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EsophagealCancerandCombinedmodalityTreatmentArunaKommareddy,M.D.Fellow,WashingtonUniversitySchoolofMedicineEsophagealCancerandCombined1EpidemiologyAround13,200caseseachyearAbout12,500deathseachyearBefore1980:SCCseeninassociationwithtobaccoandalcoholabusewasthemostcommonformOnly15%ofallcaseswereadenocarcinomaEpidemiologyAround13,200case2ChangingtrendsRecentlyadeno-carcinomaassociatedwithBarrett’smetaplasiaandseenalmostexclusivelyinmiddle-agedCaucasianmenwithGERDhasbecomethemostpredominantform.In199460%ofallesophagealcancerswereadenocarcinoma.Reasonsforthischangearenotknown.ChangingtrendsRecentlyadeno-3CurrentAJCC2002stagingCurrentAJCC2002staging4RegionalnodesCervicalEsophagus:Scalene,Internaljugular,Upperandlowercervical,Peri-esophageal,SupraclavicularIntra-thoracicesophagus:Upperperi-esophageal,Subcarinal,Lowerperi-esophageal,mediastinalnodesGastro-esophagealjunction:Loweresophageal,diaphramatic,para-cardial,leftgastricandceliacRegionalnodesCervicalEsophag5TreatmentSurgicalresectionisthestandardtreatmentforearlyesophagealcancerieStagesI,IIandmostcasesofIIIDuringthepastdecade,outcomeswithsurgeryhaveimprovedresultinginabetter5yearsurvivaldueto:BetterstagingtechniquesIncreasedrateofcurativeresectionAdecreasedrateofpostoperativedeathHowever,theproportionofpatientswhosurviveforfiveyearsremainslow30to50%-stageI15to30%-stageIIA5to15%stageIIBTreatmentSurgicalresectionis6TypesofesophagectomiesTranshiatal

Exposureisprovidedbyanuppermidlinelaparotomyandaleftneckincision.Thethoracicesophagusisbluntlydissected,andacervicalanastomosiscreated;thoracotomyisnotrequired.Drawbacks:inabilitytoperformafullthoraciclymphadenectomy,andlackofvisualizationofthemidthoracicdissection.TransthoracicTheIvorLewisesophagectomycombinesalaparotomywithrightthoracotomy,andproducesanintrathoracicanastomosis.Thistechniquepermitsdirectvisualizationofthethoracicesophagus,andallowsthesurgeontoperformalimitedlymphadenectomy.HoweverformaldissectionoflymphnodesisnotperformedTypesofesophagectomiesTransh7TypesofesophagectomiesThreefieldlymphadenectomy:WidelypracticedinJapanEnblocresectionofesophagus,azygousvein,thoracicduct,lateralpleuralsurfaces,partofpericardium&Dissectionofcervical,mediastinalandupperabdominalnodeswithRPLDperformedTwofieldlymphadenectomy:EnBlocresectionofesophagus,azygousvein,thoracicductalongwithlateralpleuralsurfacesandpartofpericardiumandmediastinalnodesanddissectionofupperabdominalnodeswithRPLDperformedTypesofesophagectomiesThree8Hulscheretal220patientsAdenoCaTransthoracicEsophagectomy(TTE)N=114Included2fieldlymphadenectomyTranshiatalEsophagectomy(THE)N=106RandomizePerioperativemorbiditywashigherafterTTENosignificantdifferenceinin-hospitalmortality(P=0.45)Afteramedianfollow-upof4.7years:70%ofpatientsdiedpostTHEand60%afterTTE(P=0.12)Medianoverallanddisease-freesurvivaldidnotdifferstatisticallybetweenthegroups.Howevertherewasatrendtowardsimprovedlong-termsurvivalat5yearswiththeTTE.NEJM2003Hulscheretal220patientsTran9PatternsofdiseaserecurrencepostsurgeryInonestudy108patientshadacurativeresectionforSCCofthethoracicesophagus.Atamedianfollow-upof20months:Recurrence:52%Mainlyextrathoracicrecurrence:41%Mainlyintrathoracicrecurrence:25%BrJSurg1996Jan;83(1):107-11

