Breast Cancer
Conditions
Keywords
Triple-Negative Early Breast Cancer, Maintenance Adjuvant Chemotherapy, Capecitabine, Basal-like genotype, Triple-Negative
Brief summary
This is a prospective, open-label, randomized phase III study assessing adjuvant capecitabine after standard chemotherapy for patients with early triple negative breast cancer.
Detailed description
Patients will be stratified as per investigational site, previous adjuvant chemotherapy (anthracyclines versus anthracyclines plus taxanes), and number of affected axillary lymph nodes (0, 1-3, \>= 4). Node negative patients must present a tumour size \> 2 cm to be eligible. At least 6 lymph nodes must be analysed to confirm the number of affected nodes. Patients will be randomised to receive: 8 courses of capecitabine 1000 mg/m2 by mouth, twice a day (p.o. bid) for 14 days, followed by a 7 day rest versus observation. Tissue samples must be analysed by a central laboratory, to confirm estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2), cytokeratins (CK) 5/6 and epidermal growth factor receptor (EGFR) status. The following data were obtained from the database of the El Alamo project. One thousand six hundred and twenty-seven (1,627) in total were considered during the years 1990 to 1997. The population is formed of patients with operable breast cancer, with surgery, positive nodes, and negative hormone receptors, or negative nodes, negative hormone receptors and T2-3 tumors. For these patient groups, estimated 5-year disease-free survival is 64.72%. Assuming an exponential distribution, the aim is to detect an increase of 64.72% to 73.7% in 5 years Disease Free survival rate corresponds to a Hazard Ratio of 0.701 and a risk reduction of about 30%, with a power of 80% using a two-tailed log-rank test at 0.05 and whereas 4 years of recruitment period and 3 years of follow-up period. We would need 255 events, 834 patients without considering any dropouts. Considering a drop-out rate of 5% post-randomization, the final sample size will be 876 patients, 438 per treatment arm. The sample size calculation was performed by the program package EAST version 5.2.
Interventions
DRUGCapecitabine
Sponsors
Hoffmann-La Roche
IBEROAMERICAN COALITION FOR BREAST ONCOLOGY RESEARCH (CIBOMA)
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). Tumours must be HER2 negative. Time window between end of adjuvant chemotherapy and study randomization must be less than 8 weeks. In patients receiving adjuvant radiotherapy, time window allowed between last session and randomisation is 4 weeks. * Surgery must consist of mastectomy or conservative surgery with axillary lymph node dissection. Margins free of disease and ductal carcinoma in-situ (DCIS) are required. Lobular carcinoma is not considered a positive margin. * Node negative patients with tumour size \> 2 cm. * Positive axillary lymph nodes defined as at least 1 out of 6 nodes with presence of disease. If sentinel node technique is used, sentinel node can be the only node affected. Patients belonging to the following classifications are eligible: pN1a (Metastases in 1-3 axillary lymph nodes, at least one metastasis greater than 2.0 mm), pN2a (Metastases in 4-9 axillary lymph nodes (at least one tumor deposit greater than 2 mm)), pN3a (Metastases in 10 or more axillary lymph nodes \[at least one tumor deposit greater than 2 mm\]; or metastases to the infraclavicular \[level III axillary lymph\] nodes). * Status of hormone receptors in primary tumour. Negative results must be available before the end of adjuvant chemotherapy. * Patients must not present evidence of metastatic disease. * Negative status of HER2 in primary tumour, known before randomization. * Adjuvant chemotherapy consisting of a minimum of 6 courses with anthracyclines and/or taxanes. * Age \>= 18 and \<= 70 years old. * Performance status (Karnofsky index) \>= 80. * Laboratory results (within 14 days prior to randomization): * Hematology: * neutrophils \>= 1.5 x 10e9/l; * platelets \>= 100x 10e9/l; * hemoglobin \>= 10 mg/dl * Hepatic function: * total bilirubin \<= 1 upper normal limit (UNL); * Aspartate aminotransferase (AST or SGOT) and Alanine aminotransferase (ALT or SGPT) \<= 2.5 UNL; * alkaline phosphatase \<= 2.5 UNL. * If values of SGOT and SGPT \> 1.5 UNL are associated to alkaline phosphatase \> 2.5 UNL, patient is not eligible. * Renal Function: * creatinine \<= 175 µmol/l (2 mg/dl). * creatinine clearance \>= 60 ml/min. * Pharmacogenetics: * one blood sample is needed for single nucleotide polymorphism (SNP) assessment. * Patients able to comply with treatment and study follow-up. * Negative pregnancy test done in the 14 previous days to randomization.
