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

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