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OncologyandTranslationalMedicine February2016,Vol.2,No.1,P1–P7DOI10.1007/s10330-015-0100-1AclinicoepidemiologicalstudyofesophagealcancerpatientsattheNationalCancerInstitute,CairoUniversity,EgyptSoumayaEzzat1,HishamElHossieny1(),MohamedAbdAlla2,AzzaNasr1,NagwanAnter1,AhmedAdel31DepartmentofRadiationOncology,NationalCancerInstitute,CairoUniversity,2DepartmentofClinicalOncology,FacultyofMedicine,CairoUniversity,3MisrUniversityforScienceandTechnology,Received:9JuneRevised:24JulyAccepted:25August

ObjectiveThepurposesofthisstudywereto(1)assesstheclinicoepidemiologicalcharacteristicsofesopha-gealcancerpatients,(2)analyzetheprognosticfactorsdeterminingtreatmentfailureandsurvival,and(3)evaluatetheresultsofvarioustreatmentmodalitiesforlocoregionalanddisseminateddiseaseandtheireffectondisease-freesurvivalandoverallsurvival(OS).MethodsClinicoepidemiologicalretrospectivedatafrom81esophagealcancerpatientstreatedattheNa-tionalCancerInstituteofCairobetween2007and2011wereevaluated.ResultsThestudyshowedthatpatientswithesophagealcancercommonlypresentwithlocallyadvanceddisease(87.7%hadT-stage3and12.3%hadT-stage4).Therewasasignificantcorrelationbetweensurgeryandsurvival;patientswhoreceivedradicalsurgeryandpostoperativeradiationhadabettermediansurvivalthanpatientswhoreceivedradicalradiotherapy(20monthsvs.16months,respectively;P=0.04).Therewasalsoasignificantstatisticalcorrelationbetweenradicalconcomitantchemoradiotherapy(NCRT)andpalliativetreatment.PatientswhoreceivedradicalNCRThadabettermediansurvivalthanpatientswhoreceivedpal-liativeradiotherapy(16monthsvs.10months,respectively;P=0.001).Themedianfollow-upperiodforallpatientswas7months.ThemedianOSofthewholegroupwas12months.TheOSafter1and2yearswas57.8%and15%,respectively.ConclusionHigh-doseNCRTisanacceptablealternativeforpatientsunfitforsurgeryorwithinoperabledisease.High-doseradiationismoreeffectivethanlow-doseradiationintermsoflocalcontrol,timetorelapse,andOS.Furtherstudyusingalargerseriesofpatientsandintroducingnewtreatmentprotocolsisnecessaryforafinalevaluation.Keywords:esophagealcancer;epidemiology;retrospectiveEsophagealcancerisamalignancywithahighmor-talityrate.IntheUnitedStates16,980peoplearediag-nosedwithesophagealcancereachyearand14,710dieofthedisease.AccordingtodatafromtheNationalCancerInstitute’sSurveillance,Epidemiology,andEndResultsProgram,the5-yearsurvivalrateforpatientswithesoph-agealcancerhasshownamodestimprovementoverthelast30years,from5%intheyears1975to1977to17%duringtheperiod2001to2007.Thesedismalresultsarethoughttoreflectthepropensityforearlytumordissemi-nationandanadvancedstageofdiseaseatdiagnosis[1].

Esophagealcancerrepresents6–8%ofallmalignan-ciesinEgypt.Affectedpatientshaveameanageof58.7yearsandthemaletofemaleratiois1.9.DatafromtheGharbeyapopulation-basedregistryconductedin2002showedthatapproximately40%ofthetumorsarefoundinthelowerthirdoftheesophagus,40%atthegastro-esophagealjunction(GEJ),13%inthemiddleesophagus,and7%intheupperesophagus.Histologically,53%ofthetumorsaresquamouscellcarcinomas(SCCs)and18%areadenocarcinomas.Duringthe1960s,intheUnitedStates,SCCsCorrespondenceto:HishamElHossieny.Email:©2016HuazhongUniversityofScienceandcountedformorethan90%ofallesophagealcancers,andesophagealadenocarcinomaswereconsideredsouncom-monthatsomeauthoritiesquestionedtheirexistence.Forthepast2decades,however,theincidenceofesophagealadenocarcinomashasincreaseddramaticallyinWesterncountries,suchthatboththesetumorsnowoccurwithalmostequalfrequency[2].Althoughsignificantadvanceshavebeenmadeinthetreatmentofesophagealcancer,thisaggressivemalignan-cycommonlypresentsaslocallyadvanceddiseasewithapoorprognosisdespiteimprovementsinthedetectionofpre-malignantlesionsonpathology[2].Managementofesophagealcancerisachallengingproblembecausemostpatientswithpotentiallymeta-staticlocallyadvanceddiseasepresentinapoorgeneralcondition.However,earlyandeffectiveneo-adjuvantchemoradiotherapy(NCRT)andsurgicalresectioncouldleadtoincreasedsurvivalTheaimsofthisstudywereasAnalyzetheclinicoepidemiologicalcharacteristicsofpatientswithesophagealcancer.Evaluatetheprognosticfactorsaffectingfailures(lo-calanddistant)andsurvival.Assesstheresultsofdifferenttreatmentmodalitiesforlocoregionalanddisseminateddiseaseandtheireffectondisease-freesurvivalandoverallsurvival(OS).MaterialsandThiswasaretrospectivestudyof81patientswithesophagealcancerwhoweretreatedattheNationalCan-cerInstituteofCairofrom2007to2011.Allpatientswithesophagealcancer,includingthosewithmetastaticdis-ease,wereeligibleforinclusion.Dataobtainedfromthepatients’filesincluded:thepatient’sserialnumber;age;familyhistory;smokinghis-tory;dateofpresentation;patient’scomplaint;clinicalexamination;biopsydate;surgerydate;typeofsurgery;tumorsite;tumorsize,histologicaltypeandgrade;lymphnodestatus;tumor-node-metastasis(TNM),chemothera-pyandradiotherapydata;timeofoccurrence;siteofre-lapse(locoregionalordistant);anddateandconditionofthepatientduringthelastvisit.StatisticalThedataweresummarizedusingdescriptivestatistics(mean,frequencies).Meanvaluesandstandarddevia-tionswerecomparedusingasimplettest(2variables).PercentageswerecomparedusingtheChi-squaretestorFisher’sexacttest.Logisticregressionwasusedwhen-everthedependentfactorwasbinaryinnatureduringmultivariateanalysis.TheKaplan-Meiertestwasusedforpredictivesurvivalrates.DatawereanalyzedusingSPSSsoftware(Version15;SPSSInstitute,USA).APvalue

than0.05wasconsideredstatisticallyThemeanageofthe81patientsincludedinthisstudywas60years;8patients(9.9%)werelessthan40yearsold.Theincidenceofesophagealcancerincreasedinpa-tientsover40yearsofageandpeakedbetween50and70yearsofage.Fifty-threepatients(65%)weremenand28werewomen(35%),withamaletofemaleratioof1.9:1.Themainpresentingcomplaintwasdysphagiaoc-curringwiththeingestionofsolidfood(reportedby45patients;53.6%)orsolidfoodandliquids(36patients;44.4%).Twenty-sixpatients(32%)complainedofnauseaandvomiting.Lossofweightwasfoundin53patientsForty-fourpatients(54%)wereheavysmokersand37patients(46%)werenon-smokers.Atthetimeofpresentation,theperformanceofthepa-tientswasrecordedusingtheEasternCooperativeOncol-ogyGroupscoringsystem.Thirty-threepatients(40.7%)hadascoreof1–2and48patients(59.3%)hadascoreofTumorstagingusingtheAmericanJointCommitteeonCancerTNMstagingsystemrevealedthatallthepa-tientshadadvanceddisease(Type3,87.7%andType4,12.3%).Positivenodalmetastaseswerefoundin61pa-tients(75.3%).Only34patients(42%)hadoperabledisease.Twentypatientsunderwenttotalesophagectomyandgastricpull-upand1patientunderwentapartialesophagectomy.Allpatientsreceivedpost-operativeradiation.Thirteenpatients(16%)weremedicallyunfitforsurgeryandre-ceivedradicalNCRTusinga10mVLAmachine.Forty-sevenpatients(58%)receivedpalliativeradia-tion,13patients(16%)receivedahighdose(50–55Gy)for5–6weeks,and34patients(42%)receivedalowdose(30Gy)for2weeks.PatientswhoreceivedradicalNCRTunderwentacompletechemotherapy(CCT)course;12/13patientsre-ceived4–6CCTcycles,comparedto2/14patientsinthepalliativeradiotherapy(PRT)group.Twelvepatientsinthepalliativegroupreceived1–3cycles.Treatmentoutcomewasevaluatedbasedontreatmentresponse,localfailure,systemicfailure,andOS.Localresponsetotreatmentwasassessedin60patientsbasedonradiologicalandclinicalinformation.Elevenpa-tients(18.3%)hadapartialresponse,10patients(38.8%)hadstaticdisease,and8patients(16.6%)hadprogressivedisease.Unfortunately,nocompleteresponseswerere-corded.Theresponsetotreatmentcouldnotbeevaluatedin26patientsduetoalackofpost-treatmentradiologicalTable1ParametersaffectinglocalP-AgeAge≤>Performance1&3&20 Highdose Lowdose PRT±CCT(CisplatinbasedPRT+ PRT– NCRT(cisplatinbasedCCT)vs.highdosePRT(without Highdose Numberofchemotherapycycles(cisplatinbased

