Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer

The purpose of this study was to evaluate the efficacy and safety of a novel oral anticancer fluoropyrimidine derivative, S-1, in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). Between June 1996 and July 1998, 62 patients with NSCLC who had not received previous chemotherapy for advanced disease were enrolled in this study. 59 patients (22 stage IIIB and 37 stage IV) were eligible for the evaluation of efficacy and safety. S-1 was administered orally, twice daily, after meals. 3 dosages of S-1 were prescribed according to body surface area (BSA) so that they would be approximately equivalent to 80 mg m−2day−1: BSA < 1.25 m2, 40 mg b.i.d.; BSA≥1.25 but <1.5 m2; 50 mg b.i.d., and BSA≥1.5 m2: 60 mg b.i.d. One cycle consisted of consecutive administration of S-1 for 28 days followed by a 2-week rest period, and cycles were repeated up to 4 times. The partial response (PR) rate of the eligible patients was 22.0% (13/59); (95% confidence interval: 12.3–34.7%). A PR was observed in 22.7% (5/22) of the stage IIIB patients and 21.6% (8/37) of the stage IV patients. The median response duration was 3.4 months (1.1–13.7 months or longer). Grade 4 neutropenia was observed in one of the 59 patients (1.7%). The grade 3 or 4 toxicities consisted of decreased haemoglobin level in 1.7% of patients (1/59), neutropenia in 6.8% (4/59), thrombocytopenia in 1.7% (1/59), anorexia in 10.2% (6/59), diarrhoea in 8.5% (5/59), stomatitis in 1.7% (1/59), and malaise in 6.8% (4/59), and their incidences were relatively low. There were no irreversible, severe or unexpected toxicities. The median survival time (MST) of all patients was 10.2 months (95% confidence interval: 7.7–14.5 months), and the one-year survival rate was 41.1%. The MST of the stage IIIB patients was 7.9 months, and that of the stage IV patients was 11.1 months. The one-year survival rates of the stage IIIB and IV patients were 30.7% and 47.4%, respectively. S-1 was considered to be an active single agent against NSCLC. Further study of S-1 with other active agents is warranted. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

In Vitro and In Vivo Activities of Syn2836, Syn2869, Syn2903, and Syn2921: New Series of Triazole Antifungal Agents

ABSTRACT The in vitro and in vivo activities of four azole compounds belonging to a new series of 2(2,4-difluorophenyl)-3-(4-substituted piperazin-1-yl)-1-(1,2,4-triazol-1-yl) butanol antifungal agents is described. The compounds were selected from a library of azole compounds synthesized by our group. The in vitro activities of Syn2869, Syn2836, Syn2903, and Syn2921 against a panel of over 240 recently collected clinical isolates of yeast and molds were determined, and the results were compared with those obtained with fluconazole (FLC), itraconazole (ITC), and amphotericin B (AMB). The MICs at which 90% of the isolates were inhibited (MIC 90 s) for the four test compounds for strains of Candida spp. ranged from &lt;0.048 to 0.78 μg/ml. All compounds were also active against FLC-resistant Candida albicans and other Candida sp. strains. Moreover, MIC 90 s for strains of Cryptococcus neoformans , Aspergillus spp., Trichophyton spp., and Microsporum spp. were also low and ranged from &lt;0.048 to 0.39 μg/ml. The test compounds produced a fungistatic pattern during the time-kill kinetic studies. In vivo studies indicated that all four test compounds have good efficacies against C. albicans in a murine systemic infection model and significantly improved the survival rates of the infected mice. The results for Syn2903 were similar to those for FLC, while the other compounds were slightly less effective but had ranges of activities similar to the range of activity of ITC. The compounds were also evaluated against an Aspergillus fumigatus systemic infection. Syn2903 was also superior to ITC, whereas the efficacy data for the other compounds were similar to those for ITC. It was concluded from the data generated for this new series of azole compounds in the studies described above that further pharmacokinetic and toxicologic evaluations are warranted prior to selection of a candidate compound for preclinical testing. </jats:p

Oral uracil-tegafur: an alternative to intravenous 5-fluorouracil?

The fluoropyrimidines have been used in the treatment of a number of tumour types over the past 40 years. Particular attention has focused on the use of 5-fluorouracil (5-FU) in colorectal cancer for which, until recently, there has been a lack of other effective chemotherapy. In an attempt to optimise the efficacy of fluoropyrimidines, a number of approaches have been used. These include alternative methods of iv. scheduling, the use of co-factors and the development of oral compounds. The aim of oral agents is to satisfy patient preference while maintaining the efficacy of sustained drug exposure seen with prolonged or continuous infusions of iv. 5-FU. One such oral compound is uracil-tegafur (UFT), which combines tegafur (ftorafur, a 5-FU prodrug) and uracil in a 1:4 molar ratio. UFT first entered Phase I trials in Japan over 20 years ago but has only recently received significant exposure in Phase II and III trials. Results from a number of Phase III studies in Europe and in the US are now becoming available. With UFT recently approved for colorectal cancer in many European countries, although not in the US, it is timely to review the current situation and future prospects for this agent