Patternsofdiseaserecurrence10Neoadjuvant/adjuvanttherapyNeo-adjuvantChemotherapyNeo-adjuvantRadiationNeo-adjuvantChemo-RadiationAdjuvantChemotherapyAdjuvantRadiationAdjuvantchemoradiationNeoadjuvant/adjuvanttherapyN11WhyNeoadjuvant/AdjuvanttherapyInmostcasesesophagealcancerisasystemicdiseaseatdiagnosis.Surgeryaloneiscurativeinasmallgroupofpatients.Patternsofrecurrencesuggestbothlocalandsystemicfailure.Disadvantages:Only50%ofpatientsrespondtotreatmentDelayinsurgeryPossibilityofselectingdrugresistantclonesWhyNeoadjuvant/Adjuvantthera12NeoadjuvantchemotherapySeveralphaseIIandIIIrandomizedstudieshavebeenconducted.Koketalstudied160patientswithSCCChemo:Cisplatin(80mg/m2)andEtoposide100mg/m2days1-5(2-4cycles)followedbytranshiatalesophagectomy.Evaluationafter2cycles.Responders:2additionalcyclesNonresponders:surgeryMediansurvival18.5Vs11months(P=0.002)NeoadjuvantchemotherapySevera13Neoadjuvantchemotherapy

KelsenetalRandomizeN=440Adeno&squamousChemotherapy&surgeryN=213Cisplatin100mg/M2day15FU1000mg/m2/ddays1-5Preop3cyclesq4weeksSurgery2-4weeksafterchemoPostopchemofor2cyclesImmediatesurgeryN=227After55.4months,therewerenosigdifferencesbetweenthetwogroups

Mediansurvival:Combination:14.9monthsSurgeryalone:16.1months(P=0.53)Oneyearsurvival:Combination:59%Surgeryalone:60%TwoYearsurvival:Combination:35%Surgeryalone:37%NEJM12/98Neoadjuvantchemotherapy

Kels14Neoadjuvantchemotherapy

KelsenetalTheadditionofchemotherapydidnotappeartoincreasethemorbidityormortalityassociatedwithsurgery.Therewerenodifferencesinsurvivalbetweenpatientswithsquamous-cellcarcinomaandthosewithadenocarcinoma.Weightlosswasasignificantpredictorofpooroutcome(P=0.03).Withtheadditionofchemotherapy,therewasnosignificantchangeintherateofrecurrenceatlocoregionalordistantsitesorDFS.Neoadjuvantchemotherapy

Kels15Neoadjuvantchemotherapy

GirlingetalChemotherapy&surgeryN=400SurgeryN=402Cisplatinand5FUPreop2cyclesq3weeksImmediatesurgeryLancet359(2002),pp.1727–1733

Mediansurvival:Combination:16.8monthsSurgeryalone:13.3months.TwoYearsurvival:Combination:43%Surgeryalone:34%OverallsurvivalBetterincombinedmodalityarmHazardratio0.79;95%CI0.67-0.93;p=0.004)DFS

Betterincombinedmodalityarm

(P=0.0014)Two4-daycycles,3weeksapart,ofcisplatin80mg/m(2)byinfusionover4hplusfluorouracil1000mg/m(2)dailybycontinuousinfusionfor4daysfollowedbysurgicalresection.Clinicianscouldchoosetogivepreoperativeradiotherapytoalltheirpatientsirrespectiveofrandomization.

Neoadjuvantchemotherapy

Girl16VariableKelsenGirlingNumber&Medianage467,62802,63TypeofCa54%adeno66%adenoTypeofSurgeryVariedVariedPreopRadiationNone9%ineachgroup%completingchemopreop71%3cycles13%2cycles90%2cycles6%one4%noneDelaybeforesurgeryMedianof93dayspostrandomization3-5weekspost2ndcycleMedianof63dayspostrandomization%receivingchemopostop38%2cycles48%none14%oneNoneChemoCisplatin5FU3preopand2postopqweeks100mg/m2day11000mg/m2day1-52preopq3weeks80mg/m21000mg/m2days1-4%chemogroupundergoingsurgery80%90%PreopstagingCXR,BariumswallowCTchestandabdomenBroncoscopy,endoscopy+or-EndoscopicUSCXRLiverUSorCTEndoscopy,broncoscopyVariableKelsenGirlingNumber&17Neo-adjuvantRadiationaloneAmeta-analysisof1147patientsfromfiverandomizedtrialsshowednosurvivalbenefit.Basedonexistingtrials,thereisnoclearevidencethatpreoperativeradiotherapyimprovesthesurvivalofpatientswithpotentiallyresectableesophagealcancer.IntJRadiatOncolBiolPhys19981;41(3):579-83

