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1、 Published online March 30,2021 https:/doi.org/10.1016/S1470-2045(21)00027-9 1ArticlesLancet Oncol 2021Published Online March 30,2021 https:/doi.org/10.1016/S1470-2045(21)00027-9Department of Medical Oncology,The Christie NHS Foundation Trust/Institute of Cancer Sciences(A Lamarca PhD,Prof J W Valle

2、 MD),Manchester Centre for Health Economics(Prof L M Davies MSc),Manchester Clinical Trials Unit(S Barber BSc,W D Ryder Grad.IS),and Division of Cancer Sciences(Prof J W Valle),University of Manchester,Manchester,UK;University of Liverpool and Clatterbridge Cancer Centre,Liverpool,UK(Prof D H Palmer

3、 PhD);Department of Cancer Medicine,Hammersmith Hospital,Imperial Colllege London,London,UK(H S Wasan MD);Guys Cancer,Guys&St Thomas NHS Foundation Trust,London,UK(P J Ross PhD);Department of Hepatobiliary Oncology,University of Birmingham and University Hospitals Birmingham NHS Foundation Trust,Bir

4、mingham,UK(Y T Ma PhD);Department of Medical Oncology,University Hospital of Nottingham NHS Trust,University of Nottingham,Nottingham,UK(A Arora MD);Bristol Haematology and Oncology Centre,Bristol,UK(S Falk MD);Department of Medical Oncology,Royal Free NHS Foundation Trust,London,UK(R Gillmore PhD);

5、Weston Park Cancer Centre,Sheffield,UK(Prof J Wadsley MA);Department of Medical Oncology,Cancer and Haematology Centre,Oxford,UK(K Patel PhD);Department of Medical Oncology,Leeds Teaching Hospitals NHS Trust,Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract can

6、cer(ABC-06):a phase 3,open-label,randomised,controlled trial Angela Lamarca,Daniel H Palmer,Harpreet Singh Wasan,Paul J Ross,Yuk Ting Ma,Arvind Arora,Stephen Falk,Roopinder Gillmore,Jonathan Wadsley,Kinnari Patel,Alan Anthoney,Anthony Maraveyas,Tim Iveson,Justin S Waters,Claire Hobbs,Safia Barber,W

7、David Ryder,John Ramage,Linda M Davies,John A Bridgewater,Juan W Valle,on behalf of the Advanced Biliary Cancer Working GroupSummaryBackground Advanced biliary tract cancer has a poor prognosis.Cisplatin and gemcitabine is the standard first-line chemotherapy regimen,but no robust evidence is availa

8、ble for second-line chemotherapy.The aim of this study was to determine the benefit derived from second-line FOLFOX(folinic acid,fluorouracil,and oxaliplatin)chemotherapy in advanced biliary tract cancer.Methods The ABC-06 clinical trial was a phase 3,open-label,randomised trial done in 20 sites wit

9、h expertise in managing biliary tract cancer across the UK.Adult patients(aged 18 years)who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer(including cholangiocarcinoma and gallbladder or ampullary carcinoma)with documented radiological disease progre

10、ssion to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 01 were randomly assigned(1:1)centrally to active symptom control(ASC)and FOLFOX or ASC alone.FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 1

11、2 cycles(oxaliplatin 85 mg/m,L-folinic acid 175 mg or folinic acid 350 mg,fluorouracil 400 mg/m bolus,and fluorouracil 2400 mg/m as a 46-h continuous intravenous infusion).Randomisation was done following a minimisation algorithm using platinum sensitivity,serum albumin concentration,and stage as st

12、ratification factors.The primary endpoint was overall survival,assessed in the intention-to-treat population.Safety was also assessed in the intention-to-treat population.The study is complete and the final results are reported.This trial is registered with ClinicalTrials.gov,NCT01926236,and EudraCT

13、,2013-001812-30.Findings Between March 27,2014,and Jan 4,2018,162 patients were enrolled and randomly assigned to ASC plus FOLFOX(n=81)or ASC alone(n=81).Median follow-up was 217 months(IQR 172308).Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group,wit

14、h a median overall survival of 62 months(95%CI 5476)in the ASC plus FOLFOX group versus 53 months(4158)in the ASC alone group(adjusted hazard ratio 069 95%CI 050097;p=0031).The overall survival rate in the ASC alone group was 355%(95%CI 252460)at 6 months and 114%(56195)at 12 months,compared with 50

15、6%(393609)at 6 months and 259%(170358)at 12 months in the ASC plus FOLFOX group.Grade 35 adverse events were reported in 42(52%)of 81 patients in the ASC alone group and 56(69%)of 81 patients in the ASC plus FOLFOX group,including three chemotherapy-related deaths(one each due to infection,acute kid

