High-Dose Combination Chemotherapy Plus Peripheral Stem Cell Transplantation Compared With Standard Combination Chemotherapy in Treating Women With High-Risk Breast Cancer

NCT ID: NCT00002784

Last Updated: 2013-04-04

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

344 participants

Study Classification

INTERVENTIONAL

Study Start Date

1996-06-30

Study Completion Date

2011-12-31

Brief Summary

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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. It is not yet known if high-dose combination chemotherapy plus peripheral stem cell transplantation is more effective than standard combination chemotherapy for breast cancer.

PURPOSE: Randomized phase III trial to compare high-dose combination chemotherapy plus peripheral stem cell transplantation with standard combination chemotherapy in treating women with stage II or stage III breast cancer.

Detailed Description

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OBJECTIVES: I. Compare the survival, disease-free survival, and systemic disease-free survival of women with high-risk, operable stage II/III breast cancer treated with three courses of dose-intensive epirubicin/cyclophosphamide (EC) supported by granulocyte colony-stimulating factor (G-CSF) and G-CSF-mobilized peripheral blood stem cells vs. standard EC followed by cyclophosphamide/methotrexate/fluorouracil. II. Compare the toxicity, duration of quality-adjusted time without symptoms and toxicity, and quality of life associated with these two treatments. III. Evaluate the cost effectiveness of these two treatments.

OUTLINE: This is a randomized study. Patients are stratified by estrogen receptor status and menopausal status. Within 6 weeks of surgery, patients in the first group receive epirubicin (preferred) or doxorubicin plus cyclophosphamide every 3 weeks for 4 courses followed by conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) every 4 weeks for 3 courses. Patients in the second group undergo stem cell mobilization and harvest with granulocyte colony-stimulating factor (G-CSF) followed within 10 weeks of surgery by high-dose chemotherapy with epirubicin and cyclophosphamide followed by peripheral blood stem cell rescue and G-CSF. All patients receive adjuvant tamoxifen, and patients who underwent lumpectomy prior to entry are required to receive adjuvant radiotherapy (radiotherapy is optional for patients who underwent mastectomy prior to entry). Patients are followed every 3 months for 2 years, then q 6 months for 3 years, then yearly.

PROJECTED ACCRUAL: 210 patients will be accrued over 4 years to provide 195 evaluable patients.

Conditions

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Breast Cancer

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Standard chemotherapy

EC/AC x 4 followed by CMF x 3 and tamoxifen to 5 years after randomization.

Group Type ACTIVE_COMPARATOR

CMF regimen

Intervention Type DRUG

Cyclophosphamide 100 mg/m2 orally days 1 - 14, methotrexate 40 mg/m2 iv days 1 and 8, 5-fluorouracil 600 mg/m2 iv days 1 and 8. Repeat every 28 days.

cyclophosphamide

Intervention Type DRUG

For high-dose EC arm: cyclophosphamide 4 gm/m2 iv as 4 divided doses. For standard chemotherapy arm: cyclophosphamide 600 mg/m2 iv day 1 of 21-day EC cycles, and cyclophosphamide 100 mg/m2 orally on days 1-14 of 28-day CMF cycles.

doxorubicin hydrochloride

Intervention Type DRUG

Doxorubicin 60 mg/m2 iv on day 1 of 21-day cycles of AC.

epirubicin hydrochloride

Intervention Type DRUG

Epirubicin 90 mg/m2 iv on day 1 of 21-day cycles of EC.

fluorouracil

Intervention Type DRUG

5-fluorouracil 600 mg/m2 iv days 1 and 8 of 28-day cycles of CMF.

methotrexate

Intervention Type DRUG

Methotrexate 40 mg/m2 iv on days 1 and 8 of 28-day cycles of CMF.

tamoxifen citrate

Intervention Type DRUG

Tamoxifen 20mg daily for 5 years or until relapse.

low-LET electron therapy

Intervention Type RADIATION

Radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution.

low-LET photon therapy

Intervention Type RADIATION

radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution.

Dose-intensive EC

High-dose EC x 3 supported by peripheral blood progenitor cells and tamoxifen to 5 years after randomization.

