Combination Chemotherapy With or Without Colony-stimulating Factors in Treating Women With Breast Cancer

NCT ID: NCT00014222

Last Updated: 2020-10-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 2104 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-12-04
• Study Completion Date: 2014-03-17

Brief Summary

RATIONALE:

1. . To compare the effects on breast cancer of three different combinations of drugs which are commonly used to treat this disease.

2. . 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.

Detailed Description

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 and 8 and oral cyclophosphamide on days 1-14. Treatment repeats every 28 days for 6 courses.
• Arm II: 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.
• Arm III: 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, day 1 of cycles 2, 3 4 and 6 (arm I), days 1 of cycles 3 and and day 1 of cycles 1 and 4 of paclitaxel (arm II), day 1 of cycles 2 and 3, day 1 of cycles 1 and 4 of paclitaxel, (arm III), 9 months, 12 months, and then annually thereafter until 5 years

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.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1: CEF

6 cycles - q 28 days (6 months) - Cyclophosphamide 75 mg/m2 - po - Days 1-14 - Epirubicin 60 mg/m2 - IV - Days 1 and 8 - 5 Fluorouracil: 500mg/m2 - IV - Days 1 and 8 + Continuous Antibiotic Prophylaxis with Cotrimoxazole 960 mg (i.e.2x480 mg tablets) po-bid or Ciprofloxacin 500 mg - po-bid

Group Type: ACTIVE_COMPARATOR

cyclophosphamide

Intervention Type: DRUG

75, 600 and 830 mg/m2

epirubicin hydrochloride

Intervention Type: DRUG

60 mg/m2

fluorouracil

Intervention Type: DRUG

500mg/m2

Arm 2: EC/T

6 cycles - q 14 days (3 months) - Epirubicin 120 mg/m2 - IV - Day 1 - Cyclophosphamide 830 mg/m2 - IV - Day 1 - Filgrastim 5μg/kg/d - SC - Days 2 - 13 + Epoetin Alfa 40,000 IU - SC - once weekly (to begin within 1 week after start of protocol therapy as needed) 21 days from last administration of EC (EC/T) 4 cycles - q 21 days (3 months) - Adriamycin 60 mg/m2 - IV - Day 1 - Cyclophosphamide 600 mg/m2 - IV - Day 1 - 21 days from last administration of AC 4 cycles - q 21 days (3 months) - Paclitaxel 175 mg/m2 IV 3 hour infusion

Group Type: ACTIVE_COMPARATOR

epoetin alfa

Intervention Type: BIOLOGICAL

40,000 IU

filgrastim

Intervention Type: BIOLOGICAL

5 mg/kg/d - days 2-13

cyclophosphamide

Intervention Type: DRUG

75, 600 and 830 mg/m2

doxorubicin hydrochloride

Intervention Type: DRUG

60 mg/m2

paclitaxel

Intervention Type: DRUG

175 mg/m2

Arm 3: AC/T

4 cycles - q 21 days (3 months) - Adriamycin 60 mg/m2 - IV - Day 1 - Cyclophosphamide 600 mg/m2 - IV - Day 1 21 days from last administration of AC 4 cycles - q 21 days (3 months) - Paclitaxel 175 mg/m2 IV 3 hour infusion

Group Type: ACTIVE_COMPARATOR

cyclophosphamide

Intervention Type: DRUG

75, 600 and 830 mg/m2

doxorubicin hydrochloride

Intervention Type: DRUG

60 mg/m2

paclitaxel

Intervention Type: DRUG

175 mg/m2

Interventions

epoetin alfa

40,000 IU

Intervention Type: BIOLOGICAL

filgrastim

5 mg/kg/d - days 2-13

Intervention Type: BIOLOGICAL

cyclophosphamide

75, 600 and 830 mg/m2

Intervention Type: DRUG

doxorubicin hydrochloride

60 mg/m2

Intervention Type: DRUG

epirubicin hydrochloride

60 mg/m2

Intervention Type: DRUG

fluorouracil

500mg/m2

Intervention Type: DRUG

paclitaxel

175 mg/m2

Intervention Type: DRUG

Eligibility Criteria

Inclusion 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 adjuvant chemotherapy regimen*
• Patients with a positive sentinel node biopsy must undergo level II axillary node dissection or sufficient nodal sampling
• 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 or more of the following criteria defining high-risk node-negative disease are met:

• Histological grade III or,
• Estrogen receptor negative or,
• 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

