[A pilot study of TS-1+CDDP therapy for highly advanced stage IV gastric cancer].

We performed a pilot study of combination chemotherapy with TS-1 and cisplatin for highly advanced gastric cancer. From June 2002, 12 patients with multiple liver metastases, carcinomatous lymphangitis or peritoneal dissemination, were enrolled in the study. TS-1 was administered at a daily dose on day 1-21 and an intermediate-dose of cisplatin (60 mg/m2) was administered on day 8. The combination was repeated in a 5-week cycle. The median administered cycles were three (one to eight). An objective response was obtained in 9 cases (75.0%) of primary sites and 6 cases of metastatic sites. No severe hematological toxicity occurred, and grade 3 stomatitis (in one case) and vomiting (in two cases) occurred as non-hematological toxicities. The improvement of clinical symptoms such as appetite loss and abdominal discomfort was obtained in 9 of 10 cases. The median survival time is 244 days. The TS-1/CDDP regimen had almost no survival benefits, but may induce relief of symptoms due to cancer and better quality of life.

A Japanese phase I study of continuous oral capecitabine in patients with malignant solid tumors.

BACKGROUND: This study aimed to evaluate the tolerability and pharmacokinetics of capecitabine, given twice daily for 6 weeks without interruption, and to identify the maximum tolerated dose (MTD) and the suggested phase II schedule. METHODS: The initial dose of capecitabine was 251 mg/m2 twice daily, without interruption, and a dose escalation schedule was planned according to a modified Fibonacci scheme. Patients received oral capecitabine twice daily for at least 6 weeks unless grade 3 or 4 toxicity was observed. Blood and urine samples were collected for pharmocokinetic analysis on days 1 and 15. RESULTS: Sixteen patients with malignant solid tumors (seven breast, seven colorectal, and two gastric) were enrolled, all of whom were evaluable. Among 4 patients treated with capecitabine 1255 mg/m2 twice daily, one experienced grade 4 hemorrhagic gastric ulcer and one experienced grade 3 skin toxicity. Consequently, this dose was defined as the MTD, and gastrointestinal and cutaneous effects were identified as dose-limiting toxicities. There was no grade 3/4 diarrhea at any dose level. There was also no grade 4 hematologic toxicity at doses below the MTD, and there were no treatment-related deaths. Two patients with breast cancer had partial responses, at capecitabine doses of 502 mg/m2 and 1255 mg/m2, twice daily. Pharmacokinetic data show that high concentrations of doxifluridine (5'-DFUR) occur in tumor cells within 2 h after administration of capecitabine. CONCLUSION: The MTD of continuous oral capecitabine over 6 weeks was 1255 mg/m2 twice daily. Because of the higher occurrence of skin disorders reported in this study with a continuous treatment regimen, an intermittent treatment regimen of 828 mg/m2, administered twice daily for 3 weeks, followed by a 1-week rest period, was recommended for phase II studies. This regimen is being evaluated in phase II studies in Japanese patients with gastric, colorectal, and breast cancers.

Randomized phase II study comparing mitomycin, cisplatin plus doxifluridine with cisplatin plus doxifluridine in advanced unresectable gastric cancer.

UNLABELLED: Various chemotherapies have been used to treat inoperable gastric cancer. Most combination therapies include cisplatin (CDDP) and fluoropyrimidine (5-FUs), which are thought of as key drugs. In the present study, we randomly compared mitomycin (MMC) and CDDP plus doxifluridine (5'-DFUR), which is an oral 5-FU and an intermediate metabolite of capecitabine (Xeloda), with CDDP plus 5'-DFUR in advanced unresectable gastric cancer. Regimen A was CDDP (70 mg/m2, by 2-hour intravenous drip infusion on day 1), MMC (7 mg/m2, injected intravenously on day 2), and oral 5'-DFUR (1200 mg/m2, on days 4 to 7, 11 to 14, 18 to 21 and 25 to 28; 3 days rest and 4 days administration). Regimen B was identical to regimen A without MMC. RESULTS: The response rate was 25.0% (8/32 patients) in Regimen A, 17.2% (5/29) in Regimen B (p=0.541). The median survival time was 241 days in Regimen A and 179 days in Regimen B (p=0.498). In Regimen A, although no significant difference was observed, end points such as response rate and suvival improved. Thus, we concluded that a randomized controlled phase III study with more subjects should be conducted.

Sequence-dependence of cisplatin and 5-fluorouracil in advanced and recurrent gastric cancer.

This randomized controlled clinical trial was designed to compare the safety and effectiveness of different sequences of treatment with cisplatin (CDDP) and 5-fluorouracil (5-FU) in patients with unresectable advanced and post-operative recurrent gastric cancer. Patients with unresectable advanced or post-operative recurrent gastric cancer were randomly assigned by a registration center to group A or B. Group A received CDDP (80 mg/m(2)) as a continuous 2-h intravenous infusion on day 1 and 5-FU (700 mg/m(2)) as a continuous intravenous infusion on days 2-5. Group B was given 5-FU (700 mg/m(2)) as a continuous intravenous infusion on days 1-4, followed by CDDP (80 mg/m(2)) as a continuous 2-h intravenous infusion on day 5. Each course of chemotherapy was repeated every 28 days. A total of 74 patients were enrolled. One patient died accidentally, and 5 could not be evaluated. Response was assessable in 68 patients. The response rate was 31.3% (10/32) in group A as compared with 13.9% (5/36) in group B. Although the response rate was higher in Group A, the difference was not significant (p=0.085). The response rate in patients with diffuse type tumors was significantly lower in group B. There was no difference between the groups in response among patients with intestinal type tumors. The median overall survival was 239 and 174 days and time to progression was 175 and 140 days in group A and group B, respectively. Although there were trends toward longer survival and time to progression in group A, the differences between the groups were not statistically significant. There was also no difference in the type or incidence of adverse reactions. The results of this controlled study indicate that the overall response rate was slightly but not significantly higher in patients who received CDDP before 5-FU. Among patients with diffuse type tumors, the response rate was significantly lower when 5-FU was administered before CDDP. Our results suggest that CDDP should be given before 5-FU in patients with gastric cancer when treated with a combination of CDDP and 5-FU.