Combination Chemotherapy in Treating Women With Breast Cancer Who Have Undergone Surgery

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which chemotherapy regimen is more effective in treating women after surgery for breast cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of paclitaxel, epirubicin, and cyclophosphamide with or without gemcitabine in treating women who have undergone surgery for breast cancer.

OBJECTIVES:

• Compare the 5-year and 10-year disease-free survival and overall survival of women with completely resected early stage breast cancer treated with adjuvant paclitaxel, epirubicin, and cyclophosphamide with or without gemcitabine.
• Compare the toxicity, dose-intensity, and tolerability of these regimens in these patients.
• Compare the serious adverse events in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to nodal status (negative vs 1-3 vs 4 or more), age (50 and under vs over 50), estrogen receptor status (negative vs weakly positive vs positive), concurrent radiotherapy (no vs yes), HER2 status (3+ overexpression vs other vs not measured), and country. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive epirubicin IV, cyclophosphamide IV, and paclitaxel IV over 3 hours on day 1. Patients also receive gemcitabine IV over 30 minutes on days 1 and 8. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive epirubicin, cyclophosphamide, and paclitaxel as in arm I.

Patients are followed every 3 months for 6 months, every 6 months for 3 years, and then annually for 6 years.

PROJECTED ACCRUAL: A total of 3,000 patients (1,500 per treatment arm) will be accrued for this study within 3-4 years.

• Drug: cyclophosphamide
• Drug: epirubicin hydrochloride
• Drug: gemcitabine hydrochloride
• Drug: paclitaxel
• Procedure: adjuvant therapy

DISEASE CHARACTERISTICS:

• Histologically confirmed newly diagnosed invasive breast cancer

  • Early stage disease

  • Completely resected disease

    • No more than 8 weeks since prior resection
• Any nodal status
• Indication for adjuvant chemotherapy
• No metastatic disease

• Hormone receptor status:

  • Estrogen receptor negative or weakly positive OR
  • Estrogen receptor positive AND progesterone receptor negative or weakly positive

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• WBC greater than 3,000/mm3
• Platelet count greater than 100,000/mm3
• Hemoglobin greater than 9 g/dL

Hepatic:

• Bilirubin normal
• AST and ALT no greater than 1.5 times normal

Renal:

• Creatinine no greater than 1.5 times normal

Other:

• Fit to receive study chemotherapy
• No active uncontrolled infection
• No other malignancy within the past 10 years except basal cell carcinoma or carcinoma in situ of the cervix
• No other concurrent medical or psychiatric problems that would preclude study
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• See Disease Characteristics
• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy

Surgery:

• See Disease Characteristics