FAC Versus FAC Plus Weekly Paclitaxel as Adjuvant Treatment of Node Negative High Risk Breast Cancer Patients
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT00129389
- Lead Sponsor
- Spanish Breast Cancer Research Group
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 1925
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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.
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Status of hormone receptors in primary tumor. Results must be available before the end of adjuvant chemotherapy.
-
Status of HER2 in primary tumor, known before randomization. Patients with Immunohistochemistry (IHC) 0 or +1 are eligible. For patients with IHC 2+, fluorescent in situ hybridization (FISH) is mandatory and result must be negative.
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Age >= 18 and <= 70 years old.
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Performance status (Karnofsky index) >= 80.
-
Normal electrocardiogram (EKG) in the 12 weeks prior to randomization. If needed, normal cardiac function must be confirmed by left ventricular ejection fraction (LVEF).
-
Laboratory results (within 14 days prior to randomization):
- Hematology: neutrophils >= 1.5 x 10^9/l; platelets >= 100x 10^9/l; hemoglobin >= 10 mg/dl;
- Hepatic function: total bilirubin <= 1 upper normal limit (UNL); Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <= 2.5 UNL; alkaline phosphatase <= 2.5 UNL. If values of AST and ALT > 1.5 UNL are associated with alkaline phosphatase > 2.5 UNL, patient is not eligible.
- Renal function: creatinine <= 175 mmol/l (2 mg/dl); creatinine clearance >= 60 ml/min.
-
Complete stage workup during the 12 weeks prior to randomization (mammograms are allowed within a 20 week time window). All patients must have a bilateral mammogram, thorax x-ray, abdominal echography and/or computed tomography (CT)-scan. If bone pain, and/or alkaline phosphatase elevation, a bone scintigraphy is mandatory. This test is recommended for all patients. Other tests, as clinically indicated.
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Patients able to comply with treatment and study follow-up.
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Negative pregnancy test done in the 14 previous days to randomization.
- 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-2.0.
- 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.
- Active uncontrolled infection.
- Active peptic ulcer; unstable diabetes mellitus.
- Previous or current history of neoplasms different from breast cancer, except for skin carcinoma, cervical in situ carcinoma, or any other tumor curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma.
- Concomitant treatment with other investigational products. Participation in other clinical trials with a non-marketed drug in the 20 previous days before randomization.
- Concomitant treatment with other therapy for cancer.
- Males.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A: FAC Doxorubicin 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. Arm A: FAC Fluorouracil 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. Arm A: FAC Cyclophosphamide 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. Arm B: FAC-wP Fluorouracil 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) Arm B: FAC-wP Paclitaxel 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) Arm B: FAC-wP Doxorubicin 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) Arm B: FAC-wP Cyclophosphamide 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)
- Primary Outcome Measures
Name Time Method Disease-free Survival (DFS) Event 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 Outcome Measures
Name Time Method Overall Survival (OS) Event Up to 5 years OS event is defined as the death from any cause.
