Docetaxel Followed by CEF (Cyclophosphamide, Epirubicin and 5-Fluorouracil) Compared to Docetaxel and Capecitabine Followed by CEX (Cyclophosphamide, Epirubicin and Capecitabine) as Adjuvant Treatment for Breast Cancer

This is an open-label, two-arm, randomized multi-center phase III trial to compare efficacy and safety of a taxane-anthracycline regimen to a taxane-anthracycline-capecitabine regimen as adjuvant treatment of early breast cancer with an intermediate-to-high risk of cancer recurrence.

Patients diagnosed with early breast cancer with an estimated risk of 25% or greater for distant recurrence within 5 years from the diagnosis will be randomly allocated to one of the following 2 arms (1:1):

• Arm A -- 3 cycles of docetaxel 80 mg/m² intravenous (i.v.) (repeated on day [d.] 22); followed by 3 cycles of CEF (cyclophosphamide 600 mg/m2 i.v., epirubicin 75mg/m² i.v., 5-fluorouracil 600 mg/m2 i.v., repeated on d. 22)
• Arm B -- 3 cycles of TX (docetaxel 60 mg/m² i.v., capecitabine twice daily 900 mg/m² given orally on days 1-15 of the cycle; cycle repeated on d. 22); followed by 3 cycles of CEX (cyclophosphamide 600 mg/m2 i.v., epirubicin 75mg/m² i.v, capecitabine twice daily 900 mg/m² on days 1-15 of the cycle; cycle repeated on d. 22)

Locoregional radiotherapy is given according to the institutional practice after completing adjuvant chemotherapy (Tx3/CEFx3 or TXx3/CEXx3).

All patients with ER and/or PgR positive disease will receive adjuvant endocrine therapy. This will consist of 1 mg p.o. anastrozole (ArimidexR) given for 60 months in women who were post-menopausal prior to chemotherapy (no menstrual periods for > 6 months) or of tamoxifen 20 mg p.o. for 60 months in women who were pre-menopausal prior to chemotherapy.

Use of trastuzumab is allowed in HER-2 positive disease.

Patients will be followed up for 5 years post-randomization.

Inclusion criteria

To be eligible for inclusion in the study, each patient must fulfill each of the criteria below.

• Have provided written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
• Be female and 18 years of age or older.
• Have histologically confirmed invasive breast cancer.
• High risk of breast cancer recurrence (> 25% within the first 5 years without adjuvant therapy, > 35% within the first 10 years) with one of the following:

• Regional node positive disease (pN+; tumor cells or tumor cell clusters < 0.2 mm in diameter are not counted as metastases);
• Pathological N0 and PgR- and tumor size > 20 mm.

Exclusion criteria

Patients who fulfill any of the following criteria will be excluded:

• > 65 years of age.
• "Special type" histology (mucinous, papillary, medullary, or tubular breast cancer), when pN0.
• ER, PgR and HER-2 status (via in situ hybridization or immunohistochemistry) not determined.
• Presence of distant metastases.
• Previous chemotherapy in the neoadjuvant setting.
• Non-ambulatory or WHO performance status > 1.
• Pregnant or lactating women. Women of childbearing potential (menstruating within 6 months of study entry or with no hysterectomy and age < 55) with either a positive or no pregnancy test at baseline.
• Women of childbearing potential unless using a reliable and appropriate contraceptive method. (Post-menopausal women must have been amenorrheic for at least 6 months to be considered of non-childbearing potential).
• More than 12 weeks between breast surgery and date of randomization.
• Organ allografts with immunosuppressive therapy required.
• Major surgery (except breast surgery) within 4 weeks prior to study treatment start, or lack of complete recovery from the effects of major surgery.
• Participation in any investigational drug study within 4 weeks preceding treatment start.
• Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant precluding informed consent or interfering with compliance for oral drug intake.
• History of another malignancy within the last five years except cured basal cell carcinoma of skin or carcinoma in situ of the uterine cervix.
• Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmia not well controlled with medication) or myocardial infarction within the last 12 months.
• Abnormal laboratory values:

• Hemoglobin < 10.0 g/dL, neutrophils < 1.5 x 10^9/L, platelet count < 120 x 10^9/L;
• Serum creatinine > 1.5 x Upper Limit of Normal (ULN);
• Creatinine clearance (calculated per Cockroft and Gault) < 50 mL/min;
• Serum bilirubin > ULN;
• ALAT > 1.5 x ULN;
• Alkaline phosphatase > 2.5 x ULN.
• Serious uncontrolled intercurrent infections or other serious uncontrolled concomitant disease.
• Lack of physical integrity of the upper gastrointestinal tract or those who have clinically significant malabsorption syndrome.
• Inability to swallow tablets.
• Life expectancy of less than 3 months.
• Unwilling or unable to comply with the protocol for the duration of the study.
• Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine.