5、消化系统肿瘤消化系统肿瘤 (6).pdf

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1、The new england journal of medicinen engl j med 362;14 nejm.org april 8,20101273original articleCisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract CancerJuan Valle,M.D.,Harpreet Wasan,M.D.,Daniel H.Palmer,M.D.,Ph.D.,David Cunningham,M.D.,Alan Anthoney,M.D.,Anthony Maraveyas,M.D.,Ph.D.,S

2、rinivasan Madhusudan,M.D.,Ph.D.,Tim Iveson,M.D.,Sharon Hughes,B.Sc.,Stephen P.Pereira,M.D.,Ph.D.,Michael Roughton,M.Sc.,and John Bridgewater,M.D.,Ph.D.,for the ABC-02 Trial Investigators*From Christie Hospital,Manchester(J.V.);Hammersmith Hospital,Imperial College Health Care Trust(H.W.),Royal Marsd

3、en Hospital(D.C.),Cancer Research United Kingdom and University College London Cancer Trials Centre(S.H.,M.R.),Institute of Hepatology,University College London(S.P.P.),and University College London Can-cer Institute(J.B.)all in London;Univer-sity Hospital Birmingham,Birmingham(D.H.P.);St.Jamess Hos

4、pital,Leeds(A.A.);Castle Hill Hospital,Hull(A.M.);Notting-ham University Hospitals,Nottingham(S.M.);and Southampton University Hos-pitals,Southampton(T.I.)all in the United Kingdom.Address reprint requests to Dr.Bridgewater at the University Col-lege London Cancer Institute,72 Huntley St.,London WC1

5、E 6AA,United Kingdom,or at j.bridgewaterucl.ac.uk.*The investigators in the Advanced Bil-iary Cancer(ABC)-02 Trial are listed in the Appendix.Drs.Valle,Wasan,and Bridgewater contributed equally to this article.This article(10.1056/NEJMoa0908721)was updated on July 7,2010,at NEJM.org.N Engl J Med 201

6、0;362:1273-81.Copyright 2010 Massachusetts Medical Society.AbstractBackgroundThere is no established standard chemotherapy for patients with locally advanced or metastatic biliary tract cancer.We initially conducted a randomized,phase 2 study involving 86 patients to compare cisplatin plus gemcitabi

7、ne with gemcitabine alone.After we found an improvement in progression-free survival,the trial was extended to the phase 3 trial reported here.MethodsWe randomly assigned 410 patients with locally advanced or metastatic cholangio-carcinoma,gallbladder cancer,or ampullary cancer to receive either cis

8、platin(25 mg per square meter of body-surface area)followed by gemcitabine(1000 mg per square meter),each administered on days 1 and 8,every 3 weeks for eight cycles,or gemcit-abine alone(1000 mg per square meter on days 1,8,and 15,every 4 weeks for six cycles)for up to 24 weeks.The primary end poin

9、t was overall survival.ResultsAfter a median follow-up of 8.2 months and 327 deaths,the median overall survival was 11.7 months among the 204 patients in the cisplatingemcitabine group and 8.1 months among the 206 patients in the gemcitabine group(hazard ratio,0.64;95%confidence interval,0.52 to 0.8

10、0;P0.001).The median progression-free sur-vival was 8.0 months in the cisplatingemcitabine group and 5.0 months in the gemcitabine-only group(P0.001).In addition,the rate of tumor control among pa-tients in the cisplatingemcitabine group was significantly increased(81.4%vs.71.8%,P=0.049).Adverse eve

11、nts were similar in the two groups,with the exception of more neutropenia in the cisplatingemcitabine group;the number of neutrope-nia-associated infections was similar in the two groups.ConclusionsAs compared with gemcitabine alone,cisplatin plus gemcitabine was associated with a significant surviv

12、al advantage without the addition of substantial toxicity.Cisplatin plus gemcitabine is an appropriate option for the treatment of patients with advanced biliary cancer.(ClinicalTrials.gov number,NCT00262769.)The new england journal of medicinen engl j med 362;14 nejm.org april 8,20101274Biliary tra

13、ct cancer is an uncom-mon cancer in developed countries.There are approximately 1200 new cases in the United Kingdom1 and 9000 new cases in the Unit-ed States per year,although the incidence is in-creasing,perhaps related to gallstone disease.2 Most patients have advanced disease at presenta-tion an

14、d relapse despite surgery.3 Although ad-vanced biliary tract cancer can have a response to chemotherapy,there is no recognized standard palliative regimen because no single randomized study has ever been sufficiently robust to define a schedule;fluoropyrimidines,4,5 cisplatin,6 and gemcitabine7,8 ha

15、ve shown activity.Gemcitabine(Gemzar,Eli Lilly)treatment for biliary tract cancer has been increasingly pre-scribed by oncologists who specialize in hepato-biliary disease because of its use in pancreatic cancer.Cisplatin is known to have an additive or synergistic effect in combination with gemcita

