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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: epirubicin hydrochloride
* Drug: tamoxifen citrate
* Drug: toremifene


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Time from randomization to death. | 17 years after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Quality of life | Quality of life will be assessed using QL Questionnaires of IBCSG. | 17 years from randomization | 
| Toxicity | Assessment of toxicity according to standard criteria. | 17 years after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II breast cancer, stage IIIA breast cancer