RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. It is not yet known if high-dose combination chemotherapy plus peripheral stem cell transplanation is more effective than standard combiantion chemotherapy for breast cancer.

PURPOSE: Randomized phase III trial to compare high-dose combination chemotherapy plus peripheral stem cell transplantation with standard combination chemotherapy in treating women with stage II or stage III breast cancer.

Condition	Treatment or Intervention	Phase
Breast Cancer	Drug: cyclophosphamide  Drug: doxorubicin  Drug: epirubicin  Drug: filgrastim  Drug: fluorouracil  Drug: mesna  Drug: methotrexate  Drug: tamoxifen	Phase III

Further Study Details: 

OBJECTIVES: I. Compare the survival, disease-free survival, and systemic disease-free survival of women with high-risk, operable stage II/III breast cancer treated with three courses of dose-intensive epirubicin/cyclophosphamide (EC) supported by granulocyte colony-stimulating factor (G-CSF) and G-CSF-mobilized peripheral blood stem cells vs. standard EC followed by cyclophosphamide/methotrexate/fluorouracil.

II. Compare the toxicity, duration of quality-adjusted time without symptoms and toxicity, and quality of life associated with these two treatments.

III. Evaluate the cost effectiveness of these two treatments.

PROTOCOL OUTLINE: This is a randomized study. Patients are stratified by estrogen receptor status and menopausal status.

Within 6 weeks of surgery, patients in the first group receive epirubicin (preferred) or doxorubicin plus cyclophosphamide every 3 weeks for 4 courses followed by conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) every 4 weeks for 3 courses.

Patients in the second group undergo stem cell mobilization and harvest with granulocyte colony-stimulating factor (G-CSF) followed within 10 weeks of surgery by high-dose chemotherapy with epirubicin and cyclophosphamide followed by peripheral blood stem cell rescue and G-CSF.

All patients receive adjuvant tamoxifen, and patients who underwent lumpectomy prior to entry are required to receive adjuvant radiotherapy (radiotherapy is optional for patients who underwent mastectomy prior to entry).

Patients are followed every 3 months for 2 years, then q 6 months for 3 years, then yearly.

PROJECTED ACCRUAL: 210 patients will be accrued over 4 years to provide 195 evaluable patients.

Ages Eligible for Study:  16 Years   -   65 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically proven breast carcinoma in one of the following categories: 10 or more involved axillary nodes; 5 or more involved axillary nodes and either: Primary tumor estrogen receptor (ER)-negative (less than 10 femtomoles per milligram of cytosol protein); T3 tumor (regardless of ER status)
• Total mastectomy or breast-conserving procedure (lumpectomy or quadrantectomy) required within 6 weeks prior to randomization; Tumor confined to breast and axillary nodes (T1a-c, T2, or T3, N1-2, M0 by the UICC staging system)
• The following conditions exclude entry: Satellite skin nodules distant from the primary tumor; Supraclavicular node involvement; Inoperable, matted axillary nodes; Fixation of primary tumor to chest wall (excluding pectoralis major); Bilateral breast cancer (any mass in opposite breast unless biopsy-proven benign); Hot spots on bone scintigram (unless confirmed to be benign); Skeletal pain of unknown cause
• Hormone receptor status: ER status determination preferred, but not required

--Prior/Concurrent Therapy--

• No prior therapy for breast cancer other than surgery (see Disease Characteristics)

--Patient Characteristics--

• Age: 16-65
• Sex: Women only
• Menopausal status: Any status
• Performance status: ECOG 0-2
• Hematopoietic: WBC at least 4,000; Platelets at least 100,000
• Hepatic: Bilirubin no greater than 1.1 mg/dL (20 micromoles/L); AST no greater than twice normal
• Renal: Creatinine no greater than 1.3 mg/dL (120 micromoles/L)
• Cardiovascular: Left ventricular ejection fraction greater than 50% by MUGA
• Other: No second malignancy except: Basal cell carcinoma; Adequately treated carcinoma in situ of the cervix; No significant nonmalignant disease that would preclude participation; No psychiatric or addictive disorder that would compromise informed consent or participation; No pregnant or nursing women; Adequate contraception strongly advised for fertile women

Australia, New South Wales
      Newcastle Mater Misericordiae Hospital, Newcastle,  New South Wales,  NSW 2310,  Australia
      Royal Prince Alfred Hospital, Sydney, Sydney,  New South Wales,  2050,  Australia
Australia, South Australia
      Queen Elizabeth Hospital, Adelaide,  South Australia,  5011,  Australia
      Royal Adelaide Hospital, Adelaide,  South Australia,  5000,  Australia
Australia, Victoria
      Royal Melbourne Hospital, Parkville,  Victoria,  3050,  Australia
Switzerland
      Centre Hospitalier Universitaire Vaudois, Lausanne,  CH-1011,  Switzerland
      Inselspital, Bern, Bern,  CH-3010,  Switzerland
      Istituto Oncologico della Svizzera Italiana, Lugano,  CH-6900,  Switzerland
      Kantonsspital - Saint Gallen, Saint Gallen,  CH-9007,  Switzerland
      Swiss Institute for Applied Cancer Research, Bern,  CH-3008,  Switzerland
      Universitaetsspital, Zurich,  CH-8091,  Switzerland

Study chairs or principal investigators

Russell Basser,  Study Chair,  International Breast Cancer Study Group   

Study ID Numbers:  CDR0000064834; IBCSG-15-95; EU-96021
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002784
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08