EC Followed Docetaxel Versus ET Followed Capecitabine as Adjuvant Chemotherapy for Node Positive Operable Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase III Trial to Compare Epirubicin and Cyclophosphamide (EC) Followed by Docetaxel (T) to Epirubicin and Docetaxel (ET) Followed by Capecitabine (X) as Adjuvant Treatment, Node Positive Breast Cancer Patients

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Capecitabine
* Drug: Epirubicin
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: EC-T<br>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. | Drug: Docetaxel<br> <br> * Other names: Taxotere;Drug: Epirubicin<br> <br> * Other names: Ellence;Drug: Cyclophosphamide<br> <br> * Other names: cytoxan;|
| Experimental: Arm B: ET-X<br>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. | Drug: Docetaxel<br> <br> * Other names: Taxotere;Drug: Capecitabine<br> <br> * Other names: Xeloda;Drug: Epirubicin<br> <br> * Other names: Ellence;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Survival (OS) Event | A participant was considered to have had a OS event if patient died from any cause. | Up to 5 years | 
| 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 | 5 years | 
| 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. | Up to 24 months | 
| 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. | Up to 30 months | 
| 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. | Up to 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adjuvant treatment, HER2 negative breast cancer, Node positive breast cancer, Oral chemotherapy