PRECLINICAL AND PHASE I STUDY OF OXALIPLATIN AND TOPOTECAN IN COMBINATION IN HUMAN CANCER.

BACKGROUND: DNA damage caused by platinum agents is frequently followed by induction of topoisomerase I, providing a rationale for use of platinum-based compounds with topoisomerase I inhibitors. MATERIALS AND METHODS: We studied the effect of a sequential schedule of oxaliplatin on day I and topotecan on days 2-5, in human colon and ovarian cancer cells in vitro, in nude mice bearing human cancer xenografts and finally in cancer patients in a phase I trial. RESULTS: We demonstrated a supra-additive effect of this combination on inhibition of colony formation and induction of apoptosis in vitro. We then demonstrated that the two agents in combination markedly inhibit tumor growth in nude mice. We translated these results into a clinical setting, conducting a phase I study in cancer patients with oxaliplatin 85 mg/m2 on day 1 and topotecan at doses escalating from 0.5 to 1.5 mg/m2 on days 2-5. Sixty cycles of treatment were administered to 18 patients affected prevalently by ovarian and colorectal cancer. Combination with topotecan 1.5 mg/m2 caused a dose-limiting toxicity. Therefore the maximum tolerated dose of topotecan was 1.25 mg/m2, at which six patients experienced a mild hematological and gastrointestinal toxicity. We also obtained evidence of clinical activity, particularly in ovarian cancer. CONCLUSIONS: Our results provide a solid biological and clinical rationale for a phase II trial at the recommended doses of oxaliplatin 85 mg/m2 and topotecan 1.25 mg/m2, possibly in ovarian cancer patients

A simplified technique for the en-bloc procurement of abdominal organs that is suitable for pancreas and small bowel transplantation.

BACKGROUND: Graft shortage makes multiorgan procurement mandatory. We describe the results of a simplified method for the en bloc procurement of multiple organs, which permits isolated transplantation of all abdominal grafts, including the pancreas and the small bowel, to different recipients. METHODS: Three hundred forty-three multiorgan procurements were done with a simplified en bloc technique. RESULTS: None of the 1374 grafts that were procured sustained injuries that potentially precluded transplantation. Seventy-two grafts that were procured from 18 donors (5%) who were diagnosed with a neoplasm were discarded. Overall, 339 grafts that were procured from 325 donors were discarded because of specific contraindications, and 963 grafts (74%) were transplanted. Ninety-seven pancreata were transplanted. In 3 instances the pancreas and the small bowel were procured simultaneously and transplanted to different recipients. A total of 287 liver grafts were also transplanted at 13 different institutions. In 42 instances, the liver was not allocated to our center. Forty liver teams (95%) from 11 different institutions agreed to procure their grafts according to the simplified en bloc technique. Our team performed 18 procurements, and a surgeon from the liver transplantation team, who was assisted by one of the members of our team, performed 22 procurements. In all, 576 kidneys were transplanted, either alone or simultaneously, with other abdominal grafts at 15 different institutions. CONCLUSIONS: This procurement method has high yields, allows pancreas and small-bowel procurement, and can be learned readily

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FLFOX-4) as first-line treatment of advanced gastric cancer patients.

Background: The purpose of this study was to assess the toxicity and clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil and folinic acid administered every 2 weeks (FOLFOX4 regimen) in patients with advanced gastric cancer (AGC). Patients and methods: Sixty-one previously untreated AGC patients were treated with oxaliplatin 85mg/m2 on day 1, folinic acid (FA) 200mg/m2 as a 2-h infusion followed by bolus 5-fluorouracil (5-FU), 400 mg/m2 and a 22-h infusion of 5-FU, 600 mg/m2, repeated for two consecutive days every 2 weeks. Results: All patients were assessable for toxicity and response to treatment. Patient characteristic were: sex (male, 38; female, 23); median age, 64 years (range, 47–75 years); Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, nine patients; 1, 39 patients; 2, 13 patients; metastatic disease, 56 patients; locally advanced disease, five patients. Four (7%) complete responses (CR) and 19 partial responses (PR) were observed (overall response rate, 38%). Stable disease (SD) was observed in 22 (36%) patients, with progressive disease (PD) in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. NCI common toxicity criteria grade 3 and 4 hematologic toxic effects were neutropenia, anemia and thrombocytopenia in 36%, 10% and 5% patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. No treatment-related deaths were observed. Conclusion: FOLFOX-4 is an active and well tolerated chemotherapy. RR, TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer