Breast Cancer
Conditions
Keywords
HER2 negative breast cancer, Node positive breast cancer, Adjuvant treatment, Oral chemotherapy
Brief summary
This is a prospective, randomised phase III trial, to compare the efficacy and safety profiles of two types of adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2) negative, node positive breast cancer patients. Control Arm: This includes 4 cycles of EC 90/600 mg/m2 day 1 every 3 weeks, followed by 4 cycles of T 100 mg/m2 day 1 every 3 weeks. Experimental Arm: This includes 4 cycles of ET 90/75 mg/m2, day 1 every 3 weeks, followed by 4 cycles of capecitabine 1250 mg/m2, twice a day, via oral intake, for 14 days, and then a one-week rest period. Premenopausal women with hormone receptor positive tumours must receive 5 years of tamoxifen after the end of chemotherapy. Postmenopausal women with hormone receptor positive tumours can receive tamoxifen or aromatase inhibitors (or both) after the end of chemotherapy. Patients may receive radiotherapy when clinically indicated.
Detailed description
Estimation of the 5-year disease-free survival in the control arm is 72%. The experimental arm is expected to increase the 5-year disease-free survival by 7% (up to 79%). With an alpha error of 0.05 and 80% power, 592 patients per arm are needed. Assuming a 17% post-randomization drop-out, 691 patients per arm are needed.
Interventions
DRUGDocetaxel
DRUGCapecitabine
DRUGEpirubicin
DRUGCyclophosphamide
Sponsors
Sanofi
Hoffmann-La Roche
Pfizer
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 diagnosis of operable invasive adenocarcinoma of the breast (T1-T3). Tumours must be HER2 negative. Time window between surgery and study randomization must be less than 60 days. * Surgery must consist of mastectomy or conservative surgery with axillary lymph node dissection. Margins free of disease and ductal carcinomas in situ (DCIS) are required. Lobular carcinoma is not considered a positive margin. * Positive axillary lymph nodes defined as at least 1 out of 10 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: TNM pathologic stage N1a, TNM pathologic stage N2a, TNM pathologic stage N3a. * Status of hormone receptors in primary tumour. Results must be available before the end of adjuvant chemotherapy. * Patients must not present evidence of metastatic disease. Status of HER2 in primary tumour, known before randomization. Patients with immune histochemistry (IHC) 0 or +1 are eligible. For patients with IHC 2+, fluorescence 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 \>= 100 x 10\^9/l; hemoglobin \>= 10 mg/dl; * Hepatic function: total bilirubin \<= 1 upper normal limit (UNL); serum glutamic-oxaloacetic transaminase (SGOT) and Serum glutamic pyruvic transaminase (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 mmol/l (2 mg/dl); creatinine clearance \>= 60 ml/min; * Pharmacogenetics: one blood sample is needed for single nucleotide polymorphism (SNP) assessment. * Complete stage workup during the 12 weeks prior to randomization (mammograms are allowed within a 20 week 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 prior 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. * Any T4 or M1 tumour. * Axillary lymph nodes: patients belonging to the following classifications are excluded: TNM pathologic stage N1b, TNM pathologic stage N1c, TNM pathologic stage N2b, TNM pathologic stage N3b, TNM pathologic stage N3c. * HER2 positive breast cancer (IHC 3+ or positive FISH result). * Pre-existing grade \>= 2 motor or sensorial neurotoxicity (National Cancer Institute Common Toxicity Criteria version 2.0 \[NCICTC v-2.0\]). * 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 from 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 tumour curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma. * Chronic treatment with corticosteroids. * Contraindications for corticosteroid administration. * Concomitant treatment with raloxifene, tamoxifen or other selective estrogen receptor modulators (SERMs), either for osteoporosis treatment or for prevention. These treatments must stop before randomisation. * 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 another therapy for cancer. * Males.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Disease-free Survival (DFS) Event | 5 years | A participant was considered to have had a DFS event if there was 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 |
|---|---|---|
| Number of Participants With Overall Survival (OS) Event | Up to 5 years | A participant was considered to have had a OS event if patient died from any cause. |
| The Number of Participants Who Experienced Adverse Events (AE) | 5 years | Safety was assessed by standard clinical and laboratory tests, and were evaluated using NCI-CTC criteria v2.0 |
| Quality of Life Questionnaire: Number of Participants With Hair Loss | Up to 24 months | Hair loss was assessed by the quality of life of the patients through the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Breast Cancer 23 (EORTC QLQ-BR23) profile questionnaire, question 4. The quality of life of the patients was evaluated before each cycle and at the end of treatment. In questionnaire, raw scores range from 0 to 100 and a high score represents a high level of functioning or Health Related Quality of Life, excluding single-item scales in which high scores represent a high level of symptoms. A difference of 10 points on the scale over baseline value was classified as the minimum clinically meaningful change in both questionnaires. |
| Quality of Life Questionnaire: Number of Participants With Hair Loss Recovery | Up to 30 months | Hair Loss Recovery was assessed by a specific Hair Toxicity Questionnaire were patients answered if the hair was less abundant than before, weaker than before or other. The questionnaire was evaluated up to two years after the end of chemotherapy. |
| Quality of Life Questionnaire: Time to Taking Off the Wig | Up to 30 months | Time to taking off the wig was assessed by a specific Hair Toxicity Questionnaire were patients answered when they stop to use the wig. The questionnaire was evaluated up to two years after the end of chemotherapy. |
Countries
Spain
Participant flow
Recruitment details
1,384 patients were recruited in 58 Spanish centers and randomized to receive EC-T (n=669) or ET-X (n=715). 5 patients received no treatment in the ET-X arm. 4 patients were not treated with the study medication to which they were randomized (n=3 EC-T arm; n=1 ET-X arm). 1,378 patients were evaluable for safety (n=667 and 711 respectively).
