Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer
Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer
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 remaining
 tumor cells.

 PURPOSE: This randomized phase III trial is studying three different combination chemotherapy
 regimens and comparing how well they work in treating women who have undergone surgery for
 node-positive breast cancer.
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
 or regional RT). Patients are randomized to 1 of 3 treatment arms.

 -  Group 1: 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.

 -  Group 2: 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.

 -  Group 3: Patients receive AC chemotherapy as in Group 2. Beginning 14 days after the
 last dose of AC, patients receive paclitaxel as in Group 2 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.

 Beginning no sooner than 3 weeks after the last dose 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.
Inclusion Criteria:

 -  The patient must consent to participate in the study and must have signed an approved
 consent form conforming with federal and institutional guidelines.

 -  The patient must have a life expectancy of at least 10 years and a Zubrod performance
 status of 0 or 1. (Comorbid conditions but not the diagnosis of breast cancer should
 be taken into consideration when determining life expectancy.)

 -  The interval between the last surgery for breast cancer staging or treatment and
 randomization must be no more than 84 days.

 -  The tumor must be invasive carcinoma of the breast on histologic examination.

 -  All of the following staging criteria must be met:

 -  By clinical and pathologic evaluation, primary tumor must be T1-3;

 -  By clinical evaluation, ipsilateral nodes must be cN0, cN1, or cN2a;

 -  By pathologic evaluation, ipsilateral nodes must be pN1 (pN1mi, pN1a, pN1b,
 pN1c), pN2a, pN3a, or pN3b (only if due to microscopic involvement of internal
 mammary node detected by sentinel lymph node dissection and with more than 3
 positive axillary lymph nodes).

 -  Patients must have an estrogen receptor (ER) analysis performed on the primary tumor
 prior to randomization. If ER analysis is negative, then progesterone receptor (PgR)
 analysis must be performed. If ER analysis is positive, PgR analysis is desired, but
 not mandatory. ("Marginal" or "borderline" results [i.e., those not definitely
 negative] will be considered positive regardless of the methodology used.)

 -  Patients must have had either a lumpectomy or a total mastectomy. Patients must have
 completed one of the following procedures for evaluation of pathologic nodal status.

 -  Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph
 nodes (This approach is strongly recommended.)

 -  Sentinel lymphadenectomy alone if one of the following criteria is met:

 -  Pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1b

 -  Surgeon elects not to remove additional non-sentinel nodes (This approach is
 strongly discouraged, but will not preclude participation in B-38.)

 -  Axillary lymphadenectomy without sentinel node isolation procedure.

 -  Patients must have no clinical or radiologic evidence of metastatic disease.

 -  Patients with either skeletal pain or alkaline phosphatase that is greater than ULN
 but less than or equal to 2.5 x ULN are eligible for inclusion in the study if bone
 scans fail to demonstrate metastatic disease. Suspicious findings on bone scan must be
 confirmed as benign by x-ray, MRI, or biopsy.

 -  Patients with aspartate transaminase (AST) or alkaline phosphatase greater than ULN
 are eligible for inclusion in the study if liver imaging fails to demonstrate
 metastatic disease and the following requirements are met at the time of
 randomization.

 -  Postoperative absolute granulocyte count (AGC) must be greater than or equal to
 1200/mm3.

 -  Postoperative platelet count must be greater than or equal to 100,000/mm3.

 -  The following criteria for postoperative evidence of adequate hepatic function
 must be met:

 -  total bilirubin must be less than or equal to ULN for the lab unless the
 patient has a grade 1 bilirubin elevation (greater than ULN to 1.5 x ULN)
 due to Gilbert's disease or similar syndrome due to slow conjugation of
 bilirubin; and

 -  alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab;
 and

 -  the AST must be less than or equal to 1.5 x ULN for the lab; and

 -  alkaline phosphatase and AST cannot both be greater than ULN.

 -  Postoperative serum creatinine must be less than or equal to ULN.

 -  At the time of randomization, the patient must have had the following: history and
 physical exam, EKG, and imaging of the chest within the past 3 months and bilateral
 mammogram within the past 6 months.

 -  Within 3 months prior to entry, the patient must have a baseline left ventricular
 ejection fraction (LVEF), measured by Multiple Gated Acquisition (MUGA) scan or
 echocardiogram, greater than or equal to lower limit of normal (LLN) for the facility
 performing the procedure and no evidence of regional wall abnormalities.

 -  Patients with a history of non-breast malignancies are eligible if they have been
 disease-free for 5 or more years prior to randomization and are deemed by their
 physician to be at low risk for recurrence. Patients with the following cancers are
 eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the
 cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous
 cell carcinoma of the skin.

 -  Special conditions for eligibility of lumpectomy patients: radiation therapy and
 surgery. Patients treated by lumpectomy must meet all the eligibility criteria in
 addition to the following:

 -  Generally, lumpectomy should be reserved for tumors less than 5 cm. However, at
 the investigator's discretion, patients treated with lumpectomy for tumors
 greater than or equal to 5 cm are eligible if eligibility criteria for lumpectomy
 are met.