• Maximum Eligible Age: 60 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

North Central Cancer Treatment Group

NETWORK

Sponsor Role: collaborator

SWOG Cancer Research Network

NETWORK

Sponsor Role: collaborator

Cancer and Leukemia Group B

NETWORK

Sponsor Role: collaborator

NCIC Clinical Trials Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mark N. Levine, MD

Role: STUDY_CHAIR

Margaret and Charles Juravinski Cancer Centre

Edith A. Perez, MD

Role: STUDY_CHAIR

Mayo Clinic

Kathy S. Albain, MD

Role: STUDY_CHAIR

Loyola University

Margot Burnell

Role: STUDY_CHAIR

Atlantic Health Sciences Corporation, Saint John NB

Hope Rugo

Role: STUDY_CHAIR

Cancer and Leukemia Group B

Locations

Sparks-Arkansas Oklahoma Cancer Treatment Centre

Fort Smith, Arkansas, United States

Hematology Oncology Services of Arkansas

Little Rock, Arkansas, United States

Scripps Cancer Center

La Jolla, California, United States

University of Colorado Cancer Centre

Aurora, Colorado, United States

Greenwich Hospital - Bendheim Cancer Center

Greenwich, Connecticut, United States

Sibley Memorial Hospital, Oncology Research

Washington D.C., District of Columbia, United States

Comprehensive Cancer Care Centre at Boca Raton

Boca Raton, Florida, United States

University of Florida

Gainesville, Florida, United States

Florida Oncology Associates

Orange Park, Florida, United States

The University of Chicago Medical Center

Chicago, Illinois, United States

Therapy Associates, Inc., Hematology/Oncology

Evansville, Indiana, United States

Lexington Oncology Assts./Central Baptist Hospital

Lexington, Kentucky, United States

Consultants in Blood Disorders and Cancer

Louisville, Kentucky, United States

CHRISTUS Schumpert Medical Center - Hem/Onc Clinic

Shreveport, Louisiana, United States

Willis-Knighton Cancer Center

Shreveport, Louisiana, United States

Maine Center for Cancer Medicine and Blood Disorders

Scarborough, Maine, United States

Maine General Medical Center

Waterville, Maine, United States

Suburban Hospital Cancer Program

Bethesda, Maryland, United States

Associates in Oncology/Hematology

Rockville, Maryland, United States

Saint Joseph Medical Center, Cancer Care Program

Towson, Maryland, United States

Baystate Regional Cancer Program

Springfield, Massachusetts, United States

St. Luke's Cancer Care Centre

Duluth, Minnesota, United States

University of Minnesota Cancer Centre

Minneapolis, Minnesota, United States

Columbia-Capitol Comprehensive Care Clinics

Jefferson City, Missouri, United States

Saint Louis University Hospital

St Louis, Missouri, United States

Nebraska Methodist Hospital

Omaha, Nebraska, United States

Creighton University Cancer Centre

Omaha, Nebraska, United States

Advanced Oncology Associates

Armonk, New York, United States

Queens Medical Associates, PC

Fresh Meadows, New York, United States

Winthrop University Hospital Onc/Hem

Mineola, New York, United States

Hematology Oncol. Associates Rockland

Nyack, New York, United States

University of Rochester

Rochester, New York, United States

Staten Island University Hospital

Staten Island, New York, United States

Our Lady of Mercy Medical Center

The Bronx, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

ECU School of Medicine, Leo Jenkins Cancer Center

Greenville, North Carolina, United States

Oncology/Hematology Care, Inc.

Cincinnati, Ohio, United States

Pottstown Memorial Regional Cancer Centre

Pottstown, Pennsylvania, United States

Santee Hematology Oncology

Sumter, South Carolina, United States

University Oncology and Hematology Associates

Chattanooga, Tennessee, United States

Lone Star Oncology Consultants, PA

Austin, Texas, United States

Center for Oncology Research and Treatment

Dallas, Texas, United States

Northern Utah Associates

Ogden, Utah, United States

Arlington-Fairfax Hematology Oncology P.C.

