Comparison of Two Combination Chemotherapy Regimens in Treating Women With Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: cyclophosphamide; adriamycin; epirubicin; fluorouracil
Intervention description: Arm 1: cyclophosphamide 600 mg/m2 IV every 21 days for 4 cycles; Arm 2: cyclophosphamide 500 mg/m2 IV every 21 days for 6 cycles; adriamycin 60 mg/m2 IV every 21 days for 4 cycles; epirubicin 100 mg/m2 IV every 21 days for 6 cycles; fluorouracil 500 mg/m2 IV every 21 days for 6 cycles
Intervention MeSH terms: Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Fluorouracil; Epirubicin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 2722.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: stage I breast cancer; stage II breast cancer

Summary:

      RATIONALE: Drugs used in chemotherapy, such as fluorouracil, epirubicin, cyclophosphamide,
      and doxorubicin, work in different ways to stop tumor cells from dividing so they stop
      growing or die. It is not yet known which combination chemotherapy regimen is more effective
      in treating breast cancer.

      PURPOSE: This randomized phase III trial is studying two combination chemotherapy regimens to
      compare how well they work in treating women who have undergone surgery for breast cancer
      that has not spread to the lymph nodes.
    

Eligibility criteria:

        Eligibility

          -  Patients must be greater than or equal to 18 years of age.

          -  The patient must have a life expectancy of at least 10 years, excluding her diagnosis
             of breast cancer. (Comorbid conditions and performance status should be taken into
             consideration, but not the diagnosis of breast cancer.)

          -  The interval between the last surgery for breast cancer treatment (lumpectomy,
             mastectomy, sentinel lymph node biopsy, axillary surgery, or re-excision of lumpectomy
             margins) and randomization must be no more than 84 days.

          -  The tumor must be invasive adenocarcinoma on histologic examination. (Patients with
             tumors that are pure tubular or mucinous adenocarcinomas are not eligible.)

          -  The primary tumor must be T1-3 by clinical and pathologic evaluation.

          -  Lymph nodes obtained from all axillary staging procedures must be pN0 according to
             pathologic staging criteria of the 6th edition of the American Joint Committee on
             Cancer (AJCC) Cancer Staging Manual.

          -  Patients must have undergone axillary nodal staging procedures, for example sentinel
             node (SN) biopsy alone, SN biopsy followed by axillary sampling or completion
             dissection, or axillary node dissection to obtain lymph nodes for pathologic
             evaluation. If the patient has palpable nodes, axillary dissection is required.

          -  Patients must have an estrogen receptor (ER) analysis performed on the primary tumor
             prior to randomization. If ER is negative, then progesterone receptor (PgR) analysis
             must be performed. If ER is positive, PgR analysis is desired, but not mandatory.
             ("Marginal" or "borderline" results [i.e., those not definitively negative] will be
             considered positive regardless of the methodology used.)

          -  Patients must have had either a lumpectomy or total mastectomy.

          -  Patients must have no clinical or radiologic evidence of metastatic disease.

          -  Patients with skeletal pain are eligible for inclusion in the study if bone scan or
             roentgenological examination fail to disclose metastatic disease. Suspicious findings
             must be confirmed as benign by x-ray, MRI, or biopsy.

          -  The patient's menopausal status must be determined prior to randomization.

               -  Pre- and postmenopausal women are eligible. The following criteria will be used
                  to define postmenopausal:

               -  a prior documented bilateral oophorectomy, or

               -  a history of at least 12 months without spontaneous menstrual bleeding, or

               -  age 55 or older with a prior hysterectomy or

               -  age 54 or younger with a prior hysterectomy without oophorectomy (or in whom the
                  status of the ovaries is unknown), with a documented follicle-stimulating hormone
                  (FSH) level demonstrating confirmatory elevation in the lab's postmenopausal
                  range.

               -  Women failing to meet one of these criteria will be classified as premenopausal.

          -  At the time of randomization, the patient must have had the following: history and
             physical exam, EKG, and PA and lateral chest x-ray or chest CT within the past 3
             months; bilateral mammogram within the past 6 months; and pelvic exam (for women who
             have a uterus and who will be receiving tamoxifen) within the past year.

          -  Within 3 months prior to entry, the patient must have a baseline LVEF measured by
             Multi Gated Acquisition (MUGA) scan or echocardiogram equal to or greater than the
             lower limit of normal for the facility performing the procedure.

          -  At the time of randomization:

               -  The postoperative absolute granulocyte count (AGC) must be greater than or equal
                  to 1500/mm3 (or greater than or equal to 1200/mm3 if, in the opinion of the
                  investigator, this represents an ethnic or racial variant of normal).

               -  Postoperative platelet count must be greater than or equal to 100,000/mm3.
                  Significant underlying hematologic disorders must be excluded when the platelet
                  count is above the ULN for the lab.

               -  There must be postoperative evidence of adequate hepatic function, i.e.,

               -  total bilirubin must be less than or equal to ULN for the lab unless the patient
                  has a chronic 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 2.5 x ULN for the lab; and

               -  the aspartate transaminase (AST) [serum glutamic-oxaloacetic transaminase (SGOT)]
                  must be less than or equal to 1.5 x ULN for the lab.

               -  There must be postoperative evidence of normal renal function (serum creatinine
                  less than or equal to ULN).

          -  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, 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 followed by breast radiation therapy 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 in 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 dissection has been performed. Patients in whom
                  tumor is still present at the resected margin after re-excision(s) must undergo
                  total mastectomy to be eligible.

               -  This is a node-negative study, therefore irradiation of regional lymph nodes is
                  prohibited in this trial.

               -  Whole breast irradiation is required unless the patient is assigned to the
                  partial breast irradiation group on NSABP B-39.

               -  Postmastectomy chest wall irradiation at the investigator's discretion is
                  permitted. However, this is a node-negative study; therefore irradiation of
                  regional lymph nodes is prohibited in this trial.

        Ineligibility

          -  Male patients are not eligible for this study.

          -  Pure tubular or mucinous adenocarcinomas.

          -  Bilateral malignancy (including 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.

          -  Suspicious palpable nodes in the ipsilateral or contralateral axilla or palpable
             supraclavicular or infraclavicular 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 lobular
             carcinoma in situ [LCIS] are eligible).

          -  Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal
             therapy administered for the currently diagnosed breast cancer prior to randomization.
             The only exceptions are:

               -  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.

               -  If patient is enrolled in NSABP B-39 and randomized to Group 2, partial breast
                  irradiation (PBI) may be completed prior to beginning treatment on NSABP B-36.

          -  Prior anthracycline therapy 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. With the exception of tamoxifen, these medications are not
             permitted while on the study.)

          -  Cardiac disease that would preclude the use of anthracyclines. This includes:

               -  any documented myocardial infarction;

               -  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

               -  poorly controlled hypertension, i.e., diastolic greater than 100 mm/Hg. (Patients
                  with hypertension that is well controlled on medication are eligible for entry.)

          -  Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would
             preclude a patient from being subjected to any of the treatment options or would
             prevent prolonged follow-up.

          -  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 investigational agents.

          -  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, breast irradiation is required. The
             following patients will be ineligible:

               -  Patients with diffuse tumors (as demonstrated on mammography) that would not be
                  considered surgically amenable to 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 ductal carcinoma in situ (DCIS). Additional surgical resections to
                  obtain free margins are allowed. Patients in whom tumor is still present after
                  the additional resection(s) must undergo mastectomy to be eligible. (Patients
                  with margins positive for LCIS are eligible without additional resection.)