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Satoh T.,Osaka University | Sakata Y.,Misawa Municipal Hospital
Expert Opinion on Pharmacotherapy | Year: 2012

Introduction: 5-Fluorouracil (5-FU)-based regimens are used worldwide as the standard treatment in chemotherapy for gastric cancer. S-1, a fourth-generation oral fluoropyrimidine that combines tegafur and two biochemical modulators: gimeracil and oteracil potassium, is now attracting considerable interest. Areas covered: This review addresses the clinical evidence of S-1 in gastrointestinal malignancies, such as gastric, colorectal, pancreatic and biliary tract cancers. S-1 has demonstrated advantages over standard therapies, in both advanced and postoperative settings, in large Phase III studies. S-1 alone or S-1 plus cisplatin is recommended in the 2010 Gastric Cancer Treatment Guidelines, by the Japanese Gastric Cancer Association. Results from Phase III studies have demonstrated that S-1 in combination with chemotherapies, such as cisplatin in gastric cancer, and irinotecan and oxaliplatin in colorectal cancers, is non-inferior to conventional 5-FU-based standard regimens, with the benefit of convenience and reduced toxicity. Expert opinion: The excellent design of S-1 aimed to reduce toxicity by avoiding certain routes of degradation, and to enhance activity by reducing catabolism. This has provided not only a suitable alternative to 5-FU, but also higher efficacy. © 2012 Informa UK, Ltd.

Narahara H.,Hiroshima University | Iishi H.,Japan National Cardiovascular Center Research Institute | Imamura H.,Sakai Municipal Hospital | Tsuburaya A.,Kanagawa Cancer Center | And 6 more authors.
Gastric Cancer | Year: 2011

Background: Irinotecan hydrochloride and S-1, an oral fluoropyrimidine, have shown antitumor activity against advanced gastric cancer as single agents in phase I/II studies. The combination of irinotecan and S-1 (IRI-S) is also active against advanced gastric cancer. This study was conducted to compare the efficacy and safety of IRI-S versus S-1 monotherapy in patients with advanced or recurrent gastric cancer. Methods: Patients were randomly assigned to oral S-1 (80 mg/m2 daily for 28 days every 6 weeks) or oral S-1 (80 mg/m 2 daily for 21 days every 5 weeks) plus irinotecan (80 mg/m 2 by intravenous infusion on days 1 and 15 every 5 weeks) (IRI-S). The primary endpoint was overall survival. Secondary endpoints included the time to treatment failure, 1- and 2-year survival rates, response rate, and safety. Results: The median survival time with IRI-S versus S-1 monotherapy was 12.8 versus 10.5 months (P = 0.233), time to treatment failure was 4.5 versus 3.6 months (P = 0.157), and the 1-year survival rate was 52.0 versus 44.9%, respectively. The response rate was significantly higher for IRI-S than for S-1 monotherapy (41.5 vs. 26.9%, P = 0.035). Neutropenia and diarrhea occurred more frequently with IRI-S, but were manageable. Patients treated with IRI-S received more courses of therapy at a relative dose intensity similar to that of S-1 monotherapy. Conclusions: Although IRI-S achieved longer median survival than S-1 monotherapy and was well tolerated, it did not show significant superiority in this study. © 2011 The Author(s).

Fukushima M.,Taiho Pharmaceutical Co | Sakamoto K.,Taiho Pharmaceutical Co | Sakata M.,Taiho Pharmaceutical Co | Nakagawa F.,Taiho Pharmaceutical Co | And 2 more authors.
Oncology Reports | Year: 2010