Participants by arm
| Arm | Count |
|---|---|
| Arm A: EC-T Epirubicin with cyclophosphamide, followed by docetaxel (EC-T): Epirubicin 90 mg/ m2 in combination with cyclophosphamide 600 mg/m2 (EC) every 21 days for 4 cycles, followed by docetaxel 100 mg/m2 (T) every 21 days for 4 cycles.
Docetaxel
Epirubicin
Cyclophosphamide | 669 |
| Arm B: ET-X Epirubicin and docetaxel followed by capecitabine (ET-X):Epirubicin 90 mg/m2 and docetaxel 75 mg/ m2 (ET) every 21 days for 4 cycles, followed by capecitabine 1,250 mg/m2 bid for 14 days, followed by a 7-day rest for 4 cycles.
Docetaxel
Capecitabine
Epirubicin | 715 |
| Total | 1,384 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 18 | 56 |
| Overall Study | Crossed to the other arm | 2 | 1 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Incorrect study treatment | 1 | 0 |
| Overall Study | Other | 3 | 2 |
| Overall Study | Physician Decision | 3 | 4 |
| Overall Study | Protocol Violation | 0 | 4 |
| Overall Study | Recurrence | 1 | 3 |
| Overall Study | Second primary | 0 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 20 |
Baseline characteristics
| Characteristic | Arm A: EC-T | Total | Arm B: ET-X |
|---|---|---|---|
| Age, Continuous | 51 years | 51 years | 51 years |
| Axillary surgery Both | 48 Participants | 85 Participants | 37 Participants |
| Axillary surgery Lymphadenectomy | 618 Participants | 1294 Participants | 676 Participants |
| Axillary surgery Sentinel node biopsy | 3 Participants | 5 Participants | 2 Participants |
| Breast surgery Breast-conserving surgery | 360 Participants | 748 Participants | 388 Participants |
| Breast surgery Mastectomy | 309 Participants | 636 Participants | 327 Participants |
| Histologic type Invasive Ductal Carcinoma | 567 Participants | 1156 Participants | 589 Participants |
| Histologic type Invasive Lobular Carcinoma | 66 Participants | 143 Participants | 77 Participants |
| Histologic type Other | 36 Participants | 85 Participants | 49 Participants |
| Histopathologic grade Grade 1 | 100 Participants | 200 Participants | 100 Participants |
| Histopathologic grade Grade 2 | 307 Participants | 645 Participants | 338 Participants |
| Histopathologic grade Grade 3 | 235 Participants | 478 Participants | 243 Participants |
| Histopathologic grade Unknown | 27 Participants | 61 Participants | 34 Participants |
| Hormone receptor status Negative | 98 Participants | 219 Participants | 121 Participants |
| Hormone receptor status Positive | 571 Participants | 1165 Participants | 594 Participants |
| Human epidermal growth factor receptor 2 (HER2) status Negative | 592 Participants | 1239 Participants | 647 Participants |
| Human epidermal growth factor receptor 2 (HER2) status Positive | 77 Participants | 142 Participants | 65 Participants |
| Human epidermal growth factor receptor 2 (HER2) status Unknown | 0 Participants | 3 Participants | 3 Participants |
| Karnofsky Performance Status (PS) PS 100 | 582 Participants | 1211 Participants | 629 Participants |
| Karnofsky Performance Status (PS) PS 80 | 9 Participants | 16 Participants | 7 Participants |
| Karnofsky Performance Status (PS) PS 90 | 75 Participants | 151 Participants | 76 Participants |
| Karnofsky Performance Status (PS) Unknown | 3 Participants | 6 Participants | 3 Participants |
| Menopausal status Postmenopausal | 320 Participants | 653 Participants | 333 Participants |
| Menopausal status Premenopausal | 349 Participants | 731 Participants | 382 Participants |
| Pathologic tumor size pT1 | 339 Participants | 666 Participants | 327 Participants |
| Pathologic tumor size pT2 | 294 Participants | 645 Participants | 351 Participants |
| Pathologic tumor size pT3 | 36 Participants | 73 Participants | 37 Participants |
| Regional lymph nodes pN1 | 450 Participants | 913 Participants | 463 Participants |
| Regional lymph nodes pN2 | 167 Participants | 348 Participants | 181 Participants |
| Regional lymph nodes pN3 | 52 Participants | 123 Participants | 71 Participants |
| Region of Enrollment Spain | 669 participants | 1384 participants | 715 participants |
| Sex: Female, Male Female | 669 Participants | 1384 Participants | 715 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 70 / 669 | 83 / 715 |
| other Total, other adverse events | 665 / 669 | 699 / 715 |
| serious Total, serious adverse events | 111 / 669 | 138 / 715 |
Outcome results
Primary
Number of Participants With Disease-free Survival (DFS) Event
A participant was considered to have had a DFS event if there was 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: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: EC-T | Number of Participants With Disease-free Survival (DFS) Event | 127 Participants |
