Breast Neoplasms
Conditions
Keywords
High risk node negative breast cancer, Disease-Free survival, Quality of life
Brief summary
This is a prospective, non-blinded randomized phase III trial. Patients will be post-surgically stratified at inclusion first according to the participating institution, then according to menopausal status and will be randomly assigned to receive either: * TAC: Docetaxel 75 mg/m2 as a 1 hour intravenous (i.v.) infusion on day 1 every 3 weeks (q3w) in combination with doxorubicin 50 mg/m2 as an i.v. bolus and cyclophosphamide 500 mg/m2 as an i.v. bolus on day 1 every 3 weeks. * FAC: 5-fluorouracil 500 mg/m2 as an i.v. bolus on day 1 every 3 weeks in combination with doxorubicin 50 mg/m2 as an i.v. bolus and cyclophosphamide 500 mg/m2 as an i.v. bolus on day 1 every 3 weeks.
Detailed description
Primary objective: * To compare disease-free survival (DFS) after treatment with docetaxel in combination with doxorubicin and cyclophosphamide (TAC) to 5-Fluorouracil in combination with doxorubicin and cyclophosphamide (FAC) as adjuvant treatment of high risk operable breast cancer patients with negative axillary lymph nodes. Secondary objectives: * To compare overall survival (OS) between the 2 above mentioned arms. * To compare toxicity and quality of life between the 2 above mentioned arms. * To evaluate pathologic markers for predicting efficacy (hormonal receptors and human epidermal growth factor receptor 2 (HER2) protein expression).
Interventions
DRUGCyclophosphamide
DRUGDocetaxel
DRUG5-fluorouracil
DRUGDoxorubicin
Sponsors
Sanofi
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 * Operable breast cancer patients (T1-T3) with negative axillary lymph nodes (10 axillary nodes dissection) and high risk criteria according to St. Gallen consensus criteria. * Histologically proven breast cancer. Interval between surgery and registration is less than 60 days. * Definitive surgical treatment must be either mastectomy, or breast conservative surgery. Margins of resected specimen from surgery must be histologically free of invasive adenocarcinoma and ductal carcinoma in-situ (DCIS). Lobular carcinoma in-situ is not considered as positive margin. * Patients without proven metastatic disease. * Estrogen and progesterone receptors performed on the primary tumour prior to randomization. * Age between 18 years and 70 years. * Karnofsky performance status index \> 80 %. * Adequate hepatic, renal and heart functions. * Adequate hematology levels. * Negative pregnancy test
Exclusion criteria
* Prior systemic anticancer therapy for breast cancer (immunotherapy, hormonotherapy, chemotherapy). * Prior anthracycline therapy or taxoids (paclitaxel, docetaxel) for any malignancy. * Prior radiation therapy for breast cancer. * Bilateral invasive breast cancer. * Pregnant, or lactating patients. * Patients of childbearing potential must implement adequate non-hormonal contraceptive measures during study treatment . * Any T4 or N1-3 or M1 breast cancer. * Pre-existing motor or sensory neurotoxicity of a severity grade 2 by NCI criteria. * Other serious illness or medical condition * Past or current history of neoplasm other than breast carcinoma. * Ipsilateral ductal carcinoma in-situ (DCIS) of the breast. * Lobular carcinoma in-situ (LCIS) of the breast. * Chronic treatment with corticosteroids unless initiated \> 6 months prior to study entry and at low dose * Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment should be stopped before study entry. * Definite contraindications for the use of corticosteroids. * Concurrent treatment with other experimental drugs. * Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry. * Concurrent treatment with any other anti-cancer therapy. * Male patients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival (DFS) Events | 10 years | DFS is calculated from the date of randomization until the first date of recurrence local, regional or distant, second primary tumor or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants Who Experienced Adverse Events (AE) | Through study treatment, and average of 4 months | Safety was assessed by standard clinical and laboratory tests (haematology, serum chemistry). AE grade were defined by the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 1.0. |
