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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

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

26、erefore,considering S-1 to have better a therapeutic index than that of gemcitabine,we investigated whether the modified GS regimen,comprising higher DI of S-1 and lower DI of gemcitabine can improve the therapeutic index of GS in ABTC.The aim of the current phase II trial was to evaluate the effica

27、cy and safety of biweekly gemcitabine in combination with a full 80 mg/m2/day(80/100/120 mg/day by BSA)dose of S-1 on days 1-10 every 2 weeks,termed the modified GS regimen,as frontline treatment in patients with ABTC.The planned DI of S-1 would be 400 mg/m2/wk in the current modified GS regimen,as

28、opposed to 373 mg/m2/wk in S-1monotherapy arm of the JCOG0805 and 280 mg/m2/wk in GS arm of both the JCOG0805 and JCOG1113 studies.9,10CorrespondenceLi-Tzong Chen,National Institute of Cancer Research,National Health Research Institutes,2F,No.367,Sheng-Li Road,Tainan 704,Taiwan,ROC.Email:leochennhri

29、.org.twFunding informationS-1 was sponsored by Taiho Pharmaceutical Co.,Ltd.Japan;while gemcitabine(Gemmis)and budget were supported by TTY Biopharma Company Limited,Taiwan.The trial was conducted by Taiwan Cooperative Oncology Group(05-07A1-CAPP23-014 and 08A1-CASP01-014),National Institute of Canc

30、er Research,National Health Research Institutes,Taiwan(CA-108-PP-22,CA-108-PP-23 and CA-108-GP-01),with the support from Taiwan Upper Gastrointestinal Cancers Clinical Trial Consortium(108-2321-B-006-014).ClinicalTrials.gov number:NCT02425137.K E Y W O R D Sbiliary tract cancer,gemcitabine,S-1Lay Su

31、mmary/Key PointsThe modified GS regimen showed acceptable treatment efficacy and favourable safety and thus can be considered an alternative doublet regimen or backbone regimen to de-velop a triplet regimen for the treatment of patients with advanced biliary tract cancer.|3CHIANG et Al.2|PATIENTS AN

32、D METHODS2.1|Patient eligibilityThe inclusion criteria for patients were as follows:(a)histologically confirmed adenocarcinoma of the biliary tract that was unresectable or metastatic,including IHCC,EHCC,GBC,and AVC,with at least 1 measurable lesion according to the response evaluation criteria in s

33、olid tumours(RECIST)version 1.1;(b)patient age 20 years;(c)an Eastern Cooperative Oncology Group performance status(ECOG PS)score of 0 or 1;(d)adequate bone marrow,hepatic,and renal func-tions(absolute neutrophil count 1500/L,platelets 100 000/L,haemoglobin 9 g/dL,serum total bilirubin level 1.5 tim

34、es the upper limit of normal ULN and 2 mg/dL or 3 mg/dL if biliary drainage was present,alanine transaminase(ALT)level 3 times the ULN or 5 times the ULN in the presence of liver metastasis,and creatinine clearance(Ccr)60 mL/min calculated by 24-hour urine collection or the Cockcroft-Gault formula);

35、and(e)no prior chemo-therapy or radiotherapy.All the patients provided written informed consent as a condition for enrolment.The exclusion criteria were as follows:(a)the presence of grade 2 or above ascites,pleural effusion,or diarrhoea;(b)previous or cur-rent brain metastasis;(c)uncontrolled activ

36、e infection or other con-comitant serious disease;(d)pregnancy or breast-feeding;(e)active cardiopulmonary disease,history of ischaemic heart disease,and/or serious concomitant systemic disorders;and(f)concurrent malig-nancy,except for those with adequately treated in situ carcinoma of the cervix,ad

37、equately treated basal cell carcinoma of the skin,or a disease-free status for 5 years after initial curative treatment for any prior malignancy.This phase II study was conducted at four member hospitals of the Taiwan Cooperative Oncology Group(TCOG).The protocol was approved by the independent ethi

38、cs committees of the individ-ual participating hospital and National Health Research Institutes,and the Department of Health,Executive Yuan,Taiwan.The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice guideline.The

39、 study is registered at ClinicalTrials.gov(NCT02425137).2.2|Study treatment and dose modificationThe modified GS regimen consisted of intravenous infusion of 800 mg/m2 gemcitabine on day 1 plus 40 mg/m2 oral S-1 twice daily after meals,accounting for a total daily dose of 80/100/120 mg on the basis

40、of the BSA(1.25/m2;1.25/m2 and 1.5/m2;or 1.5/m2),administered on days 1-10 every 2 weeks/cycle.Premedication included an intravenous bolus injection of metoclopramide and chlorpheniramine with or without dexamethasone.Prophylactic granulocyte-colony stimulating factor was administered in only those

41、patients with either grade 4 or complicated neutropenia after the first treatment cycle.The subsequent cycle could be started only if the following criteria were met on day 1:neutrophil count 1500/mm3,platelet count 75 000/mm3,total bilirubin 2 times the ULN,ALT 3 times the ULN,and all other non-hae

42、matological toxicities recovered to grade 2.If the patient failed to meet these criteria before commencing the next cycle,the chemotherapy may be de-layed by up to 2 weeks.If febrile or grade 4 neutropenia,grade 4 thrombocytopenia(or grade 3 that required platelet transfusion),or grade 3-4 non-haema

43、tological toxicities,which were considered to be gemcitabine-related,occurred,then the subsequent dose of gem-citabine would be reduced by 200 mg/m2.If grade 3-4 diarrhoea,stomatitis,rash,or non-haematological toxicities associated with S-1 occurred,then the subsequent S-1 dose would be reduced by 2

44、0 mg/day.Dose reduction of either drug was allowed only twice,with the permitted nadir dose being 400 mg/m2 for gemcitabine and 60 mg/day for S-1.However,no further dose reescalation was permitted.The treatment regimen was continued until disease progression,unacceptable toxicity,patient refusal,ado

45、ption of other systemic or definitive local therapy,or death.The actual DI was defined as the total amount of drug administered per week divided by the baseline BSA of an individual patient(mg/m2/wk)during the 12 cycles from the start of chemotherapy,with reference to the JCOG0805 study.92.3|Pre-tre

46、atment and follow-up evaluationPre-treatment evaluation included a review of the patients medical history,physical examination,assessment of blood cell counts,serum biochemical tests,electrocardiography,chest radiography,and con-trast-enhanced computed tomography or magnetic resonance imag-ing.Physi

47、cal examinations and blood tests were scheduled on day 1 of each treatment cycle.The levels of carcinoembryonic antigen(CEA)and carbohydrate antigen 19-9(CA 19-9)were measured at baseline and every 2 cycles thereafter.Radiographic follow-up was performed every 6 weeks.The tumour response would be as

48、sessed based on the RECIST version 1.1 with confirmation of objective re-sponse using 2 successive imaging studies.Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 4.0.The survival status was checked at least monthly after the end of treatment until death or lo

49、ss to follow-up.2.4|Statistical analysisThe primary endpoint was the 12-week DCR,defined as the percent-age of patients with complete/partial response CR/PR or stable dis-ease SD for 12 weeks.The secondary endpoints included objective response rate(ORR),PFS,OS,and safety profiles.Considering the DCR

50、 of patients treated with gemcitabine alone was 50%at 6 weeks in BT-22 and 45%at 8 weeks in our previous study,5,11 the p0 was set as 40%of the 12-week DCR in this study.The sample size was calculated on the basis of Simons optimal two-stage design of p1=60%,with a significance level of 0.05 and a p

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