转移性结直肠癌.ppt

转移性结直肠癌转移性结直肠癌Approximately20%ofpatientswithcolorectalcancerpresentwithestablisheddistantmetastases.DespiteconsiderableprogressStageIVpatientsarenotcurable.5-yearsurvivalrateforStageIVpatientsdiagnosedbetween1991and2000was8%.Systemicchemotherapy,endoscopictreatmentstopalliateobstruction,surgicaldiversion,andsurgicalresectionallhaveimportantrolesintreatmentofStageIVpatients.将近20%的结直肠癌患者都会发生远处转移尽管医疗技术有了很大进步，但IV期患者仍无法治愈1991-2000年IV期患者的5年生存率为8%系统的化疗，内镜治疗缓解梗阻，造瘘，手术切除都是治疗IV期患者的重要手段Forpatientswithgoodperformancestatusandminimalsymptomsfromtheirprimarycancers,standardtreatmentissystemicchemotherapy,whichiswelldocumentedtoincreasesurvivalandqualityoflife.Surgicalresectionoftheprimarytumorand,whenfeasible,ofthemetastaticlesionscanprovideexcellentpalliationandcan,insomecases,providelastingcure.Inthepastdecade,therehasbeenremarkableimprovementintheefficacyofchemotherapyforcolorectalcancer.FOLFOXorFOLFIRI.Mediansurvivalhasimprovedfrom1214monthsto21months对于一般情况好，原发肿瘤症状轻的患者，标准的治疗应为系统的化疗，可以有效的提高生存率和生活质量对于有转移患者的原发肿瘤切除，如果可以切除的话，有些情况下对病情有良好的缓解作用在过去的10年里，化疗的疗效有了显著的提高，FOLFOX、FOLFIRI方案的应用使转移癌患者的中位生存时间从12-14月提升至21个月TheclinicalpresentationofStageIVpatientsisvariable.Mostpresentwithsymptomsreferabletotheprimarytumor.Initialstagingevaluationshouldincludecolonoscopywithbiopsy,andimagingoftheprimarytumor,liver,andlungs.EndorectalultrasoundorMRIisrecommendedforrectalcancerstodocumenttheinitialTandNstage.CTscanningofthechest/abdomen/pelvisisahighlyaccurateandefficientmethodofdetectingmetastases.PETscanningdetectsoccultdiseasenotseenonCTscanin20%ofStageIVpatients.IV期肿瘤患者的临床表现是多种多样的。大部分与原发病灶有关。初始的评估手段应有：结肠镜（取活检），肿瘤、肝脏、肺部的影像学检查。经直肠腔内超声或MRI是指导临床TNM分期的重要手段。胸、腹、盆的CT检查是发现转移的准确有效的方法。PET可以发现CT发现不了的一些隐性疾病，检出率达20%。Oncetheextentofdiseaseworkupiscompleteanddistantmetastaseshavebeendocumented,thesurgeonmustmakethreeimportantjudgments.Firstiswhetherthepatientisfitforaggressivetreatment.Secondiswhethertheprimarytumorpresentsaclinicallysignificantriskofbowelobstruction.Thethirddeterminationiswhetherthepatientsmetastasescanbesurgicallyresected,andthereforetreatedwithcurativeintent当常规检查完善，并发现转移时，外科医生需要做3个判断。1患者是否适合接受手术治疗。2原发肿瘤是否有显著的梗阻风险。3转移灶是否可以手术切除。以达到治愈的目的Managementofpatientswithadvanceddiseaseisoftencomplex,andmultidisciplinaryevaluationcanbehelpfulindetermininginitialtherapy.Thesurgeonandmedicaloncologistshouldevaluatethepatientinconsultationwitharadiologistandgastroenterologist.Thegoals,priorities,andexpectedcourseoftreatmentshouldbediscussed.Forrectalcancersthatarebulkyorsymptomatic,theadviceofaradiationoncologistisoftenhelpful.晚期肿瘤病人的管理是复杂的。外科及肿瘤科医生应与放疗及消化科医生会诊。