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

Breast Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00014222
• Other study ID #: MA21
• Secondary ID: CAN-NCIC-MA21AMG
• Status: Completed
• Phase: Phase 3
• Start date: December 4, 2000
• Est. completion date: March 17, 2014

Study information

• Verified date: March 2020
• Source: Canadian Cancer Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2104
• Est. completion date: March 17, 2014
• Est. primary completion date: February 10, 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: N/A to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Biological:
• epoetin alfa
40,000 IU
• filgrastim
5 mg/kg/d - days 2-13

Drug:
• cyclophosphamide
75, 600 and 830 mg/m2
• doxorubicin hydrochloride
60 mg/m2
• epirubicin hydrochloride
60 mg/m2
• fluorouracil
500mg/m2
• paclitaxel
175 mg/m2

Locations

Country	Name	City	State
Canada	The Royal Victoria Hospital	Barrie	Ontario
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	PEI Cancer Treatment Centre,Queen Elizabeth Hospital	Charlottetown	Prince Edward Island
Canada	Hopital Charles LeMoyne	Greenfield Park	Quebec
Canada	QEII Health Sciences Center	Halifax	Nova Scotia
Canada	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario
Canada	BCCA - Cancer Centre for the Southern Interior	Kelowna	British Columbia
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	The Moncton Hospital	Moncton	New Brunswick
Canada	CHUM - Hopital Notre-Dame	Montreal	Quebec
Canada	CHUM - Hotel Dieu du Montreal	Montreal	Quebec
Canada	Hopital Maisonneuve-Rosemont	Montreal	Quebec
Canada	Lakeridge Health Oshawa	Oshawa	Ontario
Canada	Ottawa Health Research Institute - General Division	Ottawa	Ontario
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Atlantic Health Sciences Corporation	Saint John	New Brunswick
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Algoma District Cancer Program	Sault Ste. Marie	Ontario
Canada	The Scarborough Hospital	Scarborough	Ontario
Canada	Niagara Health System	St. Catharines	Ontario
Canada	Dr. H. Bliss Murphy Cancer Centre	St. John's	Newfoundland and Labrador
Canada	Northeast Cancer Center Health Sciences	Sudbury	Ontario
Canada	BCCA - Fraser Valley Cancer Centre	Surrey	British Columbia
Canada	Thunder Bay Regional Health Science Centre	Thunder Bay	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	Odette Cancer Centre	Toronto	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Trillium Health Centre - West Toronto	Toronto	Ontario
Canada	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario
Canada	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia
Canada	Windsor Regional Cancer Centre	Windsor	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Arlington-Fairfax Hematology Oncology P.C.	Arlington	Virginia
United States	Advanced Oncology Associates	Armonk	New York
United States	University of Colorado Cancer Centre	Aurora	Colorado
United States	Lone Star Oncology Consultants, PA	Austin	Texas
United States	Suburban Hospital Cancer Program	Bethesda	Maryland
United States	Comprehensive Cancer Care Centre at Boca Raton	Boca Raton	Florida
United States	Our Lady of Mercy Medical Center	Bronx	New York
United States	University Oncology and Hematology Associates	Chattanooga	Tennessee
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	Oncology/Hematology Care, Inc.	Cincinnati	Ohio
United States	Center for Oncology Research and Treatment	Dallas	Texas
United States	St. Luke's Cancer Care Centre	Duluth	Minnesota
United States	Duke University Medical Center	Durham	North Carolina
United States	Therapy Associates, Inc., Hematology/Oncology	Evansville	Indiana
United States	Sparks-Arkansas Oklahoma Cancer Treatment Centre	Fort Smith	Arkansas
United States	Queens Medical Associates, PC	Fresh Meadows	New York
United States	University of Florida	Gainesville	Florida
United States	ECU School of Medicine, Leo Jenkins Cancer Center	Greenville	North Carolina
United States	Greenwich Hospital - Bendheim Cancer Center	Greenwich	Connecticut
United States	Columbia-Capitol Comprehensive Care Clinics	Jefferson City	Missouri
United States	Scripps Cancer Center	La Jolla	California
United States	Lexington Oncology Assts./Central Baptist Hospital	Lexington	Kentucky
United States	Hematology Oncology Services of Arkansas	Little Rock	Arkansas
United States	Consultants in Blood Disorders and Cancer	Louisville	Kentucky
United States	Winthrop University Hospital Onc/Hem	Mineola	New York
United States	University of Minnesota Cancer Centre	Minneapolis	Minnesota
United States	Hematology Oncol. Associates Rockland	Nyack	New York
United States	Northern Utah Associates	Ogden	Utah
United States	Creighton University Cancer Centre	Omaha	Nebraska
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Florida Oncology Associates	Orange Park	Florida
United States	Pottstown Memorial Regional Cancer Centre	Pottstown	Pennsylvania
United States	University of Rochester	Rochester	New York
United States	Associates in Oncology/Hematology	Rockville	Maryland
United States	Saint Louis University Hospital	Saint Louis	Missouri
United States	Maine Center for Cancer Medicine and Blood Disorders	Scarborough	Maine
United States	CHRISTUS Schumpert Medical Center - Hem/Onc Clinic	Shreveport	Louisiana
United States	Willis-Knighton Cancer Center	Shreveport	Louisiana
United States	Baystate Regional Cancer Program	Springfield	Massachusetts
United States	Staten Island University Hospital	Staten Island	New York
United States	Santee Hematology Oncology	Sumter	South Carolina
United States	Saint Joseph Medical Center, Cancer Care Program	Towson	Maryland
United States	Sibley Memorial Hospital, Oncology Research	Washington	District of Columbia
United States	Maine General Medical Center	Waterville	Maine

Sponsors (4)

Lead Sponsor	Collaborator
NCIC Clinical Trials Group	Cancer and Leukemia Group B, North Central Cancer Treatment Group, Southwest Oncology Group

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (3)

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 ana

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-negativ

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.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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