Phase I study of irinotecan and S-1 combination therapy in patients with metastatic gastric cancer.
ABSTRACT Irinotecan plus intravenous 5-fluorouracil with leucovorin is effective against gastrointestinal cancer. S-1 is an oral fluoropyrimidine derivative combining tegafur with the modulators 5-chloro-2,4-dihydroxypyrimidine (a potent dihydropyrimidine dehydrogenase inhibitor), and potassium oxonate (an orotate phosphoribosyl transferase inhibitor), in a molar ratio of 1 : 0.4 : 1. S-1 has a high response rate, of about 40%, in advanced gastric cancer. A phase I study was conducted to assess the maximum tolerated dose and the recommended dose of the combination of irinotecan and S-1.
Irinotecan was given intravenously over the course of 90 min on day 1 and S-1 was given orally from days 1 to 14 of a 21-day cycle. The dose of S-1 was 80 mg/m2 per day, given in two divided doses. The dose of irinotecan was escalated in a stepwise fashion from 100 mg/m2 (level 1; n = 3), to 125 mg/m2 (level 2; n = 3), and 150 mg/m2 (level 3; n = 6).
Dose-limiting toxicity did not occur during cycle 1, and the recommended dose for phase II studies was determined to be level 3, which was associated with grade 3 diarrhea in one patient, and with refusal to continue treatment because of prolonged fatigue in two patients. Grade 3 neutropenia developed in one of three patients at level 1 and level 2, and in two of six during cycle 1 of level 3. The recommended dose was determined to be 150 mg/m2 of irinotecan on day 1 and 80 mg/m2 per day of S-1 on days 1 to 14 of a 21-day cycle. Five of seven patients with measurable lesions had a partial response.
A combination of irinotecan and S-1 can be recommended for further phase II studies in patients with gastric cancer.
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ABSTRACT: A high-performance liquid chromatography (HPLC) and gas chromatography-negative ion chemical ionization mass spectrometry (GC-NICI-MS) method was developed for the analysis of the combined antitumor drug S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate[ and active metabolite 5-fluorouracil in human plasma and urine. Tegafur was fractionated from biological fluids by extraction with dichloromethane and analyzed by HPLC. 5-Fluorouracil and 5-chloro-2,4-dihydroxypyridine were extracted with ethyl acetate from the residual layer after extraction of tegafur, and converted to pentafluorobenzyl (PFB) derivatives. Potassium oxonate was cleaned up with an anion-exchange column (Bond Elut NH2). The extracted potassium oxonate was degraded to 5-azauracil and converted to PFB derivatives. The PFB derivatives were analyzed by GC-NICI-MS. A stable isotope was employed as the internal standard in the GC-NICI-MS analysis. The limits of quantitation of tegafur, 5-fluorouracil, 5-chloro-2,4-dihydroxypyridine and potassium oxonate in plasma were 10, 1, 2 and 1 ng/ml, respectively. The reproducibility of the analytical method according to the statistical coefficients is ∼10%. The accuracy of the method is good; that is, the relative error is <10%. The methods were applied to pharmacokinetic studies of S-1 in patients.Journal of chromatography. B, Biomedical sciences and applications 03/1997;
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ABSTRACT: 5-Fluorouracil (5-FU) or a 5-FU derivative 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) has been widely prescribed for patients with gastrointestinal cancer. However, the phosphorylation of 5-FU in the digestive tract causes gastrointestinal toxicities. 5-FU is also rapidly degraded to alpha-fluoro-beta-alanine after contact with dihydropyrimidine dehydrogenase (DPDase) which is mainly present in the liver. Therefore, to overcome these metabolic events, S-1, an antitumor agent was developed, based on the biochemical modulation of FT by 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo), in a molar ratio of 1:0.4:1. The antineoplastic effect of S-1, was examined in Japanese patients with advanced gastric (G) or colorectal (C) cancer in a multicenter early phase II study involving 24 centers throughout Japan. The patients were prescribed a minimum of 2 courses of S-1 orally, with each course consisting of 75 or 50 mg (in terms of FT) twice a day for 28 days followed by withdrawal for 2 weeks. Thirty-one patients with G and 31 C were entered into this study. The clinical response and extent of toxicity were evaluated in G 28 and C 30 cases, respectively. Nine (32.1%) G patients and 14 (46.7%) C patients had been treated previously with other anticancer drugs. In G patients, there was a 53.6% (15/28) and in C patients a 16.7% (5/30) response rate (90% confidence interval G 38.4-68.1% and C 8.4-30.5%) with 15 (53.6%) (G) and 5 (16.7%) (C) partial responses (PR), and these responses persisted for 79 days (G) and 120 days (C) (median value). In particular, the response rate for the primary lesion was 27.8% (5/18) (G) and 33.3% (1/3) (C). No change (NC) in the disease was observed in 4 (14.3%) (G) and 13 (43.3%) (C) patients, and in 6 (21. 4%) (G) and 7 (23.3%) (C) the disease progressed (PD). At the time of analysis, the median survival was 298 days (G) and 358 days (C). Major adverse effects consisted of gastrointestinal symptoms and myelosuppression while toxicities of grade 3 or more occurred in 35. 7% (10/28) (G) and 33.3% (10/30) (C). Based on these data, S-1 is considered to have positive effects in patients with advanced gastrointestinal cancer.Oncology 11/1999; 57(3):202-10. · 2.17 Impact Factor
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ABSTRACT: S-1 is a novel oral anticancer drug, composed of tegafur (FT), gimestat (CDHP) and otastat potassium (Oxo) in a molar ratio of 1:0.4:1, based on the biochemical modulation of 5-fluorouracil (5-FU). CDHP inhibits dihydropyrimidine dehydrogenase (DPD), an enzyme which degrades 5-FU, and maintains prolonged 5-FU concentrations in the blood and tumours. Oxo is distributed in the gastrointestinal tract at a high concentration after oral administration and alleviates gastrointestinal toxicity due to 5-FU. S-1 improves the tumour-selective toxicity of 5-FU by the actions of two modulators, CDHP and Oxo. We conducted a late phase II clinical trial of S-1 as an open trial in patients with advanced gastric cancer, to confirm its antitumour effect and adverse reactions. 51 patients with advanced gastric cancer were enrolled in the trial. S-1 was administered orally twice daily after meals, at a standard dose of 80 mg/m2/day. One course consisted of consecutive administration for 28 days and 14 days' rest. Administration was repeated over four courses. A complete response was obtained in 1 patient and partial responses in 24 patients, producing a response rate of 49% (25/51) (95% confidence interval (CI) 35.9-62.3%). The incidence of adverse reactions was 78% (40/51) and that of adverse reactions of grades 3 and 4 was 20%. Adverse reactions of grades 3 and 4 included a decrease in the haematocrit, leucopenia, granulocytopenia, diarrhoea, malaise and proteinuria. No serious unexpected adverse reactions were observed. In conclusion, S-1 was effective and well tolerated in patients with advanced gastric cancer.European Journal of Cancer 11/1998; 34(11):1715-20. · 5.06 Impact Factor