1、W J G OWorld Journal ofGastrointestinalOncologySubmit a Manuscript:https:/World J Gastrointest Oncol 2019 November 15;11(11):1021-1030DOI:10.4251/wjgo.v11.i11.1021 ISSN 1948-5204(online)ORIGINAL ARTICLERetrospective Cohort StudyOral chemotherapy for second-line treatment in patients withgemcitabine-
2、refractory advanced pancreatic cancerSe Jun Park,Hyunho Kim,Kabsoo Shin,Myung Ah Lee,Tae Ho HongORCID number:Se Jun Park(0000-0001-5486-9818);Hyunho Kim(0000-0003-1276-713X);Kabsoo Shin(0000-0002-6709-0894);Myung AhLee(0000-0002-1204-0574);Tae HoHong(0000-0003-3864-8104).Author contributions:All aut
3、horshelped to perform the research;Park SJ was involved withmanuscript writing,draftingconception and design,acquisitionof data,performing proceduresand data analysis;Kim HH,ShinKS,Hong TH contributed towriting the manuscript;Lee MAcontributed to writing themanuscript,drafting conceptionand design,p
4、erforming proceduresand data analysis.Institutional review boardstatement:This study wasreviewed and approved by theEthics Committee of The CatholicUniversity of Korea,Seoul St.Marys Hospital.Informed consent statement:Patients were not required to giveinformed consent for the studybecause the analy
5、sis usedanonymous clinical data that wereobtained after each patient agreedto treatment by written consent.Conflict-of-interest statement:Allauthors declare no conflict-of-interest related to this research.Data sharing statement:Noadditional data are available.STROBE statement:The authorshave read t
6、he STROBE Statement-checklist of items,and themanuscript was prepared andSe Jun Park,Hyunho Kim,Kabsoo Shin,Myung Ah Lee,Division of Medical Oncology,Department of Internal Medicine,The Catholic University of Korea,Seoul St.MarysHospital,Seoul 100744,South KoreaTae Ho Hong,Department of General Surg
7、ery,The Catholic University of Korea,Seoul St.Marys Hospital,Seoul 100744,South KoreaCorresponding author:Myung Ah Lee,MD,PhD,Professor,Division of Medical Oncology,Department of Internal Medicine,Cancer research institute,College of Medicine,The CatholicUniversity of Korea,Seoul St.Marys Hospital,2
8、22 Banpo-daero,Secho-gu,Seoul 100744,South Korea.angelamdcatholic.ac.krTelephone:+82-2-22586044Fax:+82-2-5993589AbstractBACKGROUNDThere is no standard therapy for second-line treatment of gemcitabine-refractorypancreatic cancer patients with poor performance status.A combination ofchemotherapy drugs
9、 5-fluorouracil(5-FU),leucovorin,irinotecan,and oxaliplatin(FOLFIRINOX)or 5-fluorouracil/leucovorin plus nanoliposomal irinotecan canbe considered as second-line treatment for such patients;however,due totoxicity,none of the regimens are recommended for patients with poorperformance.Capecitabine or
10、S-1 has relatively low toxicity and can beconsidered a treatment option for gemcitabine-refractory pancreatic cancer.AIMTo investigate the efficacy and toxicity of oral chemotherapy as second-linetreatment in patients with pancreatic cancer.METHODSPatients who had progressive disease after first-lin
11、e gemcitabine-basedchemotherapy were retrospectively analyzed between January 2011 andDecember 2018.They were treated with capecitabine or S-1 as the second-linetreatment.Capecitabine was administered as a 2500 mg/m2 divided dose on days1-14,followed by a 1-wk rest.S-1 was taken orally based on the
12、patients bodysurface area for 28 d,followed by 2-wk of rest.Progression-free survival andoverall survival were used to compare efficacy of capecitabine and S-1.RESULTSOf the 81 patients,41 were treated with capecitabine and 40 with S-1.The medianWJGO https:/November 15,2019 Volume 11 Issue 111021rev
13、ised according to the STROBEStatement-checklist of items.Open-Access:This article is anopen-access article which wasselected by an in-house editor andfully peer-reviewed by externalreviewers.It is distributed inaccordance with the CreativeCommons Attribution NonCommercial(CC BY-NC 4.0)license,which
