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 recruitment status of this study is unknown because the information has not been verified recently.
Verified December 2009 by National Cancer Institute (NCI).
Recruitment status was  Active, not recruiting
Information provided by:
National Cancer Institute (NCI) Identifier:
First received: December 11, 2009
Last updated: August 1, 2013
Last verified: December 2009

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 Intervention Phase
Breast Cancer
Drug: cyclophosphamide
Drug: epirubicin hydrochloride
Drug: fluorouracil
Drug: methotrexate
Other: laboratory biomarker analysis
Procedure: adjuvant therapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Masking: Open Label
Primary Purpose: Treatment
Official Title: Adjuvant Treatment of Biologically Aggressive Breast Cancer (N-,N+1,3): Controlled Clinical Study

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Overall survival [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Disease-free survival [ Designated as safety issue: No ]
  • Toxicity [ Designated as safety issue: Yes ]
  • Quality of life [ Designated as safety issue: No ]
  • Efficacy in subgroups of patients [ Designated as safety issue: No ]

Estimated Enrollment: 800
Study Start Date: November 1997
Estimated Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
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.


Ages Eligible for Study:   18 Years to 70 Years
Genders 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
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Please refer to this study by its identifier: 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 Identifier (NCT Number): Identifier: NCT01031030     History of Changes
Other Study ID Numbers: IRST-IBIS-03  CDR0000661068 
Study First Received: December 11, 2009
Last Updated: August 1, 2013
Health Authority: United States: Federal Government

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
Breast Diseases
Neoplasms by Site
Skin Diseases
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Alkylating Agents
Antibiotics, Antineoplastic
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Nucleic Acid Synthesis Inhibitors
Physiological Effects of Drugs
Reproductive Control Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors processed this record on May 30, 2016