RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Colony-stimulating factors such as epoetin alfa and filgrastim may decrease the side effects of chemotherapy. It is not yet known which treatment regimen is most effective for breast cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy given with or without epoetin alfa in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer.

Condition	Treatment or Intervention	Phase
stage I breast cancer stage II breast cancer stage IIIA breast cancer stage IIIB breast cancer	Drug: cyclophosphamide  Drug: doxorubicin  Drug: epirubicin  Drug: epoetin alfa  Drug: filgrastim  Drug: fluorouracil  Drug: paclitaxel  Procedure: adjuvant therapy  Procedure: biological response modifier therapy  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy	Phase III

Further Study Details: 

OBJECTIVES: Primary

• Compare the disease-free survival of premenopausal or early postmenopausal women with previously resected node positive or high-risk node negative stage I-IIIB breast cancer treated with cyclophosphamide, epirubicin, and fluorouracil vs cyclophosphamide, epirubicin, filgrastim (G-CSF), and epoetin alfa followed by paclitaxel vs cyclophosphamide and doxorubicin followed by paclitaxel.

Secondary

• Compare the overall survival of patients treated with these regimens.
• Compare the rate of toxic effects of these regimens in this patient population.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of positive nodes (0 vs 1-3 vs 4-10 vs more than 10), type of prior surgery (total vs partial mastectomy), and estrogen receptor status (positive vs negative). Patients are randomized to one of three treatment arms.

• Arm I: Patients receive epirubicin IV and fluorouracil IV on days 1-8 and oral cyclophosphamide on days 1-14. Treatment repeats every 28 days for 6 courses.
• Patients receive epirubicin IV and cyclophosphamide IV on day 1 and filgrastim (G-CSF) subcutaneously (SC) on days 2-13. Patients with a hemoglobin < 13.0 g/dL also receive epoetin alfa SC once weekly beginning within 1 week after the start of therapy and continuing as needed. Treatment repeats every 14 days for 6 courses. Beginning 21 days after completion of epirubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and G-CSF and epoetin alfa as above. Treatment repeats every 21 days for 4 courses.
• Patients receive doxorubicin IV over 15 minutes and cyclophosphamide IV over 15 minutes on day 1. Treatment repeats every 21 days for 4 courses. Beginning 21 days after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel as in arm II.

Treatment in all arms continues in the absence of disease progression or unacceptable toxicity.

All receptor positive patients receive oral tamoxifen or anastrozole (if tamoxifen is contraindicated) for 5 years after completion of chemotherapy.

Quality of life is assessed at baseline, weeks 4, 8, 12, and 20 (arm I), weeks 4, 8, 13, and 22 (arm II), weeks 3, 9, 12, and 21 (arm III), 9 months, 12 months, and then annually thereafter.

Patients are followed at 9 months, 12 months, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,100 patients (700 per treatment arm) will be accrued for this study within 4 years.

Ages Eligible for Study:  up to  60 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast that is potentially curable
• T0-4 (dermal involvement on pathology assessment only), N0-2, M0
• No clinical T4 disease
• Previously treated with one of the following:
• Total mastectomy and level II axillary node dissection
• Partial mastectomy and level II axillary node dissection with planned breast radiotherapy after completion of study*
• Patients with a positive sentinel node biopsy must undergo level II axillary node dissection or sufficient nodal sampling NOTE: *If microscopic residual in situ or invasive disease is present at total or partial mastectomy margins, planned radiotherapy must also include a boost to the tumor bed
• No residual tumor in the axilla after dissection
• Axillary node positive
• Negative nodes allowed if the tumor is ≥ 1 cm and 1 of the following criteria defining high-risk node-negative disease are met:
• Histological grade III
• Estrogen receptor negative
• Lymphatic/vascular invasion
• Hormone receptor status:
• Estrogen receptor status known

PATIENT CHARACTERISTICS: Age:

• 60 and under

Sex:

• Female

Menopausal status:

• Pre- or postmenopausal

Performance status:

• ECOG 0-2

Life expectancy:

• At least 5 years

Hematopoietic:

• WBC ≥ 3,000/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic:

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

Renal:

• Creatinine ≤ 1.5 times ULN

Cardiovascular:

