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

A Phase III Adjuvant Trial Of Sequenced EC + Filgrastim + Epoetin Alfa Followed By Paclitaxel Versus Sequenced AC Followed By Paclitaxel Versus CEF As Therapy For Premenopausal Women And Early Postmenopausal Women Who Have Had Potentially Curative Surgery For Node Positive Or High Risk Node Negative Breast Cancer

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: cyclophosphamide; Drug: epirubicin hydrochloride; Drug: fluorouracil; Biological: epoetin alfa; Biological: filgrastim; Drug: doxorubicin hydrochloride; Drug: paclitaxel

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.

• Study Type: Interventional
• Enrollment (Actual): 2104
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • BCCA - Cancer Centre for the Southern Interior
    • Surrey, British Columbia, Canada, V3V 1Z2
      • BCCA - Fraser Valley Cancer Centre
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BCCA - Vancouver Cancer Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 6Z8
      • The Moncton Hospital
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Atlantic Health Sciences Corporation
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, AIB 3V6
      • Dr. H. Bliss Murphy Cancer Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • QEII Health Sciences Center
  • Ontario
    • Barrie, Ontario, Canada, L4M 6M2
      • The Royal Victoria Hospital
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario at Kingston
    • Kitchener, Ontario, Canada, N2G 1G3
      • Grand River Regional Cancer Centre
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Oshawa, Ontario, Canada, L1G 2B9
      • Lakeridge Health Oshawa
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Health Research Institute - General Division
    • Sault Ste. Marie, Ontario, Canada, P6B 0A8
      • Algoma District Cancer Program
    • Scarborough, Ontario, Canada, M1P 2V5
      • The Scarborough Hospital
    • St. Catharines, Ontario, Canada, L2R 7C6
      • Niagara Health System
    • Sudbury, Ontario, Canada, P3E 5J1
      • Northeast Cancer Center Health Sciences
    • Thunder Bay, Ontario, Canada, P7B 6V4
      • Thunder Bay Regional Health Science Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Odette Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Univ. Health Network-Princess Margaret Hospital
    • Toronto, Ontario, Canada, M9C 1A5
      • Trillium Health Centre - West Toronto
    • Windsor, Ontario, Canada, N8W 2X3
      • Windsor Regional Cancer Centre
  • Prince Edward Island
    • Charlottetown, Prince Edward Island, Canada, C1A 8T5
      • PEI Cancer Treatment Centre,Queen Elizabeth Hospital
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Hopital Charles LeMoyne
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM - Hopital Notre-Dame
    • Montreal, Quebec, Canada, H1T 2M4
      • Hopital Maisonneuve-Rosemont
    • Montreal, Quebec, Canada, H2W 1T8
      • CHUM - Hotel Dieu du Montreal
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre
• United States
  • Arkansas
    • Fort Smith, Arkansas, United States, 72901
      • Sparks-Arkansas Oklahoma Cancer Treatment Centre
    • Little Rock, Arkansas, United States, 72205
      • Hematology Oncology Services of Arkansas
  • California
    • La Jolla, California, United States, 92037
      • Scripps Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80010-0510
      • University of Colorado Cancer Centre
  • Connecticut
    • Greenwich, Connecticut, United States, 06830
      • Greenwich Hospital - Bendheim Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20016
      • Sibley Memorial Hospital, Oncology Research
  • Florida
    • Boca Raton, Florida, United States, 33428
      • Comprehensive Cancer Care Centre at Boca Raton
    • Gainesville, Florida, United States, 32610-0277
      • University of Florida
    • Orange Park, Florida, United States, 32073
      • Florida Oncology Associates
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • The University of Chicago Medical Center
  • Indiana
    • Evansville, Indiana, United States, 47715
      • Therapy Associates, Inc., Hematology/Oncology
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Lexington Oncology Assts./Central Baptist Hospital
    • Louisville, Kentucky, United States, 40207
      • Consultants in Blood Disorders and Cancer
  • Louisiana
    • Shreveport, Louisiana, United States, 71101
      • CHRISTUS Schumpert Medical Center - Hem/Onc Clinic
    • Shreveport, Louisiana, United States, 71103-3
      • Willis-Knighton Cancer Center
  • Maine
    • Scarborough, Maine, United States, 04074-9308
      • Maine Center for Cancer Medicine and Blood Disorders
    • Waterville, Maine, United States, 04901
      • Maine General Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Suburban Hospital Cancer Program
    • Rockville, Maryland, United States, 20850
      • Associates in Oncology/Hematology
    • Towson, Maryland, United States, 21204
      • Saint Joseph Medical Center, Cancer Care Program
  • Massachusetts
    • Springfield, Massachusetts, United States, 01107
      • Baystate Regional Cancer Program
  • Minnesota
    • Duluth, Minnesota, United States, 55802
      • St. Luke's Cancer Care Centre
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Centre
  • Missouri
    • Jefferson City, Missouri, United States, 65109
      • Columbia-Capitol Comprehensive Care Clinics
    • Saint Louis, Missouri, United States, 63110-0250
      • Saint Louis University Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Hospital
    • Omaha, Nebraska, United States, 68131
      • Creighton University Cancer Centre
  • New York
    • Armonk, New York, United States, 10504
      • Advanced Oncology Associates
    • Bronx, New York, United States, 10466
      • Our Lady of Mercy Medical Center
    • Fresh Meadows, New York, United States, 11366
      • Queens Medical Associates, PC
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital Onc/Hem
    • Nyack, New York, United States, 10960
      • Hematology Oncol. Associates Rockland
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Staten Island, New York, United States, 10305
      • Staten Island University Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 27858
      • ECU School of Medicine, Leo Jenkins Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology/Hematology Care, Inc.
  • Pennsylvania
    • Pottstown, Pennsylvania, United States, 19464
      • Pottstown Memorial Regional Cancer Centre
  • South Carolina
    • Sumter, South Carolina, United States, 29150
      • Santee Hematology Oncology
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • University Oncology and Hematology Associates
  • Texas
    • Austin, Texas, United States, 78759
      • Lone Star Oncology Consultants, PA
    • Dallas, Texas, United States, 75230
      • Center for Oncology Research and Treatment
  • Utah
    • Ogden, Utah, United States, 84403
      • Northern Utah Associates
  • Virginia
    • Arlington, Virginia, United States, 22205
      • Arlington-Fairfax Hematology Oncology P.C.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: cyclophosphamide; 75, 600 and 830 mg/m2; Drug: epirubicin hydrochloride; 60 mg/m2; Drug: fluorouracil; 500mg/m2
Active Comparator: 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	Drug: cyclophosphamide; 75, 600 and 830 mg/m2; Biological: epoetin alfa; 40,000 IU; Biological: filgrastim; 5 mg/kg/d - days 2-13; Drug: doxorubicin hydrochloride; 60 mg/m2; Drug: paclitaxel; 175 mg/m2
Active Comparator: 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	Drug: cyclophosphamide; 75, 600 and 830 mg/m2; Drug: doxorubicin hydrochloride; 60 mg/m2; Drug: paclitaxel; 175 mg/m2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Free Survival	Disease free survival was defined as the time from randomization to the time of recurrence of the primary disease. Local or nodal recurrence and metastatic disease were considered a recurrence of the primary tumour. Patients who had contralateral breast cancer or a second primary malignancy, or died from some cause other than disease were censored as relapse-free at the time of death. Patients who had not relapsed were censored at longest follow-up or at non-breast cancer death. As required, adjudication was used to assess reports of recurrence.	13 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival was defined as the time from randomization to the time of death from any cause, with censoring at longest follow-up.	13 years