Neo-adjuvantRadiationaloneA18Neoadjuvanttherapy:Chemo-radiation

PhaseIIStudiesComprehensivetextbookofThoracicOncology,Williams&WilkinsNeoadjuvanttherapy:Chemo-rad19SurgeryaloneVsCombinedmodalitytherapy.PhaseIIIstudyRandomizeN=113AdenoSurgeryN=55Cis/5FUXRTSurgeryN=58MedianSurvival:11m1yrsurvival:44%2yrsurvival:26%3yrsurvival6%MedianSurvival:16m1yrsurvival52%2yrsurvival37%3yrsurvival32%Twocoursesofchemotherapyinweeks1and65FU15mgperkgdailyforfivedaysCisplatin,75mgpersquarem2onday7Radiotherapy,40Gy,administeredin15fractionsovera3-weekperiod,beginningconcurrentlywiththefirstcourseofchemotherapy.WalshetalNEJMSurgeryaloneVsCombinedmoda20WalshetalAtthetimeofsurgery:42%ofpatientstreatedwithpreoperativemultimodaltherapywhocouldbeevaluatedhadpositivenodesormetastasesversus82%ofpatientswhounderwentsurgeryalone(P<0.001).25%ofpatientswhounderwentsurgeryaftermultimodaltherapyhadcompleteresponses,asdeterminedpathologically.NEJMVol335:462-467WalshetalAtthetimeofsur21WalshetalKaplan–MeierPlotofSurvivalofPatientswithEsophagealAdenocarcinoma,AccordingtotheIntention-to-TreatAnalysis.WalshetalKaplan–MeierPloto22SurgeryaloneVsCombinedmodalitytherapy.BossettetalRandomizeN=282SCC

T1N1,T2N0,T2N1,T3N0

SurgeryN=139Cis&XRTSurgeryN=143Medianfollow-upof55.2months

Mediansurvival:Surgeryalone:18.6monthsCombination:18.6monthsCombinedModality:Longerdisease-freesurvival(P=0.003)Longerintervalfreeoflocaldisease(P=0.01)Lowerrateofcancer-relateddeaths(P=0.002)Higherfrequencyofcurativeresection(P=0.017)Morepost-opdeaths(P=0.012Cisplatin80mg/m20-2daysbeforeXRTqweeklyx2.XRT:37Gyover2weeksSurgeryaloneVsCombinedmoda23Diseasefreesurvival:BossettetalDiseasefreesurvival:Bossett24WalshBossettNumber113282TypeofCaAdenoSquamousT1N0,T1N1,T2N0,T2N1,orT3N0

PreopstagingClinexamCXRAbdominalUSEndoscopyBronchoscopyCTonlyinselectedcasesClinexamEndoscopyBronchoscopyCTneck,chest,abdTstagebydiamoftumor,1,1-3,>3andinvasionofneibouringstrucTypeofsurgeryVariedVaried,includedlymphnodedissection>80%transthoracicChemotherapyCisplatin75mg/m2d75FU15mg/m2/d1-5Cyclerepeatedinweek6Cisplatin80mg/m20-2daysbeforeXRTweek1and4Radiation40Gyover3weeksbeginningwithweekoneofchemo37Gyover2weeksPathCR25%26%MedianSur16Vs11m18.6Vs18.6Periopmortality8.6%Vs3.6%12..3%Vs3.6%P=0.012WalshBossettNumber113282Type25UrbaetalRandomizeN=100Adeno75%SCC25%SurgeryN=50Cis/5FU/VindesineXRTSurgeryN=50Mediansurvival:17.6m3yrsurvival:16%Mediansurvival:16.9m3yrsurvival:30%(P=0.15)Cisplatin20mg/m2/dondays1through5and17through21,5FU300mg/m2/dondays1through21,andvinblastine1mg/m2/dondays1through4and17through20.XRT:1.5-Gyfractionstwicedaily,MonthroughFriover21days,toatotaldoseof45Gy.Transhiatalesophagectomywasperformedaroundday42.

Staging:CThead,chestabd,endoscopy,bariumswallow,bonescan.JThoracCardiovascSurg1997Aug;114(2):205-9UrbaetalRandomizeSurgeryCis/26UrbaetalSurvivalbypathologicresponsetochemoradiation

28%ofpatientswerehistologiccompleteresponders.Patientswithcompletehistologicresponse:Mediansurvival:49.7m1-yearsurvival:86%3-yearsurvival:64%PatientswithresidualdiseaseintheresectedspecimenMediansurvival:12m1-yearsurvival:52%3-yearsurvival19%(P=.01).UrbaetalSurvivalbypatholog27Neoadjuvanttherapy:Chemo-radiation

PhaseIIIStudiesSeriesRegimenHistology%PathologicCRSurvivalPositivenodes/metsUrbaN=100Cisplatin/5FU/Vinblastine45GyAdeno75%Squamous25%28%Median:16.9Vs17.63yr30%Vs16%P=0.15NRWalshN=1135FU/Cisplatin40gy