16、ney injury,and febrile neutropenia).The most frequently reported grade 35 FOLFOX-related adverse events were neutropenia(ten 12%patients),fatigue or lethargy(nine 11%patients),and infection(eight 10%patients).Interpretation The addition of FOLFOX to ASC improved median overall survival in patients w

17、ith advanced biliary tract cancer after progression on cisplatin and gemcitabine,with a clinically meaningful increase in 6-month and 12-month overall survival rates.To our knowledge,this trial is the first prospective,randomised study providing reliable,high-quality evidence to allow an informed di

18、scussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer.Based on these findings,FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further

19、 clinical trials.Funding Cancer Research UK,StandUpToCancer,AMMF(The UK Cholangiocarcinoma Charity),and The Christie Charity,with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.Copyright 2021 The Author(

20、s).Published by Elsevier Ltd.This is an Open Access article under the CC BY 4.0 license.Articles2 Published online March 30,2021 https:/doi.org/10.1016/S1470-2045(21)00027-9Introduction Biliary tract cancer is a term that includes cholangiocarcinoma(either intrahepatic or extrahepatic in origin)and

21、cancers of the gallbladder and ampulla of Vater.These uncommon cancers arising from the biliary tract account for less than 1%of all cancers worldwide.1 However,its incidence is increasing,primarily due to a rising incidence of intrahepatic cholangiocarcinoma.The prognosis is poor,with an allstage 5

22、year overall survival of less than 20%.1 Patients are rarely diagnosed with earlystage disease and therefore curative surgery and adjuvant therapy is only feasible for a small proportion of patients.The ABC02 study established cisplatin and gemcitabine as firstline therapy for patients with advanced

23、 biliary tract cancer2 and remains the current standard of care.Randomised studies during the past decade have failed to show an improvement in survival with the addition of biological therapies(EGFR or VEGF inhibitors);intensification of chemotherapy is under evaluation(eg,gemcitabine,cisplatin,and

24、 nabpaclitaxel;cisplatin,gemcitabine,and S1;and FOLFIRINOX oxaliplatin,leucovorin,irinotecan,and fluorouracil).35The role of secondline chemotherapy after progression on cisplatin and gemcitabine remains unclear,with no prospective randomised trials reported so far.6,7 Patients with advanced biliary

25、 tract cancer often experience a rapid decline in performance status following progression on firstline chemotherapy,and only 1525%receive secondline therapy.2,8,9 Some studies suggest that secondline chemotherapy might be of value for patients with a good performance status;8,1012 however,this theo

26、ry is subject to selection bias and has not been explored in a randomised study,and no consensus exists regarding the optimum regimen.Three groups of agents have broadly shown activity in biliary tract cancer in retrospective and prospective trials:gemcitabine,fluoropyrimidines,and platinum agents.1

27、3 Since the sensitivity to platinum agents in these malignancies is well described,2 together with the fact that switching to a fluoropyrimidinebased schedule after progression on firstline gemcitabinebased chemotherapy is considered appropriate in similar scenarios,14 it was anticipated that a fluo

28、rouracil and platinum doublet(such as oxaliplatin and fluorouracil in FOLFOX,which comprises leucovorin,fluorouracil,and oxaliplatin)was most likely to be effective.Existing phase 2 and retrospective data also supported this choice.6Novel molecular targets such as fibroblast growth factor receptor2(

29、FGFR2)fusions and isocitrate dehydrogenase1(IDH1)mutations have been identified Leeds,UK(A Anthoney MD);Department of Medical Oncology,Hull University Teaching Hospitals NHS Trust,Hull,UK(Prof A Maraveyas PhD);Department of Gastro-Intestinal Oncology,University Hospital Southampton NHS Foundation Tr

30、ust,Southampton University,Southampton,UK(Prof T Iveson MD);Kent Oncology Centre,Maidstone,UK(J S Waters PhD);Department of Clinical Oncology,Great Western Hospital,Swindon,UK(C Hobbs MSc);Hampshire Hospitals NHS Foundation Trust,Basingstoke,UK(Prof J Ramage MD);UCL Cancer Institute,University Colle

31、ge London,London,UK(Prof J A Bridgewater PhD)Correspondence to:Prof Juan W Valle,Division of Cancer Sciences,University of Manchester,Department of Medical Oncology,The Christie NHS Foundation Trust,Manchester,M20 4BX,UK juan.vallemanchester.ac.ukResearch in contextEvidence before this studyA previo

32、us systematic review by this group published in 2014 evaluated the level of evidence for the use of second-line chemotherapy for patients with advanced biliary tract cancer.As part of this systematic review,we searched MEDLINE using the search terms“(biliary tract AND chemotherapy AND second)OR(bili