16、bine in a number of different tumor types(e.g.,lung,9 bladder,10 and head and neck11 cancers).We pre-viously found an improvement in 6-month pro-gression-free survival from 47.7%to 57.1%in a randomized,phase 2 trial(the Advanced Biliary Cancer ABC-01 trial)comparing cisplatin plus gemcitabine with g

17、emcitabine alone;that trial in-volved 86 patients.12 That study was extended to become a phase 3 trial(the ABC-02 trial)with a planned recruitment total of 400 patients and a primary end point of overall survival.Methodsstudy DesignThis randomized,controlled,phase 3 trial was de-signed and developed

18、 by the ABC-02 Trial Man-agement Group under the auspices of the Upper Gastrointestinal Cancer Clinical Studies Group of the United Kingdom National Cancer Research Institute.The study was conducted by investiga-tors at 37 centers in the United Kingdom,and data were collected and analyzed at the Can

19、cer Research United Kingdom and University College London Cancer Trials Centre,London.The trial was initially designed as a randomized,phase 2 study involving 86 patients(the ABC-01 trial),conducted between February 2002 and June 2004.The trial was extended into a phase 3 trial(the ABC-02 trial)beca

20、use of an apparent benefit in progression-free survival;this extension used a similar approach to that described previously.13 The same treatment regimens and eligibility cri-teria were used in both phases.Investigators were unaware of the overall survival analysis in the ABC-01 trial,as mandated by

21、 the independent data and safety monitoring committee.This trial was approved by a research ethics committee,and all necessary regulatory approv-als were obtained.All patients were required to give written informed consent before random assignment,and the trial was conducted in ac-cordance with the

22、Declaration of Helsinki.An independent data and safety monitoring board regularly reviewed the data on safety.Lilly Oncology provided the investigators with gemcitabine at no cost but was not involved in the accrual or analysis of the data,the interpre-tation of the results,or the preparation of the

23、 manuscript.PatientsPatients were eligible for the study if they were 18 years of age or older and had received a histopatho-logical or cytologic diagnosis of nonresectable,recurrent,or metastatic biliary tract carcinoma(intrahepatic or extrahepatic cholangiocarcinoma,gallbladder cancer,or ampullary

24、 carcinoma);an Eastern Cooperative Oncology Group(ECOG)per-formance status of 0,1,or 2(on a scale ranging from 0 to 5,with lower scores indicating a high-er level of functioning);and an estimated life ex-pectancy of more than 3 months.Other eligibility criteria were adequate hematologic and biochem-

25、ical function,in particular a total bilirubin level of 1.5 times the upper limit of the normal range or less,liver-enzyme levels that were five times the upper limit of the normal range or less,renal func-tion with levels of serum urea and serum creati-nine that were less than 1.5 times the upper li

26、mit of the normal range,and a calculated glomerular filtration rate of 45 ml per minute or higher.TreatmentPatients were randomly assigned to receive cis-platin plus gemcitabine or gemcitabine alone for up to 24 weeks.In the cisplatingemcitabine group,each cycle comprised cisplatin(25 mg per square

27、meter of body-surface area)followed by gemcit-abine(1000 mg per square meter),each adminis-tered on days 1 and 8 every 3 weeks,initially for four cycles.In the gemcitabine-only group,gem-citabine was administered at a dose of 1000 mg per square meter on days 1,8,and 15 every 4 weeks,CisplatinGemcita

28、bine vs.Gemcitabine for Biliary Tract Cancern engl j med 362;14 nejm.org april 8,20101275initially for three cycles.Cisplatin plus gemcita-bine was administered on an outpatient basis as a 2-hour infusion(1 liter of 0.9%saline including cisplatin,20 mmol of potassium chloride,and 8 mmol of magnesium

29、 sulfate over 1 hour followed by 500 ml of 0.9%saline over 30 minutes before the administration of gemcitabine).All patients received gemcitabine as a 30-minute infusion.If patients did not have disease progression at 12 weeks,they could continue with another 12 weeks of the same regimen.Dose modifi

30、cations were defined per protocol,and modifications and delays were allowed for hematologic toxicity,ab-normal renal function,nausea,vomiting,periph-eral neuropathy,edema,or tinnitus.Treatment was discontinued at 24 weeks or because of disease progression,patient or clinician choice,or unac-ceptable

31、 toxic effects.Biliary obstruction per se was not considered to be disease progression in the absence of radiologically confirmed disease progression,and treatment could be recommenced after further biliary stenting and normalization of liver function.AssessmentsPatients were seen at the start of ev

32、ery cycle for a physical examination,monitoring of symptoms and toxic effects,assessment of renal function,and a complete blood count.Tumor response,mea-sured according to the Response Evaluation Cri-teria in Solid Tumors(RECIST)1.0 criteria,14 was assessed by means of computed tomography(CT)or magn

