A randomized phase III trial with dose-dense sequential chemotherapy with epirubicin/paclitaxel/Cyclophosphamide-Methotrexate-Fluorouracil (CMF) vs epirubicin/CMF/docetaxel or paclitaxel as adjuvant chemotherapy in high-risk patients with operable breast cancer.
A comparison of disease-free and overall survival following dose-dense sequential chemotherapy with epirubicin/paclitaxel/Cyclophosphamide-Methotrexate-Fluorouracil (CMF) vs epirubicin/CMF/weekly docetaxel or weekly paclitaxel as adjuvant chemotherapy in high-risk patients with operable breast cancer. A 3-arm randomized phase III study conducted by the Hellenic Cooperative Oncology Group
Hellenic Cooperative Oncology Group
1,000 participants
Jul 20, 2005
Interventional
Conditions
Summary
This is a 3-arm randomized phase III trial in high-risk breast cancer patients. Node-positive patients are randomized to sequential dose-dense epirubicin/paclitaxel/Cyclophosphamide-Methotrexate-Fluorouracil (CMF) or epirubicin/CMF/weekly docetaxel or weekly paclitaxel Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments. Ondansetron + Dexamethazone is recommended as antiemetic treatment in all patients.It is anticipated by the protocol that when trastuzumab will be licensed for the adjuvant treatment of high-risk operable breast cancer with HER-2 overexpression or HER-2 gene amplification, all such patients entered the study will be eligible to receive trastuzumab every 3 weeks for 1 year after the completion of chemotherapy. In these patients hormonal treatment with tamoxifen or anastrazole will be started concurrently with initiation of treatment with trastuzumab. All premenopausal patients with receptor positive status will receive tamoxifen p.o. daily for 5 years and goserelin (zoladex) p.o. every 3 months for 2 years. All postmenopausal patients with receptor positive status will be treated with anastrazole for 5 years.RT is required for all patients (pre- or post -menopausal), providing that they had either a partial mastectomy or tumor size > 5cm and /or more than 4 positive lymph nodes, irrespectively the type of surgery (conservative or radical).
Eligibility
Inclusion Criteria1
- Histology-confirmed epithelial cancer of the mammary gland.Pre and post menopausal patients with operable breast cancer and involved axillary lymph nodes (T 1-3 N1-2 Mo) or patients without involved axillary nodes (T1-3 N0 Mo) (i.e. those with T>= 2cm or T>1cm with at least one of the following: grade 3, age < 34 years, negative hormonal status, infiltration of blood vessels or lymphatic vessels or nerves, HER-2 (receptor tyrosine kinase) overexpression, high S fraction). White Blood Cells > 4 x 109 / l, platelets > 100 x 109 / l.Serum creatinine, Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-glutamyltransferase (gamma-GT), serum bilirubin 1.3 mg/ml inside the normal range of the participating hospital.Performance status ((World Health Organisation) ) 0 or 1. Age >= 18 years.Previous surgical treatment: Either radical surgery or, for a partial mastectomy, a histologically confirmed safe margin and the results of the axillary node dissection available.No evidence of significant cardiac disease. No previous antitumor chemotherapy or radiation.Time from surgery 2 to 8 weeks.Informed consent of the patient according to the dispositions of the Helsinki convention and its Tokyo and Venice amendments and to individual institutional policy.
Exclusion Criteria1
- History of myocardial infarction within the previous 12 months or heart failure (including cardiac insufficiency controlled by digitalis and diuretics) or arrhythmias requiring medication or uncontrolled arterial hypertension (Blood Pressure> 200/110 mm Hg). A normal baseline Left Ventricular Ejection Fraction (LVEF) should be demonstrated by multiple gate acquisition (MUGA) scan or echocardiogram (ECHO).Documented residual or metastatic disease.Prior chemotherapy, hormonal or radiation treatmentPregnant or in puerperium period women, or patients unwilling to follow adequate contraceptive methods during treatment period. History of prior cancer except for curatively treated basal-cell carcinoma of the skin or in situ carcinoma of the cervix uteri. Patients who can not fully understand and complete the inform consent form, or patients who can not follow treatment or follow up schedule.
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Interventions
Group B will be treated with epirubicin [110 mg/m2 intravenous infusion (IV)] every 2 weeks for 3 cycles followed by 3 cycles of CMF (cyclophosphamide; 840 mg/m2 IV , methotrexate; 57 mg/m2 IV and fluorouracil; 840 mg/m2 IV) every 2 weeks followed 3 weeks later by 9 weekly cycles of Docetaxel; 35 mg/m2 IV . The cumulative dose of docetaxel is 315 mg/m2. The duration of E-CMF-docetaxel chemotherapy would be identical to that of E-T-CMF (22 weeks). Group C will be treated with epirubicin (110 mg/m2 IV) every 2 weeks for 3 cycles followed by 3 cycles of CMF (cyclophosphamide; 840 mg/m2 IV, methotrexate; 57 mg/m2 IV and fluorouracil; 840 mg/m2 IV) every 2 weeks followed 3 weeks later by 9 weekly cycles of Paclitaxel 80mg/m2 IV. The cumulative dose of Paclitaxel is 720mg/m2. The duration of E-CMF-paclitaxel chemotherapy would be identical to that of E-T-CMF (22 weeks). Filgrastim 5 micrograms/kg will be given on days 2-7 of each cycle in group A and during the intensified phase of EPI and CMF treatment (all cycles of EPI/CMF) in groups B and C. Ondansetron + Dexamethazone is recommended as antiemetic treatment in all patients. It is anticipated by the protocol that when trastuzumab will be licensed for the adjuvant treatment of high-risk operable breast cancer with human epidermal growth factor receptor 2 (HER-2) overexpression or HER-2 gene amplification, all such patients entered the study will be eligible to receive trastuzumab 8 mg/kg loading dose followed by 6 mg/m2 q3 weeks for 1 year after the completion of chemotherapy. In these patients hormonal treatment with tamoxifen or anastrazole will be started concurrently with initiation of treatment with trastuzumab. All premenopausal patients with receptor positive status will receive tamoxifen 20 mg by mouth (p.o.) daily for 5 years and goserelin (zoladex) 10.8 mg p.o. every 3 months for 2 years. All postmenopausal patients with receptor positive status will be treated with anastrazole 1mg daily for 5 years. Radiotherapy (RT) is required for all patients (pre- or post -menopausal), providing that they had either a partial mastectomy or tumor size > 5cm and /or more than 4 positive lymph nodes, irrespectively the type of surgery (conservative or radical).
Locations(1)
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ACTRN12610000151033