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      Phase II study of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1)

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          Abstract

          Background:

          S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC.

          Methods:

          Patients with HER2-positive AGC received S-1 (80–120 mg per day) orally on days 1–14, cisplatin (60 mg m −2) intravenously on day 1, and trastuzumab (course 1, 8 mg kg −1; course 2 onward, 6 mg kg −1) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events.

          Results:

          A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54–80%), and the disease control rate was 94% (95% CI=84–99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%).

          Conclusions:

          Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC.

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          Most cited references12

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          Capecitabine and oxaliplatin for advanced esophagogastric cancer.

          We evaluated capecitabine (an oral fluoropyrimidine) and oxaliplatin (a platinum compound) as alternatives to infused fluorouracil and cisplatin, respectively, for untreated advanced esophagogastric cancer. In a two-by-two design, we randomly assigned 1002 patients to receive triplet therapy with epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX) or triplet therapy with epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX). The primary end point was noninferiority in overall survival for the triplet therapies containing capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with cisplatin. For the capecitabine-fluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval [CI], 0.80 to 0.99); for the oxaliplatin-cisplatin comparison, the hazard ratio for the oxaliplatin group was 0.92 (95% CI, 0.80 to 1.10). The upper limit of the confidence intervals for both hazard ratios excluded the predefined noninferiority margin of 1.23. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, overall survival was longer with EOX than with ECF, with a hazard ratio for death of 0.80 in the EOX group (95% CI, 0.66 to 0.97; P=0.02). Progression-free survival and response rates did not differ significantly among the regimens. Toxic effects of capecitabine and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy. Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer. (Current Controlled Trials number, ISRCTN51678883 [controlled-trials.com].). Copyright 2008 Massachusetts Medical Society.
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            Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial.

            To compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC). In this randomised, open-label, phase III study, patients received cisplatin (80 mg/m(2) i.v. day 1) plus oral capecitabine (1000 mg/m(2) b.i.d., days 1-14) (XP) or 5-FU (800 mg/m(2)/day by continuous infusion, days 1-5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS). A total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.63-1.04, P < 0.001 versus noninferiority margin of 1.25]. Median overall survival was 10.5 versus 9.3 months for XP versus FP (unadjusted HR = 0.85, 95% CI 0.64-1.13, P = 0.008 versus noninferiority margin of 1.25). The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%). XP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.
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              Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators.

              We have focused our attention on the development of a novel form of a tegafur-based [FT; a prodrug of 5-fluorouracil (5-FU)] antitumor agent. We have used two biochemical and pharmacological modulators of 5-FU to improve its overall activity. To potentiate the antitumor activity of FT, 5-chloro-2,4-dihydroxypyridine (CDHP) was used as a potent reversible inhibitor of 5-FU degradation. The reduction of gastrointestinal (GI) toxicity, induced in the host by 5-FU, was modulated by potassium oxonate (Oxo), an inhibitor of orotate phosphoribosyltransferase that catalyzes the phosphorylation of 5-FU, a process believed to be responsible for the toxic effects of 5-FU. When CDHP and FT were simultaneously given orally to Yoshida sarcoma-bearing rats in various molar ratios, the antitumor effect of FT was significantly potentiated by the combination consisting of at least a 0.2 versus 1 molar ratio of CDHP to FT, respectively. This augmentation of an antitumor activity was supported by potent and prolonged inhibition of dihydrouracil dehydrogenase activity (5-FU degrading activities) in the liver of tumor-bearing rats after oral CDHP (0.2:0.8 molar ratio) and furthermore by elevation and over 12 h retention of 5-FU levels in the tumors following combined administration of FT and CDHP at a molar ratio of 1:0.4, respectively. Moreover, to reduce the severe GI injury and subsequent loss of body weight, observed in parallel with an increased antitumor efficacy, Oxo was given orally to Yoshida sarcoma-bearing rats and nude rats xenografted with H-81 human gastric carcinoma, during consecutive administration of the FT-CDHP mixture. Combined treatment with Oxo and FT (1:2 molar ratio) supplemented with 0.4 molar CDHP resulted in protection of body weight loss without affecting the high antitumor efficacy of the FT-CDHP mixture. When [2-14C]FT plus CDHP was administered with Oxo, the 14C-labeled fluoronucleotide content was objectively decreased in the GI tract of the tumor-bearing rats but not in the tumor and bone marrow, which supports our initial hypothesis. Based on these promising data, we propose a suitable formulation of a FT-based anticancer drug, called S-1, and consisting of FT, CDHP and Oxo at a 1:0.4:1 molar ratio and showing tumor-selective cytotoxicity of 5-FU.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                04 March 2014
                28 January 2014
                : 110
                : 5
                : 1163-1168
                Affiliations
                [1 ]Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine , 2-2-E2, Yamadaoka, Suita 565-0871, Japan
                [2 ]Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases , 3-3-1, Nakamichi, Osaka 537-8511, Japan
                [3 ]Department of Upper Gastroenterology, Hyogo College of Medicine , 1-1, Mukogawa-cho, Nishinomiya 663-8501, Japan
                [4 ]Department of Gastroenterological Oncology, Hyogo Cancer Center , 13-70, Kitaoji-cho, Akashi 673-8558, Japan
                [5 ]Department of Medical Oncology, Kinki University Faculty of Medicine , 377-2, Ohnohigashi, Osakasayama 589-8511, Japan
                [6 ]Deparment of Medical Oncology, Keiyukai Sapporo Hospital , 1-1-14, Hondori, Sapporo 003-0027, Japan
                [7 ]Deparment of Surgery, Sakai Municipal Hospital , 1-1-1, Yasui-cho, Sakai 590-0064, Japan
                [8 ]Deparment of Medical Oncology, Osaki Citizen Hospital , 2-3-10, Furukawasenjujicho, Osaki 989-6183, Japan
                [9 ]Deparment of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine , 2-2, Yamadaoka, Osaka 565-0871, Japan
                [10 ]Graduate School of Medicine and Engineering, University of Yamanashi , 4-4-37, Takeda, Kofu 400-8510, Japan
                [11 ]Deparment of Cancer Center, Hokkaido University Hospital , North 15, West 7, Kita-ku, Sapporo 060-8638, Japan
                [12 ]Deparment of Surgery, Kaizuka City Hospital , 3-10-20, Hori, Kaizuka 597-0015, Japan
                [13 ]Deparment of Surgery, Kinki University Faculty of Medicine , 377-2, Ohnohigashi, Osakasayama 589-8511, Japan
                Author notes
                Article
                bjc201418
                10.1038/bjc.2014.18
                3950868
                24473399
                5fc49911-0568-431e-bfd3-26193300cad9
                Copyright © 2014 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 27 September 2013
                : 04 December 2013
                : 02 January 2014
                Categories
                Clinical Study

                Oncology & Radiotherapy
                trastuzumab,s-1,cisplatin,herbis
                Oncology & Radiotherapy
                trastuzumab, s-1, cisplatin, herbis

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