33、ary tract AND chemotherapy AND refractory)OR(gallbladder AND chemotherapy AND refractory)OR(cholangiocarcinoma AND chemotherapy AND refractory)”,with no publication date or language restrictions.Abstracts of the Proceedings of the Annual Meeting of the American Society of Clinical Oncology,the Europ

34、ean Society of Medical Oncology Congress since 2002,and the annual World Gastrointestinal Congress since 2006 were searched manually.Up to December,2013,25 studies were identified,which were mainly phase 2 clinical trials and retrospective series.No randomised phase 3 studies were identified.When th

35、is search of the literature was updated in December,2020,phase 3 trial-based evidence supporting the role of cytotoxic chemotherapy in this setting was still nonexistent.Therefore,before this study,it was not possible to reliably determine the real benefit from second-line chemotherapy in this setti

36、ng.Moreover,there was insufficient evidence to recommend a specific second-line chemotherapy schedule in advanced biliary tract cancer.Added value of this studyTo our knowledge,ABC-06 is the first trial to compare active symptom control alone with active symptom control combined with FOLFOX chemothe

37、rapy following progression on first-line treatment with cisplatin and gemcitabine for patients with advanced biliary tract cancer.The study met its primary endpoint and confirmed that patients who received FOLFOX chemotherapy had a longer overall survival,with a clinically meaningful increase in 6-m

38、onth and 12-month overall survival rates,than those who received active symptom control alone.This outcome was achieved with an acceptable toxicity profile.Ongoing quality of life,health economics,and translational analyses of ABC-06 will help us to understand both the impact on patients experience

39、and the cost-benefit of FOLFOX chemotherapy in this setting,and the mechanisms of primary and secondary resistance to this treatment.Implications of all the available evidenceTo our knowledge,this study is the first prospective,adequately powered,randomised trial exploring the role of chemotherapy i

40、n this setting,thus providing reliable high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer.Based on the results of ABC-06,FOLFOX should become standard-of-care chemotherapy in se

41、cond-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials.A Published online March 30,2021 https:/doi.org/10.1016/S1470-2045(21)00027-9 3as promising within phase 2 and phase 3 trials,respectively,showing benefit in the secondline setting for a selec

42、ted population of patients harbouring such aberrations(mainly those with intrahepatic cholangiocarcinoma,with approximately 15%prevalence of each).1518 However,active symptom control(ASC),including early identification and management of biliary tract and cancerrelated complications and symptom manag

43、ement arising from tumour progression,is the current standard of care for most patients diagnosed with advanced biliary tract cancer who have progressed following firstline chemotherapy,especially in the absence of targetable molecular alterations.6The ABC06 study aimed to determine if patients with

44、 advanced biliary tract cancer benefit from the addition of secondline FOLFOX to ASC,following progression to previous firstline treatment with cisplatin and gemcitabine.Methods Study design and participants The ABC06 clinical trial was a phase 3,openlabel,randomised controlled study conducted under

45、 the auspices of the UK National Cancer Research Institute Upper Gastrointestinal Cancer Studies Group.Patients were recruited across 20 centres with expertise in managing biliary tract cancer in the UK(appendix p 17).Patients were eligible if they were aged 18 years or older and had histologically

46、or cytologically verified locally advanced or metastatic biliary tract cancer(including cholangiocarcinoma,gallbladder carcinoma,and ampullary carcinoma)with documented radio logical disease progression to previous firstline cisplatin and gemcitabine chemotherapy.Any other form of firstline systemic

47、 chemotherapy or additional line of firstline chemotherapy(including rechallenge with cisplatin and gemcitabine)was not allowed.Patients who had been started on firstline cisplatin and gemcitabine for whom the cisplatin was stopped due to toxicity(with continuation of gemcitabine)were eligible.A max

48、imum of 6 weeks was allowed between disease progression to firstline treatment and the start of secondline chemotherapy as part of the ABC06 trial.All patients had to have an Eastern Cooperative Oncology Group(ECOG)performance status of 01,life expectancy of longer than 3 months,and adequate haemato

49、logical,renal,and hepatic function,with no evidence of ongoing infection or inadequate biliary drainage.Patients with clinical evidence of metastatic disease to the brain and those with clinically significant cardiovascular disease were excluded.Full details of the patient inclusion and exclusion cr

50、iteria are in the protocol(see appendix).Trial data were collected and monitored at each site,and underwent quality control and analysis at the Manchester Clinical Trials Unit(CTU;Manchester,UK).The study was sponsored by The Christie NHS Foundation Trust and conducted in accordance with the princip