Phase III Adjuvant Chemotherapy with Intensive CEF (CTX/EPI/5-FU) vs Standard CMF (CTX/MTX/5-FU) in Premenopausal Patients with Carcinoma of the Breast with Positive Axillary Nodes
Basic Trial Information
I. Compare, in a Phase III setting, the relapse-free survival and overall survival of premenopausal women with node-positive breast cancer who have undergone complete surgical resection of all known disease and are subsequently randomized to adjuvant chemotherapy consisting of intensive CEF (cyclophosphamide/epirubicin/fluorouracil) vs. standard CMF (cyclophosphamide/methotrexate/fluorouracil). II. Compare the toxicities of these two regimens when administered as adjuvant therapy in this patient population. III. Compare the quality of life among patients receiving these adjuvant chemotherapy regimens.
Breast adenocarcinoma with at least one histologically positive axillary node that has been completely resected Total or partial mastectomy with axillary node dissection required If less than total mastectomy, breast irradiation on protocol following completion of adjuvant chemotherapy required Complete resection of bilateral breast cancer required but contralateral axillary dissection optional if axilla clinically negative at surgery No evidence of microscopic residual disease in axilla following either procedure or in resection margins following total mastectomy Further excision recommended for residual microscopic margins following partial mastectomy If further excision not undertaken, boost irradiation to tumor bed in addition to breast irradiation required following chemotherapy on protocol Preoperative clinical Stage T1-3a, N0-2, M0 required Clinical Stage T4 excludes (chest wall extension; edema, including peau d'orange; skin ulceration; satellite skin nodules confined to homolateral breast; and inflammatory carcinoma) Postoperative pathologic Stage T0-4, N1-2, M0 (only T4 with dermal involvement on pathologic exam allowed) No evidence of metastatic disease on appropriate studies (e.g., chest x-ray, bone scan/x-ray, abdominal ultrasound if LFTs abnormal) Randomization within 10 weeks of initial surgical histologic diagnosis required Hormone receptor status: Not specified
No prior therapy for breast cancer Biologic therapy: Not specified Chemotherapy: No planned other cytotoxic chemotherapy Endocrine therapy: No planned tamoxifen, long-term prednisone, or other hormones Radiotherapy: No planned regional nodal or chest wall irradiation Surgery: Prior partial or total mastectomy required (see Disease Characteristics)
Age: Not specified Sex: Females only Menopausal status: Pre- or perimenopausal, i.e., one of the following: Normal menstruation Biochemical evidence of ovarian function Amenorrheic for less than 1 year Amenorrheic for 1-3 years and under age 52 Hysterectomized but with at least 1 ovary intact and under age 56 Performance status: Not specified Hematopoietic: WBC at least 3,000 ANC at least 1,500 Platelets at least 100,000 Hepatic: Bilirubin within normal limits Alkaline phosphatase within normal limits SGOT/SGPT within normal limits If LFTs are elevated, metastasis must be ruled out by abdominal ultrasound Renal: Creatinine no greater than 1.5 x normal Cardiovascular: LVEF at least 45% by MUGA No history of angina No current CHF No documented MI Other: No serious underlying medical illness or psychiatric or addictive disorder that might interfere with adequate drug delivery and follow-up No history of second malignancy except: Treated nonmelanomatous skin cancer Curatively treated cancer of the cervix, endometrium, colon, or thyroid with no evidence of active disease for at least 5 years
600 patients will be enrolled over about 4 years.
Randomized study. Patients who have undergone less than total mastectomy receive radiotherapy on Regimen A upon completion of adjuvant chemotherapy. Arm I: 3-Drug Combination Chemotherapy. CEF: Cyclophosphamide, CTX, NSC-26271; Epirubicin, EPI, NSC-256942; Fluorouracil, 5-FU, NSC-19893. Arm II: 3-Drug Combination Chemotherapy. CMF: CTX; Methotrexate, MTX, NSC-749; 5-FU. Regimen A: Radiotherapy. Breast irradiation using Co60 equipment or a linear accelerator with energies of 4 MeV or greater and (in selected cases) boost irradiation of the tumor bed with Co60 or electrons.
Pritchard KI, Munro A, O'Malley FP, et al.: Chromosome 17 centromere (CEP17) duplication as a predictor of anthracycline response: evidence from the NCIC Clinical Trials Group (NCIC CTG) MA.5 Trial. Breast Cancer Res Treat 131 (2): 541-51, 2012.[PUBMED Abstract]
Cheang MCU, Voduc D, Tu D, et al.: The responsiveness of intrinsic subtypes to adjuvant anthracyclines versus nonanthracyclines in NCIC.CTG MA.5 randomized trial. [Abstract] J Clin Oncol 29 (Suppl 15): A-1032, 2011.
O'Malley FP, Chia S, Tu D, et al.: Topoisomerase II alpha protein and responsiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial. Breast Cancer Res Treat 128 (2): 401-9, 2011.[PUBMED Abstract]
O'Malley FP, Chia S, Tu D, et al.: Topoisomerase II alpha protein overexpression has predictive utility in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5). [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-38, S18, 2006.
Pritchard KI, Shepherd LE, O'Malley FP, et al.: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354 (20): 2103-11, 2006.[PUBMED Abstract]
Shepherd LE, Parulekar W, Pritchard KI, et al.: Left ventricular function following adjuvant chemotherapy for breast cancer: the NCIC CTG MA5 experience. [Abstract] J Clin Oncol 24 (Suppl 18): A-522, 2006.
Levine MN, Pritchard KI, Bramwell VH, et al.: Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 23 (22): 5166-70, 2005.[PUBMED Abstract]
Parulekar WR, Day AG, Ottaway JA, et al.: Incidence and prognostic impact of amenorrhea during adjuvant therapy in high-risk premenopausal breast cancer: analysis of a National Cancer Institute of Canada Clinical Trials Group Study--NCIC CTG MA.5. J Clin Oncol 23 (25): 6002-8, 2005.[PUBMED Abstract]
Radice D, Redaelli A: Q-TWiST analysis of cyclophosphamide, epirubicin, fluorouracil versus cyclophosphamide, methotrexate, fluorouracil treatment for premenopausal women with node-positive breast cancer. Pharmacoeconomics 23 (1): 69-75, 2005.[PUBMED Abstract]
Pritchard KI, O'Malley FA, Andrulis I, et al.: Prognostic and predictive value of HER2/neu in a randomized trial comparing CMF to CEF in premenopausal women with axillary lymph node positive breast cancer (NCIC CTG MA.5). [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-165, 2002.
Levine MN, Bramwell VH, Pritchard KI, et al.: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16 (8): 2651-8, 1998.[PUBMED Abstract]
Levine M, Bramwell V, Bowman D, et al.: A clinical trial of intensive CEF versus CMF in premenopausal women with node positive breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 14: A-112, 103, 1995.
Gennari A, Sormani MP, Puntoni M, et al.: A pooled analysis on the interaction between HER-2 expression and responsiveness of breast cancer to adjuvant chemotherapy. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-41, S19, 2006.
Findlay B, Myles J, Levine M, et al.: Using ideal vs. actual weights to calculate chemotherapy doses in premenopausal women with stage 2 breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-56, 63, 1994.
Trial Contact Information
Trial Lead Organizations
NCIC-Clinical Trials Group
Ph: 905-527-4322 ext. 42176
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.