Adeno:25%Median16monVs11(P=0.013yr:32Vs6(P=0.01)42%vs82%P=0.001BossetN=282Cisplatin37gySCCStageIandIIonly26%Median18.6Vs18.63yr:36%vs34%26/105vs66/115(mediastinalnodes)P=0.001Neoadjuvanttherapy:Chemo-rad28Periopmortality,combinedmodalityVssurgeryaloneMortality%CRSMortality%SPLeprise97NSWalsh94NSBossett1340.012Urba24NSPeriopmortality,combinedmo293YearsurvivalcombinedmodalityVsSurgeryaloneRefCRSS3yrsur%CRS3yrsur%SPvalueLepriseSCC41451914NSWalshAC58553260.01BossettSCC&AC1431393634NSUrbaSCC&AC50503016NS3Yearsurvivalcombinedmodal30AdjuvantRadiationVschemotherapyRandomizePostSurgeryN=258RadiationCis/Vindesinex25yrsurvival:44%5yrsurvival:42%NodifferenceintimetorecurrenceorsitesofrecurrenceRadiotherapy(50Gy)2coursesofchemotherapyconsistingofcisplatin(50mg/m2)andvindesine(3mg/m2)followingcurativeresectionChest1993Jul;104(1):203-7AdjuvantRadiationVschemothe31AdjuvantChemotherapyRandomizeN=205SurgeryN=100Surgery&Cis/Vindesinex2N=1055yrsurvival:44.9%5yrsurvival:48.1%Nosignificantdifferencesinsurvivalweredetectedbetweenthetwogroups,evenwithlymphnodestratificationTransthoracicesophagectomywithlymphadenectomyCisplatin(70mg/m2)andVindesine(3mg/m2)JThoracCardiovascSurg1997Aug;114(2):205-9AdjuvantChemotherapyRandomize32AdjuvantChemotherapyInanotherstudywith242patientsrandomizedtoreceivenofurthertherapyorcisplatinand5FUasadjuvanttherapyEstimated5yrDFS58%Vs46%P=(0.05)OverallsurvivalnosignificantdifferenceNodeneg:77%Vs82%(P=0.3)Nodepos:35%Vs53(P=0.06)RoleofpostopadjuvantchemotherapycurrentlyundefinedAdjuvantChemotherapyInanothe33AdjuvantRadiationSurgery(119patients)wascomparedwithsurgicaltreatmentfollowedbyradiationtherapy(102patients).Allpatientshadacurativeesophagealresection.Radiationtherapy:45to55GraysOverallPostoperativeradiationtherapydidnotimprovesurvivalHowever,thereweresignificantlyfewerlocalrecurrencesinpatientsreceivingradiationtherapyascomparedwiththosenotreceivingradiationtherapy.

Inasubsetanalysesbenefitwaslimitedtopatientswithnegativelymphnodes(Decreasedlocalfailurefrom35%to10%)SurgGynecolObstet1991Aug;173(2):123-30

AdjuvantRadiationSurgery(11934NotcandidatesforsurgeryRadiationaloneCombinationchemoradiationNotcandidatesforsurgeryRadi35ChemoradiationVsRadiationHerscovicetalRandomizeRadiation64GyN=62Cis/5FUx4Radiation50GyN=61Medianfollowup5yrsforallptsMedianSurvival9.3m5yr0%MedianSurvival14.1m5yrsurvival27%P<0.00018yr22%Locallyadvancedadenoorsquamousesophagealcarcinoma.Cisplatin,75mg/m2intravenously,onthefirstdayofweeks1,5,8,and11.Thepatientsweregivenacontinuousinfusionoffluorouracil,1g/m2,forthefirst4daysofweeks1,5,8,and11.Radiationwasdeliveredat30Gyin15fractionsover3weeksstartingonday1,followedby20Gyin10fractionsover2weeksChemoradiationVsRadiationHe36ChemoradiationVsRadiationThetrialwasstoppedaftertheresultsin121patientsdemonstratedasignificantadvantageforsurvivalinpatientswhoreceivedcombinationtherapy.Thepatientswhoreceivedcombinedtreatmenthadfewerlocal(Plessthan0.02)andfewerdistant(Plessthan0.01)recurrences.NosignificantrelationofhistologytosurvivalnotedChemoradiationVsRadiationThe37HerscovicetalSideeffectsweregreaterinthecombinedmodalityarm8%ofpatientsincombinedmodalitytherapyexperiencedgrade4toxiceffectsand2%died.Versus2%ofpatientsinRTarmexperiencedhadgrade4toxiceffectsandtherewerenodeaths.Ofthe61patientsrandomizedtoreceivecombinedmodalitytherapy,37receivedchemotherapyasplannedand56receivedradiationtherapyasplannedsothat36ofthe61receivedboththerapiesasplanned.58/62patientsintheradiationonlyarmreceivedXRTasplannedHerscovicetalSideeffectswe38ChemoradiationAdditional69patientsweretreatedwiththesamecombinedtherapyandwereanalyzed.SimilarresultswereobtainedMediansurvival:17.2months3-yearsurvival:30%5yrsurvival:14%ChemoradiationAddition