S0221 Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in Treating Patients With Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel, use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving them after surgery may kill any remaining tumor cells. It is not yet known which combination chemotherapy regimen is more effective in treating resected breast cancer. PURPOSE: This randomized phase III trial is comparing 2 different regimens of combination chemotherapy to see how well they work in treating patients who have undergone surgery for stage I, stage II, or stage III breast cancer.

Detailed Description
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OBJECTIVES: Compare the disease-free survival of patients with node-positive or high-risk node-negative breast cancer treated with 2 different schedules of adjuvant doxorubicin, cyclophosphamide, and paclitaxel. Compare the overall survival of patients treated with these regimens. Compare the toxic effects of these regimens in these patients. Correlate outcome with putative prognostic markers in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms (arms V and VI) (arms I-IV closed 11/10/10). Arm I: (closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Arm II: (closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. Arm III: (closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. Arm IV: (closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. Arm V: Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Arm VI: Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim as in arm V. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. In all arms, treatment continues in the absence of disease progression or unacceptable toxicity. In all arms patients with HER2/neu-positive tumors also receive trastuzumab (Herceptin®) weekly or every 3 weeks beginning concurrently with paclitaxel OR 3 months after the last dose of paclitaxel and continuing for up to 52 weeks. In all arms, patients with estrogen-receptor or progesterone-receptor positive tumors receive hormonal therapy beginning within 28 days of the completion of adjuvant chemotherapy or radiotherapy (if given). After finishing study treatment patients are followed up every 6 months for 5 years and then once a year for up to 15 years. PROJECTED ACCRUAL: A total of 3,250 patients will be accrued for this study.

Official Title
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Phase III Trial of Continuous Schedule AC + G vs. Q 2 Week Schedule AC, Followed by Paclitaxel Given Either Every 2 Weeks or Weekly for 12 Weeks as Post-Operative Adjuvant Therapy in Node-Positive or High-Risk Node-Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: pegfilgrastim
* Drug: AC regimen
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed stage I-III invasive breast cancer Operable disease Stage I, II, IIIA, and IIIC (T1-3, N3a only) No T4 tumors High-risk disease, defined by 1 of the following: Tumor ≥ 2 cm in greatest diameter (includes both invasive and intraductal component) Patients with nodal status of N0+ (i.e., no cluster of tumor cells in any node greater than 0.2 mm) are considered to be node negative and must have a primary tumor ≥ 2 cm in size or have a tumor ≥ 1 cm with high risk features Patients who are node negative on the basis of a sentinel node procedure and fewer than 6 axillary nodes are removed are eligible OR at least 6 axillary or intramammary nodes must be negative Tumor ≥ 1 cm in diameter and meeting 1 of the following criteria: ER-negative and PgR-negative ER-positive or PgR-positive with a Genomic Health Recurrence Score of ≥ 26 One or more axillary or intramammary nodes are involved by metastatic breast cancer If one or more nodes is involved, a minimum of 6 axillary or intramammary nodes must have been examined histologically Patients with N0(I+) disease will be considered node negative HER2/neu-positive tumors (3+ by immunohistochemical staining or amplified by fluorescence in-situ hybridization) allowed Bilateral synchronous breast cancer diagnosed within 1 month of each other allowed provided the higher TNM stage primary tumor meets the eligibility criteria Prior modified radical mastectomy OR local excision of all tumors with axillary lymph node dissection or sentinel node resection required No more than 84 days since prior surgery for the primary tumor and/or axilla Final resection margins for the primary tumor must be histologically negative for invasive cancer and ductal carcinoma in situ Resection margins positive for lobular carcinoma in situ are allowed Hormone receptor status: Estrogen receptor status known Progesterone receptor status known PATIENT CHARACTERISTICS: Age 18 and over Sex Male or female Menopausal status Not specified Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic Absolute neutrophil count at least 1,200/mm^3 Platelet count at least 100,000/mm^3 Hepatic Bilirubin no greater than upper limit of normal (ULN) Alkaline phosphatase no greater than 2 times ULN SGOT or SGPT no greater than 2 times ULN Renal Creatinine no greater than ULN Cardiovascular No congestive heart failure No active angina pectoris LVEF greater than or equal to the lower limit of normal* by MUGA or echocardiogram NOTE: Patients age 60 and over OR with a history of hypertension Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, in situ cervical carcinoma, or lobular carcinoma in situ of the breast Prior invasive breast cancer or ductal carcinoma in situ allowed if disease-free for 5 years HIV negative PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior cytotoxic chemotherapy for this breast cancer No prior chemotherapy with an anthracycline, anthracenedione, or taxane Endocrine therapy Not specified Radiotherapy No prior radiotherapy for this malignancy At least 2 weeks since prior radiotherapy for ductal carcinoma in situ Surgery See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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 I<br>(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. | Biological: pegfilgrastim<br>* Given IV<br>Drug: AC regimen<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: doxorubicin hydrochloride<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>|
| Experimental: Arm II<br>(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. | Biological: pegfilgrastim<br>* Given IV<br>Drug: AC regimen<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: doxorubicin hydrochloride<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>|
| Active Comparator: Arm III<br>(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. | Biological: pegfilgrastim<br>* Given IV<br>Drug: AC regimen<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: doxorubicin hydrochloride<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>|
| Experimental: Arm IV<br>(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. | Biological: pegfilgrastim<br>* Given IV<br>Drug: AC regimen<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: doxorubicin hydrochloride<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>|
| Experimental: Arm V<br>Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. | Biological: pegfilgrastim<br>* Given IV<br>Drug: AC regimen<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: doxorubicin hydrochloride<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>|
| Experimental: Arm VI<br>Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim as in arm V. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. | Biological: pegfilgrastim<br>* Given IV<br>Drug: AC regimen<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: doxorubicin hydrochloride<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<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 (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5. | every 6 months (annually for mammograms) for 5 years | 
| Overall Survival | Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5. | Every 6 months for 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE Version 3.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. | Toxicity assessment was evaluated every 4 weeks while on protocol therapy. | 
| Disease-free Survival Comparison Between 2 Treatments in HR-positive, HER-2 Negative Group | Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5. | Biomarkers were measured by gene expression analysis before study entry. DFS were measured every 6 months for 5 years | 
| Overall Survival Comparison Between 2 Treatments in HR-positive, HER-2 Negative Group | Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5. | Biomarkers were measured by gene expression analysis before study entry. OS was measured every 6 months for 5 years | 
| Disease-free Survival Comparison Between 2 Treatments in HR-negative, HER-2 Negative Group | Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5. | Biomarkers were measured by gene expression analysis before study entry. DFS was measured every 6 months for 5 years | 
| Overall Survival Comparison Between 2 Treatments in HR-negative, HER-2 Negative Group | Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5. | Biomarkers were measured by gene expression analysis before study entry. OS was measured every 6 months for 5 years | 
| Disease-free Survival Comparison Between 2 Treatments in HER2-positive Group | Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5. | Biomarkers were measured by gene expression analysis before study entry. DFS was measured every 6 months for 5 years | 
| Overall Survival Comparison Between 2 Treatments in HER-2 Positive Group. | Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5. | Biomarkers were measured by gene expression analysis before study entry. OS was measured every 6 months for 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IIIC breast cancer, stage II breast cancer, stage IA breast cancer, stage IB breast cancer, male breast cancer, HER2-positive breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer