• Disease-free survival [ Designated as safety issue: No ]
  
• Overall survival and systemic disease-free survival [ Designated as safety issue: No ]
  
• Toxicity [ Designated as safety issue: Yes ]
  
• Quality of life [ Designated as safety issue: No ]
  

OBJECTIVES:

• Determine the efficacy of adjuvant induction chemotherapy with or without cyclophosphamide and methotrexate as maintenance chemotherapy in patients with stage I, II, or III breast cancer.
• Compare the disease-free survival, overall survival, and systemic disease-free survival of patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center, menopausal status (pre vs post), and approved induction chemotherapy (doxorubicin and cyclophosphamide vs other agents). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive one of the following approved adjuvant induction chemotherapy regimens:

  • AC comprising doxorubicin and cyclophosphamide IV on day 1 every 21 days for 4 courses followed by paclitaxel IV or docetaxel IV on day 1 every 21 days for 4 courses
  • EC comprising epirubicin and cyclophosphamide IV on day 1 every 21 days for 4 courses followed by paclitaxel IV or docetaxel IV on day 1 every 21 days for 4 courses
  • FAC comprising cyclophosphamide, doxorubicin, and fluorouracil IV on days 1 every 21 days for 4 courses
  • Doxorubicin every 21 days for 4 courses followed by CMF comprising cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1 and 8 every 28 days for 4 courses
  • AC OR EC and paclitaxel IV with filgrastim (G-CSF) every 14 days for 4 courses
  • FEC comprising cyclophosphamide IV, epirubicin IV and fluorouracil IV on day 1 every 21 days for 3 courses followed by docetaxel IV on day 1 every 21 days for 3 courses
  • TAC comprising docetaxel, doxorubicin, and cyclophosphamide IV on day 1 every 21 days for 6 courses
  • AT comprising doxorubicin IV and docetaxel IV every 21 days for 3 courses followed by CMF for 3 courses
• Arm II: Patients receive adjuvant induction chemotherapy as in arm I. Beginning within 56 days after the first day of the last course of induction chemotherapy, patients receive CM (maintenance chemotherapy) comprising oral cyclophosphamide once daily and oral methotrexate two times a day twice weekly for 1 year. Patients with breast-conserving surgery receive radiotherapy following completion of induction chemotherapy.

Patients with HER2-positive primary breast cancer may also receive trastuzumab (Herceptin) during or following induction, and/or during and following CM.

Quality of life is assessed at baseline, at the beginning of each course of induction chemotherapy, and at months 9, 12, 18, and 24.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: Approximately 900 patients will be accrued for this study within 5 years.