Arlington, Virginia, United States

Tom Baker Cancer Centre

Calgary, Alberta, Canada

BCCA - Cancer Centre for the Southern Interior

Kelowna, British Columbia, Canada

BCCA - Fraser Valley Cancer Centre

Surrey, British Columbia, Canada

BCCA - Vancouver Cancer Centre

Vancouver, British Columbia, Canada

CancerCare Manitoba

Winnipeg, Manitoba, Canada

The Moncton Hospital

Moncton, New Brunswick, Canada

Atlantic Health Sciences Corporation

Saint John, New Brunswick, Canada

Dr. H. Bliss Murphy Cancer Centre

St. John's, Newfoundland and Labrador, Canada

QEII Health Sciences Center

Halifax, Nova Scotia, Canada

The Royal Victoria Hospital

Barrie, Ontario, Canada

Northeast Cancer Center Health Sciences

Greater Sudbury, Ontario, Canada

Juravinski Cancer Centre at Hamilton Health Sciences

Hamilton, Ontario, Canada

Cancer Centre of Southeastern Ontario at Kingston

Kingston, Ontario, Canada

Grand River Regional Cancer Centre

Kitchener, Ontario, Canada

London Regional Cancer Program

London, Ontario, Canada

Lakeridge Health Oshawa

Oshawa, Ontario, Canada

Ottawa Health Research Institute - General Division

Ottawa, Ontario, Canada

Algoma District Cancer Program

Sault Ste. Marie, Ontario, Canada

The Scarborough Hospital

Scarborough Village, Ontario, Canada

Niagara Health System

St. Catharines, Ontario, Canada

Thunder Bay Regional Health Science Centre

Thunder Bay, Ontario, Canada

Odette Cancer Centre

Toronto, Ontario, Canada

St. Michael's Hospital

Toronto, Ontario, Canada

Mount Sinai Hospital

Toronto, Ontario, Canada

Univ. Health Network-Princess Margaret Hospital

Toronto, Ontario, Canada

Trillium Health Centre - West Toronto

Toronto, Ontario, Canada

Windsor Regional Cancer Centre

Windsor, Ontario, Canada

PEI Cancer Treatment Centre,Queen Elizabeth Hospital

Charlottetown, Prince Edward Island, Canada

Hopital Charles LeMoyne

Greenfield Park, Quebec, Canada

Hopital Maisonneuve-Rosemont

Montreal, Quebec, Canada

CHUM - Hopital Notre-Dame

Montreal, Quebec, Canada

CHUM - Hotel Dieu du Montreal

Montreal, Quebec, Canada

Allan Blair Cancer Centre

Regina, Saskatchewan, Canada

Saskatoon Cancer Centre

Saskatoon, Saskatchewan, Canada

Countries

United States; Canada

References

Burnell MJ, O'Connor EM, Chapman JW, et al.: Triple-negative receptor status and prognosis in the NCIC CTG MA.21 adjuvant breast cancer trial. [Abstract] J Clin Oncol 26 (Suppl 15): A-550, 2008.

Reference Type: RESULT

Burnell MJ, Levine MN, Chapman JA, et al.: A phase III adjuvant trial of sequenced EC + filgrastim + epoetin-alpha followed by paclitaxel compared to sequenced AC followed by paclitaxel compared to CEF in women with node-positive or high-risk node-negative breast cancer (NCIC CTG MA.21). [Abstract] J Clin Oncol 25 (Suppl 18): A-550, 2007.

Reference Type: RESULT

Burnell M, Levine M, Chapman JA, et al.: A randomized trial of CEF versus dose dense EC followed by paclitaxel versus AC followed by paclitaxel in women with node positive or high risk node negative breast cancer, NCIC CTG MA.21: results of an interim analysis. [Abstract] 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, Texas. A-53, 2006.

Reference Type: RESULT

Other Identifiers

CAN-NCIC-MA21

Identifier Type: REGISTRY

Identifier Source: secondary_id

AMGEN-CAN-NCIC-MA21

Identifier Type: OTHER

Identifier Source: secondary_id

NCCTG-CAN-NCIC-MA21

Identifier Type: OTHER

Identifier Source: secondary_id

BMS-CAN-NCIC-MA21

Identifier Type: OTHER

Identifier Source: secondary_id

JANSSEN-ORTHO-CAN-NCIC-MA21

Identifier Type: OTHER

Identifier Source: secondary_id

PFIZER-CAN-NCIC-MA21

Identifier Type: OTHER

Identifier Source: secondary_id

SWOG-CAN-NCIC-MA21

Identifier Type: OTHER

Identifier Source: secondary_id

CDR0000068520

Identifier Type: OTHER

Identifier Source: secondary_id

CALGB-CAN-NCIC-MA21

Identifier Type: OTHER

Identifier Source: secondary_id

MA21

Identifier Type: -

Identifier Source: org_study_id