14、permits others todistribute,remix,adapt,buildupon this work non-commercially,and license their derivative workson different terms,provided theoriginal work is properly cited andthe use is non-commercial.See:http:/creativecommons.org/licenses/by-nc/4.0/Manuscript source:UnsolicitedmanuscriptReceived:
15、May 20,2019Peer-review started:May 23,2019First decision:July 31,2019Revised:September 3,2019Accepted:September 12,2019Article in press:September 13,2019Published online:November 15,2019P-Reviewer:Hourneaux de MouraDT,Sun XYS-Editor:Zhang LL-Editor:AE-Editor:Qi LLtime to treatment failure in both gr
16、oups was 1.5 mo(P=0.425).The objectiveresponse rate was similar in the two groups:9.8%with capecitabine and 2.5%with S-1(P=0.359).Median progression-free survival was longer in the S-1group than in the capecitabine group(S-1 2.7 mo,capecitabine 2.0 mo,P=0.003).There was no significant difference in
17、the median overall survival between thecapecitabine and S-1 groups(4.3 mo vs 5.0 mo,P=0.092).Grade 3 or 4 hand-footsyndrome was significantly more common in the capecitabine group than in theS-1 group(14.6%vs 0%,P=0.026).CONCLUSIONCapecitabine or S-1 can be used as a second-line treatment for patien
18、ts withadvanced pancreatic cancer with poor performance status after progression to agemcitabine-based regimen.Key words:Pancreatic cancer;Gemcitabine-refractory;Capecitabine;S-1;Second-linetreatmentThe Author(s)2019.Published by Baishideng Publishing Group Inc.All rights reserved.Core tip:To date,t
19、here is no standard regimen for patients with gemcitabine-refractorypancreatic cancer with poor performance status.In this study,we compared the efficacyand toxicity of capecitabine and S-1 for such patients.The median progression freesurvival was longer in the S-1 group than in the capecitabine gro
20、up;however,there wereno statistical differences in their overall survival.Among grade 3 or 4 toxicity,hand-footsyndrome was significantly more common in the capecitabine group than in the S-1group.Thus,oral chemotherapy can be considered as a second-line treatment ingemcitabine-refractory pancreatic
21、 cancer patients with poor performance status.Citation:Park SJ,Kim H,Shin K,Lee MA,Hong TH.Oral chemotherapy for second-linetreatment in patients with gemcitabine-refractory advanced pancreatic cancer.World JGastrointest Oncol 2019;11(11):1021-1030URL:https:/cancer is one of the leading causes of ca
22、ncer-related deaths worldwide,with an overall 5-year survival rate of 5%.More than 80%of patients present withadvanced or metastatic disease1,2.For patients with locally advanced or metastaticdisease,gemcitabine plus nab-paclitaxel therapy has improved overall survival(OS)of patients compared with g
23、emcitabine monotherapy and is therefore the currentlyrecommended first-line treatment(median OS 8.7 mo vs 6.6 mo,respectively,P 0.0001;hazard ratio(HR)0.72)3.A combination of chemotherapy drugs 5-fluorouracil(5-FU),leucovorin,irinotecan,and oxaliplatin(FOLFIRINOX)therapy also showedimproved progress
24、ion-free survival(PFS)and OS compared with gemcitabinemonotherapy in patients with metastatic pancreatic cancer with good performancestatus(PS)(median PFS 6.4 vs 3.3 mo,P 0.001;median OS 11.1 vs 6.8 mo,P 0.001)4.This regimen is therefore considered as an alternative first-line treatmentoption for pa
25、tients with pancreatic cancer,as it is associated with good PS.As a second-line treatment after progressive disease following gemcitabine-basedchemotherapy,the 5-FU/leucovorin+nanoliposomal irinotecan treatment showedpromising clinical outcomes in the NAPOLI-1 trial;however,it is considered only for
