Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity.

PURPOSE: To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine. EXPERIMENTAL DESIGN: Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m(2)) was administered into the peritoneal cavity in 2 L of warmed saline on days 1, 4, 8, and 12 of a 28-day cycle. RESULTS: Thirty patients received 63 (median, 2; range, 0-6) courses. Tumors included ovary (14), uterus (2), colon (6), pancreas (3), and others (5). Dose-limiting toxicity included nausea, vomiting, diarrhea, dyspnea, fatal respiratory failure, and grade 3 elevation of alanine aminotransferase in three patients. Hematologic toxicity and pain were

Paclitaxel-based high-dose chemotherapy with autologous stem cell rescue for relapsed germ cell cancer.

We evaluated the antitumor activity of tandem cycles of high-dose chemotherapy with autologous peripheral stem cell transplantation (aPSCT) in relapsed germ cell tumors by using high-dose paclitaxel, carboplatin, etoposide, and ifosfamide. Thirty-three patients were entered, and 31 underwent protocol therapy. Paclitaxel 350 mg/m2 (5 patients) or 425 mg/m2 (26 patients) by 24-hour continuous intravenous infusion was followed by 3 daily doses of carboplatin and either etoposide (cycle 1) or ifosfamide/mesna (cycle 2). The carboplatin dose had a calculated area under the curve of 7 mg-min/mL, and the daily dose of etoposide was 20 mg/kg (cycle 1). Ifosfamide 3 g/m2/d for 3 days (with mesna uroprotection) was substituted for etoposide in cycle 2. Each cycle was supported by granulocyte colony-stimulating factor-mobilized peripheral blood stem cells. Thirty-one patients were evaluable for response, toxicity, and long-term disease control. Two patients did not undergo aPSCT because of rapid disease progression. Nineteen patients received both cycles of aPSCT, 8 progressed after cycle 1, 3 refused the second cycle, and 1 died of fungal infection during cycle 1. Twelve patients remain relapse free at a median of 67 months from the initiation of therapy. Whereas the International Germ Cell Cancer Collaborative Group category at the time of initial diagnosis did not seem to predict outcome, the patient's probability of achieving durable remission was significantly associated with the Beyer prognostic score at the time of protocol entry. Regimens containing the most active agents in relapsed nonseminomatous germ cell tumors, including high-dose paclitaxel, are well tolerated and have promising activity even in patients with poor-risk features who do not achieve durable remissions with standard therapy. The Beyer prognostic system is a valuable predictor for patients undergoing aPSCT.

Phase I trial of intraperitoneal docetaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity: dose-limiting toxicity and pharmacokinetics.

PURPOSE: The purpose of this Phase I study was to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of i.p. docetaxel and to determine the peritoneal pharmacokinetics and pharmacological advantage of this agent. EXPERIMENTAL DESIGN: Twenty-one patients with peritoneal carcinomatosis received docetaxel administered via an implanted i.p. catheter at doses of 40, 80, 100, 125, or 156 mg/m2 every 3 weeks. DLTs on course 1 were used to define the maximum tolerated dose. RESULTS: Tumor types included gastric adenocarcinoma (n=7), ovarian cancer (n=4), other gastrointestinal primaries (n=3), and other cancers (n=7). Sixty cycles of i.p. docetaxel (median, 2; range, 1-11) were delivered. DLTs occurred in two patients at the 156 mg/m2 dose level; both developed an ileus, and one patient died of neutropenic sepsis. One of five evaluable patients treated with 125 mg/m2 docetaxel i.p. developed grade 4 neutropenic sepsis and stomatitis; another patient developed renal failure attributable to glomerulonephritis and grade 3 thrombocytopenia that was not judged to be dose-limiting. One of six patients receiving 100 mg/m2 D, the recommended Phase II dose, developed grade 4 neutropenia lasting <5 days. Other non-DLT treatment-related toxicities included dehydration requiring i.v. fluids, emesis, stomatitis, constipation, and abdominal pain. Best response on protocol therapy included 7 of 18 patients with stable disease for a median of 5 cycles (range, 2-11); 11 patients progressed by the first evaluation after a median of 2 cycles (range, 1-3). There were three patients inevaluable for response who received only one cycle of i.p. docetaxel (two because of patient preference and one because of adhesion formation). Pharmacokinetic evaluation revealed mean plasma areas under the curves (AUC) at 100 and 125 mg/m2 i.p. docetaxel of 3.14 and 6.33 microM.h (ranges, 1.02-5.88 and 3.97-12.70 microM. h), respectively; the mean peritoneal AUCs were 315 and 1063 microM.h (ranges, 250-373 and 239-2222 microM.h), respectively. The mean peak plasma concentrations at 100 and 125 mg/m2 i.p. docetaxel were 0.46 and 0.66 microM, and the mean peak peritoneal concentrations at those doses were 59 and 81 microM, respectively. The median and mean pharmacological advantage calculations (AUCperitoneal/AUCplasma) across all dose levels were 152 and 181, respectively (range, 18.8-367.4). The mean peritoneal 24- and 96-h concentrations were 0.9 microM (range, 0.2-1.6 microM) and <0.1 nM, respectively. The mean time that the concentration was >0.1 microM was 31.2 h (range, 27-36.5 h). CONCLUSIONS: i.p. docetaxel can be safely delivered at a dose of 100 mg/m2 i.p. every 3 weeks. This route of administration provides a significant peritoneal pharmacological advantage while delivering systemic concentrations consistent with the administration of standard i.v. doses.