Combination Chemotherapy in Treating Women With Resected Breast Cancer

A Randomised Trial Of Standard Anthracycline-Based Chemotherapy With Fluorouracil, Epirubicin And Cyclophosphamide (FEC) Or Epirubicin And CMF (Epi-CMF) Versus FEC Followed By Sequential Docetaxel As Adjuvant Treatment For Women With Early Breast Cancer

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 and giving them after surgery may kill any tumor cells remaining after surgery. It is not yet known which combination chemotherapy regimen is more effective in treating resected stage I or stage II breast cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of different combination chemotherapy regimens in treating women who have resected stage I or stage II breast cancer.

OBJECTIVES:

• Compare the disease-free and overall survival of women with completely resected stage I or II breast cancer adjuvantly treated with fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil (EPI-CMF) versus FEC followed by sequential docetaxel.
• Compare the acute toxicity of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, estrogen receptor status (positive vs negative), and nodal status. Within 8 weeks after definitive surgery, patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients are assigned to 1 of 2 standard adjuvant chemotherapy regimens.

  • Regimen A: Patients receive fluorouracil, epirubicin, and cyclophosphamide (FEC) IV on day 1. Treatment repeats every 3 weeks for 8 courses.
  • Regimen B: Patients receive epirubicin IV on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive cyclophosphamide orally on days 1-14 or IV on days 1 and 8 and methotrexate IV and fluorouracil IV on days 1 and 8 (CMF). Treatment with CMF repeats every 4 weeks for 4 courses.

• Arm II: Patients receive 4 courses of adjuvant chemotherapy with FEC as in arm I, regimen A. Patients then receive sequential docetaxel IV over 1 hour once every 3 weeks for 4 courses.

Beginning within 4 weeks after completion of adjuvant chemotherapy, patients who are not concurrently enrolled in the Standardization of Breast Radiotherapy (START) trial receive localized radiotherapy once daily, 5 days a week, for 3-5 weeks, according to local practice.

Beginning within 4 weeks after completion of adjuvant chemotherapy, patients who are estrogen receptor and/or progesterone receptor positive receive oral tamoxifen once daily for at least 5 years.

Quality of life is assessed at baseline, before course 5, at 3-4 weeks after course 8, and then at 9, 12, 18, and 24 months after initiation of adjuvant chemotherapy.

Patients are followed every 3 months for 2 years and then every 6 months thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 3,340 patients (1,670 per treatment arm) will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed completely resected, invasive breast cancer for which adjuvant chemotherapy is indicated

• No clinical or radiological evidence of locoregional or metastatic disease

• No locally advanced tumors at diagnosis, indicated by any of the following:

  • Fixed tumors
  • Peau d'orange skin changes
  • Skin ulceration
  • Inflammatory changes (T4 or T3b, N2 disease)

• No male breast cancer

• No prior invasive breast cancer or bilateral breast cancer

• Prior ductal carcinoma in situ or lobular carcinoma in situ is allowed

• Must begin study chemotherapy within 8 weeks after definitive surgery

• Hormone receptor status:

  • Estrogen receptor and progesterone receptor status known

PATIENT CHARACTERISTICS:

Age:

• Over 18

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• WHO 0-1

Life expectancy:

• At least 2 years

Hematopoietic:

• WBC at least 3,000/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9 g/dL

Hepatic:

• Bilirubin normal
• AST no greater than 1.5 times normal
• Alkaline phosphatase no greater than 1.5 times normal

Renal:

• Creatinine no greater than 1.5 times normal

Cardiovascular:

• No myocardial infarction within the past 6 months
• No congestive heart failure

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No other invasive malignancy within the past 10 years except surgically cured nonmelanoma skin cancer or carcinoma in situ of the cervix
• No other serious medical illness that would limit life expectancy
• No psychiatric condition that would preclude informed consent
• No active uncontrolled bacterial, viral, or fungal infection

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior biologic therapy

Chemotherapy:

• See Disease Characteristics
• No prior cytotoxic chemotherapy

Endocrine therapy:

• No concurrent hormonal therapy (e.g., tamoxifen) during study chemotherapy
• No concurrent hormone replacement therapy

Radiotherapy:

• No prior radiotherapy

Surgery:

• See Disease Characteristics

Other:

• At least 4 weeks since any prior unlicensed drugs
• No other concurrent experimental drugs