Group Type EXPERIMENTAL

filgrastim

Intervention Type BIOLOGICAL

Filgrastim 10 mg/kg/d sc for 6 days after randomization.

cyclophosphamide

Intervention Type DRUG

For high-dose EC arm: cyclophosphamide 4 gm/m2 iv as 4 divided doses. For standard chemotherapy arm: cyclophosphamide 600 mg/m2 iv day 1 of 21-day EC cycles, and cyclophosphamide 100 mg/m2 orally on days 1-14 of 28-day CMF cycles.

mesna

Intervention Type DRUG

MESNA (7.2 gm/m2) on days 2 and 3 of 21-day cycles of dose-intensive EC.

tamoxifen citrate

Intervention Type DRUG

Tamoxifen 20mg daily for 5 years or until relapse.

peripheral blood stem cell transplantation

Intervention Type PROCEDURE

Peripheral blood progenitor cells (PBPC) infusion on day 5 of each 21-day cycle of dose-intensive EC.

low-LET electron therapy

Intervention Type RADIATION

Radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution.

low-LET photon therapy

Intervention Type RADIATION

radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution.

Interventions

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filgrastim

Filgrastim 10 mg/kg/d sc for 6 days after randomization.

Intervention Type BIOLOGICAL

CMF regimen

Cyclophosphamide 100 mg/m2 orally days 1 - 14, methotrexate 40 mg/m2 iv days 1 and 8, 5-fluorouracil 600 mg/m2 iv days 1 and 8. Repeat every 28 days.

Intervention Type DRUG

cyclophosphamide

For high-dose EC arm: cyclophosphamide 4 gm/m2 iv as 4 divided doses. For standard chemotherapy arm: cyclophosphamide 600 mg/m2 iv day 1 of 21-day EC cycles, and cyclophosphamide 100 mg/m2 orally on days 1-14 of 28-day CMF cycles.

Intervention Type DRUG

doxorubicin hydrochloride

Doxorubicin 60 mg/m2 iv on day 1 of 21-day cycles of AC.

Intervention Type DRUG

epirubicin hydrochloride

Epirubicin 90 mg/m2 iv on day 1 of 21-day cycles of EC.

Intervention Type DRUG

fluorouracil

5-fluorouracil 600 mg/m2 iv days 1 and 8 of 28-day cycles of CMF.

Intervention Type DRUG

mesna

MESNA (7.2 gm/m2) on days 2 and 3 of 21-day cycles of dose-intensive EC.

Intervention Type DRUG

methotrexate

Methotrexate 40 mg/m2 iv on days 1 and 8 of 28-day cycles of CMF.

Intervention Type DRUG

tamoxifen citrate

Tamoxifen 20mg daily for 5 years or until relapse.

Intervention Type DRUG

peripheral blood stem cell transplantation

Peripheral blood progenitor cells (PBPC) infusion on day 5 of each 21-day cycle of dose-intensive EC.

Intervention Type PROCEDURE

low-LET electron therapy

Radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution.

Intervention Type RADIATION

low-LET photon therapy

radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution.

Intervention Type RADIATION

Eligibility Criteria

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Inclusion Criteria

DISEASE CHARACTERISTICS: Histologically proven breast carcinoma in one of the following categories: 10 or more involved axillary nodes 5 or more involved axillary nodes and either: Primary tumor estrogen receptor (ER)-negative (less than 10 femtomoles per milligram of cytosol protein) T3 tumor (regardless of ER status) Total mastectomy or breast-conserving procedure (lumpectomy or quadrantectomy) required within 6 weeks prior to randomization Tumor confined to breast and axillary nodes (T1a-c, T2, or T3, N1-2, M0 by the UICC staging system) The following conditions exclude entry: Satellite skin nodules distant from the primary tumor Supraclavicular node involvement Inoperable, matted axillary nodes Fixation of primary tumor to chest wall (excluding pectoralis major) Bilateral breast cancer (any mass in opposite breast unless biopsy-proven benign) Hot spots on bone scintigram (unless confirmed to be benign) Skeletal pain of unknown cause Hormone receptor status: ER status determination preferred, but not required

PATIENT CHARACTERISTICS: Age: 16-65 Sex: Women only Menopausal status: Any status Performance status: ECOG 0-2 Hematopoietic: WBC at least 4,000 Platelets at least 100,000 Hepatic: Bilirubin no greater than 1.1 mg/dL (20 micromoles/L) AST no greater than twice normal Renal: Creatinine no greater than 1.3 mg/dL (120 micromoles/L) Cardiovascular: Left ventricular ejection fraction greater than 50% by MUGA Other: No second malignancy except: Basal cell carcinoma Adequately treated carcinoma in situ of the cervix No significant nonmalignant disease that would preclude participation No psychiatric or addictive disorder that would compromise informed consent or participation No pregnant or nursing women Adequate contraception strongly advised for fertile women

