Comparison of the pharmacokinetics of S-1, an oral anticancer agent, in Western and Japanese patients.
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OBJECTIVE: S-1 is an oral anticancer agent combining tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with potassium oxonate (oteracil) and gimeracil (CDHP) respectively to mitigate gastrointestinal toxicity and increase the half-life of 5-FU. This article presents a population pharmacokinetic analysis of these four compounds in Western cancer patients. The second objective was to compare the pharmacokinetics of S-1 in Western and Japanese patients. METHODS: A single dose (25-45 mg/m2) of S-1 was administered to 60 patients. In each patient, 6 concentrations of FT, 5-FU, oteracil and CDHP were measured over 24 hr. Using NONMEM, oteracil and CDHP were analyzed separately, and the individual estimates of CDHP parameters were included in the joint analysis of FT and 5-FU. We used validation techniques to assess differences between the two populations, and finally we compared the exposures in Western and Japanese patients using simulations. RESULTS: A compartmental model describing the PK of the 4 compounds was developed. The influence of CDHP on the elimination of 5-FU was well described by an enzymatic inhibition model. The model provided a good fit for all compounds. The pharmacokinetics for 5-FU and oteracil were similar between Western and Japanese patients, but apparent differences in exposure to 5-FU resulted from different total doses due to different body sizes. (+info)
Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer.
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A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40 mg m(-2) b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg m(-2) depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg m(-2), because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg m(-2). In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1-8). The incidences of severe (grades 3-4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9-90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity. (+info)
Histological complete response in a case of advanced gastric cancer treated by chemotherapy with S-1 plus low-dose cisplatin and radiation.
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A 76-year-old male was diagnosed with stage IV (cT4, cN2, cP0, cH0, cM0) gastric carcinoma with a type 3 tumor in the cardia with lymph node metastases, determined by gastrofiberscope and abdominal computed tomography (CT). The patient was treated with chemotherapy consisting of S-1 and low-dose cisplatin (CDDP) during the first cycle (3 weeks). S-1 was orally administered at a dose of 100 mg/day (60 mg/m(2)/day) on days 1-21. CDDP was infused at a dose of 10 mg/day (6 mg/m(2)/day) on days 1-5, 8-12 and 15-19. After this cycle, the clinical response was evaluated as no change (NC). In the second cycle, radiation therapy (2 Gy/day for 5 days/week) was initiated along with the chemotherapy. The CDDP dose was decreased to 7.5 mg/day because of the grade 3 thrombocytopenia and grade 2 leukocytopenia that occurred during the first cycle. The second cycle was stopped at a total radiation dose of 48 Gy due to grade 3 thrombocytopenia and grade 2 leukocytopenia. Examination after this treatment showed remarkable reduction of tumor volume in the primary lesion and lymph nodes, which was defined as a partial response (PR). The patient then underwent total gastrectomy with D1 lymph node dissection. The postoperative course was uneventful without surgical complications. At this time, no gastric cancer cells were detected in the resected specimen, including the primary lesion and lymph nodes, confirming a pathological complete response (CR grade 3). Thus, the chemo-radiation treatment regimen described here may be a potent tool to control advanced gastric carcinoma. (+info)
UFT/leucovorin and oxaliplatin alternated with UFT/leucovorin and irinotecan in metastatic colorectal cancer.
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A total of 41 metastatic colorectal cancer (CRC) patients received tegafur/uracil (UFT)+leucovorin (LV)+oxaliplatin alternated with UFT/LV+irinotecan. The overall response rate was 58.5% (95% confidence interval, 42.2-73.3%), and the median progression-free survival was 8.8 months. There were no grade 4 toxicities; 12 patients (29%) experienced grade 3 diarrhoea. There were no cases of hand-foot syndrome. This alternating regimen seems to be effective and well tolerated in the first-line treatment of patients with metastatic CRC. (+info)
Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials.
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PURPOSE: Adjuvant therapy of colorectal cancer with oral fluorinated pyrimidines is attractive because of its ease of administration and good tolerability. The purpose of this meta-analysis is to assess the survival and disease-free survival benefits of treating patients after surgical resection of a primary colorectal tumor with oral fluoropyrimidines for 1 year. PATIENTS AND METHODS: This meta-analysis was performed on individual data from three randomized trials conducted by the Japanese Foundation for Multidisciplinary Treatment for Cancer involving a total of 5,233 patients with stages I to III colorectal cancer. RESULTS: The overall hazard ratio in favor of oral therapy was 0.89 for survival (95% CI, 0.80 to 0.99; P =.04), and 0.85 for disease-free survival (95% CI, 0.77 to 0.93; P <.001). Thus oral therapy reduced the risk of death by 11% and the risk of recurrence or death by 15%. There was no significant heterogeneity between trials, nor did the benefit of oral therapy depend on tumor stage (I, II, or III), tumor site (rectum or colon), patient age, or patient sex. CONCLUSION: Oral fluoropyrimidines improve disease-free survival and survival of patients after resection of early-stage colorectal cancer. These observations support the use of these agents alone after resection of early-stage disease, as well as further testing of oral agents in combination with new drugs that have recently shown antitumor activity in advanced colorectal cancer. (+info)
Loss of heterozygosity at the thymidylate synthase (TS) locus on chromosome 18 affects tumor response and survival in individuals heterozygous for a 28-bp polymorphism in the TS gene.