• LVEF ≥ limit of normal by MUGA or echocardiogram
• No arrhythmia requiring ongoing treatment
• No congestive heart failure
• No documented coronary artery disease

Other:

• No other malignancy except:
• Adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• Ductal or lobular carcinoma in situ that has been curatively treated by surgery alone
• Other prior malignancies (except breast cancer) curatively treated more than 5 years prior to study entry
• No serious underlying medical illness or psychiatric or addictive disorder that would preclude study compliance
• No known hypersensitivity to E. coli-derived products, mammalian-cell derived products, or any study agents
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective non-hormonal contraception

PRIOR CONCURRENT THERAPY: Biologic therapy:

• No prior immunotherapy for breast cancer
• No concurrent pegfilgrastim or darbepoetin alfa (Arm II)
• Allowed on arms 1 and 3 if medically necessary

Chemotherapy:

• No prior chemotherapy for breast cancer

Endocrine therapy:

• No prior hormonal therapy for breast cancer
• No concurrent hormone replacement therapy
• No concurrent selective estrogen-receptor modulators (e.g., raloxifene for the treatment or prevention of osteoporosis)
• No concurrent oral contraceptives (i.e., birth control pills)
• No other concurrent aromatase inhibitors

Radiotherapy:

• See Disease Characteristics
• No prior radiotherapy for breast cancer

Surgery:

• See Disease Characteristics
• No more than 12 weeks since prior total or partial mastectomy (including re-excision of margins)

Other:

• At least 30 days since prior investigational drugs
• No other concurrent investigational drugs
• Concurrent bisphosphonates for the treatment or prevention of osteoporosis allowed

