12-93: Hormone Therapy and Chemotherapy in Treating Perimenopausal or Postmenopausal Women With Node-Positive Breast Cancer

Sponsor

ETOP IBCSG Partners Foundation (Other)

Overall Status

Completed

CT.gov ID

NCT00002529

Collaborator

(none)

452

Enrollment

Locations

Arms

207

Duration (Months)

22.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: epirubicin hydrochloride Drug: tamoxifen citrate Drug: toremifene	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

452 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

May 1, 1993

Actual Primary Completion Date :

Aug 1, 2010

Actual Study Completion Date :

Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AC with concurrent tamoxifen AC for 4 cycles with concurrent tamoxifen for 5 years	Drug: cyclophosphamide cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days Drug: doxorubicin hydrochloride doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous. Drug: epirubicin hydrochloride epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous. Drug: tamoxifen citrate Tamoxifen 20 mg daily.
Experimental: AC followed by tamoxifen AC for 4 cycles followed by tamoxifen to 5 years from randomization.	Drug: cyclophosphamide cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days Drug: doxorubicin hydrochloride doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous. Drug: epirubicin hydrochloride epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous. Drug: tamoxifen citrate Tamoxifen 20 mg daily.
Experimental: Tamoxifen alone Tamoxifen alone for 5 years.	Drug: tamoxifen citrate Tamoxifen 20 mg daily.
Experimental: AC with concurrent toremifene AC for 4 cycles with concurrent toremifene for 5 years.	Drug: cyclophosphamide cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days Drug: doxorubicin hydrochloride doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous. Drug: epirubicin hydrochloride epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous. Drug: toremifene Toremifene 60 mg daily.
Experimental: AC followed by toremifene AC for 4 cycles followed by toremifene to 5 years from randomization.	Drug: cyclophosphamide cyclophosphamide 600 mg/m2 i.v. day 1) every 21 days Drug: doxorubicin hydrochloride doxorubicin 60 mg/m2 i.v. day 1) every 21 days, intravenous. Drug: epirubicin hydrochloride epirubicin 90 mg/m2 i.v. day 1) every 21 days, intravenous. Drug: toremifene Toremifene 60 mg daily.
Experimental: Toremifene alone Toremifene alone for 5 years.	Drug: toremifene Toremifene 60 mg daily.

Outcome Measures

Primary Outcome Measures

Overall survival [17 years after randomization]
Time from randomization to death.

Secondary Outcome Measures

Disease-free and systemic disease-free survival. [17 years from randomization]
Time from randomization to recurrence, metastasis, appearance of a second primary tumor or death.
Quality of life [17 years from randomization]
Quality of life will be assessed using QL Questionnaires of IBCSG.
Toxicity [17 years after randomization]
Assessment of toxicity according to standard criteria.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 70 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Newcastle Mater Misericordiae Hospital	Newcastle	New South Wales	Australia	NSW 2310
2	Royal Prince Alfred Hospital, Sydney	Sydney	New South Wales	Australia	2050
3	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
4	Anti-Cancer Council of Victoria, Melbourne	Carlton South	Victoria	Australia	3053
5	Sir Charles Gairdner Hospital, Perth	Perth	Western Australia	Australia	6009
6	Centro di Riferimento Oncologico - Aviano	Aviano		Italy	33081
7	Universita di Brescia	Brescia		Italy	25124
8	Istituto Europeo Di Oncologia	Milano		Italy	20141
9	Ospedale Civile Rimini	Rimini		Italy	47037
10	Ospedale San Eugenio	Rome		Italy	00144
11	Auckland Adventist Hospital	Auckland		New Zealand	5
12	Institute of Oncology, Ljubljana	Ljubljana		Slovenia	Sl-1000
13	Groote Schuur Hospital, Cape Town	Cape Town		South Africa	7925
14	Sahlgrenska University Hospital	Gothenburg (Goteborg)		Sweden	S-413 45
15	University Hospital	Basel		Switzerland	CH-4031
16	Inselspital, Bern	Bern		Switzerland	CH-3010
17	Centre Hospitalier Universitaire Vaudois	Lausanne		Switzerland	CH-1011
18	Hopital des Cadolles, Neuchatel	Neuchatel		Switzerland	2000
19	Kantonsspital - Saint Gallen	Saint Gallen		Switzerland	CH-9007
20	Universitaetsspital	Zurich		Switzerland	CH-8091