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

A Clinical Trial Of Adjuvant Therapy Comparing Six Cycles Of 5-Fluorouracil, Epirubicin And Cyclophosphamide (FEC) To Four Cycles Of Adriamycin And Cyclophosphamide (AC) In Patients With Node-Negative 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.)