Arizona
      CCOP - Mayo Clinic Scottsdale Oncology Program, Scottsdale,  Arizona,  85259-5404,  United States; Recruiting
Arkansas
      Arkansas Cancer Institute, Pine Bluff,  Arkansas,  71603,  United States; Recruiting
      Genesis Cancer Center, Hot Springs,  Arkansas,  71913,  United States; Recruiting
      Little Rock Hematology-Oncology Associates, Little Rock,  Arkansas,  72205,  United States; Recruiting
      Sparks Regional Medical Center, Fort Smith,  Arkansas,  72901-5128,  United States; Recruiting
California
      Scripps Cancer Center at Scripps Clinic, La Jolla,  California,  92037,  United States; Recruiting
      Shasta Regional Medical Center, Redding,  California,  96001-0853,  United States; Recruiting
Colorado
      University of Colorado Cancer Center at University of Colorado Health Sciences Center, Aurora,  Colorado,  80010,  United States; Recruiting
Connecticut
      Greenwich Hospital Association, Greenwich,  Connecticut,  06830,  United States; Recruiting
District of Columbia
      Sibley Memorial Hospital, Washington,  District of Columbia,  20016,  United States; Recruiting
Florida
      Lynn Regional Cancer Center of Boca Raton Community Hospital, Boca Raton,  Florida,  33466,  United States; Recruiting
      Mayo Clinic - Jacksonville, Jacksonville,  Florida,  32224,  United States; Recruiting
      Orange Park Cancer Center, Orange Park,  Florida,  32073,  United States; Recruiting
      University of Florida Shands Cancer Center, Gainesville,  Florida,  32610-0232,  United States; Recruiting
Georgia
      CCOP - Atlanta Regional, Atlanta,  Georgia,  30342-1701,  United States; Recruiting
Hawaii
      MBCCOP - Hawaii, Honolulu,  Hawaii,  96813,  United States; Recruiting
Illinois
      Cardinal Bernardin Cancer Center at Loyola University Medical Center, Maywood,  Illinois,  60153-5589,  United States; Recruiting
      CCOP - Carle Cancer Center, Urbana,  Illinois,  61801,  United States; Recruiting
      La Grange Oncology Associates, La Grange,  Illinois,  60525,  United States; Recruiting
      Swedish-American Regional Cancer Center, Rockford,  Illinois,  61104-2315,  United States; Recruiting
      University of Chicago Cancer Research Center, Chicago,  Illinois,  60637-1470,  United States; Recruiting
Indiana
      Evansville Cancer Center, Evansville,  Indiana,  47715,  United States; Recruiting
      Northern Indiana Oncology Associates - South Bend, South Bend,  Indiana,  46617,  United States; Recruiting
Iowa
      CCOP - Cedar Rapids Oncology Project, Cedar Rapids,  Iowa,  52403-1206,  United States; Recruiting
      CCOP - Iowa Oncology Research Association, Des Moines,  Iowa,  50309-1016,  United States; Recruiting
      Siouxland Hematology-Oncology, Sioux City,  Iowa,  51101-1733,  United States; Recruiting
Kansas
      CCOP - Wichita, Wichita,  Kansas,  67214-3882,  United States; Recruiting
Kentucky
      Central Baptist Hospital, Lexington,  Kentucky,  40503,  United States; Recruiting
      Consultants in Blood Disorders and Cancer, Louisville,  Kentucky,  40207,  United States; Recruiting
      Graves-Gilbert Clinic, Bowling Green,  Kentucky,  42102-9007,  United States; Recruiting
Louisiana
      Cancer Treatment Center at Christus Schumpert St. Mary Place, Shreveport,  Louisiana,  71101,  United States; Recruiting
      CCOP - Ochsner, New Orleans,  Louisiana,  70121,  United States; Recruiting
      Willis - Knighton South Center for Women's Health, Shreveport,  Louisiana,  71118,  United States; Recruiting
Maine
      Maine Center for Cancer Medicine and Blood Disorders - Scarborough, Scarborough,  Maine,  04074,  United States; Recruiting
      Maine General Medical Center - Waterville, Waterville,  Maine,  04901,  United States; Recruiting
Maryland
      Associates in Oncology and Hematology, Rockville,  Maryland,  20850,  United States; Recruiting
      St. Joseph Medical Center, Towson,  Maryland,  21204,  United States; Recruiting
      Suburban Hospital Cancer Program, Bethesda,  Maryland,  20817,  United States; Recruiting
Massachusetts
      Baystate Regional Cancer Program at D'Amour Center for Cancer Care, Springfield,  Massachusetts,  01199,  United States; Recruiting
Minnesota
      Cancer Care Center at St. Luke's Hospital, Duluth,  Minnesota,  55805,  United States; Recruiting