1–3 Analysisofthecorrelationbetweenthelocalresponsetotreatment(measuredasthepercentageofpersistentorpartialtumorregressionafter6months)andtheprog-nosticparameterswasperformedusingthelog-ranktest(Table1).Amongpatientswithperformancestatus1and2,53%hadpartialregression(PR)and6.7%hadprogressivedis-easecomparedto22%and54.6%,respectively,amongpatientswithperformancestatus3and4;thedifferencewasstatisticallysignificant(P=0.01).HighdosesofradiationeitheraloneorwithNCRT(50–65Gy/5-6wks)achievedPRin62%ofpatientscomparedtoin18%whenusinglow-doseradiation(30Gy/2wks);thedifferencewasstatisticallysignificant(P=0.044).Patientswhoreceived4–6cyclesofCCTachievedaPRin62%comparedtonoregressioninpatientswhore-ceived1–3cycles(P=0.06).Therewerenostatisticaldif-ferencesamongpatientsbasedonage,histologicaltype,orT-stage.Aftersurgicalexcision,only1patienthadalocalre-currence14monthsaftersurgery;hereceivedadditionalradiationandCCT.Ninepatientshadsystemicfailure,6hadbone

ses,2hadlungmetastases,and1hadperitonealnodules.TheOSwasestimatedusingtheKaplanandMeiertest,anddifferentprognosticparameterswerecomparedwiththelog-ranktest.AllsignificantvariableswereenteredintotheCoxProportionalHazardsModel(sex,site,T-stage,N-stage,andThemedianfollow-upperiodforallpatientswas7months.ThemedianOSwas12months.TheOSafter1and2yearswas57.8%and15%,respectively(Fig.1).Analysisoftheparametersaffecting(OSshowedthattheOSwasnotaffectedbyage,histologicaltype,T-stage,orN-stage.Performancestatus,tumorsite,andtreatmentmodal-ityhadastatisticallysignificantimpactonOS(Table2).The1-yearOSofpatientswithperformancestatus1vs.47.3%and10.2monthsforpatientswithperformancestatus3and4(P=0.01;Fig.2).Patientswithtumorslocatedinthemiddlethirdoftheesophagushadamediansurvivalof16.4months,whichwasbetterthanthesurvivalofpatientswithtumorsintheupperormiddlethirdoftheesophagus.The2-yearOSofpatientswithGEJtumorswas27%,andthemedianTable2Parametersaffecting 1-year2-yearMedian AllAge≤≤>1&3&Upper0MiddleLower0T NPositivelymphNegativelymph Undifferentiated Surgery+posterative Surgery+posterativeSurgery+posterativeHighdose0Lowdose0LowdosePRT±CCT(CisplatinbasedchemothPRT+CCT0PRT–00NCRTvs.highdosePRT(withoutchemotherapy)NCRT(cisplatinbasedchemotherapy)Highdose0Numberofchemotherapy

