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. Celecoxib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining chemotherapy with celecoxib may kill more tumor cells. It is not yet known which combination chemotherapy regimen with or without celecoxib is more effective in treating breast cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of two combination chemotherapy regimens with or without celecoxib in treating women who have undergone surgery for breast cancer that has not spread to the lymph nodes.

Condition	Treatment or Intervention	Phase
stage I breast cancer stage II breast cancer	Drug: celecoxib  Drug: cyclophosphamide  Drug: doxorubicin  Drug: epirubicin  Drug: fluorouracil  Procedure: adjuvant therapy  Procedure: chemotherapy  Procedure: enzyme inhibitor therapy  Procedure: radiation therapy	Phase III

Further Study Details: 

OBJECTIVES: Primary

• Compare disease-free survival of women with node-negative breast cancer treated with adjuvant fluorouracil, epirubicin, and cyclophosphamide with or without celecoxib vs doxorubicin and cyclophosphamide with or without celecoxib.

Secondary

• Compare survival, recurrence-free interval, and distant recurrence-free interval in patients treated with these regimens.
• Compare the incidence of second malignancy in patients treated with celecoxib vs placebo.
• 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 short- and long-term symptoms or benefits associated with celecoxib, in terms of quality of life, in these patients.
• 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 LVEF with self-reported physical functioning in patients treated with these regimens.
• Compare the efficacy of these regimens in patients with HER2/neu and/or topoisomerase-2-alpha gene amplification.
• Compare the efficacy of celecoxib in patients whose tumors express or do not express cyclo-oxygenase-2.

OUTLINE: This is a randomized, double-blind, placebo-controlled, 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 chemotherapy arms.
• Arm I: 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 II: 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.
• Within 21 days after initiation of chemotherapy, all patients are further randomized to 1 of 2 celecoxib therapy arms.
• Arm I: Patients receive oral celecoxib twice daily for 3 years.
• Arm II: Patients receive oral placebo twice daily for 3 years. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

All patients with ER- or PR-positive tumors receive oral tamoxifen or an oral aromatase inhibitor daily beginning within 3-12 weeks after the completion of chemotherapy and continuing for 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.

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 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 3.25 years.

Ages Eligible for Study:  21 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive adenocarcinoma of the breast
• Primary tumor T1-3 by clinical and pathologic evaluation
• No T4 disease
• No pure tubular or mucinous adenocarcinoma
• No bilateral malignancy, including ductal carcinoma (DCIS) or a mass or mammographic abnormality in the opposite breast unless it is proven benign by biopsy
• No diffuse tumors by mammography that would not be amenable to lumpectomy
• Eligible if undergone mastectomy
• Lymph nodes negative by standard hematoxylin and eosin (H&E) staining
• Lymph nodes positive by immunohistochemistry but negative by H&E staining allowed
• Must have undergone one of the following axillary nodal staging procedures:
• Sentinel node (SN) biopsy alone
• SN biopsy followed by axillary sampling or complete dissection
• Axillary node dissection* to obtain lymph nodes for pathologic evaluation NOTE: *Required if patient has palpable nodes in the ipsilateral or contralateral axilla or palpable supraclavicular or infraclavicular nodes
• Must have undergone either a lumpectomy or total mastectomy within the past 84 days
• If lumpectomy has been performed, margins must be histologically confirmed free of invasive tumor or DCIS
• If tumor is found to be present in margins, further surgical resection or total mastectomy must be performed until clear margins are achieved
• Margins that are positive for lobular carcinoma (LCIS) do not require further resection
• No other clinically dominant mass or mammographically suspicious abnormality within the ipsilateral breast remnant
• Must be biopsied and demonstrated to be histologically benign OR surgically removed with clear margins
• No prior breast cancer, including DCIS
• Prior LCIS allowed
• No clinical or radiologic evidence of metastatic disease
• Patients with skeletal pain must be free of metastases by bone scan or roentgenological examination
• Suspicious findings must be confirmed as benign by x-ray, MRI, or biopsy
• Hormone receptor status:
• Any status is eligible, but status must be determined before randomization

