edited for CO药理药效研究 动物模型.docx

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editedforCO药理药效研究动物模型

Articletype:

Overview;

Title:

TheValueofElectiveLymphNodeIrradiationinDefinitiveConcurrentChemoradiotherapyforEsophagealCancer.

Abstract

Esophagealcancerremainsoneofthemostlethalcarcinomasandconcurrentchemoradiotherapyhasbeenacceptedasthestandardnon-surgicaltreatment.However,noconsistentconclusionshavebeenreachedwhetherelectivelymphnodeirradiation（ENI）shouldbedelivered.Therefore,weperformedasystematicreviewoftheliteratureonthefeasibilityandvalueofENIduringdefinitiveconcurrentchemoradiotherpayforesophagealcancer.AliteraturesearchbasedonPubMedelectronicdatabaseswascarriedouttoselectstudiesincludingdefinitelyconcurrentchemoradiotherapywithENIforesophagealcancer.Allofthestudieswereevaluatedcarefullyregardingwithacuteandlatetoxicities,treatment-relateddeath,patternsoffailureandoverallsurvival.Fourteenstudieswereidentifiedwithatotalof975patientsincluded.ConcurrentchemoradiotherapywithENIwasfeasiblewithacceptableacuteandlatetoxicities.ThelocalregionalcontrolrateseemstobehigherwithENI,comparingwithstudieswhichomittedENI.However,noobviousoverallsurvivalbenefitwithENIwasindicatedinthisreview.Inconclusion,thelocalregionalcontrolrateseemstobehigherwithENIinconcurrentchemoradiotherapyforesophagealcancerandnoobviousbetterOSresultswereindicatedinthisreview.Therefore,thevalueofENIremainscontroversialandfurtherprospectivephaseIIItrialsinthissettingarehighlywarranted.

KeyWords:

Esophagealcancer;chemoradiotherapy;electivelymphnodeirradiation.

Introduction

Esophagealcarcinomaistheeighthmostcommoncancerandsixthcauseofcancerdeathwithapproximately480000newcasesand400000deathsannuallyworldwide[1-3].Esophagealcancerremainsoneofthemostlethalcarcinomasandtheprognosisisdismalwithsurgeryorradiotherapy（RT）alone.Surgeryisthestandardtreatmentforpatientswithresectableesophagealcancercurrently.Concurrentchemoradiotherapy（CCRT）hasbeenconsideredasthestandardnon-surgicaltreatmentforesophagealcancerbasedontheresultsofRadiationTherapyOncologyGroup（RTOG）85-01trial[4]and94-05trial[5].However,thereweredisagreementsbetweenthetwotrialssuchaselectivelymphnodeirradiation（ENI）wasusedinRTOG85-01butwasomittedinRTOG94-05.Subsequently,theincidenceoflocal-regionalfailurerate（44.3%）wasapparentlydecreasedinRTOG85–01thanthestandardarminRTOG94-05（55%）,whichsuggestedthatENIcouldimprovelocal-regionalcontrolrate.Betterlocal-regionalcontrolratewithENIwasalsoreportedinsomestudies[4,6-10]butnotinotherstudies[11-16],andthusnoconsistentconclusionscouldbereached.Todate,onlyonesmallsamplesizedprospectiveclinicaltrial[17]hasbeenfocusedonthevalueofENIinCCRTforcervicalandupper-thoracicesophagealcancerandtheconclusionswereinconclusive.Therefore,theroleofENIinCCRTforesophagealcancerremainscontroversial.

Esophagealcarcinomasarepronetospreadaxiallytoregionallymphaticsandhighincidenceofoccultregionallymphnodemetastasiswasrevealedbysurgery[18-21].Atotalof20patients（26%）werefoundtohavenodemetastasisinthedissectednecklymphnodeswhiletheprimarylesionswerelocatedatupper/middle/loweresophagus（7/42/28patientsrespectively）[18].Betteroverallsurvival（OS）withprophylacticthree-fieldlymphnodedissectionhadbeenreportedinesophagealcancer[18,19,22].Intheory,CCRTwithENImayimprovelocalcontrolandthusimproveOSinlinewiththebenefitofthree-fieldlymphnodedissectionincurativesurgery.

ThepurposeofthisstudywastoreviewthevalueofENIinCCRTforesophagealcancerregardingwithtoxicities，local-regionalcontrolrateandOS.OnlyarticleswithENIindefinitelyCCRTwerereviewed.

Methodsandmaterials

ThisreviewwasdesignedtoinvestigatethefeasibilityandvalueofENIindefinitivelyCCRTforpatientswithesophagealcancer.TheliteraturesearchwasconductedwithassistancefromaresearchlibrarianinthedatabaseofPubMed,toidentifyallclinicalstudiessince1980includingdefinitelyCCRTwithENIinesophagealcancer.Thefollowingtermswereexploredandusedforsearch:

（esophagealOResophagusORoesophageal）AND（cancerORcarcinomaORneoplasm）ANDchemotherapyANDradiotherapy.Studieswereexcludedasfollowing:

neoadjuvantoradjuvantchemoradiotherapycombinedwithsurgery;combinedwithtargettherapy;notpublishedinEnglish;notpublishedinfulltext;phase

study;withothersiteofcancers.Theabstractsofarticleswerereviewedbythetwoinvestigators.Irrelevantcitationswereremovedaccordingtothecriteriamentionedabove,thuscreatingapreliminarysetofpotentiallyrelevantpublications.Secondly,thefulltextarticlesweredistributedtothetworeviewersalongwithanevaluationformcustomizedforreviewingthetreatmentoutcomesforENIinCCRT.Tworeviewersindependentlyevaluatedanumberofallocatedarticlesandextractedinformationregardingstudydesign,studypopulation,methods,outcomemeasures,resultsandconclusionsforeacharticle.Theevaluationresultswerecomparedandre-evaluateduntilconsensuswasreachedbetweentworeviewersordecidedbythecorrespondingauthor.Whencompleteinformationwasnotavailable,attemptsweremadetocontactthecorrespondingauthorsofthestudiesforadditionalinformation.Fourteenstudieswithatotalof975patientswereincludedandthecharacteristicwasshowninTable1.