| Best Score During Study for Global Health Status Scale | 120 weeks | The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) was used. Questionnaires were self-administered to patients during the 14 days prior to randomisation baseline, at six prospective time points corresponding to chemotherapy cycles, with the time window related to each chemotherapy cycle defined as the period between the day following the first chemotherapy dose of the corresponding cycle and the day of the first dose of the following cycle, and then at 44, 68 and 120 weeks of the study. The Global Health Status Scale has been used, which is calculated with questions 29 and 30 from the EORTC QLQ-C30. From this scale, the best score is the highest score observed during study (of all the questionnaires completed by patient). In this scale, scores range from 0 to 100 and a high score represents a high level of functioning or HRQoL. |
| Number of Disease Free Survival Events in Hormone-receptor Positive and Human Epidermal Growth Factor Receptor 2 (HER2) Positive Status Subgroup | 10 year | Hormone-receptor status and HER2 receptor status was analysed in Paraffin-embedded tumor samples obtained at the time of surgery, and were processed centrally. Disease-Free Survival (DFS) is defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer or death from any cause whichever occurs first. |
| Overall Survival (OS) | 10 years | OS was determined from the date of randomization until the date of death for any reason. OS is calculated from the date of randomization up to the first date of death by any cause. |
| Disease Free Survival in Hormonal Receptor Negative and HER2 Positive Subgroup | 10 year | Hormone-receptor status and HER2 receptor status was analysed in Paraffin-embedded tumor samples obtained at the time of surgery, and were processed centrally. |
| Disease Free Survival in Hormonal Receptor Negative and HER2 Negative Subgroup | 10 year | Hormone-receptor status and HER2 receptor status was analysed in Paraffin-embedded tumor samples obtained at the time of surgery, and were processed centrally. Disease-Free Survival (DFS) is defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer or death from any cause whichever occurs first. |
| Disease Free Survival in Hormonal Receptor Positive and HER2 Negative Subgroup | 10 year | Hormone-receptor status and HER2 receptor status was analysed in Paraffin-embedded tumor samples obtained at the time of surgery, and were processed centrally. Disease-Free Survival (DFS) is defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer or death from any cause whichever occurs first. |
Countries
Spain
Participant flow
Recruitment details
For the different subsets (Hormone-receptor Positive and HER2 PositiveStatus Subjects, Hormonal Receptor Positive and HER2 Negative Subjects, etc.), were assessed by central determination, and no all patients had tumor sample available.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: FAC FAC (5-fluorouracil, doxorubicin, cyclophosphamide): 5-fluorouracil 500 mg/m2 iv on day 1, each 3 weeks, in combination with doxorubicin 50 mg/m2 iv and cyclophosphamide 500 mg/m2 iv
5-fluorouracil
Doxorubicin
Cyclophosphamide | 521 |
| Arm B: TAC TAC (docetaxel, doxorubicin, cyclophosphamide): Docetaxel 75 mg/m2 iv on day 1, each 3 weeks, in combination with doxorubicin 50 mg/m2 iv and cyclophosphamide 500 mg/m2 iv
Docetaxel
Doxorubicin
Cyclophosphamide | 539 |
| Total | 1,060 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Treatment not received | 2 | 11 |
Baseline characteristics
| Characteristic | Arm B: TAC | Arm A: FAC | Total |
|---|---|---|---|
| Age, Continuous | 50 years | 49 years | 49 years |
| Hormone-receptor status Negative | 192 Participants | 170 Participants | 362 Participants |
| Hormone-receptor status Positive | 344 Participants | 349 Participants | 693 Participants |
| Hormone-receptor status Unknown | 3 Participants | 2 Participants | 5 Participants |
| Menopausal status Postmenopausal | 254 Participants | 249 Participants | 503 Participants |
