Combination Chemotherapy in Treating Women With Stage I, Stage II, or Stage IIIA (cT1-3, N0-1, M0) Breast Cancer and Positive Axillary Lymph Nodes
Combination Chemotherapy in Treating Women With Stage I, Stage II, or Stage IIIA (cT1-3, N0-1, M0) Breast Cancer and Positive Axillary Lymph Nodes
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so
 they stop growing or die. Giving combination chemotherapy after surgery may kill any tumor
 cells remaining following surgery. It is not yet known which regimen of combination
 chemotherapy is more effective in treating breast cancer with positive axillary lymph nodes.

 PURPOSE: Randomized phase III trial to compare the effectiveness of different regimens of
 combination chemotherapy in treating women who have undergone surgery for stage I, stage II,
 or stage IIIA breast cancer with positive axillary lymph nodes.
OBJECTIVES:

 -  Compare the efficacy of adjuvant doxorubicin, cyclophosphamide, and docetaxel given
 concurrently vs adjuvant doxorubicin and cyclophosphamide followed by docetaxel, in
 terms of overall survival and disease-free survival, of women with breast cancer and
 positive axillary lymph nodes.

 -  Compare the efficacy of adjuvant doxorubicin and docetaxel vs regimens containing
 cyclophosphamide in these patients.

 -  Compare the toxic effects of these regimens in these patients.

 -  Compare the quality of life of patients treated with these regimens. (Quality of life
 substudy closed to accrual as of 7/20/01.)

 -  Compare the differences in amenorrhea in premenopausal women in each treatment arm and
 its relationship to symptoms, quality of life (quality of life substudy closed to
 accrual as of 7/20/01), disease-free survival, and overall survival.

 OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
 participating center, number of positive nodes (1-3 vs 4-9 vs at least 10), sequential
 tamoxifen or anastrozole administration (yes vs no), and type of prior surgery and
 radiotherapy plan (mastectomy with no local or regional radiotherapy vs mastectomy with local
 and/or regional radiotherapy vs lumpectomy with local radiotherapy vs lumpectomy with local
 and regional radiotherapy). Patients are randomized to one of three treatment arms.

 -  Arm 1: Patients receive doxorubicin IV over 15 minutes and cyclophosphamide IV over 30
 minutes every 21 days for 4 courses. Three weeks after the last dose of this
 combination, patients receive docetaxel IV over 1 hour every 21 days for 4 courses.

 -  Arm 2: Patients receive doxorubicin IV over 15 minutes and docetaxel IV over 1 hour
 every 21 days for 4 courses.

 -  Arm 3: Patients receive doxorubicin IV over 15 minutes, cyclophosphamide IV over 30
 minutes, and docetaxel IV over 1 hour every 21 days for 4 courses.

 Patients in all arms who are estrogen receptor-positive and/or progesterone receptor-positive
 receive oral tamoxifen daily for 5 years beginning within 3-12 weeks of completion of
 chemotherapy. Patients who are postmenopausal may receive alternative hormonal therapy at the
 discretion of the treating physician.

 Some patients may receive postmastectomy radiotherapy on SWOG-S9927 or NCIC-MA.20 after
 recovery from chemotherapy.

 Quality of life and menstrual history are assessed before randomization, on day 1 of course
 4, and at 6, 12, 18, and 24 months. (Quality of life substudy closed to accrual as of
 7/20/01.)

 Patients are followed every 6 months for 5 years and then annually thereafter.

 PROJECTED ACCRUAL: A total of 5,300 patients will be accrued for this study within 4-5 years.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed invasive adenocarcinoma of the breast

 -  Confined to the breast and ipsilateral axilla on clinical exam

 -  Stage I, II, or IIIA (cT1-3, N0-1, M0)

 -  At least one axillary lymph node with evidence of tumor on histologic exam

 -  Sentinel node biopsy allowed if followed by axillary dissection

 -  No suspicious palpable nodes in the contralateral axilla or palpable
 supraclavicular or infraclavicular nodes, unless proven on biopsy to not be
 involved with tumor

 -  No bilateral malignancy or mass in the opposite breast, unless mass is histologically
 proven to be benign

 -  Must have undergone either a prior total mastectomy and axillary dissection (modified
 radical mastectomy) OR

 -  Prior lumpectomy and axillary dissection

 -  Patients must receive radiotherapy after randomization (not before) AND after
 chemotherapy

 -  Margins must be clear

 -  No ipsilateral lymph nodes that are fixed to one another or to other structures
 (N2 disease) and/or any positive nonaxillary lymph nodes (intramammary nodes are
 considered axillary nodes)