Results

1.Clinicaltargetvolume（CTV）forENI.

TherearesomeslightdifferencesinliteratureregardingtheCTVofENI.Atlarge,theCTVofENIincludedthewholethoracicesophagusandperiesophageallymphnodes.Fortheboostfield,marginswereusuallyatleast2-5cminthecraniocaudaldirectionfortheprimarytumor,and1-2cminthelateraldirectionforadjacentmediastinum.

Forcervicalesophagealcancer,supraclavicularregionwereincludedintheCTVofENI.However,lowermediastinallymphnodalregionwasexcludedbysomeauthors[23].

Forupperthoracicesophagealcarcinoma,theCTVofENIincludedsuperiormediastinallymphnodesalonebysomeauthors[7].SupraclavicularfossanodeswereincludedintheCTVforENIinmoststudies[4,6,9,10,12,13,24].

TheCTVofENIincludedmediastinalandperigastriclymphnodesforcarcinomaofthemiddlethoracicesophagus[7].SupraclavicularfossawasalsoincludedintheCTVofENIinmanystudies[4,9,10,12,24].

Thesupraclavicularnodeswerenotincludedwhilelesionswerelocatedinthelowerthirdoftheesophagus[4,6,16,24].PerigastricnodeswereincludedinENIforlowerthoracicesophagealcarcinoma[7,10,23]andceliaclymphnodalregionwerealsoincludedinmanystudies[6,7,10,13,23].

2.FeasibilityofCCRTwithENI

2.1Acutetoxicities.

Althoughacutetoxicitiesofgrade3orhigherwerefrequentlyreported（Table2）,CCRTappliedwithENIwasfeasible.Leukopeniaandesophagitiswerethemostcommontoxicitiesnotedinliterature.Theincidenceofleukopenia（grade3orhigher）variedfrom24%to82.3%,andthatofesophagitisvariedfrom6%to35%.Othercommontoxicitiesincludednausea,vomitting,anemia,infection,stomatitis,thrombocytopeniaandcardiacischemia.

2.2Latetoxicities.

Only6papersdetailedlatetoxicities（Table2）.Cardiacrelatedtoxicitieswerethemostcommonlatetoxicitiesandtheincidencevariedfrom0to16%,mostofpatientssufferedfrompericardialeffusion.Theincidenceofgrade3orgreateresophagus-relatedtoxicities（dysphagia,stenosis,fistula）variedfrom0to13%.Theincidenceofpneumonitisvariedfrom0to5.9%.Pleuraleffusionoccurredin0to5%patients.Onecaseofgastrointestinalhemorrhagewasreported.

2.3Treatment-relateddeath.

Atotalof25deathswerereportedtobeassociatedwithtreatmentandtheincidenceoftreatment-relateddeathvariedfrom0to12.5%withpooledestimatesof2.6%[4,6,8,10-12,15,24].Onthewhole,eightpatientsdiedfrompneumonitis,6diedfromesophagusrelated（mainlyfistula）,4fromupper-gastrointestinalhemorrhage.Eachonepatientdiedfrompericarditis,pleuraleffusion,myocardialinfarction,renalfailureandneutropenicsepsisrespectively.Inaddition,twopatientsdiedathomewithoutdefinedcause4and10weeksaftertreatment[24].

3.Completeresponserate

Completeremission（CR）ratewithENIinthisreviewvariedfrom33%to75%.ItseemsthatCRrateswerecomparablebetweenhigherdose（around60Gy）andlowerdose（around50Gy）withENI.

4.PatternsoffailurewithENI

Inordertoevaluatethepatternsoffailure,localregionalfailurewasdefinedasthefirstsiteoffailure（localpersistencepluslocalregiongalrecurrence）inthisreview.Distantfailurewasdefinedasfailureinanysitebeyondtheprimarytumorandregionallymphnodesaccordingly.Someauthorsdefinedlocalregionalfailureaslocalregionalfailurewithoutdistantfailure,whileotherauthorsdefinedlocalregionalfailureaslocalregionalfailurebothwithandwithoutdistantfailure.Wedefinedlocalregionalfailurerate1（LRFR1）astheincidenceoflocalregionalfailurewithoutdistantfailureandlocalregionalfailurerate2（LRFR2）astheincidenceoflocalregionalfailurebothwithandwithoutdistantfailure.LocalregionalfailurepatterninallofthearticlesincludedinthisreviewwasshowninTable3.Forallofthestudiesincludedinthisreview（patientsinstage

-

）,LRFR1rangedfrom26.5%to54.68%andLRFR2rangedfrom29.4%to61%.Weanalyzedthesearticlesasawholegroup,thepooledestimatesofLRFR1andLRFR2were45.6%and52.3%r