FAC Versus FAC Plus Weekly Paclitaxel as Adjuvant Treatment of Node Negative High Risk Breast Cancer Patients

Phase 3

Completed

• Conditions: Breast Cancer
• Interventions: Drug: Fluorouracil; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Paclitaxel

• 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.

Study Timeline

• Study Start: 2003-09-19
• Study First Submitted: 2005-08-10
• Study First Submitted QC: 2005-08-10
• Study First Posted: 2005-08-11
• Primary Completion: 2013-10-01
• Study Completion: 2013-10-01
• Results First Submitted: 2019-01-25
• Results First Submitted QC: 2019-04-26
• Results First Posted: 2019-07-12
• Status Verified: 2023-03
• Last Update Submitted: 2023-03-03
• Last Update Posted: 2023-03-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 1925

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.

• 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.

• Age >= 18 and <= 70 years old.

• 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.

• Patients able to comply with treatment and study follow-up.

• Negative pregnancy test done in the 14 previous days to randomization.

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-2.0.
• 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 Univ. De Elche; 🇪🇸 Elche, Alicante, Spain

Hospital General de Elda; 🇪🇸 Elda, Alicante, Spain

Complejo Hospitalario de Manresa; 🇪🇸 Manresa, Barcelona, Spain

Consorci Sanitari Parc Tauli; 🇪🇸 Sabadell, Barcelona, Spain

Hospital del Espíritu Santo; 🇪🇸 Santa Coloma De Gramenet, Barcelona, Spain

Consorci Sanitari Terrassa; 🇪🇸 Terrassa, Barcelona, Spain

Hospital Mutua Terrassa; 🇪🇸 Terrassa, Barcelona, Spain

Hospital General Jerez de la Frontera; 🇪🇸 Jerez De La Frontera, Cadiz, Spain

Hospital Provincial de Castellón; 🇪🇸 Castellón De La Plana, Castellón, Spain

Hospital Comarcal de Barbastro; 🇪🇸 Barbastro, Huesca, Spain

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