NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Study of Adjuvant CAF (Cyclophosphamide/Doxorubicin/Fluorouracil) vs Adjuvant CAF Followed by Intensification with High-Dose Cyclophosphamide/Thiotepa plus Autologous Stem Cell Rescue in Women with Stage II/III Breast Cancer At High Risk of Recurrence
Standard Chemotherapy Compared With High-Dose Combination Chemotherapy and Stem Cell Transplantation in Treating Women With Stage II or Stage III Breast Cancer
Basic Trial Information
|Phase III||Treatment||Closed||15 to 60||NCI||EST-2190|
CLB-9496, SWOG-9061, INT-0121, E2190
I. Compare sites and rates of recurrence, disease-free survival, overall survival, and toxicity of adjuvant chemotherapy with CAF (cyclophosphamide, doxorubicin, fluorouracil) vs. adjuvant CAF followed by marrow ablation with cyclophosphamide/thiotepa and autologous stem cell rescue in women with Stage II/III breast cancer and 10 or more positive lymph nodes. II. Evaluate prospectively the incidence and degree of occult marrow contamination with breast cancer cells at the time of study entry and following CAF chemotherapy by analyzing samples of marrow using a panel of monoclonal antibodies specific for breast cancer. III. Document the changes in psychosocial function that occur during treatment on either regimen, and compare post-treatment recovery of psychosocial function. IV. Establish a bank of paraffin-embedded tumor samples for future laboratory study.
Biopsy-proven epithelial carcinoma of the breast with at least 10 involved lymph nodes Stage II/III disease Synchronous bilateral breast cancer eligible provided primaries occurred within 6 weeks of each other Contralateral intraductal cancer eligible The following conditions exclude: T4 disease Apocrine, adenoidcystic, or squamous carcinoma Inflammatory carcinoma of the breast Lesions fixed to skin or chest wall Peau d'orange skin changes Asynchronous bilateral infiltrating breast cancer Radical or modified radical mastectomy or breast-sparing surgery with axillary dissection required within 12 weeks of entry Negative surgical margins required Type of procedure, number of nodes examined, number of positive nodes, and tumor size must be reported Breast-sparing surgery must have included wide excision (i.e., removal of gross tumor plus normal breast tissue) Bone marrow aspirate, bilateral core biopsy, and bone scan must be negative for tumor Aspiration and biopsy not required for patients who received 1 or 2 courses of any doxorubicin-based chemotherapy prior to entry Hormone receptor status: Estrogen and progesterone receptor status must be determined by either biochemical or immunohistochemical assays
Biologic therapy: No prior therapy with colony stimulating factors for breast cancer Chemotherapy: 1 or 2 prior courses of any doxorubicin-based chemotherapy allowed provided documentation of treatment is available Endocrine therapy: No prior hormonal therapy for breast cancer except up to 21 days of tamoxifen that is stopped prior to entry Prior postmenopausal estrogen therapy allowed but must be discontinued prior to entry Radiotherapy: No prior radiotherapy Postoperative radiotherapy required on study Surgery: Surgery completed no more than 12 weeks prior to entry Surgery completed no more than 12 weeks prior to start of chemotherapy in patients who receive one or two courses of doxorubicin-based chemotherapy prior to randomization
Age: 15 to 60 Sex: Women only Menopausal status: Pre- or postmenopausal Performance status: ECOG 0 or 1 Hematopoietic: (obtained within 2 weeks prior to entry) WBC at least 4,000 Platelet count at least 100,000 Hepatic: (obtained within 2 weeks prior to entry) Bilirubin no more than 1.2 times normal AST (or ALT) no more than 1.2 times normal Alkaline phosphatase no more than 1.2 times normal Renal: Not specified Cardiovascular: Left ventricular ejection fraction (by MUGA) at least 50% or equal to or greater than the lower limit of institutional normal No prior angina pectoris requiring nitrate therapy No myocardial infarction within 6 months No uncontrolled congestive heart failure No uncontrolled hypertension No major ventricular arrhythmia Pulmonary: FEV1 at least 60% of predicted DLCO (corrected) at least 60% of predicted Lung volume at least 60% Lung volume not required if uncorrected FEV1 and DLCO greater than 80% No symptomatic obstructive or restrictive lung disease Other: No symptomatic CNS disease of any etiology No insulin-dependent diabetes mellitus No uncompensated major thyroid dysfunction No uncompensated major adrenal dysfunction HIV negative No prior malignancy within 5 years except: In situ breast cancer (lobular or ductal) Inactive nonmelanomatous skin cancer In situ cervical cancer No pregnant or nursing women Assessment of insurance coverage required
534 patients will be accrued over an estimated 6 years.
This is a randomized study. Patients are stratified by participating institution, estrogen-receptor status, age, and menopausal status. Patients begin treatment within 72 hours of randomization. The first group receives conventional adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) every 4 weeks for a total of 6 courses. Bone marrow and/or peripheral blood stem cells (PBSC) are harvested and stored 4-8 weeks after the last dose of CAF. Cytokine priming is permitted. The second group receives CAF and undergoes bone marrow harvest as in the first group. Then, patients receive high-dose cyclophosphamide and thiotepa, followed by autologous bone marrow or PBSC rescue. GM-CSF or G-CSF support is recommended. Irradiation of the remaining breast tissue and/or chest wall and regional lymphatics begins within 4 weeks after chemotherapy in the first group and within 8 weeks after stem cell rescue in the second group. All patients who are estrogen receptor or progesterone receptor positive also receive oral tamoxifen daily for 5 years. Patients are followed for progression and survival.
Gor PP, Su HI, Gray RJ, et al.: Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. Breast Cancer Res 12 (3): R26, 2010.[PUBMED Abstract]
Gor PP, Gray RJ, Horn M, et al.: Association of polymorphic drug metabolizing enzymes (DME) with outcomes in breast cancer patients treated on the ECOG 2190/Intergroup 0121 (E2190/Int0121) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-596, 2007.
DeMichele A, Gray R, Horn M, et al.: Genetic polymorphisms in the IL-6 promoter region are associated with breast cancer outcomes in E2190/Intergroup 0121. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-6026, S264-5, 2006.
Tallman M, Gray R, Robert N, et al.: Phase III study of conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem cell transplantation in patients with stage II and III breast cancer at high risk of recurrence (INT 0121). [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-19, 2003.
Tallman MS, Gray R, Robert NJ, et al.: Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 349 (1): 17-26, 2003.[PUBMED Abstract]
Trial Contact Information
Trial Lead Organizations
Eastern Cooperative Oncology Group
Southwest Oncology Group
Cancer and Leukemia Group B
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.