combination chemotherapy in treating patients with early stage breast cancer that has been removed by surgery

Conditions: Breast Cancer

Summary: rationale: drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. giving more than one drug (combination chemotherapy) may kill more tumor cells. giving combination chemotherapy after surgery may kill any remaining tumor cells. it is not yet known which combination chemotherapy regimen is more effective in treating early stage breast cancer that has been removed by surgery. purpose: this randomized phase iii trial is studying four different combination chemotherapy regimens to compare how well they work in treating patients with early stage breast cancer that has been removed by surgery.

objectives: primary * compare the disease-free survival (dfs) of patients with completely resected early stage breast cancer receiving 1 of 2 different schedules of adjuvant chemotherapy comprising epirubicin, cyclophosphamide, methotrexate, and fluorouracil versus 1 of 2 different schedules of adjuvant chemotherapy comprising epirubicin and capecitabine. secondary * compare overall survival (os) and distant disease-free survival (dfs). * compare the tolerability (including serious adverse events \[sae\], dose-intensity, and toxicity) of these regimens. * determine the detailed toxicity of these regimens. * determine the quality of life of a subset of these patients. outline: this is a multi-center, randomized study. patients are stratified according to participating center, nodal status (n0 vs n1-3 vs n≥ 4), age (≤ 50 years vs \> 50 years), and estrogen receptor (er) status (negative vs positive). patients are randomized to 1 of 4 treatment arms. * arm i: patients receive epirubicin on day 1. treatment repeats every 3 weeks for 4 courses. patients then receive cyclophosphamide orally once daily on days 1-14 or iv on days 1 and 8 and methotrexate and fluorouracil on days 1 and 8. treatment repeats every 28 days for 4 courses. * arm ii: patients receive epirubicin on day 1 and pegfilgrastim on day 2. treatment repeats every 2 weeks for 4 courses. patients then receive cyclophosphamide, methotrexate and fluorouracil as in arm i. * arm iii: patients receive epirubicin as in arm i. patients then receive oral capecitabine twice daily on days 1-14. treatment with capecitabine repeats every 3 weeks for 4 courses. * arm iv: patients receive epirubicin and pegfilgrastim as in arm ii. patients then receive capecitabine as in arm iii. in all arms, treatment continues in the absence of unacceptable toxicity. beginning 3-6 months later, all patients may undergo radiotherapy at the discretion of the principal investigator. patients with er- and/or progesterone receptor-positive disease then receive tamoxifen citrate or an aromatase inhibitor for up to 5 years. quality of life is assessed in a cohort of 1,000 patients in week 6, week 8 or 12, and week 20 or 24 during treatment and then at 12 and 24 months after randomization. after completion of study therapy, patients are followed every 6 months for 2 years and then annually for at least 10 years. peer reviewed and funded or endorsed by cancer research uk. projected accrual: a total of 4,400 patients will be accrued for this study.

Eligibility criteria:
disease characteristics: * histological diagnosis of invasive breast carcinoma * cytological proof of malignancy alone is not sufficient * early stage disease (t0-3, n0-2, m0) without clinical suspicion or evidence of distant metastases on routine staging * no locally advanced breast cancer (t4 and/or n3 disease) * completely resected disease by breast-conserving surgery with axillary node clearance or modified radical mastectomy within the past 4-8 weeks * negative surgical margins required, unless either of the following are true: * deep surgical margins after full thickness resection * noninvasive cancer at surgical margins for which a mastectomy is planned after completion of study chemotherapy * no contraindication for or refusal of postoperative radiotherapy in patients who underwent prior breast-conserving surgery * definite indication for adjuvant chemotherapy * no prior or current invasive breast cancer or bilateral breast cancer * prior surgically-treated ductal carcinoma in situ or lobular carcinoma in situ allowed * hormone receptor status: * estrogen receptor- and/or progesterone receptor-positive or -negative tumor patient characteristics: * sex: male or female * menopausal status: premenopausal or postmenopausal * no previous malignancy except basal cell carcinoma, carcinoma in situ of the cervix, or any cancer from which the patient has been disease-free for 10 years and for which treatment consisted solely of resection * ecog status 0 or 1 * hemoglobin \> 9 g/dl * wbc \> 3,000/mm³ * platelet count \> 10,000/mm³ * bilirubin normal (unless due to known gilbert's disease) * ast and alt ≤ 1.5 times upper limit of normal (uln) * albumin normal * creatinine ≤ 1.5 times uln * creatinine clearance \> 50 ml/min * no active, uncontrolled infection * not pregnant or nursing * fertile patients must use effective contraception * no concurrent medical, psychiatric, or geographic problems that might prevent completion of treatment or follow-up * available for a minimum of 5 years' follow-up * no known serious viral infection such as active hepatitis b, hepatitis c, or hiv * no significant cardiac disease, such as impaired left ventricular function or active angina requiring regular anti-anginal medication and/or resulting in restricted physical activity * no history of significant renal impairment or disease prior concurrent therapy: * no simultaneous participation in the active intervention phase of another treatment trial * not being approached or recruited for another trial within 2 months of study entry * no previous chemotherapy, hormonal therapy or radiotherapy for the treatment of pre-invasive or invasive cancer except for either of the following: * previous radiotherapy for basal cell carcinoma * previous preoperative endocrine therapy, provided there was no evidence of progression during this therapy, it lasted for less than 6 weeks in duration, and it was stopped at least one month prior to trial entry * concurrent luteinizing hormone-releasing hormone analog therapy allowed for premenopausal patients * more than 4 weeks since prior hormone replacement therapy (hrt) or pre-operative endocrine therapy * no prior breast conserving surgery if there is a contradiction for or refusal of postoperative radiotherapy

Keywords: stage i breast cancer stage ii breast cancer stage iiia breast cancer male breast cancer