Approximately8%29%ofpatientswithcolorectalcancerinitiallypresentwithsymptomsofpartialorcompletebowelobstruction.Forpatientswithadvancedobstruction,nonresectivepalliativeoptionsincludelasertherapy,fulguration,colonicself-expandingmetalstents,andcreationofadivertingstoma.将近8-29%结直肠癌患者以全或不全性肠梗阻为首发表现。对于晚期肿瘤梗阻患者，不可切除的姑息治疗包括：激光、电灼、肠内自扩张支架、造瘘。Lasertherapyhasbeenusedforpalliationofobstructingrectalcancersforthepasttwodecades.However,lasertherapyisonlyfordistalcolonandrectum,andisrarelyusedtotreatproximallesions.Complicationssuchasbleeding,perforation,andseverepainhavebeenreportedin5%15%ofpatients.过去20年，激光治疗用于缓解直肠癌所致的梗阻症状。激光治疗仅适用于末端结肠和直肠，几乎不用于近端结肠并发症主要有：出血、穿孔、剧痛。报道的发生率为5-15%。Surgicalfulgurationofrectalcancersisanothermethodofopeningtherectallumen.Fulguration,incombinationwithendoluminaldebulking,canremovealargevolumeoftumor;however,unlikelasertherapy,thisprocedurerequireshospitaladmissionandregionalorgeneralanesthesia.电灼疗法是另一种打通直肠腔的方法。电灼结合经直肠腔内减瘤，可以去除大块的肿瘤组织。需要住院，麻醉支持。In1991,colonicstentshavebecomeanimportantmethodofpalliationforobstructionincolorectalcancerpatients,especiallythosewithunresectablemetastaticdisease.Theseself-expandingmetallicstentscanpotentiallydilatethelumentoanear-normaldiameter,providingquickreliefofsymptomsand,insomecases,allowingendoscopicassessmentoftheproximalcolon.Complicationsincludedstentmigrationresultinginexpulsion,reobstruction,andintractabletenesmus.Stentingofcancersinthemidandlowrectummayresultinincontinence.Complicationsoncolonicstentsincludestentmalpositioning,migration,tumoringrowth,tumorovergrowth,perforation,stoolimpaction,bleeding,tenesmus,andpostprocedurepain.结肠支架自1991年出现以来，已成为晚期结直肠癌梗阻患者姑息治疗的重要方法，特别是那些转移灶无法切除的患者。自我扩张的金属支架可以扩张肠腔近乎正常直径，快速的缓解梗阻，甚至有些患者还可容结肠镜通过，以完善近端结肠的检查。并发症主要有移位、脱出、再次梗阻、里急后重感、肿瘤向支架网内生长、肿瘤生长超过了支架的覆盖、穿孔、出血、便嵌塞。Theroleofbowelresectioninpatientswithunresectablemetastasesiscontroversial.NorandomizeddatademonstratingasurvivalbenefitforbowelresectioninStageIVpatients.However,palliativeresectionoftheprimarytumordoesprovidedurablelocalcontrol,isgenerallywelltolerated,andcanbenefitmanyStageIVpatients.ItsshownthatStageIVpatientsreceivingsystemicchemotherapyhaveincreasedlengthandqualityoflife.Withmodernmultidrugregimens,thebeneficialimpactofchemotherapycontinuestoincrease.Thus,standardmanagementforpatientswithunresectablemetastaticcolorectalcancerissystemicchemotherapy.对转移灶无法切除的患者行肠切除的作用仍存争议没有数据表明手术对IV期患者的生存率有更多益处然而，切除原发肿瘤对局部控制的益处确实惠及很多IV期患者。有数据支持系统化疗可以延长生存期提高生活质量，而且现代药物的进步以及多药物联合化疗确实使疗效得到了提高。所以对于转移灶不可切除的结直肠癌标准的治疗方案应该选择系统化疗。Theproperuseofelectivecolon/rectalresectioninnonobstructedpatientsisasourceofcontinuingdebate.Oncologistsproperlycitelossofperformancestatus,riskofsurgicalcomplications,anddelayinchemotherapyasmajordownsidestopalliativeresection.Surgeons,however,understandthatelectiveoperationshaveafarlowermorbiditythanemergencysurgeryandfearhavingtooperateonpatientswhoobstructwhilereceivingchemotherapyorwhopresentwithmoreadvanceddiseaseaftermultiplecyclesofineffectivechemotherapy.