<1–3cycles(cisplatinbased004–6cycles(cisplatinbasedsurvivaltimewas12months.Patientswithtumorsinthemiddlethirdoftheesophagushada16%survivalandamediansurvivaltimeof16months.Patientswithtumorsintheupperorlowerthirdoftheesophagushada0%survival(P=0.036;Fig.3).PatientswhounderwentsurgicaltreatmentfollowedbyposterativeradiotherapyhadthebestOS(85.7%)after1year(P<0.001;Fig.4).PatientswhounderwentsurgicaltreatmentfollowedbyposterativeradiotherapyhadbetterOS(85.7%)after

1year,thanthosepatientswhoreceivedNCRTwithoutsurgicalintervention(74.6%;P=0.04;Fig.5).amongpatientswhoreceivedhigh-dosePRT(45–50Gy).Forpatientswhoreceivedlow-dosePRT(30Gy),theme-diansurvivalwas7months(P=0.037;Fig.6).Patientswhoreceivedhigh-dosePRTwithoutCCThadanOSof38.4%at1year.Patientswhoreceivedradi-calNCRT(cisplatin-basedCCT)hadanOSof74.6%at1year(P=0.047;Fig.7),asignificantdifference. Fig.1OScurveofthepatient Fig.4OSbasedontypeofFig.2OSbasedonperformance Fig.5OSbasedonsurgeryvs.radicalconcomitantFig.3OSbasedontumor Fig.6OSbasedonpalliativeradiotherapyTherewasalsoasignificantdifferenceinsurvivaltimebasedonPRTwithandwithoutCCT.Patientswhore-ceivedPRTconcomitantwithCCT(cisplatin-basedCCT)hadamediansurvivalof10.2months;thosewhore-ceivedPRTonlywithoutCCThadamediansurvivalof5.2months(P=0.007;Fig.

Patientswhoreceived4–6CCTcycleshadanOSof76%at1yearcomparedtopatientswhoreceivedonly1–3CCTcyclesandhadanOSof0%at1year(P=0.001;Fig.9). Fig.7OSbasedonthepalliativeradiotherapydosevs.radicalcon-comitantchemoradiotherapy

Fig.8OSbasedonthepalliativeradiotherapydosewithandwithoutFig.9OSbasedonthenumberofchemotherapyThisstudyprofiledesophagealdiseaseamongEgyptianpatientsandanalyzedtheresultsofdifferenttreatmentmodalitiesandtheireffectonlocoregionalcontrol,dis-tantmetastases,andOS.Ourfindingswerecomparabletodatareportedintheliteratureregardingthepredominanceinmenandtumorsitepredilection;however,weobservedayoungeragein-cidence(49%ofourpatientswerebelow60yearsofage)andalatepresentationamongourpatients.Inourstudy,theclinicalstage,histologicaltype,treat-mentmodality,andradiationdoseweresignificantpa-rametersthataffectedOSandlocalcontrol.Smokingwasconsideredanetiologicalriskfactorforesophagealcan-cer;54%ofthepatientswereheavysmokers(morethan20cigarettes/day).ThisalsowasreportedbyFreedmanetal.,whoconsideredtobaccoandalcoholabuseasmajorriskfactorsforSCC,whereastheuseoftobaccoisamod-erateestablishedriskfactorforadenocarcinoma[4].Cooketal.reportedthattheriskofesophagealSCCdecreased