PRIOR CONCURRENT THERAPY: No prior therapy for breast cancer other than surgery (see Disease Characteristics)
Minimum Eligible Age

16 Years

Maximum Eligible Age

65 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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ETOP IBCSG Partners Foundation

NETWORK

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Russell Basser, MD

Role: STUDY_CHAIR

Melbourne Health

Locations

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Newcastle Mater Misericordiae Hospital

Newcastle, New South Wales, Australia

Site Status

Royal Prince Alfred Hospital, Sydney

Sydney, New South Wales, Australia

Site Status

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Site Status

Queen Elizabeth Hospital

Adelaide, South Australia, Australia

Site Status

Royal Melbourne Hospital

Parkville, Victoria, Australia

Site Status

Swiss Institute for Applied Cancer Research

Bern, , Switzerland

Site Status

Inselspital, Bern

Bern, , Switzerland

Site Status

Centre Hospitalier Universitaire Vaudois

Lausanne, , Switzerland

Site Status

Istituto Oncologico della Svizzera Italiana

Lugano, , Switzerland

Site Status

Kantonsspital - Saint Gallen

Sankt Gallen, , Switzerland

Site Status

Universitaetsspital

Zurich, , Switzerland

Site Status

Countries

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Australia Switzerland

References

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Pestalozzi BC, Zahrieh D, Mallon E, Gusterson BA, Price KN, Gelber RD, Holmberg SB, Lindtner J, Snyder R, Thurlimann B, Murray E, Viale G, Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol. 2008 Jun 20;26(18):3006-14. doi: 10.1200/JCO.2007.14.9336. Epub 2008 May 5.

Reference Type BACKGROUND
PMID: 18458044 (View on PubMed)

Keshaviah A, Dellapasqua S, Rotmensz N, Lindtner J, Crivellari D, Collins J, Colleoni M, Thurlimann B, Mendiola C, Aebi S, Price KN, Pagani O, Simoncini E, Castiglione Gertsch M, Gelber RD, Coates AS, Goldhirsch A. CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials. Ann Oncol. 2007 Apr;18(4):701-8. doi: 10.1093/annonc/mdl492. Epub 2007 Jan 20.

Reference Type BACKGROUND
PMID: 17237474 (View on PubMed)

Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. doi: 10.1093/annonc/mdp024. Epub 2009 May 25.

Reference Type RESULT
PMID: 19468030 (View on PubMed)

International Breast Cancer Study Group; Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. doi: 10.1200/JCO.2005.03.5196.

Reference Type RESULT
PMID: 16421418 (View on PubMed)

Basser RL, Abraham R, To LB, Fox RM, Green MD. Cardiac effects of high-dose epirubicin and cyclophosphamide in women with poor prognosis breast cancer. Ann Oncol. 1999 Jan;10(1):53-8. doi: 10.1023/a:1008390203340.

Reference Type RESULT
PMID: 10076722 (View on PubMed)

Basser RL, To LB, Collins JP, Begley CG, Keefe D, Cebon J, Bashford J, Durrant S, Szer J, Kotasek D, Juttner CA, Russell I, Maher DW, Olver I, Sheridan WP, Fox RM, Green MD. Multicycle high-dose chemotherapy and filgrastim-mobilized peripheral-blood progenitor cells in women with high-risk stage II or III breast cancer: five-year follow-up. J Clin Oncol. 1999 Jan;17(1):82-92. doi: 10.1200/JCO.1999.17.1.82.

Reference Type RESULT
PMID: 10458221 (View on PubMed)

Basser RL, To LB, Begley CG, Juttner CA, Maher DW, Szer J, Cebon J, Collins JP, Russell I, Olver I, et al. Adjuvant treatment of high-risk breast cancer using multicycle high-dose chemotherapy and filgrastim-mobilized peripheral blood progenitor cells. Clin Cancer Res. 1995 Jul;1(7):715-21.

Reference Type RESULT
PMID: 9816037 (View on PubMed)

Other Identifiers

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IBCSG-15-95

Identifier Type: -

Identifier Source: secondary_id

EU-96021

Identifier Type: -

Identifier Source: secondary_id

CDR0000064834

Identifier Type: -

Identifier Source: org_study_id

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