Biomedical subjects
John H Fetting
Publications and source records attributed to John H Fetting.
A Phase II study of the polyamine analog N1,N11-diethylnorspermine (DENSpm) daily for five days every 21 days in patients with previously treated metastatic breast cancer.
PURPOSE: Polyamines are ubiquitous intracellular polycationic molecules essential for cell growth and differentiation. Polyamine analogs down-regulate ornithine decarboxylase, induce spermidine/spermine N1-acetyltransferase, deplete natural polyamine pools, inhibit growth, and induce programmed cell death in breast cancer models. This study evaluated the activity of the first-generation analog DENSpm in women with metastatic breast cancer. EXPERIMENTAL DESIGN: The overall accrual goal was 34 patients (30 evaluable) in a two-stage design. The second stage of accrual was to proceed if > or =2 among first 15 evaluable patients were progression free at 4 months. The primary objective was to determine whether > or =20% of metastatic breast cancer patients treated with DENSpm as second- or third-line therapy remained progression free after 4 months. RESULTS: Sixteen patients (median age, 52 years; range, 34-65; median performance status, 1; range, 0-1) enrolled in the first stage received 43 cycles (median, 2; range, 1-6) of 100 mg/m2 DENSpm as a 15-min infusion i.v. on days 1-5 every 21 days. All 16 patients were evaluable for toxicity; 15 were evaluable for response. All patients had disease progression by 4 months, and the study closed after the first stage of accrual. The main toxicities included grade 1-2 abdominal pain, transient perioral numbness, nausea, and grade 1 thrombocytopenia. Two patients had grade 3 abdominal pain during cycle 2 infusion: one was hospitalized, and another was subsequently retreated at 80% dose without pain recurrence. CONCLUSIONS: Although this dose and administration schedule of DENSpm was quite tolerable, no evidence of clinical activity was detected. Encouraging preclinical activity of polyamine analogs alone and in combination with cytotoxic drugs supports the continued evaluation of newer-generation polyamine analogs for the treatment and prevention of breast cancer.
A phase I toxicity and feasibility trial of sequential dose-dense induction chemotherapy with doxorubicin, paclitaxel, and 5-fluorouracil followed by high dose consolidation for high-risk primary breast cancer.
PURPOSE: We studied sequential dose-dense doxorubicin, paclitaxel, and 5-fluorouracil (A-T-F) before high dose chemotherapy (HDC) with autologous peripheral blood stem cell support (PBSCT). Our aims were to determine the maximum tolerated dose (MTD) of 5-FU in the dose-dense regimen and to determine the impact of dose-dense chemotherapy on HDC/PBSCT. METHODS: Patients with Stage IIIB or Stage II or IIIA breast cancer with > or = 4 involved ipsilateral lymph nodes were treated with nine cycles of chemotherapy at 14-day intervals. The regimen was doxorubicin at 80 mg/m2 x 3, followed by paclitaxel at 140 mg/m2 over 96 h x 3, then 5-FU at doses of 1285, 1470, or 1655 mg/m2 by continuous intravenous infusion over 72 h x 3. Patients then underwent a G-CSF-stimulated peripheral blood stem cell (PBSC) apheresis prior to receiving HDC with autologous PBSCT. RESULTS: We identified 1285 mg/m2 as the MTD of 5-FU in this regimen. 5-FU-related DLTs included hand-foot syndrome, mucositis, and facial edema with somnolence. Unexpectedly, 3/19 treated patients developed congestive heart failure that prevented planned HDC. Compared to standard dose doxorubicin-containing adjuvant therapy, the dose-dense regimen also decreased CD34+ PBSC yields by about 40% (p = 0.049), requiring that 50% of patients have a supplemental bone marrow harvest. There was no difference in time to neutrophil, platelet, and red blood cell recovery after HDC. CONCLUSIONS: This regimen resulted in an unacceptably high rate of cardiac toxicity and is not recommended for further testing. It may be feasible to use a different schedule of 5-FU-containing dose-dense chemotherapy, particularly for the induction therapy of high-risk primary breast cancer prior to novel targeted therapies.