Combination Chemotherapy With or Without Colony-stimulating Factors in Treating Women With Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: . To compare the effects on breast cancer of three different combinations of drugs which are commonly used to treat this disease. . It is not yet known which treatment regimen is most effective for breast cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy given with or without epoetin alfa in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer.

Detailed Description
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OBJECTIVES: Primary Compare the disease-free survival of premenopausal or early postmenopausal women with previously resected node positive or high-risk node negative stage I-IIIB breast cancer treated with cyclophosphamide, epirubicin, and fluorouracil vs cyclophosphamide, epirubicin, filgrastim (G-CSF), and epoetin alfa followed by paclitaxel vs cyclophosphamide and doxorubicin followed by paclitaxel. Secondary Compare the overall survival of patients treated with these regimens. Compare the rate of toxic effects of these regimens in this patient population. Compare the quality of life of patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of positive nodes (0 vs 1-3 vs 4-10 vs more than 10), type of prior surgery (total vs partial mastectomy), and estrogen receptor status (positive vs negative). Patients are randomized to one of three treatment arms. Arm I: Patients receive epirubicin IV and fluorouracil IV on days 1 and 8 and oral cyclophosphamide on days 1-14. Treatment repeats every 28 days for 6 courses. Arm II: Patients receive epirubicin IV and cyclophosphamide IV on day 1 and filgrastim (G-CSF) subcutaneously (SC) on days 2-13. Patients with a hemoglobin < 13.0 g/dL also receive epoetin alfa SC once weekly beginning within 1 week after the start of therapy and continuing as needed. Treatment repeats every 14 days for 6 courses. Beginning 21 days after completion of epirubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and G-CSF and epoetin alfa as above. Treatment repeats every 21 days for 4 courses. Arm III: Patients receive doxorubicin IV over 15 minutes and cyclophosphamide IV over 15 minutes on day 1. Treatment repeats every 21 days for 4 courses. Beginning 21 days after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel as in arm II. Treatment in all arms continues in the absence of disease progression or unacceptable toxicity. All receptor positive patients receive oral tamoxifen or anastrozole (if tamoxifen is contraindicated) for 5 years after completion of chemotherapy. Quality of life is assessed at baseline, day 1 of cycles 2, 3 4 and 6 (arm I), days 1 of cycles 3 and and day 1 of cycles 1 and 4 of paclitaxel (arm II), day 1 of cycles 2 and 3, day 1 of cycles 1 and 4 of paclitaxel, (arm III), 9 months, 12 months, and then annually thereafter until 5 years Patients are followed at 9 months, 12 months, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 2,100 patients (700 per treatment arm) will be accrued for this study within 4 years.

Official Title
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A Phase III Adjuvant Trial Of Sequenced EC + Filgrastim + Epoetin Alfa Followed By Paclitaxel Versus Sequenced AC Followed By Paclitaxel Versus CEF As Therapy For Premenopausal Women And Early Postmenopausal Women Who Have Had Potentially Curative Surgery For Node Positive Or High Risk Node Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: epoetin alfa
* Biological: filgrastim
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: epirubicin hydrochloride
* Drug: fluorouracil
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the breast that is potentially curable T0-4 (dermal involvement on pathology assessment only), N0-2, M0 No clinical T4 disease Previously treated with one of the following: Total mastectomy and level II axillary node dissection Partial mastectomy and level II axillary node dissection with planned breast radiotherapy after completion of adjuvant chemotherapy regimen* Patients with a positive sentinel node biopsy must undergo level II axillary node dissection or sufficient nodal sampling If microscopic residual in situ or invasive disease is present at total or partial mastectomy margins, planned radiotherapy must also include a boost to the tumor bed No residual tumor in the axilla after dissection Axillary node positive Negative nodes allowed if the tumor is ≥ 1 cm and 1 or more of the following criteria defining high-risk node-negative disease are met: Histological grade III or, Estrogen receptor negative or, Lymphatic/vascular invasion Hormone receptor status: Estrogen receptor status known PATIENT CHARACTERISTICS: Age: 60 and under Sex: Female Menopausal status: Pre- or postmenopausal Performance status: ECOG 0-2 Life expectancy: At least 5 years Hematopoietic: WBC ≥ 3,000/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic: Bilirubin ≤ 1.5 times upper limit of normal (ULN) Renal: Creatinine ≤ 1.5 times ULN Cardiovascular: LVEF ≥ limit of normal by MUGA or echocardiogram No arrhythmia requiring ongoing treatment No congestive heart failure No documented coronary artery disease Other: No other malignancy except: Adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix Ductal or lobular carcinoma in situ that has been curatively treated by surgery alone Other prior malignancies (except breast cancer) curatively treated more than 5 years prior to study entry No serious underlying medical illness or psychiatric or addictive disorder that would preclude study compliance No known hypersensitivity to E. coli-derived products, mammalian-cell derived products, or any study agents Not pregnant or nursing Negative pregnancy test Fertile patients must use effective non-hormonal contraception PRIOR CONCURRENT THERAPY: Biologic therapy: No prior immunotherapy for breast cancer No concurrent pegfilgrastim or darbepoetin alfa (Arm II) Allowed on arms 1 and 3 if medically necessary Chemotherapy: No prior chemotherapy for breast cancer Endocrine therapy: No prior hormonal therapy for breast cancer No concurrent hormone replacement therapy No concurrent selective estrogen-receptor modulators (e.g., raloxifene for the treatment or prevention of osteoporosis) No concurrent oral contraceptives (i.e., birth control pills) No other concurrent aromatase inhibitors Radiotherapy: See Disease Characteristics No prior radiotherapy for breast cancer Surgery: See Disease Characteristics No more than 12 weeks since prior total or partial mastectomy (including re-excision of margins) Other: At least 30 days since prior investigational drugs No other concurrent investigational drugs Concurrent bisphosphonates for the treatment or prevention of osteoporosis allowed

