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1、Liver International.2020;00:19.| Received:11 January 2020|Revised:17 May 2020|Accepted:18 May 2020DOI:10.1111/liv.14538 O R I G I N A L A R T I C L EMulticentre,phase II study of gemcitabine and S-1 in patients with advanced biliary tract cancer:TG1308 studyNai-Jung Chiang1,2,3|Ming-Huang Chen4,5|Sh
2、ih-Hung Yang6|Chiun Hsu6|Chia-Jui Yen1,3|Hsiao-Hui Tsou7,8|Yung-Yeh Su1,2,3|Jen-Shi Chen9|Yan-Shen Shan1,10|Li-Tzong Chen2,3,11Jen-Shi Chen,Yan-Shen Shan,and Li-Tzong Chen contributed equally to the manuscript.Abbreviations:ABTC,advanced biliary tract cancer;ALT,alanine transaminase;AVC,ampulla of v
3、ater cancer;BSA,body surface area;BTC,biliary tract cancer;CA19-9,carbohydrate antigen 19-9;CEA,carcinoembryonic antigen;CI,confidence interval;CR,complete response;DCR,disease control rate;EHCC,extrahepatic cholangiocarcinoma;GBC,gallbladder cancer;GC,gemcitabine and cisplatin;GS,gemcitabine and S-
4、1;HR,hazard ratio;IHCC,intrahepatic cholangiocarcinoma;ITT,intention-to-treat;mFOLFOX,modified oxaliplatin and 5-FU plus leucovorin;ORR,objective response rate;OS,overall survival;PFS,progression-free survival;PP,per-protocol;PR,partial response;RECIST,response evaluation criteria in solid tumors;SD
5、,stable disease;SLOG,GS plus oxaliplatin and leucovorin;TCOG,Taiwan Cooperative Oncology Group;ULN,upper limit of normal.1Institute of Clinical Medicine,College of Medicine,National Cheng Kung University,Tainan,Taiwan2National Institute of Cancer Research,National Health Research Institutes,Tainan,T
6、aiwan3Division of Hematology and Oncology,Department of Internal Medicine,National Cheng Kung University Hospital,Tainan,Taiwan4Department of Oncology,Taipei Veterans General Hospital,Taipei,Taiwan5School of Medicine,National Yang Ming University,Taipei,Taiwan6Department of Oncology,National Taiwan
7、University Hospital and Graduate Institute of Oncology,National Taiwan University College of Medicine,Taipei,Taiwan7Institute of Population Health Sciences,National Health Research Institutes,Zhunan,Taiwan8Graduate Institute of Biostatistics,College of Public Health,China Medical University,Taichung
8、,Taiwan9Division of Hematology and Oncology,Department of Internal Medicine,Linkou Chang Gung Memorial Hospital and Chang Gung University,Taoyuan,Taiwan10Department of Surgery,National Cheng Kung University Hospital,Tainan,Taiwan11Department of Internal Medicine,Kaohsiung Medical University Hospital
9、 and Kaohsiung Medical University,Kaohsiung,TaiwanAbstractBackground&Aims:Gemcitabine plus cisplatin(GC)remains the standard,frontline therapy for advanced biliary tract cancer(ABTC).The JCOG1113 study suggested that gemcitabine plus S-1(GS)had noninferior median overall survival and compara-ble inc
10、idence of significant neutropenia as compared to GC treatments.This study evaluates the efficacy and safety of a modified GS regimen.Methods:The eligible patients with chemonaive,measurable ABTC received 800 mg/m2 of gemcitabine on day 1 and 80 mg/m2/day of S-1(80/100/120 mg for patients with body s
11、urface 1.25/1.25 and 1.5/1.5 m2 respectively).The primary end-point was the 12-week disease control rate(12-week DCR:objective response and stable disease 12 weeks).Per the p0=40%and p1=60%(/=0.05/0.2)assump-tion,Simons optimal two-stage design indicated 12-week DCR in 24 of 46 evalu-able patients f
12、or significant activity.Tumour responses were assessed every 6 weeks.Results:Fifty-one patients were enrolled and most of them had intrahepatic chol-angiocarcinoma(64.7%),metastatic disease(84.3%)and disease-related symptoms(82.4%).On intention-to-treat analysis,11(21.6%)patients showed partial resp