33、etic resonance imaging(MRI)at week 12 and again at week 24 in patients who completed treatment(confirmatory scans were not required).Tumor control was defined as a complete response,a partial response,or stable disease.For the end point of progression-free survival,progressive dis-ease was defined a

34、s either objective tumor pro-gression based on RECIST 1.0 criteria or the confirmed emergence of local nonprimary,met-astatic,or nodal disease.After the end of the study treatment,patients were seen in the clinic every 3 months.Follow-up visits consisted of clin-ical assessment and either CT or MRI

35、to assess tumor progression.Once progressive disease was documented,patients underwent follow-up for sur-vival only.Statistical AnalysisThe primary outcome was overall survival,and the secondary outcomes were progression-free sur-vival,tumor response,and adverse events.The trial was designed to have

36、 80%power to detect an increase in median survival from 8 months in pa-tients receiving gemcitabine alone to 11 months in patients receiving cisplatin plus gemcitabine.A total of 354 patients would be required to reach 315 events,based on the use of the log-rank test with a two-sided significance le

37、vel of 5%and as-suming that the trial would recruit for 3 years with at least 6 months of follow-up for each pa-tient.To allow for dropouts and to ensure that we had sufficient evidence to meet the trial objec-tives,we aimed to recruit 400 patients.Patients were randomly assigned by telephone by the

38、 Can-cer Research United Kingdom and University Col-lege London Cancer Trials Centre,which coordi-nated the trial.Randomization was conducted with the use of a minimization algorithm strati-fied according to the primary tumor site,extent of disease(locally advanced vs.metastatic),per-formance status

39、,previous therapy,and recruiting center.All analyses were performed on an intention-to-treat basis.Overall survival was calculated from the date of randomization until the date of death.Progression-free survival was measured from ran-domization until the date of disease progression or death.Patients

40、 who did not have disease pro-gression and patients who died were excluded at the date of their last follow-up.Overall survival and progression-free survival were analyzed with the use of KaplanMeier curves and the log-rank test.A Cox proportional-hazards model was used to estimate the hazard ratios

41、.Toxic effects were categorized according to the National Cancer In-stitutes Common Toxicity Criteria for Adverse Events,version 3.All analyses were performed with the use of Stata 10.1 software(Stata).The database was closed for analysis in June 2009.ResultsWe recruited 410 patients from 37 centers

42、 in the United Kingdom across the National Cancer Re-search Network between February 2002 and Octo-ber 2008.A total of 204 patients received cisplatin plus gemcitabine,and 206 received gemcitabine alone(Fig.1).The median follow-up time was 8.2 months.At the time of the final analysis,327 deaths had

43、occurred,and 362 patients(88.3%)had tumor progression.Baseline characteristics were well balanced between the two groups(Table 1).The new england journal of medicinen engl j med 362;14 nejm.org april 8,20101276There was an insignificant difference between the numbers of patients with locally advance

44、d disease in the two groups(27.0%in the cisplatingem-citabine group vs.23.8%in the gemcitabine-only group,P=0.46).The majority of patients had ei-ther a histologic or a cytologic diagnosis of an adenocarcinoma or a carcinoma(99.0%).Two pa-tients had an adenosquamous tumor;one was a squamous-cell car

45、cinoma and one was a carcino-sarcoma.Treatment ComplianceAt the end of the first 12 weeks,treatment com-pliance was similar in the two groups,with 66.5%receiving three cycles of gemcitabine alone and 73.5%receiving four cycles of cisplatin plus gem-citabine;however,in the treatment period over-all,m

46、ore patients in the gemcitabine-only group discontinued planned treatment prematurely,pri-marily because of disease progression(49 patients in the gemcitabine-only group vs.26 patients in the cisplatingemcitabine group,P=0.004).This discontinuation is reflected in the median dura-tion of treatment(1

47、4 weeks in the gemcitabine-only group vs.21 weeks in the cisplatingemcit-abine group,P=0.003).Significantly more patients in the cisplatingemcitabine group than patients in the gemcitabine-only group went on to start the second 12 weeks of treatment(63%vs.52%,P=0.02).In the first 12 weeks of treatme

48、nt,an average of 92%of the planned dose was delivered to patients in the gemcitabine-only group,as com-pared with 95%in the cisplatingemcitabine group(P=0.95);however,in the second 12 weeks,the average was 69%in the gemcitabine-only group as compared with 88%in the cisplatingemcitabine group(P=0.046

49、).Among the 72 patients who went on to receive second-line therapy,13 of 36 patients in the gemcitabine-only group(36%)re-ceived a platinum-based agent as compared with 10 of 36 patients in the cisplatingemcitabine group(28%)(P=0.45).Four patients from each group received no treatment during the tri

50、al(Fig.1).Tables 1 through 3 in the Supplementary Appen-dix,available with the full text of this article at NEJM.org,provide details of noncompliance and dose modifications.Tumor ResponseObjective tumor response was measurable in 303 patients(patients were not required to have mea-surable disease at