Trial Locations
- Locations (68)
Hospital General de Elda
🇪🇸Elda, Alicante, Spain
Consorci Sanitari Terrassa
🇪🇸Terrassa, Barcelona, Spain
Hospital Clínico Universitario de Salamanca
🇪🇸Salamanca, Spain
Hospital del Mar
🇪🇸Barcelona, Spain
Hospital Clinic i Provincial
🇪🇸Barcelona, Spain
Hospital Puerta del Mar
🇪🇸Cadiz, Spain
Hospital Reina Sofía
🇪🇸Córdoba, Spain
Complejo Hospitalario de Jaén
🇪🇸Jaén, Spain
Hospital General Yagüe
🇪🇸Burgos, Spain
Hospital General de Guadalajara
🇪🇸Guadalajara, Spain
Hospital Ruber Internacional
🇪🇸Madrid, Spain
Hospital Doce de Octubre
🇪🇸Madrid, Spain
Hospital de la Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Hospital General de Vic
🇪🇸Barcelona, Spain
Hospital de Móstoles
🇪🇸Móstoles, MAdrid, Spain
Hospital Universitario de Canarias
🇪🇸La Laguna, Santa Cruz De Tenerife, Spain
Hospital Insular de Gran Canaria
🇪🇸Las Palmas De Gran Canaria, Las Palmas, Spain
Hospital Sant Joan de Reus
🇪🇸Reus, Tarragona, Spain
Hospital General Univ. De Elche
🇪🇸Elche, Alicante, Spain
Hospital Virgen de la Arrixaca
🇪🇸El Palmar, Murcia, Spain
Hospital Comarcal de Barbastro
🇪🇸Barbastro, Huesca, Spain
Hospital de Basurto
🇪🇸Bilbao, Spain
ICO Hospital Universitari Josep Trueta
🇪🇸Gerona, Spain
Hospital General de Ciudad Real
🇪🇸Ciudad Real, Spain
Hospital Virgen de la Luz
🇪🇸Cuenca, Spain
Hospital Xeral Calde
🇪🇸Lugo, Spain
Hospital Universitario La Princesa
🇪🇸Madrid, Spain
Hospital Ramón y Cajal
🇪🇸Madrid, Spain
Hospital Puerta de Hierro
🇪🇸MAdrid, Spain
Hospital Clínico San Carlos
🇪🇸Madrid, Spain
CIOCC Hospital Norte-Sanchinarro
🇪🇸Madrid, Spain
Complejo Hospitalario Virgen de la Victoria
🇪🇸Málaga, Spain
Hospital Morales Messeguer
🇪🇸Murcia, Spain
Hospital Sta María Nai
🇪🇸Orense, Spain
Hospital Carlos Haya
🇪🇸Málaga, Spain
Hospital General Río Carrión
🇪🇸Palencia, Spain
Instituto Oncológico de Guipuzcoa
🇪🇸San Sebastián, Spain
Hospital de Donostia
🇪🇸San Sebastián, Spain
Hospital Universitario Marqués de Valdecilla
🇪🇸Santander, Spain
Hospital Univ. Virgen del Rocío
🇪🇸Sevilla, Spain
Hospital Universitario de Valme
🇪🇸Sevilla, Spain
Hospital Virgen de la Salud
🇪🇸Toledo, Spain
Hospital Universitario La Fe
🇪🇸Valencia, Spain
Hospital Clínico Universitario de Valencia
🇪🇸Valencia, Spain
Hospital Arnau de Vilanova
🇪🇸Valencia, Spain
Hospital Provincial de Zamora
🇪🇸Zamora, Spain
Hospital Lozano Blesa
🇪🇸Zaragoza, Spain
Hospital Miguel Servet
🇪🇸Zaragoza, Spain
Consorci Sanitari Parc Tauli
🇪🇸Sabadell, Barcelona, Spain
Hospital del Espíritu Santo
🇪🇸Santa Coloma De Gramenet, Barcelona, Spain
Hospital Mutua Terrassa
🇪🇸Terrassa, Barcelona, Spain
Hospital Provincial de Castellón
🇪🇸Castellón De La Plana, Castellón, Spain
Fundación Hospital de Alcorcón
🇪🇸Alcorcón, MAdrid, Spain
Complejo Hospitalario Juan Canalejo
🇪🇸A Coruña, Spain
Hospital General Universitario de Alicante
🇪🇸Alicante, Spain
Hospital de la Ribera
🇪🇸Alzira, Valencia, Spain
Hospital Policlínico Vigo POVISA
🇪🇸Vigo, Pontevedra, Spain
Hospital Virgen de los Lirios
🇪🇸Alicante, Spain
Complejo Hospitalario de Albacete
🇪🇸Albacete, Spain
Clínica Corochan S.A.
🇪🇸Barcelona, Spain
Centro Oncológico de Galicia
🇪🇸A Coruña, Spain
Hospital Germans Trias i Pujol
🇪🇸Badalona, Spain
Hospital Txagorritxu
🇪🇸Vitoria, Spain
Hospital General Jerez de la Frontera
🇪🇸Jerez De La Frontera, Cadiz, Spain
Hospital Madrid- Montepríncipe
🇪🇸Boadilla Del Monte, Madrid, Spain
Complejo Hospitalario de Manresa
🇪🇸Manresa, Barcelona, Spain
Instituto Valenciano de Oncología
🇪🇸Valencia, Spain
Hospital La Paz
🇪🇸Madrid, Spain