PATIENT CHARACTERISTICS: Age

• 21 and over

Sex

• Female

Menopausal status

• Postmenopausal, defined by 1 of the following:
• Prior documented bilateral oophorectomy
• No spontaneous menstrual bleeding within the past 12 months
• 55 years of age or older with a prior hysterectomy
• 54 years of age or younger with a prior hysterectomy without oophorectomy (or in whom the status of ovaries is unknown) with a documented follicle-stimulating hormone level demonstrating confirmatory elevation in the postmenopausal range OR
• Premenopausal

Performance status

• Not specified

Life expectancy

• At least 10 years, excluding the diagnosis of breast cancer

Hematopoietic

• Absolute granulocyte count ≥ 1,500/mm^3 (1,200/mm^3 if due to ethnic or racial variance)
• Platelet count ≥ 100,000/mm^3
• No significant underlying hematologic disorders causing platelet count to be > upper limit of normal (ULN)

Hepatic

• Bilirubin normal (≤ 1.5 times ULN if due to Gilbert's syndrome)
• Alkaline phosphatase < 2.5 times ULN
• AST ≤ 1.5 times ULN

Renal

• Creatinine normal

Cardiovascular

• LVEF normal by MUGA or echocardiogram
• No myocardial infarction
• No angina pectoris requiring anti-anginal medication
• No history of congestive heart failure
• No serious cardiac arrhythmia requiring medication
• No severe conduction abnormality
• No valvular disease with documented cardiac function compromise
• No poorly controlled hypertension (i.e., diastolic > 100 mm Hg)
• No symptomatic peripheral vascular disease or carotid disease
• No cardiac disease that would preclude anthracycline therapy

Pulmonary

• No aspirin-sensitive asthma

Other

• No history of upper gastrointestinal bleeding
• No history of duodenal or gastric ulcer
• No known hypersensitivity to any COX-2 inhibitor, sulfonamide, aspirin, or NSAID
• No rheumatologic or skeletal disorders requiring chronic NSAIDs or steroid therapy
• No other malignancy within the past 5 years except adequately treated carcinoma of the cervix, melanoma , or basal cell or squamous cell skin cancer
• No non-malignant systemic disease that would preclude study participation or prolonged follow-up
• No psychiatric or addictive disorder that would preclude giving informed consent
• Not pregnant or nursing
• Fertile patients must use effective barrier contraception

PRIOR CONCURRENT THERAPY: Biologic therapy

• No prior biologic therapy for breast cancer

Chemotherapy

• No prior chemotherapy for breast cancer
• No prior anthracyclines

Endocrine therapy

• Prior hormonal therapy for breast cancer allowed provided therapy was ≤ 28 days in duration
• No concurrent oral or parenteral sex hormones (e.g., hormone replacement therapy or birth control pills)
• No concurrent luteinizing hormone releasing-hormone agonists or antagonists (e.g., goserelin)
• No concurrent selective estrogen-receptor modulators (e.g., raloxifene or tamoxifen) for breast cancer or breast cancer prevention

Radiotherapy

• No prior radiotherapy for breast cancer
• No concurrent regional nodal radiotherapy
• No concurrent partial breast radiotherapy

Surgery

• See Disease Characteristics

Other

• No concurrent fluconazole or lithium
• No concurrent cyclo-oxygenase-2 (COX-2) inhibitors
• No concurrent non-steroidal anti-inflammatory drugs (NSAIDs)
• No concurrent salicylates
• Cardioprotective doses (≤ 81 mg/day or 325 mg every other day) of aspirin allowed
• No other concurrent investigational agents for breast cancer

Texas
      Baylor College of Medicine, Houston,  Texas,  77030,  United States

Study chairs or principal investigators

Richard M. Elledge, MD,  Study Chair,  Baylor College of Medicine   

Study ID Numbers:  CDR0000372952; NSABP-B-36; NCT00087178
Record last reviewed:  February 2005
Last Updated:  February 8, 2005
Record first received:  July 8, 2004
ClinicalTrials.gov Identifier:  NCT00087178
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08