Chemoradiotherapy is a useful treatment strategy in patients with locally advanced cancers. In particular, combination of 5-fluorouracil (5-FU) with X-ray irradiation is effective for the treatment of some types of gastrointestinal cancers. We investigated the antitumor effects of combination treatment with X-ray and S-1, a unique formulation of 5-FU, on human cancer xenografts in nude mice and compared the efficacy of this treatment to that of radiotherapy combined with cisplatin, UFT, another oral 5-FU prodrug, and intravenous 5-FU. Tumors implanted into the left hind legs of mice were treated with a dose of 2 or 5 Gy X-ray irradiation on days 1 and 8, and S-1, UFT and 5-FU were administered for 14 days. The efficacy of combined treatment with 8.3 mg/kg S-1 and 2 Gy X-ray irradiation in treating non-small cell lung cancer xenografts (Lu-99 and LC-11) was significantly higher than that of treatment with S-1 alone or 2 Gy X-ray irradiation alone, and the antitumor activity of combined treatment was similar to that of 5 Gy X-ray irradiation alone. Although 8.3 mg/kg S-1 and 17.5 mg/kg UFT had equivalent antitumor activity; the antitumor efficacy of combination treatment with S-1 and 2 Gy X-ray irradiation on LC-11 tumors was significantly higher than that of combination treatment with UFT and 2 Gy X-ray irradiation. Combination treatment with S-1 and X-ray irradiation was also more effective against pancreatic tumors than combination treatment with intravenous 5-FU and X-ray irradiation. To elucidate the reason for the increased antitumor efficacy of combination treatment with S-1 and X-ray irradiation, the antitumor effect of gimeracil, one of the components of S-1, was tested in combination with 2 Gy X-ray irradiation. These experiments demonstrated that gimeracil enhanced the efficacy of X-ray irradiation against lung as well as head and neck cancer xenografts in a dose-dependent manner. Furthermore, we observed decreased expression of γ-H2AX protein, a marker of DNA repair, in LC-11 tumors treated with X-ray irradiation and gimeracil compared to that observed in tumors treated with X-ray irradiation alone, suggesting that gimeracil may inhibit rapid repair of X-ray-induced DNA damage in tumors. The present study suggests that chemoradiotherapy using S-1 acts through a novel mechanism and may prove useful in treating patients with locally advanced cancers whose disease progression is difficult to control using chemotherapy alone.

Satoh T.,Kinki University | Satoh T.,Osaka University | Ura T.,Aichi Cancer Center | Yamada Y.,National Cancer Center Hospital | And 11 more authors.
Cancer Science | Year: 2011

Irinotecan-induced severe neutropenia is associated with homozygosity for the UGT1A1*28 or UGT1A1*6 alleles. In this study, we determined the maximum-tolerated dose (MTD) of irinotecan in patients with UGT1A1 polymorphisms. Patients who had received chemotherapy other than irinotecan for metastatic gastrointestinal cancer were enrolled. Patients were divided into three groups according to UGT1A1 genotypes: wild-type (*1/*1); heterozygous (*28/*1, *6/*1); or homozygous (*28/*28, *6/*6, *28/*6). Irinotecan was given every 2weeks for two cycles. The wild-type group received a fixed dose of irinotecan (150mg/m 2) to serve as a reference. The MTD was guided from 75 to 150mg/m 2 by the continual reassessment method in the heterozygous and homozygous groups. Dose-limiting toxicity (DLT) and pharmacokinetics were evaluated during cycle 1. Of 82 patients enrolled, DLT was assessable in 79 patients (wild-type, 40; heterozygous, 20; and homozygous, 19). Dose-limiting toxicity occurred in one patient in the wild-type group, none in the heterozygous group, and six patients (grade 4 neutropenia) in the homozygous group. In the homozygous group, the MTD was 150mg/m 2 and the probability of DLT was 37.4%. The second cycle was delayed because of neutropenia in 56.3% of the patients given the MTD. The AUC 0-24h of SN-38 was significantly greater (P<0.001) and more widely distributed in the homozygous group. Patients homozygous for the UGT1A1*28 or UGT1A1*6 allele can receive irinotecan in a starting dose of 150mg/m 2, but many required dose reductions or delayed treatment in subsequent cycles. UMIN Clinical Trial Registration number: UMIN000000618. © 2011 Japanese Cancer Association.

Komatsu Y.,Hokkaido University | Takahashi Y.,International University of Health and Welfare | Kimura Y.,Nippon Telegraph and Telephone | Oda H.,Kushiro Rosai Hospital | And 10 more authors.
Anti-Cancer Drugs | Year: 2011

The pharmacokinetics of irinotecan vary markedly between individuals. This study sought to compare tailored irinotecan and S-1 therapy with S-1 monotherapy for the treatment of patients with advanced/recurrent gastric cancer. Patients with advanced/recurrent gastric cancer were randomized to receive tailored irinotecan and S-1 (arm A) therapy or S-1 therapy alone (arm B). Arm A received S-1 (80-120 mg/m/day) for 14 days, with irinotecan on days 1 and 15. The initial irinotecan dose of 75 mg/m (level 0) was adjusted for toxicity during an earlier course. In arm B, S-1 (80-120 mg/day) was administered alone for 28 days, followed by 14 days without therapy. Ninety-five patients were randomized (48 patients to arm A and 47 patients to arm B). The response rate of the primary tumor (Japanese criteria) was 25.0% in arm A (12 of 48 patients) and 14.9% in arm B (seven of 47 patients), whereas the response rates according to Response Evaluation Criteria In Solid Tumors were 27.8% (10 of 36) versus 21.9% (seven of 32). Hematological toxicity, anorexia, and diarrhea were significantly more common in arm A, but both arms had similar grades 3-4 toxicities. These findings suggest the usefulness of tailored irinotecan and S-1 therapy for gastric cancer. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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