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

Breast Cancer Clinical Trial

— 12-93  

Official title:

Adjuvant Therapy for Post/Perimenopausal Patients With Node Positive Breast Cancer Who Are Suitable for Endocrine Therapy Alone.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00002529
• Other study ID #: CDR0000078385
• Secondary ID: IBCSG-12-93EU-93
• Status: Completed
• Phase: Phase 3
• First received: November 1, 1999
• Last updated: April 3, 2013
• Start date: May 1993
• Est. completion date: August 2010

Study information

• Verified date: July 2012
• Source: International Breast Cancer Study Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentSwitzerland: Swissmedic
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 452
• Est. completion date: August 2010
• Est. primary completion date: August 2010
• Accepts healthy volunteers: No
• Gender: Female
• Age group: N/A to 70 Years

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• cyclophosphamide
cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days
• doxorubicin hydrochloride
doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous.
• epirubicin hydrochloride
epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous.
• tamoxifen citrate
Tamoxifen 20 mg daily.
• toremifene
Toremifene 60 mg daily.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Anti-Cancer Council of Victoria, Melbourne	Carlton South	Victoria
Australia	Newcastle Mater Misericordiae Hospital	Newcastle	New South Wales
Australia	Sir Charles Gairdner Hospital, Perth	Perth	Western Australia
Australia	Royal Prince Alfred Hospital, Sydney	Sydney	New South Wales
Italy	Centro di Riferimento Oncologico - Aviano	Aviano
Italy	Universita di Brescia	Brescia
Italy	Istituto Europeo Di Oncologia	Milano
Italy	Ospedale Civile Rimini	Rimini
Italy	Ospedale San Eugenio	Rome
New Zealand	Auckland Adventist Hospital	Auckland
Slovenia	Institute of Oncology, Ljubljana	Ljubljana
South Africa	Groote Schuur Hospital, Cape Town	Cape Town
Sweden	Sahlgrenska University Hospital	Gothenburg (Goteborg)
Switzerland	University Hospital	Basel
Switzerland	Inselspital, Bern	Bern
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Hopital des Cadolles, Neuchatel	Neuchatel
Switzerland	Kantonsspital - Saint Gallen	Saint Gallen
Switzerland	Universitaetsspital	Zurich

Sponsors (1)

Lead Sponsor	Collaborator
International Breast Cancer Study Group

Countries where clinical trial is conducted

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

References & Publications (7)

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. — View Citation

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. — View Citation

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. — View Citation

Kenne Sarenmalm E, Odén A, Ohlén 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. — View Citation

Keshaviah A, Dellapasqua S, Rotmensz N, Lindtner J, Crivellari D, Collins J, Colleoni M, Thürlimann 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. Epub 2007 Jan 20. — View Citation

Pagani O, Gelber S, Simoncini E, Castiglione-Gertsch M, Price KN, Gelber RD, Holmberg SB, Crivellari D, Collins J, Lindtner J, Thürlimann 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. — View Citation

Pestalozzi BC, Zahrieh D, Mallon E, Gusterson BA, Price KN, Gelber RD, Holmberg SB, Lindtner J, Snyder R, Thürlimann 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Time from randomization to death.	17 years after randomization	No
Secondary	Disease-free and systemic disease-free survival.	Time from randomization to recurrence, metastasis, appearance of a second primary tumor or death.	17 years from randomization	No
Secondary	Quality of life	Quality of life will be assessed using QL Questionnaires of IBCSG.	17 years from randomization	No
Secondary	Toxicity	Assessment of toxicity according to standard criteria.	17 years after randomization	Yes