13、onse,whereas 21(41.2%)showed stable disease 12 weeks.The progression-free and over-all survival were 5.4 months(95%confidence interval CI:3.5-7.0),and 12.7 months(95%CI:6.1-15.6)respectively.The study met its primary endpoint with a 12-week DCR of 69.6%in 46 evaluable patients.Grade 3/4 treatment-re
14、lated adverse event-soccurred in 6%of patients of all individual items.The mean dose intensities of S-1 and gemcitabine were 87.1%and 92.5%respectively.Conclusions:Modified GS showed moderate efficacy with a favourable safety profile in ABTC patients,thus mandating further assessment.This is an open
15、 access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License,which permits use and distribution in any medium,provided the original work is properly cited,the use is non-commercial and no modifications or adaptations are made.2020 The Authors.Liver International
16、 published by John Wiley&Sons Ltd2|CHIANG et Al.1|BACKGROUNDBiliary tract cancers(BTCs)are classified as intrahepatic cholan-giocarcinoma(IHCC),extrahepatic cholangiocarcinoma(EHCC),gallbladder cancer(GBC),and ampulla of vater cancer(AVC)based on the anatomic origin.The incidence of BTC is increasin
17、g globally and generally higher in Asian countries than in Western countries.1 According to the Taiwan Cancer Registration,1637 new,cyto-/pathologically proven cases of biliary tract adenocarcinoma were reported in 2016,including 837 and 800 cases of IHCC and EHCC/GBC respectively.2 Complete surgica
18、l resection remains the main-stay of treatment for patients with early-stage disease.3 However,most patients present with unresectable,advanced BTC(ABTC)at diagnosis,4 and intravenous administration of 1000 mg/m2 of gemcitabine plus 25 mg/m2 of cisplatin on days 1 and 8,every 21 days(GC regimen)has
19、been considered the standard frontline therapy according to the UK ABC-02 and Japanese BT-22 stud-ies.5-7 However,treatment with GC requires vigorous hydration and administration of potent antiemetics to prevent cisplatin-re-lated adverse events,7 and results in grade 3/4 neutropenia sig-nificantly
20、frequently in the Asian population(56.1%in BT-22 and 25.3%in ABC-02).5,6S-1,the newer-generation oral fluoropyrimidine,was approved for treatment of patients with ABTC in Japan in 2007 on the basis of the results of a multicentre phase II trial,with an objective response rate(ORR)of 35%and median pr
21、ogression-free survival(PFS)and overall survival(OS)rates of 3.7 and 9.4 months respectively.8 In the randomised phase II JCOG0805 study,patients treated with GS,com-prising gemcitabine(1000 mg/m2 on days 1 and 8)plus a reduced dose of S-1(60 mg/m2,60/80/100 mg/day on the basis of the body surface a
22、rea BSA)on days 1-14 every 3 weeks showed better median OS(12.5 months vs 9.0 months)than those treated with S-1 monother-apy at the regular dose(80 mg/m2,80/100/120 mg/day based on BSA)on days 1-28 every 6 weeks.9 In a subsequent randomized phase III JCOG1113 trial,patients treated with GS showed n
23、on-inferior median OS compared with those treated with GC(15.1 months vs 13.4 months,hazard ratio HR=0.945 with one-sided,non-inferiority P=.046),10 validating the GS regimen as an alternative standard of care for Japanese patients with ABTC.Despite being more effective,the treatment with GS resulte
24、d in consistent 60%of grade 3/4 neutropenia,and required frequent dose modification in both the JCOG0805 and JCOG1113 studies.9,10 In the GS arm of JCOG1113,the relative mean dose intensity(DI)of gem-citabine and S-1 was 76.2%and 75.3%respectively.10 Furthermore,comparison of the monotherapy arm in
25、the BT-22 and JCOG0805 studies indicated that patients treated with S-1 had comparable but numerically better ORR(17.4%vs 11.9%),median PFS(4.2 months vs 3.7 months),median OS(9.0 months vs 7.7 months),and safety profiles(grade 3/4 neutropenia,4.0%vs 38.1%)than those treated with gemcitabine.5,10 Th
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