Ages Eligible for Study
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Maximum Age: 60 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 1: CEF<br>6 cycles - q 28 days (6 months) - Cyclophosphamide 75 mg/m2 - po - Days 1-14 - Epirubicin 60 mg/m2 - IV - Days 1 and 8 - 5 Fluorouracil: 500mg/m2 - IV - Days 1 and 8 + Continuous Antibiotic Prophylaxis with Cotrimoxazole 960 mg (i.e.2x480 mg tablets) po-bid or Ciprofloxacin 500 mg - po-bid | Drug: cyclophosphamide<br>* 75, 600 and 830 mg/m2<br>Drug: epirubicin hydrochloride<br>* 60 mg/m2<br>Drug: fluorouracil<br>* 500mg/m2<br>|
| Active Comparator: Arm 2: EC/T<br>6 cycles - q 14 days (3 months) - Epirubicin 120 mg/m2 - IV - Day 1 - Cyclophosphamide 830 mg/m2 - IV - Day 1 - Filgrastim 5μg/kg/d - SC - Days 2 - 13 + Epoetin Alfa 40,000 IU - SC - once weekly (to begin within 1 week after start of protocol therapy as needed) 21 days from last administration of EC (EC/T) 4 cycles - q 21 days (3 months) - Adriamycin 60 mg/m2 - IV - Day 1 - Cyclophosphamide 600 mg/m2 - IV - Day 1 - 21 days from last administration of AC 4 cycles - q 21 days (3 months) - Paclitaxel 175 mg/m2 IV 3 hour infusion | Biological: epoetin alfa<br>* 40,000 IU<br>Biological: filgrastim<br>* 5 mg/kg/d - days 2-13<br>Drug: cyclophosphamide<br>* 75, 600 and 830 mg/m2<br>Drug: doxorubicin hydrochloride<br>* 60 mg/m2<br>Drug: paclitaxel<br>* 175 mg/m2<br>|
| Active Comparator: Arm 3: AC/T<br>4 cycles - q 21 days (3 months) - Adriamycin 60 mg/m2 - IV - Day 1 - Cyclophosphamide 600 mg/m2 - IV - Day 1 21 days from last administration of AC 4 cycles - q 21 days (3 months) - Paclitaxel 175 mg/m2 IV 3 hour infusion | Drug: cyclophosphamide<br>* 75, 600 and 830 mg/m2<br>Drug: doxorubicin hydrochloride<br>* 60 mg/m2<br>Drug: paclitaxel<br>* 175 mg/m2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | Disease free survival was defined as the time from randomization to the time of recurrence of the primary disease. Local or nodal recurrence and metastatic disease were considered a recurrence of the primary tumour. Patients who had contralateral breast cancer or a second primary malignancy, or died from some cause other than disease were censored as relapse-free at the time of death. Patients who had not relapsed were censored at longest follow-up or at non-breast cancer death. As required, adjudication was used to assess reports of recurrence. | 13 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from randomization to the time of death from any cause, with censoring at longest follow-up. | 13 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer