Clinical trial NCT00014222: Combination Chemotherapy With or Without Colony-stimulating Factors in Treating Women With Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: North Central Cancer Treatment Group
name: SWOG Cancer Research Network
name: Cancer and Leukemia Group B
First posted: 2003-01-27
Enrollment: 2104
Sex: FEMALE
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Disease Free Survival
timeFrame: 13 years
Secondary outcomes:
measure: Overall Survival
timeFrame: 13 years
Other outcomes:
Locations:
city: Fort Smith
country: United States
facility: Sparks-Arkansas Oklahoma Cancer Treatment Centre
state: Arkansas
city: Little Rock
country: United States
facility: Hematology Oncology Services of Arkansas
state: Arkansas
city: La Jolla
country: United States
facility: Scripps Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Centre
state: Colorado
city: Greenwich
country: United States
facility: Greenwich Hospital - Bendheim Cancer Center
state: Connecticut
city: Washington
country: United States
facility: Sibley Memorial Hospital, Oncology Research
state: District of Columbia
city: Boca Raton
country: United States
facility: Comprehensive Cancer Care Centre at Boca Raton
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Orange Park
country: United States
facility: Florida Oncology Associates
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Evansville
country: United States
facility: Therapy Associates, Inc., Hematology/Oncology
state: Indiana
city: Lexington
country: United States
facility: Lexington Oncology Assts./Central Baptist Hospital
state: Kentucky
city: Louisville
country: United States
facility: Consultants in Blood Disorders and Cancer
state: Kentucky
city: Shreveport
country: United States
facility: CHRISTUS Schumpert Medical Center - Hem/Onc Clinic
state: Louisiana
city: Shreveport
country: United States
facility: Willis-Knighton Cancer Center
state: Louisiana
city: Scarborough
country: United States
facility: Maine Center for Cancer Medicine and Blood Disorders
state: Maine
city: Waterville
country: United States
facility: Maine General Medical Center
state: Maine
city: Bethesda
country: United States
facility: Suburban Hospital Cancer Program
state: Maryland
city: Rockville
country: United States
facility: Associates in Oncology/Hematology
state: Maryland
city: Towson
country: United States
facility: Saint Joseph Medical Center, Cancer Care Program
state: Maryland
city: Springfield
country: United States
facility: Baystate Regional Cancer Program
state: Massachusetts
city: Duluth
country: United States
facility: St. Luke's Cancer Care Centre
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Centre
state: Minnesota
city: Jefferson City
country: United States
facility: Columbia-Capitol Comprehensive Care Clinics
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Omaha
country: United States
facility: Creighton University Cancer Centre
state: Nebraska
city: Armonk
country: United States
facility: Advanced Oncology Associates
state: New York
city: Bronx
country: United States
facility: Our Lady of Mercy Medical Center
state: New York
city: Fresh Meadows
country: United States
facility: Queens Medical Associates, PC
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital Onc/Hem
state: New York
city: Nyack
country: United States
facility: Hematology Oncol. Associates Rockland
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Staten Island
country: United States
facility: Staten Island University Hospital
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greenville
country: United States
facility: ECU School of Medicine, Leo Jenkins Cancer Center
state: North Carolina
city: Cincinnati
country: United States
facility: Oncology/Hematology Care, Inc.
state: Ohio
city: Pottstown
country: United States
facility: Pottstown Memorial Regional Cancer Centre
state: Pennsylvania
city: Sumter
country: United States
facility: Santee Hematology Oncology
state: South Carolina
city: Chattanooga
country: United States
facility: University Oncology and Hematology Associates
state: Tennessee
city: Austin
country: United States
facility: Lone Star Oncology Consultants, PA
state: Texas
city: Dallas
country: United States
facility: Center for Oncology Research and Treatment
state: Texas
city: Ogden
country: United States
facility: Northern Utah Associates
state: Utah
city: Arlington
country: United States
facility: Arlington-Fairfax Hematology Oncology P.C.
state: Virginia
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Kelowna
country: Canada
facility: BCCA - Cancer Centre for the Southern Interior
state: British Columbia
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Moncton
country: Canada
facility: The Moncton Hospital
state: New Brunswick
city: Saint John
country: Canada
facility: Atlantic Health Sciences Corporation
state: New Brunswick
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: QEII Health Sciences Center
state: Nova Scotia
city: Barrie
country: Canada
facility: The Royal Victoria Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Regional Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Health Research Institute - General Division
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
state: Ontario
city: Scarborough
country: Canada
facility: The Scarborough Hospital
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Sudbury
country: Canada
facility: Northeast Cancer Center Health Sciences
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
state: Ontario
city: Toronto
country: Canada
facility: Trillium Health Centre - West Toronto
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre
state: Ontario
city: Charlottetown
country: Canada
facility: PEI Cancer Treatment Centre,Queen Elizabeth Hospital
state: Prince Edward Island
city: Greenfield Park
country: Canada
facility: Hopital Charles LeMoyne
state: Quebec
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hotel Dieu du Montreal
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
Study officials:
affiliation: Margaret and Charles Juravinski Cancer Centre
name: Mark N. Levine, MD
role: STUDY_CHAIR
affiliation: Mayo Clinic
name: Edith A. Perez, MD
role: STUDY_CHAIR
affiliation: Loyola University
name: Kathy S. Albain, MD
role: STUDY_CHAIR
affiliation: Atlantic Health Sciences Corporation, Saint John NB
name: Margot Burnell
role: STUDY_CHAIR
affiliation: Cancer and Leukemia Group B
name: Hope Rugo
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.