      CCOP - Duluth, Duluth,  Minnesota,  55805,  United States; Recruiting
      Mayo Clinic Cancer Center, Rochester,  Minnesota,  55905,  United States; Recruiting
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States; Recruiting
Missouri
      Columbia Comprehensive Cancer Care Clinic, Columbia,  Missouri,  65201,  United States; Recruiting
      Saint Louis University Cancer Center, Saint Louis,  Missouri,  63110,  United States; Recruiting
Nebraska
      Cancer Center at Creighton University Medical Center, Omaha,  Nebraska,  68131-2197,  United States; Recruiting
      CCOP - Missouri Valley Cancer Consortium, Omaha,  Nebraska,  68106,  United States; Recruiting
      Methodist Hospital Cancer Center at Nebraska Methodist Hospital - Omaha, Omaha,  Nebraska,  68114-4199,  United States; Recruiting
New Jersey
      Somerset Medical Center, Somerville,  New Jersey,  08876,  United States; Recruiting
      Valley Hospital - Ridgewood, Ridgewood,  New Jersey,  07450-2736,  United States; Recruiting
New York
      Advanced Oncology Associates, Armonk,  New York,  10504,  United States; Recruiting
      Hematology-Oncology Associates of Rockland, P.C., New City,  New York,  10956,  United States; Recruiting
      James P. Wilmot Cancer Center at University of Rochester Medical Center, Rochester,  New York,  14642,  United States; Recruiting
      Nalitt Cancer Institute at Staten Island University Hospital, Staten Island,  New York,  10305,  United States; Recruiting
      Queens Medical Associates, PC, Fresh Meadows,  New York,  11365,  United States; Recruiting
      Winthrop University Hospital, Mineola,  New York,  11501,  United States; Recruiting
North Carolina
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States; Recruiting
      Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital, Greenville,  North Carolina,  27858-4354,  United States; Recruiting
North Dakota
      CCOP - Merit Care Hospital, Fargo,  North Dakota,  58122,  United States; Recruiting
      Medcenter One Health System, Bismarck,  North Dakota,  58501-5505,  United States; Recruiting
Ohio
      CCOP - Dayton, Dayton,  Ohio,  45429,  United States; Recruiting
      CCOP - Toledo Community Hospital, Toledo,  Ohio,  43623-3456,  United States; Recruiting
      Gabrail Cancer Center - Canton Office, Canton,  Ohio,  44718,  United States; Recruiting
      Lawrence M. Stallings Medical Practice, Wooster,  Ohio,  44691,  United States; Recruiting
      Oncology Hematology Care, Incorporated - Mt. Auburn/Taft Road, Cincinnati,  Ohio,  45242,  United States; Recruiting
Pennsylvania
      Cancer Center of Drexel University College of Medicine, Philadelphia,  Pennsylvania,  19129,  United States; Recruiting
      CCOP - Geisinger Clinic and Medical Center, Danville,  Pennsylvania,  17822-2001,  United States; Recruiting
      Central Montgomery Medical Center, Lansdale,  Pennsylvania,  19446-1200,  United States; Recruiting
      Pottstown Memorial Regional Cancer Center, Pottstown,  Pennsylvania,  19464,  United States; Recruiting
South Carolina
      CCOP - Upstate Carolina, Spartanburg,  South Carolina,  29303,  United States; Recruiting
      Santee Hematology Oncology, Sumter,  South Carolina,  29150,  United States; Recruiting
South Dakota
      CCOP - Sioux Community Cancer Consortium, Sioux Falls,  South Dakota,  57104,  United States; Recruiting
      Rapid City Regional Hospital, Rapid City,  South Dakota,  57709,  United States; Recruiting
Tennessee
      Associates in Oncology and Hematology, Chattanooga,  Tennessee,  37404,  United States; Recruiting
Texas
      Lone Star Oncology - Austin, Austin,  Texas,  78759,  United States; Recruiting
      Medical City Dallas Hospital, Dallas,  Texas,  75230,  United States; Recruiting
Utah
      Cancer Associates of Northern Utah, Ogden,  Utah,  84403,  United States; Recruiting
Virginia
      Arlington-Fairfax Hematology/Oncology, PC, Arlington,  Virginia,  22205,  United States; Recruiting
      Northern Virginia Oncology Group, P.C., Fairfax,  Virginia,  22031,  United States; Recruiting
Wyoming
      Ivinson Memorial Hospital, Laramie,  Wyoming,  82070,  United States; Recruiting
Canada, British Columbia
      British Columbia Cancer Agency - Centre for the Southern Interior, Kelowna,  British Columbia,  V1Y 5L3,  Canada; Recruiting
