Phase III Randomized Study of CTX Given as Standard Dose vs Individual-Dose Intensification vs Cumulative-Dose Intensification in an Adjuvant Regimen of AC (DOX/CTX) with G-CSF in Women with Node-Positive Breast Cancer
Basic Trial Information
|Phase III||Treatment||Completed||18 to physiologic 75||NCI||NSABP-B-25|
I. Determine whether larger but fewer doses of cyclophosphamide (CTX) improve disease-free and overall survival when administered to patients with axillary node-positive breast cancer randomized to postoperative adjuvant chemotherapy with standard dose/schedule AC (doxorubicin/cyclophosphamide) vs. a dose-intense schedule with the same cumulative dose of CTX. II. Determine whether disease-free and overall survival are improved when these patients are randomized to increased dose-intensity and cumulative-dose CTX vs. the same dose intensity of CTX administered over a shorter period (lower cumulative dose) in the AC regimen.
Histologically proven invasive carcinoma of the breast with at least 1 histologically positive ipsilateral axillary node definitively removed by either: Total mastectomy with axillary dissection Lumpectomy with axillary dissection (Radical mastectomy not allowed) The interval between histologic diagnosis and definitive surgery must not exceed 42 days The interval between definitive surgery and initiation of protocol therapy must not exceed 35 days Histology established by excisional, incisional, or needle biopsy and aspiration cytology Tumor confined to breast and ipsilateral axilla on clinical examination Tumor must be movable relative to underlying pectoral muscle, chest wall, and overlying skin Palpable axillary nodes must be movable in relation to the chest wall, neurovascular bundle, and each another, and must be no greater than 2 cm in largest diameter The following conditions are specifically excluded: Inflammatory carcinoma Ulceration Erythema Peau d'orange or any degree of skin edema Satellite nodules Parasternal nodules Edema of the arm Infiltration of the skin (tethering, skin dimpling, and nipple inversion are not to be interpreted as skin infiltration, and patients with these conditions are eligible) Bilateral breast cancer (any mass in the contralateral breast must be proved benign by biopsy) Distant metastases Patients with bone pain must have negative bone scan and/or x-ray Patients with palpable contralateral axillary nodes or palpable supraclavicular or infraclavicular nodes must have biopsy proof of absence of tumor ER and PR assays must be performed on the primary tumor Any ER and PR status allowed Recommended methods of determination include: Dextran-coated charcoal or sucrose density Enzyme immunoassay (EIA) Immunocytochemical assay (ER-ICA and PR-ICA) Lumpectomy patients must additionally meet the following requirements: Tumor clinically no greater than 5 cm in greatest diameter Diffuse tumors on xeroradiography or mammography unless amenable to lumpectomy Breast of a size to permit cosmetically acceptable resection Histologically negative resection margins 1 additional surgical procedure allowed to achieve negative margins Second procedure must be within 28 days of histologic diagnosis If margins are positive following a second surgical procedure, total mastectomy is required for eligibility Any other dominant mass in the ipsilateral breast remnant must be biopsied and shown to be histologically benign
Biologic therapy: No prior therapy for breast cancer Chemotherapy: No prior therapy for breast cancer Endocrine therapy: No prior therapy for breast cancer; oophorectomy for other reasons allowed, but radiation castration excludes Hormonal therapy other than that stipulated by protocol (e.g., birth control, replacement) must be discontinued on entry Radiotherapy: No prior therapy for breast cancer Radiotherapy prior to randomization not allowed in lumpectomy patients Surgery: Total resection of tumor (total mastectomy/axillary dissection or lumpectomy/axillary dissection) required within 35 days of initiation of treatment Patients who have undergone radical mastectomy are ineligible Partial excision of the pectoralis major muscle does not constitute radical mastectomy Definitive surgery must have been performed within 28 days following histologic diagnosis
Age: 18 to physiologic 75 Sex: Not specified Menopausal status: Not specified Performance status: Not specified Life expectancy: At least 10 years excluding breast cancer Hematopoietic: (obtained postoperatively) WBC at least 4,000 Platelets at least 100,000 Hepatic: (obtained postoperatively) Bilirubin within normal limits SGOT or SGPT within normal limits Renal: (obtained postoperatively) Creatinine within normal limits Cardiovascular: No documented MI No angina pectoris requiring medication No history of CHF No arrhythmia associated with heart failure or cardiac dysfunction No valvular disease with documented cardiac dysfunction No cardiomegaly on chest x-ray No poorly controlled hypertension (diastolic greater than 100 mm Hg) Other: No known hypersensitivity to E. coli-derived drug preparations No nonmalignant systemic disease that would preclude protocol therapy or prevent prolonged follow-up No second malignancy except: Effectively treated nonmelanomatous skin cancer In situ cervical cancer treated by surgery only No pregnant women No psychiatric or addictive disorder that would preclude informed consent
2,400 patients (800/arm) will be accrued over an estimated 3 years.
Randomized study. Patients 50 years of age or older at time of definitive surgery, regardless of ER or PR status, are treated on Regimen A concomitantly with chemotherapy; those who underwent lumpectomy are treated on Regimen B following completion of chemotherapy. Arm I: 2-Drug Combination Chemotherapy with Hematologic Toxicity Attenuation. AC: Doxorubicin, DOX, NSC-123127; Cyclophosphamide, CTX, NSC-26271; with Granulocyte Colony Stimulating Factor (Amgen), G-CSF, NSC-614629. Standard dose/schedule. Arm II: 2-Drug Combination Chemotherapy with Hematologic Toxicity Attenuation. AC; with G-CSF. Intensified CTX dose/short schedule. Arm III: 2-Drug Combination Chemotherapy with Hematologic Toxicity Attenuation. AC; with G-CSF. Intensified CTX dose/standard schedule. Regimen A: Antiestrogen Therapy. Tamoxifen, TMX, NSC-180973. Regimen B: Radiotherapy. Breast irradiation using Co60 or x-rays with minimum energy of 4 MeV.
Fisher B, Anderson S, DeCillis A, et al.: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17 (11): 3374-88, 1999.[PUBMED Abstract]
Wapnir IL, Anderson SJ, Mamounas EP, et al.: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol 24 (13): 2028-37, 2006.[PUBMED Abstract]
Swain SM, Wilson JW, Mamounas EP, et al.: Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer. J Natl Cancer Inst 96 (7): 516-23, 2004.[PUBMED Abstract]
Taghian A, Jeong JH, Mamounas E, et al.: Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol 22 (21): 4247-54, 2004.[PUBMED Abstract]
Wapnir I, Anderson S, Tan-Chiu E, et al.: Ipsilateral breast tumor recurrence (IBTR) and survival in NSABP node-positive breast cancer protocols. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A315, 2000.
Trial Contact Information
Trial Lead Organizations
National Surgical Adjuvant Breast and Bowel Project
Ph: 412-359-3336; 866-680-0004
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.