Hormone Therapy and Chemotherapy in Treating Perimenopausal or Postmenopausal Women With Node-Positive Breast Cancer

NCT ID: NCT00002529

Last Updated: 2013-04-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 452 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1993-05-31
• Study Completion Date: 2010-08-31

Brief Summary

RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy may fight breast cancer by blocking the uptake of estrogen. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with hormone therapy may kill more tumor cells. It is not yet known which treatment regimen is more effective for breast cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of hormone therapy during or after combination chemotherapy or hormone therapy alone in treating perimenopausal or postmenopausal women who have stage II or stage IIIA breast cancer.

Detailed Description

OBJECTIVES: I. Compare overall survival and local and systemic disease-free survival produced by adjuvant chemoendocrine therapy with 4 courses of anthracycline/cyclophosphamide and concurrent vs. sequential tamoxifen (TMX) or toremifene (TOR) in peri- and postmenopausal women with node-positive breast cancer who are considered suitable for endocrine therapy alone. II. Evaluate these same endpoints in patients randomized to chemoendocrine therapy vs. endocrine therapy alone. III. Evaluate these same endpoints in patients randomized to TMX vs. TOR as the endocrine therapy agent. IV. Compare the quality of life of patients treated on these regimens. V. Compare the toxic effects of these regimens.

OUTLINE: This is a randomized study. Patients are stratified by type of primary therapy and participating institution. Therapy must begin within 6 weeks of surgery. Patients in the first group receive doxorubicin (or epirubicin) and cyclophosphamide every 28 days for a total of 4 cycles and oral tamoxifen daily for 5 years, beginning day 1 of chemotherapy. Patients in the second group receive the same chemotherapy with oral tamoxifen initiated on day 8 of the fourth chemotherapy cycle and continued for 5 years. Patients in the third group receive oral tamoxifen daily for 5 years. Patients in the fourth group are treated the same as the first group, only tamoxifen is replaced by toremifene. Patients in the fifth group are treated the same as the second group, only tamoxifen is replaced by toremifene. Patients in the sixth group receive oral toremifene daily for 5 years. The timing of optional radiotherapy for patients with less than total mastectomy in each group is based on institutional policy; radiotherapy is administered for 5-6 weeks to the remaining breast tissue, chest wall, and lung. Patients are followed every 3 months for 1 year, every 6 months for 2 years, and yearly thereafter.

PROJECTED ACCRUAL: 1,140 patients will be accrued over approximately 9 years, with 1 additional year of follow-up.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

AC with concurrent tamoxifen

AC for 4 cycles with concurrent tamoxifen for 5 years

Group Type: EXPERIMENTAL

cyclophosphamide

Intervention Type: DRUG

cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days

doxorubicin hydrochloride

Intervention Type: DRUG

doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous.

epirubicin hydrochloride

Intervention Type: DRUG

epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous.

tamoxifen citrate

Intervention Type: DRUG

Tamoxifen 20 mg daily.

AC followed by tamoxifen

AC for 4 cycles followed by tamoxifen to 5 years from randomization.

Group Type: EXPERIMENTAL

cyclophosphamide

Intervention Type: DRUG

cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days

doxorubicin hydrochloride

Intervention Type: DRUG

doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous.

epirubicin hydrochloride

Intervention Type: DRUG

epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous.

tamoxifen citrate

Intervention Type: DRUG

Tamoxifen 20 mg daily.

Tamoxifen alone

Tamoxifen alone for 5 years.

Group Type: EXPERIMENTAL

tamoxifen citrate

Intervention Type: DRUG

Tamoxifen 20 mg daily.

AC with concurrent toremifene

AC for 4 cycles with concurrent toremifene for 5 years.

Group Type: EXPERIMENTAL

cyclophosphamide

Intervention Type: DRUG

cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days

doxorubicin hydrochloride

Intervention Type: DRUG

doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous.

epirubicin hydrochloride

Intervention Type: DRUG

epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous.

toremifene

Intervention Type: DRUG

Toremifene 60 mg daily.

AC followed by toremifene

AC for 4 cycles followed by toremifene to 5 years from randomization.

Group Type: EXPERIMENTAL

cyclophosphamide

Intervention Type: DRUG

cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days

doxorubicin hydrochloride

Intervention Type: DRUG

doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous.

epirubicin hydrochloride

Intervention Type: DRUG

epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous.

toremifene

Intervention Type: DRUG

Toremifene 60 mg daily.

Toremifene alone

Toremifene alone for 5 years.

Group Type: EXPERIMENTAL

toremifene

Intervention Type: DRUG

Toremifene 60 mg daily.

Interventions

cyclophosphamide

cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days

Intervention Type: DRUG

doxorubicin hydrochloride

doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous.

Intervention Type: DRUG

epirubicin hydrochloride

epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous.

Intervention Type: DRUG

tamoxifen citrate

Tamoxifen 20 mg daily.

Intervention Type: DRUG

toremifene

Toremifene 60 mg daily.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS: Histologically proven stage T1-3, pN1, M0 carcinoma of the breast considered suitable for adjuvant treatment with endocrine therapy alone Estrogen receptor at least 10 fmol/mg cytosol protein or positive on immunohistochemical assay Potentially curative resection within 6 weeks of entry by one of the following: Total mastectomy with negative margins Breast-conserving procedure (lumpectomy or quadrantectomy) for tumors less than 5 cm Adequate re-resection or mastectomy within 4 weeks of initial surgery required if margins are positive after initial surgery Axillary clearance (not sampling) required at surgery, with at least 1 node positive upon histopathologic examination of at least 8 nodes Suspicious manifestations of metastatic disease (e.g., hot spots on bone scan, skeletal pain of unknown cause) must be proven benign No bilateral breast cancer Any mass in contralateral breast must be proven benign by biopsy

PATIENT CHARACTERISTICS: Age: 70 and under Sex: Women only Menopausal status: Peri/postmenopausal, i.e.: More than 6 months since last normal menstrual period (LNMP) with no prior hysterectomy and no hormone replacement therapy (HRT) Prior hysterectomy and no HRT and either age greater than 55 or age 55 or less with postmenopausal LH, FSH, and E2 levels On HRT and either age 50 or greater or LNMP more than 6 months prior to starting HRT Performance status: Not specified Hematopoietic: WBC greater than 4,000 Platelets greater than 100,000 Hepatic: Bilirubin less than 1.1 mg/dL (20 micromoles/L) AST less than 60 IU/L Renal: Creatinine less than 1.3 mg/dL (120 micromoles/L) Other: No nonmalignant systemic disease that would preclude protocol therapy or prolonged follow-up No psychiatric or addictive disorder that would preclude informed consent No prior or concurrent second malignancy except: Nonmelanomatous skin cancer Adequately treated in situ carcinoma of the cervix Geographically accessible for follow-up

PRIOR CONCURRENT THERAPY: No prior therapy for breast cancer other than potentially curative surgery (see Disease Characteristics)

• Maximum Eligible Age: 70 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

ETOP IBCSG Partners Foundation

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Edda Simoncini, MD

Role: STUDY_CHAIR

Spedali Civili di Brescia

Locations

Newcastle Mater Misericordiae Hospital

Newcastle, New South Wales, Australia

Royal Prince Alfred Hospital, Sydney

Sydney, New South Wales, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Anti-Cancer Council of Victoria, Melbourne

