Breast Cancer
Conditions
Keywords
Node negative, high risk breast cancer., Prognostic gene profile., Saint Gallen high risk criteria., Weekly paclitaxel.
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.
Interventions
DRUGFluorouracil
Arm A: FAC Arm B: FAC-wP
DRUGDoxorubicin
Arm A: FAC Arm B: FAC-wP
DRUGCyclophosphamide
Arm A: FAC Arm B: FAC-wP
DRUGPaclitaxel
Arm B: FAC-wP
Sponsors
Bristol-Myers Squibb
Spanish Breast Cancer Research Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Event | Up to 5 years | OS event is defined as the death from any cause. |
Countries
Spain
Participant flow
Recruitment details
1925 patients from 67 Spanish sites were assigned to receive FAC-wP (n=951) or FAC (n=974). 8 patients received no treatment (5 FAC-wP, 3 FAC), and 17 were not treated with the study medication to which they were randomly assigned (1 FAC, 16 FAC-wP). A total of 1,917 patients were evaluable for safety (931 FAC-wP, 986 FAC).
Participants by arm
| Arm | Count |
|---|---|
| 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. | 974 |
| 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) | 951 |
| Total | 1,925 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 19 | 87 |
| Overall Study | Crossed to the other arm | 1 | 16 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Not eligible | 1 | 2 |
| Overall Study | Physician Decision | 0 | 4 |
| Overall Study | Protocol Violation | 0 | 6 |
| Overall Study | Relapse | 1 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 23 |
Baseline characteristics
| Characteristic | Arm A: FAC | Arm B: FAC-wP | Total |
|---|---|---|---|
| Age, Continuous | 50.95 years | 50.89 years | 50.92 years |
| Axillary surgery Lymphadenectomy | 559 Participants | 551 Participants | 1110 Participants |
| Axillary surgery Lymphadenectomy + Sentinel node biopsy | 13 Participants | 16 Participants | 29 Participants |
| Axillary surgery Sentinel node biopsy | 402 Participants | 384 Participants | 786 Participants |
| Histologic grade G1: Well differenciated | 64 Participants | 61 Participants | 125 Participants |
| Histologic grade G2: Moderately differenciated | 446 Participants | 434 Participants | 880 Participants |
| Histologic grade G3: Poorly differenciated | 429 Participants | 420 Participants | 849 Participants |
| Histologic grade GX: Differenciation cannot be assessed | 35 Participants | 36 Participants | 71 Participants |
| Histologic type Invasive Ductal Carcinoma | 832 Participants | 813 Participants | 1645 Participants |
| Histologic type Invasive Lobular Carcinoma | 71 Participants | 89 Participants | 160 Participants |
| Histologic type Other | 71 Participants | 49 Participants | 120 Participants |
| Hormonal receptors ER negative and/or PR negative | 261 Participants | 258 Participants | 519 Participants |
| Hormonal receptors ER positive and/or PR positive | 713 Participants | 693 Participants | 1406 Participants |
| Human Epidermal growth factor Receptor 2 (HER2) status HER2 negative | 858 Participants | 846 Participants | 1704 Participants |
| Human Epidermal growth factor Receptor 2 (HER2) status HER2 positive | 95 Participants | 86 Participants | 181 Participants |
| Human Epidermal growth factor Receptor 2 (HER2) status Unknown | 21 Participants | 19 Participants | 40 Participants |
| Karnofsky Performance Status (PS) Not done | 2 Participants | 0 Participants | 2 Participants |
| Karnofsky Performance Status (PS) PS 100 | 873 Participants | 863 Participants | 1736 Participants |
| Karnofsky Performance Status (PS) PS 80 | 8 Participants | 7 Participants | 15 Participants |
| Karnofsky Performance Status (PS) PS 90 | 91 Participants | 81 Participants | 172 Participants |
| Menopausal status Peri/postmenopausal | 502 Participants | 469 Participants | 971 Participants |
| Menopausal status Premenopausal | 472 Participants | 482 Participants | 954 Participants |
| Race/Ethnicity, Customized Caucasian | 960 Participants | 935 Participants | 1895 Participants |
| Race/Ethnicity, Customized Hispanic | 10 Participants | 12 Participants | 22 Participants |
| Race/Ethnicity, Customized Oriental | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Female | 974 Participants | 951 Participants | 1925 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Triple-negative disease Non triple-negative disease | 735 Participants | 708 Participants | 1443 Participants |
| Triple-negative disease Triple-negative disease | 218 Participants | 224 Participants | 442 Participants |
| Triple-negative disease Unknown | 21 Participants | 19 Participants | 40 Participants |
| Tumor size T1 | 557 Participants | 569 Participants | 1126 Participants |
| Tumor size T2 | 403 Participants | 369 Participants | 772 Participants |
| Tumor size T3 | 14 Participants | 13 Participants | 27 Participants |
| Type of surgery Conservative | 713 Participants | 686 Participants | 1399 Participants |
| Type of surgery Mastectomy | 261 Participants | 265 Participants | 526 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 40 / 974 | 31 / 951 |
| other Total, other adverse events | 442 / 974 | 523 / 951 |
| serious Total, serious adverse events | 60 / 974 | 61 / 951 |
Outcome results
Primary
Disease-free Survival (DFS) Event
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.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: FAC | Disease-free Survival (DFS) Event | 98 Participants |
| Arm B: FAC-wP | Disease-free Survival (DFS) Event | 71 Participants |
Secondary
Overall Survival (OS) Event
OS event is defined as the death from any cause.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: FAC | Overall Survival (OS) Event | 40 Participants |
| Arm B: FAC-wP | Overall Survival (OS) Event | 31 Participants |