Exclusion criteria
* Prior therapy with anthracyclines or taxanes (paclitaxel or docetaxel) for any malignancy. * 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. * Bilateral invasive breast cancer. * Any T4 or M1 tumour. * Axillary lymph nodes: patients belonging to the following classifications are excluded: pN1b (Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected), pN1c (Metastases in 1-3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected), pN2b (Metastases in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases), pN3b (Metastases in clinically detected ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected), pN3c (Metastases in ipsilateral supraclavicular lymph nodes). * 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 to breast cancer, except for skin carcinoma, cervical in situ carcinoma, or any other tumour curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma. * History of hypersensitivity to capecitabine, fluorouracil. * Patients lacking physical integrity of upper gastrointestinal tract or with history of bad absorption syndrome. * History of dihydropyrimidine dehydrogenase (DPD) deficiency. * Anticoagulant treatment with coumadin anticoagulants. * Current treatment with sorivudine or its chemical family. * Concomitant treatment with other investigational products. Participation in other clinical trials with a non-marketed drug in the 30 previous days before randomization. * Concomitant treatment with other therapy for cancer. * Males.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival (DFS) Events | 5 years | DFS was measured from the date of randomization assignment in the intent to treat (ITT) population to loco-regional or distant recurrence, second primary malignancy or death date, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival (DFS) Events by Phenotype | 5 years | DFS was measured from the date of randomization assignment in the intent to treat (ITT) population to loco-regional or distant recurrence, second primary malignancy or death date, whichever occurred first. |
| Overall Survival (OS) Event | 5 years | OS event is defined as the death from any cause. |
| The Number of Participants Who Experienced Adverse Events (AE) | 5 years | Safety will be 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). |
Countries
Spain
Participant flow
Recruitment details
Between October 2006 and September 2011, 876 patients were recruited, across 80 institutions in 8 countries (Spain, Brazil, Chile, Colombia, Ecuador, Mexico, Peru, and Venezuela)
Participants by arm
| Arm | Count |
|---|---|
| Xeloda (Capecitabine) 1000 mgrs/m2 twice a day, tablets, 8 cycles
Capecitabine | 448 |
| Observation Observation. No intervention. | 428 |
| Total | 876 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 34 | 1 |
| Overall Study | Death | 4 | 2 |
| Overall Study | Disease relapse | 9 | 13 |
| Overall Study | Interruption of treatment > 3 weeks | 11 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Other | 12 | 5 |
| Overall Study | Protocol Violation | 5 | 1 |
| Overall Study | Second Primary Malignancy | 0 | 1 |
| Overall Study | Sponsor´s decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 33 | 6 |
Baseline characteristics
| Characteristic | Xeloda (Capecitabine) | Observation | Total |
|---|---|---|---|
| Age, Continuous | 50 years | 49 years | 49 years |
| Axillary surgery axillary lymph node dissection +/- SLNB | 349 Participants | 306 Participants | 655 Participants |
| Axillary surgery sentinel lymph node biopsy (SLNB) | 99 Participants | 122 Participants | 221 Participants |
| Breast surgery Conservative | 237 Participants | 242 Participants | 479 Participants |
| Breast surgery Mastectomy | 205 Participants | 185 Participants | 390 Participants |
| Breast surgery Missing data | 6 Participants | 1 Participants | 7 Participants |
| Chemotherapy regimens Anthracyclines and taxanes-based | 301 Participants | 290 Participants | 591 Participants |
| Chemotherapy regimens Anthracyclines-based | 147 Participants | 138 Participants | 285 Participants |
| Histologic grade Grade 1 | 15 Participants | 12 Participants | 27 Participants |
| Histologic grade Grade 2 | 82 Participants | 81 Participants | 163 Participants |
| Histologic grade Grade 3 | 323 Participants | 299 Participants | 622 Participants |
| Histologic grade Unknown | 28 Participants | 36 Participants | 64 Participants |
| Histologic type Invasive ductal carcinoma | 395 Participants | 369 Participants | 764 Participants |
| Histologic type Invasive lobular carcinoma | 9 Participants | 10 Participants | 19 Participants |
| Histologic type Other | 44 Participants | 49 Participants | 93 Participants |
| Karnofsky Index Performance Status 100 | 383 Participants | 344 Participants | 727 Participants |
| Karnofsky Index Performance Status 80 | 8 Participants | 17 Participants | 25 Participants |
| Karnofsky Index Performance Status 90 | 57 Participants | 67 Participants | 124 Participants |
| Menopausal status at diagnosis Postmenopausal | 312 Participants | 288 Participants | 600 Participants |
