S0221 Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in Treating Patients With Breast Cancer
S0221 Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in Treating Patients With Breast Cancer
RATIONALE: Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel,
 use different ways to stop tumor cells from dividing so they stop growing or die. Combining
 more than one drug and giving them after surgery may kill any remaining tumor cells. It is
 not yet known which combination chemotherapy regimen is more effective in treating resected
 breast cancer.

 PURPOSE: This randomized phase III trial is comparing 2 different regimens of combination
 chemotherapy to see how well they work in treating patients who have undergone surgery for
 stage I, stage II, or stage III breast cancer.
OBJECTIVES:

 -  Compare the disease-free survival of patients with node-positive or high-risk
 node-negative breast cancer treated with 2 different schedules of adjuvant doxorubicin,
 cyclophosphamide, and paclitaxel.

 -  Compare the overall survival of patients treated with these regimens.

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

 -  Correlate outcome with putative prognostic markers in patients treated with these
 regimens.

 OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment
 arms (arms V and VI) (arms I-IV closed 11/10/10).

 -  Arm I: (closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day
 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10.
 Treatment repeats every 14 days for 6 courses.

 Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive
 paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14
 days for 6 courses.

 -  Arm II: (closed 11/10/10) Patients receive doxorubicin IV on day 1, oral
 cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days
 for 15 courses.

 Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and
 pegfilgrastim as in arm I.

 -  Arm III: (closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and
 pegfilgrastim or G-CSF as in arm I.

 Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive
 paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.

 -  Arm IV: (closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as
 in arm II.

 Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm
 III.

 -  Arm V: Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and
 pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients
 receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2.
 Treatment repeats every 14 days for 6 courses.

 Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive
 paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14
 days for 6 courses.

 -  Arm VI: Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim as in arm V.

 Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive
 paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.

 In all arms, treatment continues in the absence of disease progression or unacceptable
 toxicity.

 In all arms patients with HER2/neu-positive tumors also receive trastuzumab (Herceptin®)
 weekly or every 3 weeks beginning concurrently with paclitaxel OR 3 months after the last
 dose of paclitaxel and continuing for up to 52 weeks.

 In all arms, patients with estrogen-receptor or progesterone-receptor positive tumors receive
 hormonal therapy beginning within 28 days of the completion of adjuvant chemotherapy or
 radiotherapy (if given).

 After finishing study treatment patients are followed up every 6 months for 5 years and then
 once a year for up to 15 years.

 PROJECTED ACCRUAL: A total of 3,250 patients will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed stage I-III invasive breast cancer

 -  Operable disease

 -  Stage I, II, IIIA, and IIIC (T1-3, N3a only)

 -  No T4 tumors

 -  High-risk disease, defined by 1 of the following:

 -  Tumor ≥ 2 cm in greatest diameter (includes both invasive and intraductal
 component)

 -  Patients with nodal status of N0+ (i.e., no cluster of tumor cells in any
 node greater than 0.2 mm) are considered to be node negative and must have a
 primary tumor ≥ 2 cm in size or have a tumor ≥ 1 cm with high risk features

 -  Patients who are node negative on the basis of a sentinel node procedure and
 fewer than 6 axillary nodes are removed are eligible OR at least 6 axillary
 or intramammary nodes must be negative

 -  Tumor ≥ 1 cm in diameter and meeting 1 of the following criteria:

 -  ER-negative and PgR-negative

 -  ER-positive or PgR-positive with a Genomic Health Recurrence Score of ≥ 26

 -  One or more axillary or intramammary nodes are involved by metastatic breast
 cancer

 -  If one or more nodes is involved, a minimum of 6 axillary or intramammary
 nodes must have been examined histologically

 -  Patients with N0(I+) disease will be considered node negative

 -  HER2/neu-positive tumors (3+ by immunohistochemical staining or amplified by
 fluorescence in-situ hybridization) allowed

 -  Bilateral synchronous breast cancer diagnosed within 1 month of each other allowed
 provided the higher TNM stage primary tumor meets the eligibility criteria

 -  Prior modified radical mastectomy OR local excision of all tumors with axillary lymph
 node dissection or sentinel node resection required

 -  No more than 84 days since prior surgery for the primary tumor and/or axilla

 -  Final resection margins for the primary tumor must be histologically negative for
 invasive cancer and ductal carcinoma in situ

 -  Resection margins positive for lobular carcinoma in situ are allowed

 -  Hormone receptor status:

 -  Estrogen receptor status known

 -  Progesterone receptor status known

 PATIENT CHARACTERISTICS:

 Age

 -  18 and over

 Sex

 -  Male or female

 Menopausal status

 -  Not specified

 Performance status

 -  Zubrod 0-2

 Life expectancy

 -  Not specified

 Hematopoietic

 -  Absolute neutrophil count at least 1,200/mm^3

 -  Platelet count at least 100,000/mm^3

 Hepatic

 -  Bilirubin no greater than upper limit of normal (ULN)

 -  Alkaline phosphatase no greater than 2 times ULN

 -  SGOT or SGPT no greater than 2 times ULN

 Renal

 -  Creatinine no greater than ULN

 Cardiovascular

 -  No congestive heart failure

 -  No active angina pectoris

 -  LVEF greater than or equal to the lower limit of normal* by MUGA or echocardiogram
 NOTE: Patients age 60 and over OR with a history of hypertension

 Other

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  No other malignancy within the past 5 years except adequately treated basal cell or
 squamous cell skin cancer, in situ cervical carcinoma, or lobular carcinoma in situ of
 the breast

 -  Prior invasive breast cancer or ductal carcinoma in situ allowed if disease-free
 for 5 years

 -  HIV negative

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  Not specified

 Chemotherapy

 -  No prior cytotoxic chemotherapy for this breast cancer

 -  No prior chemotherapy with an anthracycline, anthracenedione, or taxane

 Endocrine therapy

 -  Not specified

 Radiotherapy

 -  No prior radiotherapy for this malignancy

 -  At least 2 weeks since prior radiotherapy for ductal carcinoma in situ

 Surgery

 -  See Disease Characteristics