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Cyclophosphamide, Methotrexate, and Fluorouracil, With or Without Epirubicin Hydrochloride, in Treating Women Who Have Undergone Surgery for Breast Cancer (Group III Closed to New Patients as of 12/7/2009)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01031030
Recruitment Status : Unknown
Verified December 2009 by National Cancer Institute (NCI).
Recruitment status was:  Active, not recruiting
First Posted : December 14, 2009
Last Update Posted : August 2, 2013
Information provided by:

Study Description
Brief Summary:

RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide, methotrexate, fluorouracil, and epirubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving cyclophosphamide together with methotrexate and fluorouracil before, after, or without epirubicin hydrochloride is more effective in treating patients with breast cancer that can be removed by surgery.

PURPOSE: This randomized phase III trial is comparing three regimens of cyclophosphamide given together with methotrexate and fluorouracil, with or without epirubicin hydrochloride, to see how well it works in treating women who have undergone surgery for breast cancer. (Group III was closed to new patients as of 12/7/2009.)

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: cyclophosphamide Drug: epirubicin hydrochloride Drug: fluorouracil Drug: methotrexate Other: laboratory biomarker analysis Procedure: adjuvant therapy Phase 3

Detailed Description:



  • To determine the impact of adjuvant chemotherapy comprising epirubicin hydrochloride followed by cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, methotrexate, and fluorouracil followed by epirubicin hydrochloride versus cyclophosphamide, methotrexate, and fluorouracil on overall survival of patients with biologically aggressive, resectable, node-negative or node-positive breast cancer.


  • To assess the disease-free survival and patterns of relapse in these patients.
  • To assess the tolerance to and toxicity of treatment in these patients.
  • To determine the quality of life of these patients.
  • To verify the effectiveness of these treatments in different subgroups of patients.
  • To collect, retrospectively, information on the expression of tumor suppressor gene p53, oncogene c-erbB-2, and bcl-2 protein involved in apoptosis. (exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to center, lymph node status (N0 vs N1-3), and estrogen receptor status (negative vs positive). Patients are randomized to 1 of 3 treatment arms.

  • Arm I: Beginning 4-6 weeks following surgery, patients receive epirubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1-8. Treatment repeats every 4 weeks for 4 courses.
  • Arm II: Beginning 4-6 weeks following surgery, patients receive cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1-8. Treatment repeats every 4 weeks for 4 courses. Patients then receive epirubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks for 4 courses.
  • Arm III (closed to accrual as of 12/7/2009): Beginning 4-6 weeks following surgery, patients receive cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1-8. Treatment repeats every 4 weeks for 6 courses.

Patients with estrogen receptor-positive disease receive tamoxifen daily for 5 years after completing chemotherapy.

After completion of study therapy, patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually for 5 years.

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Allocation: Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Adjuvant Treatment of Biologically Aggressive Breast Cancer (N-,N+1,3): Controlled Clinical Study
Study Start Date : November 1997
Estimated Primary Completion Date : December 2010

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
U.S. FDA Resources

Arms and Interventions

Outcome Measures

Primary Outcome Measures :
  1. Overall survival

Secondary Outcome Measures :
  1. Disease-free survival
  2. Toxicity
  3. Quality of life
  4. Efficacy in subgroups of patients

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No


  • Histologically confirmed breast cancer

    • Underwent radical mastectomy, guadrantectomy, or tumorectomy with axillary node dissection within the past 4-6 weeks
    • Biologically aggressive disease
    • At least 10 lymph nodes removed

      • Node-negative (> 1 cm, or > 2 cm if histology is favorable, esp. tubular carcinoma and/or prevalent intraductal component > 50%) tumors OR node-positive (1-3) tumors, meeting the following criteria:

        • High thymidine-labeling index (> 3%)
        • Poorly differentiated tumor (grade III)
        • High S-phase fraction (> 10% by flow cytometry)
        • High Ki67/MIB1 expression (< 20%)
  • No bilateral breast cancer
  • No T4a, inoperable T4b, T4c, or T4d disease
  • Any estrogen receptor status (positive, negative, unknown)
  • No distant metastases


  • Any menopause status
  • WBC ≥ 3,500/mL
  • ANC ≥ 1,500/mL
  • Platelet count ≥ 120,000/mL
  • AST and ALT ≤ 1.5 times upper limit of normal (ULN)
  • Creatinine ≤ 1.5 mg/mL
  • Bilirubin ≤ 1.5 times ULN
  • Not pregnant
  • Geographically accessible for follow-up
  • No prior breast cancer and/or other cancer except for carcinoma in situ of the cervix or basal cell skin cancer treated with radical intent
  • No significant alterations in cardiovascular function
  • No serious psychiatric disorders
  • No impaired renal or liver function


  • See Disease Characteristics
Contacts and Locations

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): NCT01031030

Sponsors and Collaborators
Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Principal Investigator: Dino Amadori, MD Morgagni-Pierantoni Ospedale
More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT01031030     History of Changes
Other Study ID Numbers: IRST-IBIS-03
CDR0000661068 ( Registry Identifier: PDQ (Physician Data Query) )
First Posted: December 14, 2009    Key Record Dates
Last Update Posted: August 2, 2013
Last Verified: December 2009

Keywords provided by National Cancer Institute (NCI):
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors