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

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.)