Multicenter Randomized Phase III Trial to Compare 6 FAC Cycles vs 4 FAC Cycles Followed by 8 Weekly Paclitaxel Administrations, as Adjuvant Treatment for Node Negative Operable Breast Cancer Patients
Overview
- Phase
- Phase 3
- Intervention
- Fluorouracil
- Conditions
- Breast Cancer
- Sponsor
- Spanish Breast Cancer Research Group
- Enrollment
- 1925
- Locations
- 68
- Primary Endpoint
- Disease-free Survival (DFS) Event
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a prospective, open-label, randomized, phase III trial. Patients will be stratified after breast surgery, as per investigational site; menopausal status; node negative diagnosis, as per sentinel-node technique versus lymphadenectomy; hormone receptor status (positive versus negative).
Detailed Description
Patients will be randomized to: * Fluorouracil, doxorubicin, and cyclophosphamide (FAC) x 6 (cycles): 5-fluorouracil 500 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2 day 1, every 3 weeks, for 6 cycles. * FAC x 4 (cycles) → Paclitaxel x 8 (cycles): 5-fluorouracil 500 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2 day 1, every 3 weeks, for 4 cycles, followed by 8 administrations of weekly paclitaxel 100 mg/m2 Premenopausal women with hormone receptor positive tumors must receive tamoxifen 20 mg daily for 5 years, after the end of chemotherapy. Postmenopausal women with hormone receptor positive tumors are allowed to receive aromatase inhibitors as initial adjuvant hormone therapy or after tamoxifen. All patients with breast conservative surgery must receive radiotherapy. Estimated 5-year disease-free survival in the control arm (FAC x 6) is expected to be 80%. It is expected that disease-free survival will increase by 5% in the experimental arm (FAC-paclitaxel). 906 patients per arm must be recruited, to detect this difference with an alpha error of 0.05 and 80% power. Assuming a 6% post-randomization drop-out rate, 960 patients per arm are needed, 1920 in total.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent.
- •Histological diagnoses of operable invasive adenocarcinoma of the breast (T1-T3). Tumors must be Human Epidermal Growth Factor Receptor 2 (HER2) negative. Patients must be free of disease in the axilla (node negative). If lymphadenectomy is done, at least 10 nodes must be examined. If sentinel node technique is used, sentinel node must be free of disease. Patients must present at least one high risk criterion (St. Gallen, 1998) as follows:
- •Tumor size \> 2 cm; and/or
- •ER and Progesterone Receptor (PgR) negative; and/or
- •Histological grade 2-3; and/or
- •Age \< 35 years old.
- •Time window between surgery and study randomization must be less than 60 days.
- •Surgery must consist of mastectomy or conservative surgery. Margins free of disease and ductal carcinoma in situ (DCIS) are required. Lobular carcinoma is not considered a positive margin.
- •Patients must not present evidence of metastatic disease.
- •Status of hormone receptors in primary tumor. Results must be available before the end of adjuvant chemotherapy.
Exclusion Criteria
- •Prior systemic therapy for breast cancer.
- •Prior therapy with anthracyclines or taxanes (paclitaxel or docetaxel) for any malignancy.
- •Prior radiotherapy for breast cancer.
- •Bilateral invasive breast cancer.
- •Pregnant or lactating women. Adequate contraceptive methods must be used during chemotherapy and hormone therapy treatments. Negative pregnancy test in the 14 previous days to randomization.
- •Any T4 or N1-3 or M1 tumor.
- •HER2 positive breast cancer (IHC 3+ or positive FISH result).
- •Pre-existing grade \>=2 motor or sensorial neurotoxicity by the National Cancer Institute Common Toxicity Criteria (NCICTC) v-2.
- •Any other serious medical pathology, such as congestive heart failure, unstable angina, history of myocardial infarction during the previous year, uncontrolled hypertension or high risk arrhythmias.
- •History of neurological or psychiatric disorders, which could preclude the patients to free informed consent.
Arms & Interventions
Arm A: FAC
FAC X 6 The standard arm consisted of six cycles of FAC (fluorouracil 500 mg/m2, doxorubicin 50mg/m2, and cyclophosphamide 500mg/m2) administered once every 3 weeks.
Intervention: Fluorouracil
Arm A: FAC
FAC X 6 The standard arm consisted of six cycles of FAC (fluorouracil 500 mg/m2, doxorubicin 50mg/m2, and cyclophosphamide 500mg/m2) administered once every 3 weeks.
Intervention: Doxorubicin
Arm A: FAC
FAC X 6 The standard arm consisted of six cycles of FAC (fluorouracil 500 mg/m2, doxorubicin 50mg/m2, and cyclophosphamide 500mg/m2) administered once every 3 weeks.
Intervention: Cyclophosphamide
Arm B: FAC-wP
FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)
Intervention: Fluorouracil
Arm B: FAC-wP
FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)
Intervention: Doxorubicin
Arm B: FAC-wP
FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)
Intervention: Cyclophosphamide
Arm B: FAC-wP
FAC X 4 + 8 weekly Paclitaxel (wP) Patients in the experimental arm received four cycles of the FAC regimen followed by eight weekly administrations of paclitaxel (100mg/m2 per dose)
Intervention: Paclitaxel
Outcomes
Primary Outcomes
Disease-free Survival (DFS) Event
Time Frame: Up to 5 years
DFS is defined as the evidence of local, regional or metastatic recurrence, second primary cancer (with the exception of carcinoma of squamous cells or basal cells of the skin, cervical carcinoma in situ or lobular or ductal carcinoma in situ of the breast) or death for any reason.
Secondary Outcomes
- Overall Survival (OS) Event(Up to 5 years)