Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

High-Dose Combination Chemotherapy Plus Peripheral Stem Cell Transplantation Compared With Standard Combination Chemotherapy in Treating Women With High-Risk Breast Cancer (15-95)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
International Breast Cancer Study Group
ClinicalTrials.gov Identifier:
NCT00002784
First received: November 1, 1999
Last updated: April 3, 2013
Last verified: July 2012
  Purpose

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.


Condition Intervention Phase
Breast Cancer
Biological: filgrastim
Drug: CMF regimen
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Drug: epirubicin hydrochloride
Drug: fluorouracil
Drug: mesna
Drug: methotrexate
Drug: tamoxifen citrate
Procedure: peripheral blood stem cell transplantation
Radiation: low-LET electron therapy
Radiation: low-LET photon therapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Trial of High-dose Epirubicin and Cyclophosphamide x 3 Supported by Peripheral Blood Progenitor Cells Versus Anthracycline and Cyclophosphamide x 4 Followed by Cyclophosphamide, Methotrexate, and 5-fluorouracil x 3 as Adjuvant Treatment for High Risk Operable Stage ii and Stage Iii Breast Cancer in Premenopausal and Young Postmenopausal (Less Than or Equal to 65 Yrs) Patients.

Resource links provided by NLM:


Further study details as provided by International Breast Cancer Study Group:

Primary Outcome Measures:
  • Disease-free survival. [ Time Frame: 16 years after randomization. ] [ Designated as safety issue: No ]
    Time from randomization to recurrence (including recurrence isolated to the breast), metastasis, appearance of a second primary tumor, or death from any cause, whichever occurs first.


Secondary Outcome Measures:
  • Overall survival. [ Time Frame: 16 years after randomization. ] [ Designated as safety issue: No ]
    Time from randomization to death from any cause.

  • Toxicity. [ Time Frame: 5 years after randomization. ] [ Designated as safety issue: Yes ]
    Morbidity information was recorded using standard toxicity criteria.

  • Quality of life. [ Time Frame: 16 years after randomization. ] [ Designated as safety issue: No ]
    Quality of life was assessed using standard International Breast Cancer Study Group instruments.


Enrollment: 344
Study Start Date: June 1996
Study Completion Date: December 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Standard chemotherapy
EC/AC x 4 followed by CMF x 3 and tamoxifen to 5 years after randomization.
Drug: 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.
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.
Drug: doxorubicin hydrochloride
Doxorubicin 60 mg/m2 iv on day 1 of 21-day cycles of AC.
Drug: epirubicin hydrochloride
Epirubicin 90 mg/m2 iv on day 1 of 21-day cycles of EC.
Drug: fluorouracil
5-fluorouracil 600 mg/m2 iv days 1 and 8 of 28-day cycles of CMF.
Drug: methotrexate
Methotrexate 40 mg/m2 iv on days 1 and 8 of 28-day cycles of CMF.
Drug: tamoxifen citrate
Tamoxifen 20mg daily for 5 years or until relapse.
Radiation: 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.
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.
Experimental: Dose-intensive EC
High-dose EC x 3 supported by peripheral blood progenitor cells and tamoxifen to 5 years after randomization.
Biological: filgrastim
Filgrastim 10 mg/kg/d sc for 6 days after randomization.
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.
Drug: mesna
MESNA (7.2 gm/m2) on days 2 and 3 of 21-day cycles of dose-intensive EC.
Drug: tamoxifen citrate
Tamoxifen 20mg daily for 5 years or until relapse.
Procedure: peripheral blood stem cell transplantation
Peripheral blood progenitor cells (PBPC) infusion on day 5 of each 21-day cycle of dose-intensive EC.
Radiation: 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.
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.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   16 Years to 65 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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)

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00002784

Locations
Australia, New South Wales
Newcastle Mater Misericordiae Hospital
Newcastle, New South Wales, Australia, NSW 2310
Royal Prince Alfred Hospital, Sydney
Sydney, New South Wales, Australia, 2050
Australia, South Australia
Queen Elizabeth Hospital
Adelaide, South Australia, Australia, 5011
Royal Adelaide Hospital
Adelaide, South Australia, Australia, 5000
Australia, Victoria
Royal Melbourne Hospital
Parkville, Victoria, Australia, 3050
Switzerland
Inselspital, Bern
Bern, Switzerland, CH-3010
Swiss Institute for Applied Cancer Research
Bern, Switzerland, CH-3008
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland, CH-1011
Istituto Oncologico della Svizzera Italiana
Lugano, Switzerland, CH-6900
Kantonsspital - Saint Gallen
Saint Gallen, Switzerland, CH-9007
Universitaetsspital
Zurich, Switzerland, CH-8091
Sponsors and Collaborators
International Breast Cancer Study Group
Investigators
Study Chair: Russell Basser, MD Melbourne Health
  More Information

Additional Information:
Publications:

Responsible Party: International Breast Cancer Study Group
ClinicalTrials.gov Identifier: NCT00002784     History of Changes
Other Study ID Numbers: CDR0000064834, IBCSG-15-95, EU-96021
Study First Received: November 1, 1999
Last Updated: April 3, 2013
Health Authority: United States: Federal Government
Switzerland: Swissmedic

Keywords provided by International Breast Cancer Study Group:
stage II breast cancer
stage IIIA breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Cyclophosphamide
Doxorubicin
Epirubicin
Fluorouracil
Liposomal doxorubicin
Methotrexate
Tamoxifen
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Alkylating Agents
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Hormonal
Antirheumatic Agents
Bone Density Conservation Agents
Dermatologic Agents
Enzyme Inhibitors
Estrogen Antagonists
Estrogen Receptor Modulators
Folic Acid Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on November 25, 2014