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Thymidylate synthase (TS), the target enzyme of the fluoropyrimidine class of drugs, has a 28-bp repeat polymorphism in the promoter region that has been associated with response of tumors to 5-fluorouracil-based therapy. Patients homozygous for the double repeat (2R/2R) in the TS gene have an overall better outcome from treatment than patients homozygous for the triple repeat (3R/3R). However, due to loss of heterozygosity at the TS locus on chromosome 18 in cancer cells, heterozygous 2R/3R individuals can acquire the 2R/loss or the 3R/loss genotype in their tumors. The purpose of this study was to determine whether the response of colorectal cancer to fluoropyrimidine therapy is associated with the resulting tumor TS genotype when loss of heterozygosity occurs in tumor DNA. A total of 30 colorectal cancer patients treated with the fluoropyrimidine-based combination S-1, all of whom had stage IV disease, were studied. The response rate to S-1 in this group of patients was 13 of 30 (43%). The heterozygous 2R/3R genotype was found in 22 of 30 normal tissues, whereas 10 (45%) of the matched cancer tissues showed only the 2R-sequence band (2R/loss), and 7 cancer tissues (32%) showed only the 3R-sequence band (3R/loss). The response rate of the 2R/loss tumor genotype patients was 80% (8 of 10) compared with 14% (1 of 7) in the 3R/loss genotype group (P = 0.029). Patients with tumor 3R/loss genotypes had significantly lower survival than 2R/loss genotypes. Heterozygous patients with a 2R/loss tumor genotype had the same survival as 2R/2R patients, whereas patients with a 2R/3R tumor genotype had a short survival similar to homozygous 3R/3R genotypes. These results show that: (a) response to 5-fluorouracil-based therapy is determined by tumor genotype; and (b) the 3R repeat is a direct negative determinant of outcome. (+info)
Inhibition of metastasis of tumor cells overexpressing thymidine phosphorylase by 2-deoxy-L-ribose.
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Thymidine phosphorylase (TP) catalyzes the reversible conversion of thymidine to thymine, thereby generating 2-deoxy-D-ribose-1-phosphate, which upon dephosphorylation forms 2-deoxy-D-ribose (D-dRib), a degradation product of thymidine. We have previously shown that D-dRib promotes angiogenesis and chemotaxis of endothelial cells and also confers resistance to hypoxia-induced apoptosis in some cancer cell lines. 2-Deoxy-L-ribose (L-dRib), a stereoisomer of D-dRib, can inhibit D-dRib anti-apoptotic effects and suppressed the growth of KB cells overexpressing TP (KB/TP cells) transplanted into nude mice. In this study, we examined the ability of L-dRib to suppress metastasis of KB/TP cells using two different models of metastasis. The antimetastatic effect of L-dRib was first investigated in a liver-metastasis model in nude mice inoculated with KB/TP cells. Oral administration of L-dRib for 28 days at a dose of 20 mg/kg/day significantly reduced the number of metastatic nodules in the liver and suppressed angiogenesis and enhanced apoptosis in KB/TP metastatic nodules. Next, we compared the ability of L-dRib and tegafur alone or in combination to decrease the number of metastatic nodules in organs in the abdominal cavity in nude mice receiving s.c. of KB/TP cells into their backs. L-dRib (20 mg/kg/day) was significantly (P < 0.05) more efficient than tegafur (100 mg/kg/day) in decreasing the number of metastatic nodules in organs in the abdominal cavity. By in vitro invasion assay, L-dRib also reduced the number of invading KB/TP cells. L-dRib anti-invasive activity may be mediated by its ability to suppress the enhancing effect of TP and D-dRib on both mRNA and protein expression of vascular endothelial growth factor and interleukin-8 in cultured KB cells. These findings suggest that L-dRib may be useful in a clinical setting for the suppression of metastasis of tumor cells expressing TP. (+info)
Adjuvant immunochemotherapy with oral Tegafur/Uracil plus PSK in patients with stage II or III colorectal cancer: a randomised controlled study.
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Intravenous fluorouracil and leucovorin is the standard adjuvant treatment for stage III colon cancer. However, oral adjuvant chemotherapy is attractive because it has low toxicity and greater convenience. We investigated the benefits of oral protein-bound polysaccharide K (PSK) with tegafur/uracil (UFT) as an adjuvant in stage II and III colorectal cancer. Patients were assigned to groups that received either 3 g PSK plus 300 mg UFT, or 300 mg UFT alone orally each day for a 2-year period following intravenous mitomycin C. Of 207 registered patients, 205 with stage II (n=123) or III (n=82) were analysed. The 5-year disease-free survival was 73.0% (95% CI 65.6-80.4%) with PSK (n=137) and 58.8% (95% CI 47.1-70.5%) in the controls (n=68) (P=0.016). Polysaccharide K reduced the recurrence by 43.6% (95% CI 4.5-66.7%) and mortality by 40.2% (95% CI -12.5 to 68.3%). The 5-year survival was 81.8% (95% CI 75.3-88.2%) in the PSK group and 72.1% (95% CI 61.4-82.7%) in the control group (P=0.056). In stage III patients, disease-free and overall survivals in patients receiving PSK were increased significantly: 60.0% (95% CI 47.1-72.9%) and 74.6% (95% CI 63.0-86.1%) in the PSK group as compared with 32.1% (95% CI 14.8-49.4%) and 46.4% (95% CI 28.0-64.9%) in the controls (P=0.002 and 0.003, respectively). Polysaccharide K prevented recurrence, particularly lung metastases (P=0.02; odds ratio 0.27; 95% CI 0.09-0.77). In the models, the presence of regional metastases (relative risk, 2.973; 95% CI 1.712-5.165; P<0.001), omission of PSK (relative risk, 2.106; 95% CI 1.221-3.633; P=0.007), and higher primary tumour (relative risk, 4.398; 95% CI 1.017-19.014; P=0.047) were each significant indicators of recurrence. Adverse effects were mild and compliance was good. Oral PSK with UFT reduced recurrence in stage II and III colorectal cancer, and increased survival in stage III. (+info)