| Menopausal status at diagnosis Premenopausal | 136 Participants | 140 Participants | 276 Participants |
| Nodal status 1-3 positive nodes | 121 Participants | 124 Participants | 245 Participants |
| Nodal status ≥4 positive nodes | 77 Participants | 61 Participants | 138 Participants |
| Nodal status Missing data | 6 Participants | 1 Participants | 7 Participants |
| Nodal status Negative | 244 Participants | 242 Participants | 486 Participants |
| Phenotype by immunohistochemistry (IHC) Basal | 319 Participants | 309 Participants | 628 Participants |
| Phenotype by immunohistochemistry (IHC) Non-basal | 129 Participants | 119 Participants | 248 Participants |
| Race/Ethnicity, Customized Black | 16 Participants | 11 Participants | 27 Participants |
| Race/Ethnicity, Customized Caucasian | 313 Participants | 309 Participants | 622 Participants |
| Race/Ethnicity, Customized Hispanic | 107 Participants | 97 Participants | 204 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 11 Participants | 23 Participants |
| Radiation therapy No | 91 Participants | 81 Participants | 172 Participants |
| Radiation therapy Unknown | 5 Participants | 1 Participants | 6 Participants |
| Radiation therapy Yes | 352 Participants | 346 Participants | 698 Participants |
| Region of Enrollment Brazil | 71 participants | 68 participants | 139 participants |
| Region of Enrollment Chile | 19 participants | 23 participants | 42 participants |
| Region of Enrollment Colombia | 6 participants | 3 participants | 9 participants |
| Region of Enrollment Ecuador | 9 participants | 9 participants | 18 participants |
| Region of Enrollment Mexico | 61 participants | 52 participants | 113 participants |
| Region of Enrollment Peru | 7 participants | 12 participants | 19 participants |
| Region of Enrollment Spain | 272 participants | 260 participants | 532 participants |
| Region of Enrollment Venezuela | 3 participants | 1 participants | 4 participants |
| Sex: Female, Male Female | 448 Participants | 428 Participants | 876 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Stage at diagnosis Stage I | 62 Participants | 74 Participants | 136 Participants |
| Stage at diagnosis Stage II | 270 Participants | 271 Participants | 541 Participants |
| Stage at diagnosis Stage III | 106 Participants | 80 Participants | 186 Participants |
| Stage at diagnosis Unknown | 10 Participants | 3 Participants | 13 Participants |
| Type of prior Chemotherapy Adjuvant (only) | 353 Participants | 352 Participants | 705 Participants |
| Type of prior Chemotherapy Missing data | 6 Participants | 1 Participants | 7 Participants |
| Type of prior Chemotherapy Neoadjuvant (+/- adjuvant) | 89 Participants | 75 Participants | 164 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 71 / 448 | 73 / 428 |
| other Total, other adverse events | 416 / 436 | 271 / 425 |
| serious Total, serious adverse events | 23 / 436 | 6 / 425 |
Outcome results
Primary
Disease Free Survival (DFS) Events
DFS was measured from the date of randomization assignment in the intent to treat (ITT) population to loco-regional or distant recurrence, second primary malignancy or death date, whichever occurred first.
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Xeloda (Capecitabine) | Disease Free Survival (DFS) Events | 105 Participants |
| Observation | Disease Free Survival (DFS) Events | 120 Participants |
Secondary
Disease Free Survival (DFS) Events by Phenotype
DFS was measured from the date of randomization assignment in the intent to treat (ITT) population to loco-regional or distant recurrence, second primary malignancy or death date, whichever occurred first.
Time frame: 5 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Xeloda (Capecitabine) | Disease Free Survival (DFS) Events by Phenotype | Basal Phenotype | 84 Participants |
| Xeloda (Capecitabine) | Disease Free Survival (DFS) Events by Phenotype | Non basal Phenotype | 21 Participants |
| Observation | Disease Free Survival (DFS) Events by Phenotype | Basal Phenotype | 86 Participants |
| Observation | Disease Free Survival (DFS) Events by Phenotype | Non basal Phenotype | 34 Participants |
Secondary
Overall Survival (OS) Event
OS event is defined as the death from any cause.
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Xeloda (Capecitabine) | Overall Survival (OS) Event | 71 Participants |
| Observation | Overall Survival (OS) Event | 73 Participants |
Secondary
The Number of Participants Who Experienced Adverse Events (AE)
Safety will be 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).
Time frame: 5 years
Population: The analysis of toxicity was made in all study patients who had received at least 1 treatment cycle, or who had completed the observation period equivalent to 1 cycle.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Xeloda (Capecitabine) | The Number of Participants Who Experienced Adverse Events (AE) | 416 Participants |
| Observation | The Number of Participants Who Experienced Adverse Events (AE) | 271 Participants |