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

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ClinicalTrials.gov Identifier: NCT00014222
Recruitment Status : Completed
First Posted : January 27, 2003
Results First Posted : March 10, 2020
Last Update Posted : October 5, 2020
Sponsor:
Collaborators:
North Central Cancer Treatment Group
Southwest Oncology Group
Cancer and Leukemia Group B
Information provided by (Responsible Party):
Canadian Cancer Trials Group ( NCIC Clinical Trials Group )

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.


Condition or disease Intervention/treatment Phase
Breast Cancer Biological: epoetin alfa Biological: filgrastim Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: epirubicin hydrochloride Drug: fluorouracil Drug: paclitaxel Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 4, 2000
Actual Primary Completion Date : February 10, 2014
Actual Study Completion Date : March 17, 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

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
Biological: epoetin alfa
40,000 IU

Biological: filgrastim
5 mg/kg/d - days 2-13

Drug: cyclophosphamide
75, 600 and 830 mg/m2

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




Primary Outcome Measures :
  1. Disease Free Survival [ Time Frame: 13 years ]
    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.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: 13 years ]
    Overall survival was defined as the time from randomization to the time of death from any cause, with censoring at longest follow-up.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 60 Years   (Child, Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00014222


Locations
Show Show 78 study locations
Sponsors and Collaborators
NCIC Clinical Trials Group
North Central Cancer Treatment Group
Southwest Oncology Group
Cancer and Leukemia Group B
Investigators
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Study Chair: Mark N. Levine, MD Margaret and Charles Juravinski Cancer Centre
Study Chair: Edith A. Perez, MD Mayo Clinic
Study Chair: Kathy S. Albain, MD Loyola University
Study Chair: Margot Burnell Atlantic Health Sciences Corporation, Saint John NB
Study Chair: Hope Rugo Cancer and Leukemia Group B
Publications of Results:
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.

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Responsible Party: NCIC Clinical Trials Group
ClinicalTrials.gov Identifier: NCT00014222    
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 )
First Posted: January 27, 2003    Key Record Dates
Results First Posted: March 10, 2020
Last Update Posted: October 5, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Canadian Cancer Trials Group ( NCIC Clinical Trials Group ):
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Cyclophosphamide
Doxorubicin
Liposomal doxorubicin
Fluorouracil
Epirubicin
Epoetin Alfa
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antimetabolites