Collaborators and Investigators

• Sponsor: NCIC Clinical Trials Group
• Collaborators: Southwest Oncology Group; Cancer and Leukemia Group B; North Central Cancer Treatment Group
• Investigators: Study Chair: Mark N. Levine, MD, Margaret and Charles Juravinski Cancer Centre; Study Chair: Margot Burnell, Atlantic Health Sciences Corporation, Saint John NB; Study Chair: Hope Rugo, Cancer and Leukemia Group B

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2000
• Primary Completion (Actual): February 10, 2014
• Study Completion (Actual): March 17, 2014

Study Registration Dates

• First Submitted: April 10, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): October 5, 2020
• Last Update Submitted That Met QC Criteria: September 11, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage I breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Hematinics; Cyclophosphamide; Paclitaxel; Fluorouracil; Epirubicin; Epoetin Alfa; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: MA21; CAN-NCIC-MA21 (Registry Identifier: PDQ Identifier); AMGEN-CAN-NCIC-MA21 (Other Identifier: Drug Industry); NCCTG-CAN-NCIC-MA21 (Other Identifier: Participating group identifier); BMS-CAN-NCIC-MA21 (Other Identifier: Drug Industry); JANSSEN-ORTHO-CAN-NCIC-MA21 (Other Identifier: Drug Industry); PFIZER-CAN-NCIC-MA21 (Other Identifier: Drug Industry); SWOG-CAN-NCIC-MA21 (Other Identifier: Participating group identifier); CDR0000068520 (Other Identifier: PDQ); CALGB-CAN-NCIC-MA21 (Other Identifier: Participating group)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No