 -  The margins of the resected specimen must be histologically free of invasive
 tumor and DCIS as determined by the local pathologist. In patients for whom
 pathologic examination demonstrates tumor present at the line of resection,
 additional operative procedures may be performed to obtain clear margins. This is
 permissible even if axillary evaluation has been completed. Patients in whom
 tumor is still present at the resected margin after re-excision(s) must undergo
 total mastectomy to be eligible. (Patients with margins positive for lobular
 carcinoma in situ (LCIS) are eligible without additional resection.)

 -  Irradiation of regional lymph nodes is optional, but plans for radiation therapy
 must be declared by the investigator prior to randomization for stratification
 purposes.

 -  Special conditions for eligibility of mastectomy patients: radiation therapy o
 Postmastectomy chest wall and/or regional nodal irradiation is optional. Plans for
 radiation in mastectomy patients must be declared by the investigator prior to
 randomization for stratification purposes.

 Ineligibility Criteria

 -  Male patients are not eligible for this study. Women with one or more of the following
 conditions or prior therapies are also ineligible for this study:

 -  Tumor that has been determined to be human epidermal growth factor receptor 2
 (HER2)-positive by immunohistochemistry (3+) or by fluorescent in situ hybridization
 (positive for gene amplification).

 -  Contralateral breast cancer (invasive or DCIS) or a mass or mammographic abnormality
 in the opposite breast suspicious for malignancy unless there is biopsy proof that the
 mass is not malignant.

 -  Primary tumor staged as T4 for any reason.

 -  Clinical nodal stages including cN2b and cN3 or pathologic nodal stages including
 pN0(i+), pN2b, pN3b with clinically apparent internal mammary nodes, or pN3c.

 -  Suspicious nodes in the contralateral axilla or suspicious supraclavicular nodes.
 Patients with these conditions are considered ineligible unless there is biopsy
 evidence that these are not involved with tumor.

 -  Prior history of breast cancer, including DCIS (patients with a history of LCIS are
 eligible).

 -  Treatment, including radiation therapy, chemotherapy, and/or hormonal therapy
 administered for the currently diagnosed breast cancer prior to randomization. One
 exception is hormonal therapy, which may have been given for up to a total of 28 days
 anytime after diagnosis and before study entry. In such a case, hormonal therapy must
 stop at or before randomization and be re-started, if indicated, following
 chemotherapy. A second exception is radiation therapy for patients enrolled in NSABP
 B-39 and assigned to partial breast irradiation (Group 2). These patients may have
 received RT prior to B-38 study entry.

 -  Prior therapy with anthracyclines or taxanes for any malignancy.

 -  Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement
 therapy, etc. (These patients are eligible if this therapy is discontinued prior to
 randomization.)

 -  Therapy with any hormonal agents such as raloxifene (Evista®), tamoxifen, or other
 selective estrogen-receptor modulators (SERMs), either for osteoporosis or breast
 cancer prevention. (Patients are eligible only if these medications are discontinued
 prior to randomization.

 -  Cardiac disease that would preclude the use of anthracyclines. This includes:

 -  history of myocardial infarction documented by elevated cardiac enzymes or
 regional wall abnormalities on assessment of left ventricular (LV) function;

 -  angina pectoris that requires the use of anti-anginal medication;

 -  any history of documented congestive heart failure;

 -  serious cardiac arrhythmia requiring medication;

 -  severe conduction abnormality;

 -  valvular disease with documented cardiac function compromise; and

 -  uncontrolled hypertension defined as blood pressure greater than 160/100 on
 antihypertensive therapy.

 -  Conditions that would prohibit administration of corticosteroids.

 -  Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI's
 Common Terminology Criteria for Adverse Events Version 3.0.

 -  Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would
 preclude a patient from receiving any of the treatment options or would prevent
 prolonged follow-up.

 -  History of hepatitis B or C.

 -  Pregnancy or lactation at the time of proposed randomization. Women of reproductive
 potential must agree to use an effective non-hormonal method of contraception.

 -  Concurrent treatment with other investigational agents for the treatment of breast
 cancer.

 -  Psychiatric or addictive disorders or other conditions that, in the opinion of the
 investigator, would preclude the patient from meeting the study requirements.

 -  Special conditions for ineligibility of lumpectomy patients: radiation therapy and
 surgery

 -  For patients treated by lumpectomy, whole breast irradiation is required.

 -  The following patients will be ineligible:

 -  Patients with diffuse tumors (as demonstrated on mammography) treated with
 lumpectomy. (These patients are eligible if they undergo mastectomy.)

 -  Patients treated with lumpectomy in whom there is another clinically dominant
 mass or mammographically suspicious abnormality within the ipsilateral breast
 remnant. Such a mass must be biopsied and demonstrated to be histologically
 benign prior to randomization or, if malignant, must be surgically removed with
 clear margins.

 -  Patients in whom the margins of the resected specimen are involved with invasive
 tumor or DCIS.