substantiallyaftersmokingcessationInourstudy,theOSat1yearofpatientswhohadSCCwas54.7%comparedto60.3%amongadenocarcinomapatients.SimilarresultswerereportedbyRice[6].Wefoundasignificantlybettersurvivalwithsurgicaltreatmentfollowedbypost-operativeNCRTcomparedtosurgeryalone.TheOSat1and2yearsamongpatientswhounderwentsurgeryfollowedbyposterativeradio-therapywas88.9%and31%,respectively.However,only30%to40%ofpatientshadpotentiallyresectablediseaseatthetimeofpresentation.Amongpatientswhodidnotundergosurgeryandwhoweretreatedusingothermo-dalitiessuchasradicalNCRTandPRT,the1-yearsur-vivalwas61.9%and36.1%,respectively,asignificantdifference(P<0.001).TheseresultswerecomparabletothoseofWalshetal.whoobservedthatwhilesurgeryhadbeenthestandardtreatmentforearlyesophagealcancer,only5%to20%ofthoseundergoingsurgeryalonelivedfor3to5years[7].Adelsteinetalevaluatedpost-operativeNCRTintu-morswithpositivenodesandfoundthatthe4-yearOSandlocoregionalcontrolwere86%and56%,respective-ly,whichwerebetterthansurgeryalone[8].Kofoedetalreportedthatpost-operativeNCRThasbeenassociatedwithasurvivalbenefitinlymphnode-positivepatients;the3-yearOSafterpost-operativeNCRTwas37%comparedto24%aftersurgeryalone[9].ThebetterresultsreportedbyAdelsteinetal.andKo-foedetal.mightbeexplainedbytheprevalenceofearlystageandlowerthirdesophagealtumorsamongtheirpa-Inourstudy,theOSofradicalNCRTandhigh-dosePRT(45–60Gy)alonewerecompared,andwefoundthat,despitethepoorOSrateswithbothtreatmentmodalities,patientswhoreceivedNCRThadabetterOSthanthosewhoreceivedradiationalone(61.9%vs.51.2%,respec-tively;P=0.002).Conroyetalalsoreportedtheefficacyofradicaltreat-mentinpatientswithlocallyadvancedesophagealcan-cer.Atamedianfollow-upof18months,themedianOStimewas23months[10].ComparableresultswerealsoreportedbyCooperetal.whocomparedPRTalonevs.NCRTinpatientswithlocoregionalthoracicesophagealcancer.HereportedasignificantsurvivaladvantageforNCRT(5-yearOS27%vs.0%).Owingtotheresultsofthistrial,definitiveNCRTwasconsideredthestandardofcareforpatientswithin-operabledisease[11].ConclusionsandAsesophagealcancerisaveryaggressivetumor,mostpatientspresentwithadvancedlate-stagediseasethatisbeyondradicaltreatment.Healtheducationandscreen-ingprogramsareadvisableforearliertumordetectionbecausethetumorstageisthemostimportantprognosticfactorforbettersurvivalrates.High-doseNCRTisanacceptablealternativeforpa-tientsunfitforsurgeryorwithinoperabledisease.High-doseradiationismoreeffectivethanlow-doseradiationregardinglocalcontrol,timetorelapse,andFurtherstudiesinalargerpatientseriesandincludingnewtreatmentprotocolsisnecessaryforafinalevalua-tion.Patientsshouldbecomemoreinvolvedinclinicaltrialstoachievethebesttreatmentstrategyforthisag-gressivedisease.ConflictsofSiegelR,WardE,BrawleyO,JemalA.Cancerstatistics,2011:theimpactofeliminatingsocioeconomicandracialdisparitiesonprema-

turecancerdeaths.CACancerJClin,2011,61:EnzingerPC,MayerRJ.Esophagealcancer.NEnglJMed,2003,349:2241–2252.PolednaAP.TrendsinsurvivalforbothhistologictypesofesophagealcancerinUSsurveillance,epidemiologyandendresultsareas.IntJCancer,2003,105:98–100.FreedmanND,AbnetCC,LeitzmannMF,etal.Aprospectivestudyoftobacco,alcohol,andtheriskofesophagealandgastriccancersubtypes.AmJEpidemiol,2007,165:1424–1433.CookMB,KamangarF,WhitemanDC,etal.Cigarettesmokingandadenocarcinomasoftheesophagusandesophagogastricjunction:apooledanalysisfromtheinternationalBEACONconsortium.JNatlCancerInst,2010,102:1344–1353.RiceTW,RuschVW,Apperson-HansenC,etal.Worldwideesopha-gealcancercollaboration.DisEsopha