Comparison of Two Combination Chemotherapy Regimens in Treating Women With Breast Cancer
Comparison of Two Combination Chemotherapy Regimens in Treating Women With Breast Cancer
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.
OBJECTIVES:

 Primary

 -  Compare disease-free survival of women with node-negative breast cancer treated with
 adjuvant fluorouracil, epirubicin, and cyclophosphamide vs doxorubicin and
 cyclophosphamide.

 Secondary

 -  Compare survival, recurrence-free interval, and distant recurrence-free interval in
 patients treated with these regimens.

 -  Compare adverse events in patients treated with these regimens.

 -  Compare quality of life, with regard to physical functioning, vitality, symptoms, and
 rates of post-chemotherapy amenorrhea, in premenopausal patients treated with these
 regimens.

 -  Determine the effect of induction of post-chemotherapy amenorrhea on disease-free
 survival in premenopausal patients treated with these regimens.

 -  Correlate post-chemotherapy amenorrhea and disease-free survival with hormone receptor
 status in premenopausal patients treated with these regimens.

 -  Correlate changes in left ventricular ejection fraction (LVEF) with self-reported
 physical functioning in patients treated with these regimens.

 -  Compare the efficacy of these regimens in patients with Human Epidermal Growth Factor
 Receptor 2 (HER2)/neu and/or topoisomerase-2-alpha gene amplification.

 OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
 hormone receptor status (estrogen receptor [ER] positive or progesterone receptor [PR]
 positive vs ER negative or PR negative) and type of prior surgery (lumpectomy vs total
 mastectomy). Patients are randomized to 1 of 2 treatment arms.

 -  Arm 1: Patients receive doxorubicin IV over 15 minutes followed by cyclophosphamide IV
 over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses.

 -  Arm 2: Patients receive fluorouracil IV, epirubicin IV over 15 minutes, and
 cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 6
 courses.

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

 All patients with ER- or PR-positive tumors receive hormonal therapy daily beginning within
 3-12 weeks after the completion of chemotherapy and continuing for at least 5 years.

 All patients who have undergone prior lumpectomy undergo whole-breast radiotherapy beginning
 as soon as possible after the completion of chemotherapy. Patients who have undergone prior
 total mastectomy may undergo chest wall radiotherapy at the investigator's discretion.
 Patients assigned to the partial breast irradiation (PBI) group of protocol NSABP-B-39
 undergo PBI according to protocol-specific guidelines.

 Quality of life is assessed at baseline, on day 1 of course 4 of chemotherapy, and then every
 6 months for 3 years.

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

 PROJECTED ACCRUAL: A total of 2,700 patients (1,350 per treatment arm) will be accrued for
 this study within 3.75 years.
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.)