Fluorouracil, Epirubicin, and Cyclophosphamide Alone or Followed by Paclitaxel for Early Breast Cancer

Phase III Study to Compare 6 Courses of FEC (Fluorouracil, Epirubicin and Cyclophosphamide) vs. 4 Courses of FEC Followed by 8 Weekly Paclitaxel Administrations, as Adjuvant Treatment for Node Positive Operable BC Patients

The efficacy of adjuvant chemotherapy is limited in patients with a high risk of recurrence.

Also, for axillary positive node patients, optimum chemotherapy regimens are still under discussion. Some previous studies suggest that, in the subset of node-positive patients, treatments based on sequential administration of anthracyclines and taxanes are more efficient. Paclitaxel dose-dense (weekly) administration renders an improved therapeutic index (activity/toxicity).

The study is designed to compare 6 courses of FEC scheme (600/90/600), a combination of proven efficacy in node positive breast cancer patients, versus 4 FEC courses followed by 8 weekly paclitaxel administrations (100mg/m2).

The study hypothesis is that 5-year disease-free survival in the control arm will be 60%. The investigators expect to increase this by 8% with the experimental treatment. With an alpha error of 0.05, 80% power, and a post-randomization estimated drop-out rate of 10%, 1250 patients are needed, 625 per arm.

The primary endpoint of study-5-year disease-free survival (DFS) will be assessed by Kaplan Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular markers. Associations and interactions will be assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests will be two-sided.

Inclusion Criteria:

• Written informed consent.
• Histological diagnosis of breast cancer.
• Node positive operable breast cancer (stages II-III).
• Breast cancer surgery, consisting of radical mastectomy or conservative surgery, plus lymphadenectomy with at least 6 extirpated nodes. Surgery must have happened in the 8 weeks prior to randomisation.
• Age >=18 and <= 70 years old.
• Negative pregnancy test. Adequate contraceptive method during the study participation.
• Performance status of 90-100 (Karnofsky index) or ECOG <=1.
• Haemoglobin >= 10 g/dl; neutrophils > 1,500/cc; platelets > 100,000/cc.
• Adequate hepatic function with bilirubin, SGOT and SGPT < 1.5 x upper normal limit (UNL).
• Adequate cardiac function documented by left ventricular ejection fraction (LVEF).
• Adequate renal function with creatinine < 1.5 mg/dl.

Exclusion Criteria:

• Previous chemotherapy, hormone therapy and/or radiotherapy for breast cancer.
• Bilateral breast cancer. Lobular in situ carcinoma.
• Previous or current malignancies, except for basal skin carcinoma, cervical in situ carcinoma or superficial bladder carcinoma, adequately treated.
• History of arrhythmias and/or congestive heart failure or cardiac blocking grade 2-3; history of myocardial infarction in 6 months before recruitment.
• Inability for treatment and study compliance.
• Pregnant or lactating women.
• Active infection.
• History of hypersensitivity to cremophor or cyclosporine.
• Pre-existing grade 2 motor or sensorial neurotoxicity (National Cancer Institute Common Toxicity Criteria [NCI CTC]).
• Hormonal receptor status not determined.
• Any other criteria which, in investigator's opinion, may jeopardize patient's security or compliance.
• Administration of other investigational product in the 30 days prior to randomisation; current participation in another clinical trial.