet

    Copenhagen, 2100

Other trials in Denmark

France1 site

  • Institut Bergonie

    Bordeaux, 33076

Other trials in France

Switzerland1 site

  • Kantonsspital - St. Gallen

    Sankt Gallen, CH-9007

Other trials in Switzerland

About this study

Official title: A Phase III Study to Evaluate Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women With Receptor (ER and/or PgR) Positive Tumors

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.

Read the 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.

Conditions
Breast Cancer
Being tested
letrozole, tamoxifen citrate
Keywords
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
Medical subject headings
Breast Neoplasms, Breast Carcinoma In Situ, Carcinoma, Ductal, Breast

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • letrozoleDrug

    Letrozole 2.5 mg daily oral administration.

  • tamoxifen citrateDrug

    Tamoxifen 20 mg daily oral administration.

Study groups in NCT00004205
Study groupRoleWhat they receive
TamoxifenExperimentalTamoxifen for 5 years after randomization.
Receives: Drug: tamoxifen citrate
LetrozoleExperimentalLetrozole for 5 years after randomization.
Receives: Drug: letrozole
Tamoxifen, then letrozoleExperimentalTamoxifen for 2 years after randomization, then letrozole for the next 3 years.
Receives: Drug: letrozole; Drug: tamoxifen citrate
Letrozole, then tamoxifenExperimentalLetrozole for 2 years after randomization, then tamoxifen for the next 3 years.
Receives: Drug: letrozole; Drug: tamoxifen citrate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Disease free survival.

    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

    Measured: Up to end of year 2015

Secondary outcomes (3)

  1. Overall survival

    Time from randomization to death from any cause, assessed up to end of year 2015, for a maximum of 17 years

    Measured: Up to end of year 2015

  2. Safety

    Morbidity information will be recorded using the Adverse Event Form (AE).

    Measured: 5 years after randomization.

  3. Systemic relapse

    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

    Measured: Up to end of year 2015

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jan 2003 (estimated)
  2. Study startMar 1998
  3. Primary completionDec 2008
  4. Study completion30 Jun 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
8,028 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00004205
Sponsor's protocol ID
CDR0000067451
Other IDs
IBCSG-18-98, DAN-DBCG-IBCSG-1-98, FRE-FNCLCC-IBCSG-1-98, EU-99022, NOVARTIS-2026703019, BIG-1-98
Acronym
BIG 1-98
Status last verified
Dec 2017
First submitted
21 Jan 2000
Last updated
12 Dec 2017
Results posted
No
Data monitoring committee
Yes

Publications

  • Lipsitz M, Delea TE, Guo A. Cost effectiveness of letrozole versus anastrozole in postmenopausal women with HR+ early-stage breast cancer. Curr Med Res Opin. 2010 Oct;26(10):2315-28. doi: 10.1185/03007995.2010.510784.

    PubMed 20731528

  • 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.

  • Delea TE, El-Ouagari K, Karnon J, Sofrygin O. 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. 2008 Apr;108(3):375-87. doi: 10.1007/s10549-007-9607-7. Epub 2007 Jul 26.

    PubMed 17653859

  • Delea TE, Karnon J, Sofrygin O, Thomas SK, Papo NL, Barghout V. Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in hormone receptor-positive postmenopausal women with early-stage breast cancer. Clin Breast Cancer. 2007 Jun;7(8):608-18. doi: 10.3816/CBC.2007.n.018.

    PubMed 17592673

  • Buzdar A, Chlebowski R, Cuzick J, Duffy S, Forbes J, Jonat W, Ravdin P. Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer. Curr Med Res Opin. 2006 Aug;22(8):1575-85. doi: 10.1185/030079906X120940.

    PubMed 16870082

  • Scott LJ, Keam SJ. Letrozole : in postmenopausal hormone-responsive early-stage breast cancer. Drugs. 2006;66(3):353-62. doi: 10.2165/00003495-200666030-00010.

    PubMed 16526826

  • Wardley AM. Emerging data on optimal adjuvant endocrine therapy: Breast International Group trial 1-98/MA.17. Clin Breast Cancer. 2006 Feb;6 Suppl 2:S45-50. doi: 10.3816/cbc.2006.s.003.

    PubMed 16595026

  • Leyland-Jones B, Gray KP, Abramovitz M, Bouzyk M, Young B, Long B, Kammler R, Dell'Orto P, Biasi MO, Thurlimann B, Harvey V, Neven P, Arnould L, Maibach R, Price KN, Coates AS, Goldhirsch A, Gelber RD, Pagani O, Viale G, Rae JM, Regan MM; BIG 1-98 Collaborative Group. ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer. Breast Cancer Res Treat. 2015 Dec;154(3):543-55. doi: 10.1007/s10549-015-3634-6. Epub 2015 Nov 21.

    PubMed 26590813

  • Colleoni M, Giobbie-Hurder A, Regan MM, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Lang I, Smith I, Chirgwin J, Pienkowski T, Wardley A, Price KN, Gelber RD, Coates AS, Goldhirsch A. Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study. J Clin Oncol. 2011 Mar 20;29(9):1117-24. doi: 10.1200/JCO.2010.31.6455. Epub 2011 Feb 14.

    PubMed 21321298

  • 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.

  • Ejlertsen B, Aldridge J, Nielsen KV, Regan MM, Henriksen KL, Lykkesfeldt AE, Muller S, Gelber RD, Price KN, Rasmussen BB, Viale G, Mouridsen H; Danish Breast Cancer Cooperative Group the BIG 1-98 Collaborative Group and the International Breast Cancer Study Group. Prognostic and predictive role of ESR1 status for postmenopausal patients with endocrine-responsive early breast cancer in the Danish cohort of the BIG 1-98 trial. Ann Oncol. 2012 May;23(5):1138-1144. doi: 10.1093/annonc/mdr438. Epub 2011 Oct 10.

    PubMed 21986093

  • 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.

  • Phillips KA, Aldridge J, Ribi K, Sun Z, Thompson A, Harvey V, Thurlimann B, Cardoso F, Pagani O, Coates AS, Goldhirsch A, Price KN, Gelber RD, Bernhard J. Cognitive function in postmenopausal breast cancer patients one year after completing adjuvant endocrine therapy with letrozole and/or tamoxifen in the BIG 1-98 trial. Breast Cancer Res Treat. 2011 Feb;126(1):221-6. doi: 10.1007/s10549-010-1235-y. Epub 2010 Nov 3.

    PubMed 21046229

  • Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Lang I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thurlimann B; BIG 1-98 Collaborative Group; International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8.1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. doi: 10.1016/S1470-2045(11)70270-4. Epub 2011 Oct 20.

    PubMed 22018631

  • Regan MM, Price KN, Giobbie-Hurder A, Thurlimann B, Gelber RD; International Breast Cancer Study Group and BIG 1-98 Collaborative Group. Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer. Breast Cancer Res. 2011 May 26;13(3):209. doi: 10.1186/bcr2837.

    PubMed 21635709

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing letrozole and tamoxifen citrate in people with Breast Cancer, run by ETOP IBCSG Partners Foundation at 3 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Denmark, France, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Disease free survival. (time frame: Up to end of year 2015). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00004205, which also lists 58 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Dec 2017.

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