 -  No histologically evident invasive tumor or ductal carcinoma in situ

 -  No diffuse tumors by mammography that would not be surgically amenable to
 lumpectomy

 -  No other dominant mass in the ipsilateral breast remnant unless one of the
 following is true:

 -  Histologically benign

 -  Surgically removed with clear margins if malignant

 -  No ulceration, erythema, infiltration of the skin or underlying chest wall (complete
 fixation), peau d'orange, or skin edema of any magnitude

 -  Tethering or dimpling of the skin or nipple inversion allowed

 -  No metastatic disease

 -  Skeletal pain allowed if bone scan negative for metastases

 -  Hormone receptor status:

 -  Estrogen and progesterone status determined

 PATIENT CHARACTERISTICS:

 Age:

 -  greater than or equal to 18 years

 Sex:

 -  Female

 Menopausal status:

 -  Not specified

 Performance status:

 -  Not specified

 Life expectancy:

 -  At least 10 years, excluding diagnosis of cancer

 Hematopoietic:

 -  Absolute neutrophil count at least 1,500/mm^3 (may be less, if in the opinion of the
 investigator, this represents an ethnic or racial variation)

 -  Platelet count at least 100,000/mm^3* NOTE: *If platelet count is above the upper
 limit of normal (ULN), significant underlying hematologic disorders must be excluded

 Hepatic:

 -  Bilirubin no greater than ULN

 -  Alkaline phosphatase less than 2.5 times ULN*

 -  SGOT less than 1.5 times ULN*

 -  No nonmalignant systemic hepatic disease that would preclude study participation NOTE:
 *Alkaline phosphatase and SGOT cannot both be greater than ULN

 Renal:

 -  Creatinine no greater than normal

 -  No nonmalignant systemic renal disease that would preclude study participation

 Cardiovascular:

 -  No nonmalignant systemic cardiovascular disease that would preclude study
 participation

 -  LVEF at least lower limit of normal (LLN) by MUGA or echocardiogram

 -  No active cardiac disease that would preclude use of doxorubicin or docetaxel,
 including the following:

 -  Any prior myocardial infarction

 -  Angina pectoris requiring anti-anginal medication

 -  History of congestive heart failure

 -  Cardiac arrhythmia requiring medication

 -  Severe conduction abnormality

 -  Valvular disease with documented cardiac function compromise

 -  Cardiomegaly on chest x-ray or ventricular hypertrophy on EKG, unless LVEF at
 least LLN

 -  Poorly controlled hypertension (diastolic greater than 100 mm/Hg)

 -  Hypertension well controlled by medication allowed

 Other:

 -  No grade 2 or greater peripheral neuropathy

 -  No other prior malignancy within the past 5 years except:

 -  Effectively treated squamous cell or basal cell skin cancer

 -  Surgically treated carcinoma in situ of the cervix

 -  Segmentally resected lobular carcinoma in situ of the ipsilateral or
 contralateral breast

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective barrier contraception

 -  No nonmalignant systemic disease that would preclude study participation

 -  No diabetes with morning fasting blood glucose of 200 mg/dL or greater

 -  No psychiatric or addictive disorders that would preclude informed consent

 -  No contraindication to corticosteroids that would preclude study participation

 PRIOR CONCURRENT THERAPY:

 Biologic therapy:

 -  No prior immunotherapy for breast cancer

 Chemotherapy:

 -  No prior chemotherapy for breast cancer

 -  No prior anthracyclines or taxanes

 -  No other concurrent investigational chemotherapy

 Endocrine therapy:

 -  No prior hormonal therapy for breast cancer

 -  No concurrent hormonal birth control methods or other hormonal therapy

 -  No concurrent raloxifene, including for osteoporosis

 -  Concurrent low-dose topical estrogen in the form of conjugated estrogen ring or
 conjugated estrogen vaginal cream (dose no more than 0.3 mg or 1/8 of an applicator
 applied vaginally 3 times a week) allowed

 Radiotherapy:

 -  See Disease Characteristics

 -  No prior radiotherapy for this malignancy

 Surgery:

 -  See Disease Characteristics

 -  No more than 84 days since prior surgery for breast cancer (e.g., lumpectomy,
 mastectomy, sentinel node biopsy, axillary dissection, or re-excision of lumpectomy
 margins)

 Other:

 -  No prior systemic therapy for this malignancy

 -  No concurrent medications that alter cardiac conduction (e.g., digitalis, beta
 blockers, or calcium-channel blockers) for cardiac arrhythmia, angina, or congestive
 heart failure (allowed if administered for other reasons [e.g., hypertension])

 -  Concurrent bisphosphonates allowed