| Arm B: ET-X | Number of Participants With Disease-free Survival (DFS) Event | 170 Participants |
Secondary
Number of Participants With Overall Survival (OS) Event
A participant was considered to have had a OS event if patient died from any cause.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: EC-T | Number of Participants With Overall Survival (OS) Event | 70 Participants |
| Arm B: ET-X | Number of Participants With Overall Survival (OS) Event | 83 Participants |
Secondary
Quality of Life Questionnaire: Number of Participants With Hair Loss
Hair loss was assessed by the quality of life of the patients through the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Breast Cancer 23 (EORTC QLQ-BR23) profile questionnaire, question 4. The quality of life of the patients was evaluated before each cycle and at the end of treatment. In questionnaire, raw scores range from 0 to 100 and a high score represents a high level of functioning or Health Related Quality of Life, excluding single-item scales in which high scores represent a high level of symptoms. A difference of 10 points on the scale over baseline value was classified as the minimum clinically meaningful change in both questionnaires.
Time frame: Up to 24 months
Population: 360 patients completed a questionnaire specifically on hair loss 1-2 years after the end of chemotherapy
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: EC-T | Quality of Life Questionnaire: Number of Participants With Hair Loss | Complete hair loss | 165 Participants |
| Arm A: EC-T | Quality of Life Questionnaire: Number of Participants With Hair Loss | Partial hair loss | 9 Participants |
| Arm A: EC-T | Quality of Life Questionnaire: Number of Participants With Hair Loss | No hair loss | 1 Participants |
| Arm B: ET-X | Quality of Life Questionnaire: Number of Participants With Hair Loss | Complete hair loss | 176 Participants |
| Arm B: ET-X | Quality of Life Questionnaire: Number of Participants With Hair Loss | Partial hair loss | 8 Participants |
| Arm B: ET-X | Quality of Life Questionnaire: Number of Participants With Hair Loss | No hair loss | 1 Participants |
Secondary
Quality of Life Questionnaire: Number of Participants With Hair Loss Recovery
Hair Loss Recovery was assessed by a specific Hair Toxicity Questionnaire were patients answered if the hair was less abundant than before, weaker than before or other. The questionnaire was evaluated up to two years after the end of chemotherapy.
Time frame: Up to 30 months
Population: 360 patients completed a questionnaire specifically on hair loss 1-2 years after the end of chemotherapy. Arm A: 174 and Arm B 184 patients suffer hair loss
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: EC-T | Quality of Life Questionnaire: Number of Participants With Hair Loss Recovery | Less abundant than before | 52 Participants |
| Arm A: EC-T | Quality of Life Questionnaire: Number of Participants With Hair Loss Recovery | Weaker than before | 55 Participants |
| Arm A: EC-T | Quality of Life Questionnaire: Number of Participants With Hair Loss Recovery | Other | 67 Participants |
| Arm B: ET-X | Quality of Life Questionnaire: Number of Participants With Hair Loss Recovery | Less abundant than before | 26 Participants |
| Arm B: ET-X | Quality of Life Questionnaire: Number of Participants With Hair Loss Recovery | Weaker than before | 30 Participants |
| Arm B: ET-X | Quality of Life Questionnaire: Number of Participants With Hair Loss Recovery | Other | 128 Participants |
Secondary
Quality of Life Questionnaire: Time to Taking Off the Wig
Time to taking off the wig was assessed by a specific Hair Toxicity Questionnaire were patients answered when they stop to use the wig. The questionnaire was evaluated up to two years after the end of chemotherapy.
Time frame: Up to 30 months
Population: There is only information about take off the wig in 241 patients: Arm A: 111 and Arm B 130
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: EC-T | Quality of Life Questionnaire: Time to Taking Off the Wig | 8.35 Months |
| Arm B: ET-X | Quality of Life Questionnaire: Time to Taking Off the Wig | 6.03 Months |
Secondary
The Number of Participants Who Experienced Adverse Events (AE)
Safety was assessed by standard clinical and laboratory tests, and were evaluated using NCI-CTC criteria v2.0
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: EC-T | The Number of Participants Who Experienced Adverse Events (AE) | 665 Participants |
| Arm B: ET-X | The Number of Participants Who Experienced Adverse Events (AE) | 699 Participants |