NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Comparison of Adjuvant Chemotherapy with CMF vs CAF with vs without Long-Term Endocrine Therapy with TMX in High-Risk Node-Negative Breast Cancer Patients and a Natural History Follow-Up Study in Low-Risk Node-Negative Patients
Basic Trial Information
|Phase III||Treatment||Closed||pre- and postmenopausal||NCI||SWOG-8897|
CLB-8897, EST-2188, INT-0102
I. Compare, in a Phase III Intergroup setting, disease-free survival and overall survival of high-risk primary node-negative breast cancer patients randomly assigned to adjuvant chemotherapy with 6 courses of CAF (cyclophosphamide/adriamycin/5-fluorouracil) vs. 6 courses of CMF (cyclophosphamide/methotrexate/5-fluorouracil). II. Assess the value of 5 years of tamoxifen therapy vs. no tamoxifen therapy following completion of adjuvant chemotherapy. III. Compare the toxicities of these treatments. IV. Assess the prognostic significance of ploidy and % S phase as determined by DNA flow cytometry in patients with small, occult invasive breast cancer treated by surgery or surgery and radiotherapy only. V. Evaluate disease-free survival and overall survival of patients with low-risk invasive breast cancer (as characterized by receptor status, tumor size, and % S phase) who are treated with local therapy only. (Accrual closed to low-risk patients as of 9/91).
Histologically documented invasive adenocarcinoma of the breast with negative axillary nodes (pathologic stage T1-3a, N0, M0) Apocrine, adenoidcystic, and squamous carcinomas and sarcomas specifically excluded Patients must be within 12 weeks (15 weeks for patients requiring a second registration) of definitive surgery and must begin protocol therapy within 1 working day of registration Radical, modified radical, or breast-sparing surgery and levels I and II axillary node dissection with analysis of at least 6 nodes required If margins are positive, re-excision permitted prior to entry Patients with positive deep mastectomy margins excluded Type of surgery, number of nodes examined, and tumor size (size of only largest tumor in patients with more than 1 discrete mass) must be reported Patients electing breast-sparing procedure (partial mastectomy or lumpectomy) must have had total excisional biopsy including a small rim of normal tissue and a level I and II axillary dissection; the tumor must be no greater than 5 cm in greatest diameter, and clinical and mammographic examination must demonstrate the absence of multicentric lesions Date of definitive surgery defined as day of axillary dissection in patients undergoing lumpectomy Tumor must be movable in relation to chest wall No peau d'orange skin changes, skin ulcerations, or inflammatory changes allowed No evidence of metastatic disease on chest x-ray, contralateral mammogram, and any other indicated imaging studies Prestudy chest x-ray and mammogram must be performed prior to registration and no earlier than 3 months prior to definitive surgery No bilateral breast cancer Patients found to have ductal carcinoma in situ without invasion in the contralateral breast are eligible only if a contralateral mastectomy has been done Hormone receptor status: Any ER or PgR status accepted ER and PgR status must be determined by biochemical methods or ELISA with monoclonal antibodies on the primary tumor (immunohistochemical assay not acceptable) Receptor assay may be done on intraductal tumor if there is insufficient infiltrating tumor available
Biologic therapy: Not specified Chemotherapy: No prior chemotherapy Endocrine therapy: No prior hormonal therapy except up to 14 days of tamoxifen started by an outside physician and stopped prior to registration Radiotherapy: All patients with breast-sparing surgery must receive radiotherapy on protocol as follows: High-risk patients are irradiated before or after adjuvant chemotherapy Uncertain-risk patients not irradiated before chemotherapy must be irradiated after chemotherapy if found to be high-risk or within 15 weeks of surgery if found to be low-risk Radiotherapy given before chemotherapy must be completed before registration No patients with a modified radical mastectomy may receive postoperative radiotherapy Surgery: Radical, modified radical, or breast-sparing surgery and levels I and II axillary node dissection with analysis of at least 6 nodes required (as detailed above) Other: Previous treatment with estrogen- or progesterone-containing preparations for reasons unrelated to breast cancer permitted, but such therapy must be discontinued prior to registration
Age: Not specified Sex: Females only Menopausal status: Pre- or postmenopausal Performance status: Not specified Hematopoietic: (within 2 weeks of registration) WBC at least 3,500 Platelets at least 100,000 Hepatic: (within 2 weeks of registration) Bilirubin no greater than 1.2 x ULN SGOT or SGPT no greater than 1.2 x ULN Alkaline phosphatase no greater than 1.2 x ULN Renal: (within 2 weeks of registration) Creatinine no greater than 1.5 mg/dl Cardiovascular: No history of ischemic heart disease No history of CHF Normal ejection fraction by MUGA scan required if clinically indicated Other: No pre-existing medical condition precluding protocol therapy, e.g.: No severe diabetes No active ulcer disease No uncontrolled hypertension No significant psychiatric disease No active second malignancy within previous 5 years except: Nonmelanomatous skin cancer In situ carcinoma of the cervix No pregnant or lactating women Effective contraception required of fertile women
1,300 patients will be required on each treatment arm, and it is anticipated that an additional 900 low-risk patients will be registered on the no treatment part of the trial. Accrual should be complete in about 3 years, and 4 additional years will be required for follow-up.
