RATIONALE: Drugs used in chemotherapy, such as docetaxel, doxorubicin , cyclophosphamide, paclitaxel, and gemcitabine work in 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 after surgery.

PURPOSE: Randomized phase II trial to compare the effectiveness of three different combination chemotherapy regimens in treating women who have undergone surgery for node-positive breast cancer.

Condition	Treatment or Intervention	Phase
stage II breast cancer stage IIIA breast cancer stage IIIC breast cancer	Drug: cyclophosphamide  Drug: docetaxel  Drug: doxorubicin  Drug: gemcitabine  Drug: paclitaxel  Procedure: adjuvant therapy  Procedure: chemotherapy  Procedure: radiation therapy	Phase III

OBJECTIVES: Primary

• Compare disease-free survival in women with node-positive breast cancer treated with 3 different adjuvant chemotherapy regimens comprising dose-dense doxorubicin, cyclophosphamide, paclitaxel, and gemcitabine vs docetaxel, doxorubicin, and cyclophosphamide vs dose-dense doxorubicin, cyclophosphamide, and paclitaxel.

Secondary

• Compare overall survival, recurrence-free interval, and distant recurrence-free interval, in patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of positive lymph nodes (1-3 vs 4-9 vs ≥ 10), hormone receptor status (estrogen receptor [ER]- and progesterone receptor [PgR]- negative vs ER- and/or PgR-positive), type of prior surgery and planned radiotherapy (lumpectomy and local radiotherapy [RT] without regional RT vs lumpectomy and local RT with regional RT vs mastectomy without RT vs mastectomy with local and/or regional RT). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive doxorubicin IV over 15 minutes, cyclophosphamide IV over 30 minutes, and docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for 6 courses.
• Arm II: Patients receive AC chemotherapy comprising doxorubicin IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 14 days for 4 courses. Beginning 14 days after the last dose of AC, patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 4 courses.
• Arm III: Patients AC chemotherapy as in arm II. Beginning 14 days after the last dose of AC, patients receive paclitaxel as in arm II and gemcitabine IV over 30-60 minutes on day 1. Treatment repeats every 14 days for 4 courses. In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Beginning 3-12 weeks after the last dose of chemotherapy, patients with ER-positive and/or PgR-positive tumors receive hormonal therapy comprising tamoxifen and/or an aromatase inhibitor .

Beginning no sooner than 3 weeks after the last course of chemotherapy, patients treated with lumpectomy undergo whole-breast radiotherapy. Patients treated with mastectomy may undergo chest wall and/or regional nodal radiotherapy.

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

PROJECTED ACCRUAL: A total of 4,800 patients will be accrued for this study within 4 years.

Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive breast cancer, meeting all of the following staging criteria:
• Primary tumor T1-3 by clinical and pathological evaluation
• Ipsilateral lymph nodes cN0, cN1, or cN2a by clinical evaluation
• Ipsilateral lymph nodes pN1 (pN1mi, pN1a, pN1b, or pN1c), pN2a, pN3a, or pN3b* by pathologic evaluation
• Must have completed 1 of the following procedures for evaluation of pathological nodal status:
• Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes
• Sentinel lymphadenectomy alone allowed provided 1 of the following criteria is met:
• Pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1B
• Randomized to arm not undergoing axillary dissection on protocol
• No additional non-sentinel lymph nodes are removed
• Axillary lymphadenectomy without sentinel lymph node isolation procedure NOTE: *Only if due to microscopic involvement of internal mammary node detected by sentinel lymph node dissection AND has > 3 positive axillary lymph nodes
• Must have undergone prior lumpectomy or total mastectomy
• Lumpectomy patients:
• Surgical margins must be histologically free of invasive tumor AND ductal carcinoma in situ (DCIS) (lobular carcinoma in situ [LCIS] allowed)
• Additional operative procedures may be performed to obtain clear margins* even if axillary evaluation has been completed
• No diffuse tumors* by mammography
• No other clinically dominant mass or mammographically suspicious abnormality within the ipsilateral breast unless proven to be histologically benign OR if malignant, surgically removed with clear margins
• Planned whole breast irradiation required NOTE: *Patients with persistent positive margins or diffuse tumors must undergo total mastectomy to be eligible for this study
• No more than 84 days since last surgery for breast cancer staging or treatment
• No clinical or radiologic evidence of metastatic disease
• No contralateral breast cancer (invasive breast cancer or DCIS)
• No mass or mammographic abnormality in the opposite breast suspicious for malignancy unless there is biopsy evidence that the mass is not malignant
• No suspicious nodes in the contralateral axilla or suspicious supraclavicular nodes unless there is biopsy evidence of no tumor involvement
• No prior breast cancer, including DCIS
• LCIS allowed
• Hormone receptor status:
• Estrogen receptor (ER) status known
• Progesterone receptor status known only if ER-negative