Carlton South, Victoria, Australia

Sir Charles Gairdner Hospital, Perth

Perth, Western Australia, Australia

Centro di Riferimento Oncologico - Aviano

Aviano, , Italy

Universita di Brescia

Brescia, , Italy

Istituto Europeo Di Oncologia

Milan, , Italy

Ospedale Civile Rimini

Rimini, , Italy

Ospedale San Eugenio

Rome, , Italy

Auckland Adventist Hospital

Auckland, , New Zealand

Institute of Oncology, Ljubljana

Ljubljana, , Slovenia

Groote Schuur Hospital, Cape Town

Cape Town, , South Africa

Sahlgrenska University Hospital

Gothenburg (Goteborg), , Sweden

University Hospital

Basel, , Switzerland

Inselspital, Bern

Bern, , Switzerland

Centre Hospitalier Universitaire Vaudois

Lausanne, , Switzerland

Hopital des Cadolles, Neuchatel

Neuchâtel, , Switzerland

Kantonsspital - Saint Gallen

Sankt Gallen, , Switzerland

Universitaetsspital

Zurich, , Switzerland

Countries

Australia; Italy; New Zealand; Slovenia; South Africa; Sweden; Switzerland

References

Gianni L, Gelber S, Ravaioli A, Price KN, Panzini I, Fantini M, Castiglione-Gertsch M, Pagani O, Simoncini E, Gelber RD, Coates AS, Goldhirsch A. Second non-breast primary cancer following adjuvant therapy for early breast cancer: a report from the International Breast Cancer Study Group. Eur J Cancer. 2009 Mar;45(4):561-71. doi: 10.1016/j.ejca.2008.10.011. Epub 2008 Dec 4.

Reference Type: BACKGROUND

PMID: 19062268 (View on PubMed)

Kenne Sarenmalm E, Oden A, Ohlen J, Gaston-Johansson F, Holmberg SB. Changes in health-related quality of life may predict recurrent breast cancer. Eur J Oncol Nurs. 2009 Dec;13(5):323-9. doi: 10.1016/j.ejon.2009.05.002. Epub 2009 Jul 12.

Reference Type: BACKGROUND

PMID: 19596212 (View on PubMed)

Pagani O, Gelber S, Simoncini E, Castiglione-Gertsch M, Price KN, Gelber RD, Holmberg SB, Crivellari D, Collins J, Lindtner J, Thurlimann B, Fey MF, Murray E, Forbes JF, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93. Breast Cancer Res Treat. 2009 Aug;116(3):491-500. doi: 10.1007/s10549-008-0225-9. Epub 2008 Oct 25.

Reference Type: BACKGROUND

PMID: 18953651 (View on PubMed)

Pestalozzi BC, Zahrieh D, Mallon E, Gusterson BA, Price KN, Gelber RD, Holmberg SB, Lindtner J, Snyder R, Thurlimann B, Murray E, Viale G, Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol. 2008 Jun 20;26(18):3006-14. doi: 10.1200/JCO.2007.14.9336. Epub 2008 May 5.

Reference Type: BACKGROUND

PMID: 18458044 (View on PubMed)

Keshaviah A, Dellapasqua S, Rotmensz N, Lindtner J, Crivellari D, Collins J, Colleoni M, Thurlimann B, Mendiola C, Aebi S, Price KN, Pagani O, Simoncini E, Castiglione Gertsch M, Gelber RD, Coates AS, Goldhirsch A. CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials. Ann Oncol. 2007 Apr;18(4):701-8. doi: 10.1093/annonc/mdl492. Epub 2007 Jan 20.

Reference Type: BACKGROUND

PMID: 17237474 (View on PubMed)

Gianni L, Panzini I, Li S, Gelber RD, Collins J, Holmberg SB, Crivellari D, Castiglione-Gertsch M, Goldhirsch A, Coates AS, Ravaioli A; International Breast Cancer Study Group (IBCSG). Ocular toxicity during adjuvant chemoendocrine therapy for early breast cancer: results from International Breast Cancer Study Group trials. Cancer. 2006 Feb 1;106(3):505-13. doi: 10.1002/cncr.21651.

Reference Type: BACKGROUND

PMID: 16369994 (View on PubMed)

International Breast Cancer Study Group; Pagani O, Gelber S, Price K, Zahrieh D, Gelber R, Simoncini E, Castiglione-Gertsch M, Coates AS, Goldhirsch A. Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93. Ann Oncol. 2004 Dec;15(12):1749-59. doi: 10.1093/annonc/mdh463.

Reference Type: BACKGROUND

PMID: 15550579 (View on PubMed)

Other Identifiers

IBCSG-12-93

Identifier Type: OTHER

Identifier Source: secondary_id

EU-93015

Identifier Type: -

Identifier Source: secondary_id

NCI-F93-0010

Identifier Type: -

Identifier Source: secondary_id

CDR0000078385

Identifier Type: -

Identifier Source: org_study_id