| Menopausal status Premenopausal | 285 Participants | 272 Participants | 557 Participants |
| Region of Enrollment Germany | 30 participants | 26 participants | 56 participants |
| Region of Enrollment Poland | 22 participants | 20 participants | 42 participants |
| Region of Enrollment Spain | 487 participants | 475 participants | 962 participants |
| Sex: Female, Male Female | 539 Participants | 521 Participants | 1060 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Surgery Breast-conserving surgery: Without radiation | 24 Participants | 24 Participants | 48 Participants |
| Surgery Breast-conserving surgery: With radiation | 287 Participants | 247 Participants | 534 Participants |
| Surgery Mastectomy: Without radiation | 206 Participants | 230 Participants | 436 Participants |
| Surgery Mastectomy: With radiation | 22 Participants | 20 Participants | 42 Participants |
| Tumor grade Grade 1 | 38 Participants | 34 Participants | 72 Participants |
| Tumor grade Grade 2 | 216 Participants | 230 Participants | 446 Participants |
| Tumor grade Grade 3 | 259 Participants | 231 Participants | 490 Participants |
| Tumor grade Unknown | 26 Participants | 26 Participants | 52 Participants |
| Tumor size ≤2 cm | 285 Participants | 249 Participants | 534 Participants |
| Tumor size >2 to 5 cm | 241 Participants | 258 Participants | 499 Participants |
| Tumor size >5 cm | 13 Participants | 13 Participants | 26 Participants |
| Tumor size Unknown | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 57 / 519 | 53 / 532 |
| other Total, other adverse events | 519 / 519 | 532 / 532 |
| serious Total, serious adverse events | 21 / 519 | 119 / 532 |
Outcome results
Primary
Disease-free Survival (DFS) Events
DFS is calculated from the date of randomization until the first date of recurrence local, regional or distant, second primary tumor or death.
Time frame: 10 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: FAC | Disease-free Survival (DFS) Events | 127 events |
| Arm B: TAC | Disease-free Survival (DFS) Events | 112 events |
Secondary
Best Score During Study for Global Health Status Scale
The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) was used. Questionnaires were self-administered to patients during the 14 days prior to randomisation baseline, at six prospective time points corresponding to chemotherapy cycles, with the time window related to each chemotherapy cycle defined as the period between the day following the first chemotherapy dose of the corresponding cycle and the day of the first dose of the following cycle, and then at 44, 68 and 120 weeks of the study. The Global Health Status Scale has been used, which is calculated with questions 29 and 30 from the EORTC QLQ-C30. From this scale, the best score is the highest score observed during study (of all the questionnaires completed by patient). In this scale, scores range from 0 to 100 and a high score represents a high level of functioning or HRQoL.
Time frame: 120 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: FAC | Best Score During Study for Global Health Status Scale | 79.30 score on a scale | Standard Deviation 17.64 |
| Arm B: TAC | Best Score During Study for Global Health Status Scale | 77.78 score on a scale | Standard Deviation 18.87 |
Secondary
Disease Free Survival in Hormonal Receptor Negative and HER2 Negative Subgroup
Hormone-receptor status and HER2 receptor status was analysed in Paraffin-embedded tumor samples obtained at the time of surgery, and were processed centrally. Disease-Free Survival (DFS) is defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer or death from any cause whichever occurs first.
Time frame: 10 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: FAC | Disease Free Survival in Hormonal Receptor Negative and HER2 Negative Subgroup | 29 events |
| Arm B: TAC | Disease Free Survival in Hormonal Receptor Negative and HER2 Negative Subgroup | 28 events |
Secondary
Disease Free Survival in Hormonal Receptor Negative and HER2 Positive Subgroup
Hormone-receptor status and HER2 receptor status was analysed in Paraffin-embedded tumor samples obtained at the time of surgery, and were processed centrally.