      British Columbia Cancer Agency, Vancouver,  British Columbia,  V5Z 4E6,  Canada; Recruiting
      Fraser Valley Cancer Centre at Surrey Memorial Hospital, Surrey,  British Columbia,  V3V 1Z2,  Canada; Recruiting
      Nanaimo Cancer Clinic at Nanaimo Regional General Hospital, Nanaimo,  British Columbia,  V9S 2B7,  Canada; Recruiting
Canada, Manitoba
      CancerCare Manitoba, Winnipeg,  Manitoba,  R3E 0V9,  Canada; Recruiting
Canada, New Brunswick
      Moncton Hospital, Moncton,  New Brunswick,  E1C 6ZB,  Canada; Recruiting
      Saint John Regional Hospital, Saint John,  New Brunswick,  E2L 4L2,  Canada; Recruiting
Canada, Newfoundland and Labrador
      Newfoundland Cancer Treatment and Research Foundation, St. Johns,  Newfoundland and Labrador,  A1B 3V6,  Canada; Recruiting
Canada, Nova Scotia
      Nova Scotia Cancer Centre at Queen Elizabeth II Health Sciences Centre, Halifax,  Nova Scotia,  B3H 1V7,  Canada; Recruiting
Canada, Ontario
      Algoma Regional Cancer Program at Sault Area Hospital, Sault Sainte Marie,  Ontario,  P6A 2C4,  Canada; Recruiting
      Cancer Care Ontario - Windsor Regional Cancer Centre, Windsor,  Ontario,  N8W 2X3,  Canada; Recruiting
      Cancer Care Ontario-London Regional Cancer Centre, London,  Ontario,  N6A 4L6,  Canada; Recruiting
      Cancer Centre of Southeastern Ontario, Kingston,  Ontario,  K7L 5P9,  Canada; Recruiting
      Durham Regional Cancer Centre at Lakeridge Health Oshawa, Oshawa,  Ontario,  L1G 2B9,  Canada; Recruiting
      Grand River Regional Cancer Centre at Grand River Hospital, Kitchner,  Ontario,  N2G 1G3,  Canada; Recruiting
      Hotel Dieu Health Sciences Hospital - Niagara, St. Catharines,  Ontario,  L2R 5K3,  Canada; Recruiting
      Margaret and Charles Juravinski Cancer Centre, Hamilton,  Ontario,  L8V 5C2,  Canada; Recruiting
      Mount Sinai Hospital - Toronto, Toronto,  Ontario,  M5G 1X5,  Canada; Recruiting
      Northeastern Ontario Regional Cancer Centre, Sudbury,  Ontario,  P3E 5J1,  Canada; Recruiting
      Ottawa Regional Cancer Centre at Ottawa Hospital - General Campus, Ottawa,  Ontario,  K1H 1C4,  Canada; Recruiting
      Peterborough Oncology Clinic, Peterborough,  Ontario,  K9H 7B6,  Canada; Recruiting
      Regional Cancer Care at Thunder Bay Regional Health Sciences Centre, Thunder Bay,  Ontario,  P7B 6V4,  Canada; Recruiting
      Royal Victoria Hospital of Barrie, Barrie,  Ontario,  L4M 6M2,  Canada; Recruiting
      Scarborough Hospital - General Site, Scarborough,  Ontario,  M1P 2V5,  Canada; Recruiting
      St. Joseph's Health Centre - Toronto, Toronto,  Ontario,  M6R 1B5,  Canada; Recruiting
      St. Michael's Hospital - Toronto, Toronto,  Ontario,  M5B 1W8,  Canada; Recruiting
      Toronto General Hospital, Toronto,  Ontario,  M5G 2C4,  Canada; Recruiting
      Toronto Sunnybrook Regional Cancer Centre, Toronto,  Ontario,  M4N 3M5,  Canada; Recruiting
      Trillium Health Centre - Mississauga, Mississauga,  Ontario,  L5B 1B8,  Canada; Recruiting
Canada, Prince Edward Island
      Prince Edward Island Cancer Centre at Queen Elizabeth Hospital, Charlottetown,  Prince Edward Island,  C1A 8T5,  Canada; Recruiting
Canada, Quebec
      Centre Hospitalier de l'Universite de Montreal, Montreal,  Quebec,  H2L 4M1,  Canada; Recruiting
      Hopital Charles Lemoyne, Greenfield Park,  Quebec,  J4V 2H1,  Canada; Recruiting
      Hotel Dieu de Montreal, Montreal,  Quebec,  H2W 1T8,  Canada; Recruiting
      Maisonneuve-Rosemont Hospital, Montreal,  Quebec,  H1T 2M4,  Canada; Recruiting
Canada, Saskatchewan
      Allan Blair Cancer Centre at Pasqua Hospital, Regina,  Saskatchewan,  S4T 7T1,  Canada; Recruiting
      Saskatoon Cancer Centre, Saskatoon,  Saskatchewan,  S7N 4H4,  Canada; Recruiting

Study chairs or principal investigators

Mark Norman Levine, MD,  Study Chair,  Margaret and Charles Juravinski Cancer Centre   
Edith A. Perez, MD,  Study Chair,  Mayo Clinic - Jacksonville   
Kathy S. Albain, MD,  Loyola University   

Study ID Numbers:  CDR0000068520; CAN-NCIC-MA21; AMGEN-CAN-NCIC-MA21; NCCTG-CAN-NCIC-MA21; BMS-CAN-NCIC-MA21; JANSSEN-ORTHO-CAN-NCIC-MA21; PFIZER-CAN-NCIC-MA21; NCT00014222; SWOG-CAN-NCIC-MA.21
Record last reviewed:  March 2005
Last Updated:  March 28, 2005
Record first received:  April 10, 2001
ClinicalTrials.gov Identifier:  NCT00014222
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08