26、patients with Eastern Cooperative Oncology Group(ECOG)PS 0-1,due to treatment-related toxicity5,6.To date,treatment with fluoropyrimidine-based combinationregimens in gemcitabine-refractory pancreatic cancer patients with poor PS,iscontroversial.Capecitabine,a prodrug of 5-FU,is one of the options a
27、s a second-line agent aftergemcitabine failure in patients with pancreatic cancer and poor PS7.Capecitabine hasshown a relatively good response as a first-line treatment in patients with metastaticpancreatic cancer,with a response rate of 24%7,8.S-1 is a fourth-generation oralfluoropyrimidine that c
28、ombines tegafur(5-FU prodrug)with two modulators,5-WJGO https:/November 15,2019 Volume 11 Issue 11Park SJ et al.Oral chemotherapy for pancreatic cancer1022chloro-2,4-dihydroxypyridine(gimeracil)and potassium oxonate(oteracil)in a molarratio of 1:0.4:1.According to some randomized studies,S-1 as seco
29、nd-linechemotherapy in gemcitabine-pretreated advanced pancreatic cancer showed arelatively high disease control rate,and was well tolerated with acceptable toxicity9,10.In this study,we retrospectively analyzed the comparable efficacy and toxicity ofcapecitabine or S-1 as a second-line treatment in
30、 patients with advanced or metastaticpancreatic cancer.MATERIALS AND METHODSPatientsFrom January 2011 to December 2018,we analyzed the medical records of patientsdiagnosed with pancreatic cancer in our Department of Oncology.Patients aged atleast 19 years,with histologically confirmed,locally advanc
31、ed,recurrent or metastaticpancreatic adenocarcinoma,who were previously treated with gemcitabine-basedfirst-line chemotherapy,were eligible for this study if they met the following inclusioncriteria:ECOG PS 0-2;measurable or evaluable lesions according to the ResponseEvaluation Criteria in Solid Tum
32、ors(RECIST version 1.0)criteria;progression ofdisease with gemcitabine-based chemotherapy as first-line therapy;adequatehematological,liver,and renal functions(hemoglobin 9.0 g/dL,white blood cellcount 4000/mm3,absolute neutrophil count 1000/mm3,platelet count 100000/mm3,total bilirubin 1.5-fold hig
33、her than the upper normal limit,serumtransaminase 3-fold higher than the upper normal limit,creatinine 1.5,50 mg twice daily for a BSA 1.25-1.5,and 40 mg twicedaily for a BSA 1.25)for 28 days,followed by a 14-d rest.This treatment course wasrepeated until disease progression,unacceptable toxicities,
34、or patients refusal tocontinue.Chemotherapy dose adjustments were allowed.Tumor responses to treatment were evaluated every 3 cycles in the capecitabinegroup and every 2 cycles in the S-1 group.Toxicity was assessed after chemotherapyfor every cycle.Imaging evaluations were performed with computed t
35、omography andmagnetic resonance imaging at the discretion of the attending physician.Imagingtests were analyzed by radiologists at our institution according to RECIST version 1.0.Toxicities were graded according to the National Cancer Institutes CommonTerminology Criteria for Adverse Events,version
36、4.0.Chemotherapy dose intensitywas the total amount of drug given in a fixed unit of time(cumulative dose/treatmentduration).This study was approved by the Institutional Review Board of The CatholicUniversity of Korea,Seoul St.Marys Hospital(KC18RESI0535).Statistical analysisResponses were assessed
37、objectively according to RECIST version 1.0.The objectiveresponse rate represented the percentage of patients with a complete response(CR)orpartial response(PR)among those with measurable lesions.The primary endpointwas PFS,defined as the time interval between capecitabine or S-1 treatment initiatio
38、nand time of disease progression based on imaging studies or death,whicheveroccurred first.OS was estimated from the date of capecitabine or S-1 initiation to thedate of death or last follow-up visit.Time to treatment failure(TTF)was measuredfrom the date of capecitabine or S-1 initiation to the dat