Time frame: 10 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: FAC | Disease Free Survival in Hormonal Receptor Negative and HER2 Positive Subgroup | 6 events |
| Arm B: TAC | Disease Free Survival in Hormonal Receptor Negative and HER2 Positive Subgroup | 5 events |
Secondary
Disease Free Survival in Hormonal Receptor Positive and HER2 Negative Subgroup
Hormone-receptor status and HER2 receptor status was analysed in Paraffin-embedded tumor samples obtained at the time of surgery, and were processed centrally. Disease-Free Survival (DFS) is defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer or death from any cause whichever occurs first.
Time frame: 10 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: FAC | Disease Free Survival in Hormonal Receptor Positive and HER2 Negative Subgroup | 50 events |
| Arm B: TAC | Disease Free Survival in Hormonal Receptor Positive and HER2 Negative Subgroup | 37 events |
Secondary
Number of Disease Free Survival Events in Hormone-receptor Positive and Human Epidermal Growth Factor Receptor 2 (HER2) Positive Status Subgroup
Hormone-receptor status and HER2 receptor status was analysed in Paraffin-embedded tumor samples obtained at the time of surgery, and were processed centrally. Disease-Free Survival (DFS) is defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer or death from any cause whichever occurs first.
Time frame: 10 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: FAC | Number of Disease Free Survival Events in Hormone-receptor Positive and Human Epidermal Growth Factor Receptor 2 (HER2) Positive Status Subgroup | 6 events |
| Arm B: TAC | Number of Disease Free Survival Events in Hormone-receptor Positive and Human Epidermal Growth Factor Receptor 2 (HER2) Positive Status Subgroup | 6 events |
Secondary
Overall Survival (OS)
OS was determined from the date of randomization until the date of death for any reason. OS is calculated from the date of randomization up to the first date of death by any cause.
Time frame: 10 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: FAC | Overall Survival (OS) | 57 Participants with mortality event |
| Arm B: TAC | Overall Survival (OS) | 53 Participants with mortality event |
Secondary
The Number of Participants Who Experienced Adverse Events (AE)
Safety was assessed by standard clinical and laboratory tests (haematology, serum chemistry). AE grade were defined by the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 1.0.
Time frame: Through study treatment, and average of 4 months
Population: The safety analysis was conducted on all patients who started at least one infusion of the study treatment (Arm A 519, and Arm B 532).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: FAC | The Number of Participants Who Experienced Adverse Events (AE) | Number patients with One AE | 519 participants |
| Arm A: FAC | The Number of Participants Who Experienced Adverse Events (AE) | One G3-4 or severe treatment-emergent AE | 88 participants |
| Arm A: FAC | The Number of Participants Who Experienced Adverse Events (AE) | One serious treatment-emergent AE | 22 participants |
| Arm A: FAC | The Number of Participants Who Experienced Adverse Events (AE) | One serious G3-4 treatment-emergent AE | 10 participants |
| Arm A: FAC | The Number of Participants Who Experienced Adverse Events (AE) | Number of patients discontinued due to AE | 4 participants |
| Arm A: FAC | The Number of Participants Who Experienced Adverse Events (AE) | Number patients death due to AE | 0 participants |
| Arm B: TAC | The Number of Participants Who Experienced Adverse Events (AE) | One serious G3-4 treatment-emergent AE | 55 participants |
| Arm B: TAC | The Number of Participants Who Experienced Adverse Events (AE) | Number patients with One AE | 532 participants |
| Arm B: TAC | The Number of Participants Who Experienced Adverse Events (AE) | Number patients death due to AE | 1 participants |
| Arm B: TAC | The Number of Participants Who Experienced Adverse Events (AE) | One G3-4 or severe treatment-emergent AE | 151 participants |
| Arm B: TAC | The Number of Participants Who Experienced Adverse Events (AE) | Number of patients discontinued due to AE | 25 participants |
| Arm B: TAC | The Number of Participants Who Experienced Adverse Events (AE) | One serious treatment-emergent AE | 119 participants |