Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Cyclophosphamide; Docetaxel; Gemcitabine; Paclitaxel; Doxorubicin
Intervention description: Group 1: cyclophosphamide 500 mg/m2 IV every 21 days for 6 cycles
Group 2 and Group 3: cyclophosphamide 600 mg/m2 IV every 14 days for 4 cycles; 75 mg/m2 IV every 21 days for 6 cycles; 2000 mg/m2 IV every 14 days for 4 cycles; 175 mg/m2 IV every 14 days for 4 cycles; Group 1: 50 mg/m2 IV every 21 days for 6 cycles
Group 2 and Group 3: 60 mg/m2 IV every 14 days for 4 cycles
Intervention MeSH terms: Paclitaxel; Docetaxel; Cyclophosphamide; Gemcitabine; Doxorubicin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4894.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: stage II breast cancer; stage IIIA breast cancer; stage IIIC breast cancer

Summary:

      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.
    

Eligibility criteria:

        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.