39、e of last administration due todisease progression,unacceptable toxicity,or cancer-related complications.Kaplan-Meier analysis was performed for both treatment groups to obtain medianOS and median PFS.The HR and 95%confidence intervals(CIs)for OS and PFS wereestimated using a stratified Cox regressi
40、on model.Relative dose intensity wascalculated as the ratio between administered dose and planned dose,expressed as apercentage.Statistical significance was considered when P values 0.05(two-sided).Statistical analyses were performed using IBM SPSS for Windows version 24.0(IBMSPSS Inc.,Armonk,New Yo
41、rk,United States)and GraphPad Prism version 8.0(GraphPad Software Inc.,San Diego,CA,United States).WJGO https:/November 15,2019 Volume 11 Issue 11Park SJ et al.Oral chemotherapy for pancreatic cancer1023RESULTSPatient characteristicsFrom January 1,2011 to December 31,2018,a total of 81 patients were
42、 found to beeligible for this study.Forty-one patients were treated with capecitabine and 40 weretreated with S-1.Patient baseline characteristics in the two groups were well balanced(Table 1).Median age was 61 years(range 39-77 years)in the capecitabine group and63 years in the S-1 group(range 41-7
43、8 years).Nearly one-quarter of the patients inboth groups exhibited ECOG PS 2.Although not statistically significant,thecapecitabine group had more patients with lesions that were initially unresectablecompared with the S-1 group.(56%vs 35%,respectively,P=0.057).As first-linechemotherapy,gemcitabine
44、 plus erlotinib was given to most patients in thecapecitabine group(76%),and gemcitabine plus nab-paclitaxel was given to mostpatients in the S-1 group(60%).Overall,1(2%)of 41 patients in the capecitabinegroup and 4(10%)of 40 patients in the S-1 group had received two or more previouslines of therap
45、y.Treatment results and efficacyThe median duration of treatment for capecitabine was 1.7 mo and for S-1 it was 2.0mo.Median relative dose intensity was 0.92 in the capecitabine group and 1.0 in the S-1 group,with no statistically significant difference(P=0.986,Table 2).The medianTTF in both groups
46、was 1.5 mo(range:Capecitabine 0.5-6.7 mo,S-1 0.3-5.7 mo,P=0.425).As of April 2019,the median duration of follow-up was 2.8 mo(1.1-12.1 mo)inthe capecitabine group and 4.8 mo(0.6-14.2 mo)in the S-1 group.The objective response rate was 9.8%(PR=4)in the capecitabine group and 2.5%(PR=1)in the S-1 grou
47、p with no statistical difference between the two groups(P=0.359,Table 3).PFS was shorter in the capecitabine group(median 2.0 mo;95%CI 1.5-2.4)than in the S-1 group(median 2.7 mo;95%CI 2.4-2.8).The stratified HR fordisease progression or death was 1.90(95%CI 1.20-3.01;P=0.003).(Figure 1A).Therewere
48、no statistical differences in OS between the two treatment groups.The medianOS was 4.3 mo(95%CI 2.9-5.7)in the capecitabine group compared with 5.0 mo(95%CI 2.8-7.1)in the S-1 group(HR for death 1.49;95%CI 0.94-2.35,P=0.092)(Figure1B).In the capecitabine group,median PFS was 2.1 mo(95%CI 1.4-2.8)for
49、 the 5-FU-exposed group and 1.9 mo(95%CI 1.4-2.4)for the 5-FU-unexposed group(HR fordisease progression 0.89;95%CI 0.47-1.7,P=0.720)(Figure 2A).Median OS was 5.0mo(95%CI 1.6-8.4)for the 5-FU-exposed group,and 3.6 mo(95%CI 1.9-5.3)for the 5-FU-unexposed group(HR for death 0.83;95%CI 0.44-1.57,P=0.492
50、)(Figure 2C).Inthe S-1 group,median PFS was 2.8 mo(95%CI 2.4-3.1)for the 5-FU-exposed groupand 2.7 mo(95%CI 2.2-3.1)for the unexposed group(HR for disease progression 0.69;95%CI 0.36-1.33,P=0.205)(Figure 2B).Median OS for the 5-FU-exposed group was6.5 mo(95%CI 3.9-9.0)and for the 5-FU-unexposed grou