Value of tamoxifen therapy vs no tamoxifen therapy at 5 years
Prognostic significance of ploidy and % S phase as determined by DNA flow cytometry
Randomized study. Patients with occult, small, or mammographically detected invasive tumors too small for biochemical ER assay are registered and observed without adjuvant therapy, as are those with ER-positive and/or PgR-positive tumors less than 2 cm in diameter and less than 4.4% S phase for diploid tumors or less than 7.0% S phase for aneuploid tumors or tumors 1 cm or less in size with unknown % S phase because of insufficient tumor (as of 9/91, entry is closed to low-risk patients). All others (i.e., those with ER-negative and PgR-negative tumors; ER-positive and/or PgR-positive tumors at least 2 cm in size; ER-positive tumor less than 2 cm with at least 4.4% S phase for diploid tumors or at least 7.0% S phase for aneuploid tumors; tumors larger than 1 cm with unknown % S phase; and tumors with unknown % S phase for reasons other than insufficient tumor) are considered high-risk and are randomized on Arms I-IV. Patients with multiclonal tumors are considered high-risk if any clone qualifies as high-risk. All patients who had a breast-sparing surgical procedure receive radiotherapy on Regimen A, either prior to initiation or after completion of chemotherapy; radiotherapy given prior to chemotherapy must be completed before registration. Arm I: 3-Drug Combination Chemotherapy. CMF: Cyclophosphamide, CTX, NSC-26271; Methotrexate, MTX, NSC-740; 5-Fluorouracil, 5-FU, NSC-19893. Arm II: 3-Drug Combination Chemotherapy. CAF: CTX; Doxorubicin, Adriamycin, ADR, NSC-123127; 5-FU. Arm III: 3-Drug Combination Chemotherapy followed by Antiestrogen Therapy. CMF; followed by Tamoxifen, TMX, NSC-180973. Arm IV: 3-Drug Combination Chemotherapy followed by Antiestrogen Therapy. CAF; followed by TMX. Regimen A: Radiotherapy. Irradiation of the breast and underlying chest wall using megavoltage equipment with photon energies of up to 6 MeV followed by an optional boost to the tumor bed using direct electrons or Iridium-192 implants.
Yao S, Barlow WE, Albain KS, et al.: Manganese superoxide dismutase polymorphism, treatment-related toxicity and disease-free survival in SWOG 8897 clinical trial for breast cancer. Breast Cancer Res Treat 124 (2): 433-9, 2010.[PUBMED Abstract]
Ambrosone CB, Barlow WE, Reynolds W, et al.: Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897. J Clin Oncol 27 (30): 4973-9, 2009.[PUBMED Abstract]
Choi JY, Barlow WE, Albain KS, et al.: Nitric oxide synthase variants and disease-free survival among treated and untreated breast cancer patients in a Southwest Oncology Group clinical trial. Clin Cancer Res 15 (16): 5258-66, 2009.[PUBMED Abstract]
Ganz PA, Hussey MA, Moinpour CM, et al.: Late cardiac effects of adjuvant chemotherapy in breast cancer survivors treated on Southwest Oncology Group protocol s8897. J Clin Oncol 26 (8): 1223-30, 2008.[PUBMED Abstract]
Ambrosone CB, Barlow W, Yeh I-T: Pharmacogenetics and breast cancer treatment outcomes: results on oxidative stress-related genotypes (MPO, MnSOD) from a Southwest Oncology Group intergroup trial (INT-0102). [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-37, S18, 2006.
Ambrosone CB, Choi JY, Barlow W, et al.: Pharmacogenetics and breast cancer treatment outcomes: results on oxidative stress related genotypes (MPO, MNSOD) from a Southwest Oncology Group trial (S8897). [Abstract] Int J Biol Markers 22 (1): 61-2, 2006.
Hutchins LF, Green SJ, Ravdin PM, et al.: Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 23 (33): 8313-21, 2005.[PUBMED Abstract]
Pierce LJ, Hutchins LF, Green SR, et al.: Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23 (1): 24-9, 2005.[PUBMED Abstract]
Pierce LJ, Hutchins L, Green SJ, et al.: Sequencing of tamoxifen (TAM) and radiotherapy (RT) with breast conservation (BCT) in early stage breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-39, 10, 2003.
Hutchins L, Green S, Ravdin P, et al.: CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node negative patients: first results of intergroup trial INT 0102. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A2, 1a, 1998.
Hershman DL, Unger JM, Barlow WE, et al.: Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol 27 (13): 2157-62, 2009.[PUBMED Abstract]
Hershman D, Unger J, Barlow W, et al.: Treatment quality and outcome of African American vs. European American breast cancer patients: retrospective analysis of Southwest Oncology Group studies S8814/S8897. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-3049, S140-1, 2006.
Goldhirsch A, Gelber RD, Yothers G, et al.: Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr (30): 44-51, 2001.[PUBMED Abstract]
Albain KS, Green SR, Lichter AS, et al.: Influence of patient characteristics, socioeconomic factors, geography, and systemic risk on the use of breast-sparing treatment in women enrolled in adjuvant breast cancer studies: an analysis of two intergroup trials. J Clin Oncol 14 (11): 3009-17, 1996.[PUBMED Abstract]
Trial Contact Information
Trial Lead Organizations
Southwest Oncology Group
Cancer and Leukemia Group B
Ph: 212-639-5319; 800-525-2225
Eastern Cooperative Oncology Group
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.