PATIENT CHARACTERISTICS: Age

• Not specified

Sex

• Female

Menopausal status

• Not specified

Performance status

• Zubrod 0-1

Life expectancy

• At least 10 years

Hematopoietic

• Absolute granulocyte count ≥ 1,200/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ upper limit of normal (ULN)* (1.5 times ULN if due to Gilbert's disease or similar syndrome)
• Alkaline phosphatase < 2.5 times ULN*
• AST ≤ 1.5 times ULN*
• No hepatic disease that would preclude study participation NOTE: *Bilirubin, AST, OR alkaline phosphatase > ULN allowed provided no metastatic liver disease is present on imaging

Renal

• Creatinine ≤ ULN
• No renal disease that would preclude study participation

Cardiovascular

• LVEF ≥ lower limit of normal by echocardiogram or MUGA
• No cardiac disease that would preclude the use of anthracyclines, including any of the following:
• History of myocardial infarction documented by elevated cardiac enzymes or regional wall abnormalities
• Angina pectoris requiring anti-anginal medication
• Documented history of congestive heart failure
• Serious cardiac arrhythmia requiring medication
• Severe conduction abnormality
• Valvular disease with documented cardiac function compromise
• Uncontrolled hypertension, defined as blood pressure > 160/100 mm Hg with antihypertensive therapy
• No other cardiovascular disease that would preclude study participation

Other

• Not pregnant or nursing
• Fertile patients must use effective non-hormonal contraception
• No other malignancy within the past 5 years except treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or melanoma in situ
• Considered to be low-risk for recurrence
• No condition that would preclude corticosteroid administration
• No sensory or motor neuropathy ≥ grade 2
• No other nonmalignant systemic disease that would preclude study participation
• No psychiatric or addictive disorder or other condition that would preclude study participation

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for breast cancer
• No prior anthracycline or taxane therapy for any malignancy

Endocrine therapy

• See Disease Characteristics
• Prior hormonal therapy for breast cancer allowed provided the duration of therapy was ≤ 28 days
• No concurrent sex hormonal therapy (e.g., birth control pills, ovarian hormone replacement therapy, or Femring®)
• Concurrent Vagifem® or Estring® for the management of vaginal or urinary symptoms allowed
• No concurrent raloxifene, tamoxifen, or other selective estrogen-receptor modulators (SERMs) for osteoporosis or breast cancer prevention

Radiotherapy

• See Disease Characteristics
• No prior radiotherapy for breast cancer
• No concurrent partial breast irradiation (lumpectomy patients)
• Concurrent irradiation of regional lymph nodes allowed

Surgery

• See Disease Characteristics

Other

• Concurrent calcium supplements, cholecalciferol (vitamin D), calcitonin (e.g., Miacalcin®), or bisphosphonates (e.g., Actonel® or Fosamax®) for the management of osteoporosis allowed
• No other concurrent investigational agents for the treatment of breast cancer

Study chairs or principal investigators

Sandra M. Swain, MD,  Study Chair,  National Cancer Institute (NCI)   

Study ID Numbers:  CDR0000390286; NSABP-B-38
Record last reviewed:  September 2004
Record first received:  October 6, 2004
ClinicalTrials.gov Identifier:  NCT00093795
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-10-20