对未梗阻的患者选择性的行结、直肠切除术是否恰当仍是争论的源泉。内科医生担心患者一般情况变糟、术后并发症的风险、以及因为手术所耽误的化疗时间。外科医生的理由是择期手术比急症手术解决梗阻的并发症发病率更低，尤其是经过数个周期化疗之后，以及肿瘤恶化使手术难度加大。Studiesdocumentthatsurgicalresectioncanachieveexcellentpalliationoflocalsymptoms.Forpatientswithnonobstructingprimarytumors,upfronttreatmentwithchemotherapyisfavoredbecause,inthiseraofincreasinglyeffectivechemotherapyItshouldberememberedthatthegoaloftherapyiseffectivepalliation,andsurgicalresectionremainsthemosteffectiveanddurablelocaltreatmentoption.一些研究得出的结论手术干预可以很好的缓解局部症状。对于尚无梗阻迹象的原发肿瘤，化疗更受青睐，这也得益于化疗药物的发展和效果的提高。需要记得的是，对于晚期肿瘤患者的治疗目的是有效的缓解症状，所以手术切除仍是对局部症状最有效持久控制的选择。Ofthe150,000newcasesofprimarycolorectalcancerdiagnosedintheUnitedStateseachyear,approximately60%ofthesepatientswilldeveloplivermetastasesandaboutone-thirdwillhavediseaselimitedtotheliver.Ofthoseabletoundergocompletehepaticresection,25%35%achievelong-termsurvival.Therefore,onlyasmallpercentageoftheoverallnumberofpatientswithmetastaticcolorectalcancerarecuredbyliversurgeryItshouldbenoted,however,thatwithimprovementsinchemotherapy,surgicaltechnique,andablativetechniques,thenumberofpatientseligibleforhepaticsurgeryisontherise.美国每年新增原发结直肠癌约15万，将近60%的患者会发生肿瘤转移，其中大约1/3为肝转移。对于能够接受肝切除的患者，25-35%能延长生命。所以只有很少一部分人能够被肝手术治愈。值得注意的是，随着化疗药物、外科技术和消融技术的进步，越来越多的患者可以接受肝切除。Beforethe1980s,mosthepaticmetastaseswereleftuntreated.Severalinvestigatorshaveretrospectivelystudieduntreatedpatients,documentingmediansurvivalsof510months;long-termsurvivalwasrarelyseen.Nonetheless,someinvestigatorsretrospectivelyidentifiedpatientswithisolated,potentiallyresectablehepaticmetastaseswhowereleftuntreated.Inthesepatientswithlimitedmetastasesisolatedtotheliver,whowouldotherwisebepotentialcandidatesforsurgery,3-yearsurvivalwas14%23%and5-yearsurvivalwas2%8%.eveninthebestofcircumstances,5-yearsurvivalofpatientswithuntreatedlivermetastasesisdistinctlyuncommon.在19世纪80年代之前，大部分肝转移是不治疗的。回顾性研究指出如果肝转移癌不予治疗，中位生存时间是5-10个月，长生存期极为罕见。一些研究回顾了转移灶孤立有切除可能却没有切除的患者，3年生存率14-23%，5年生存率2-8%即便在最佳的条件下，不治疗肝转移的话，患者活过5年的极为罕见。Acarefulextentofdiseaseworkupshouldbeinitiated.First,acompleteevaluationofthecolonviacolonoscopyshouldbeperformedwithinayearofpresentation;thisaddressestheissueofsynchronousandmetachronouscolonicneoplasms,aswellastheissueoflocalrecurrence(especiallyinrectalcancers).Completecrosssectionalimagingoftheabdomenandpelviswithhigh-qualityCTisalsoessential,toruleoutextrahepaticdisease.PETscanningisroutinelyperformedbecauseofearlyprospectivedatadocumentingitsutility.TheinformationobtainedfromPETscanningchangesmanagementdecisionsinpatientswithrecurrentcolorectalcarcinoma20%50%ofthetime.ThemajorstrengthofPETscanningseemstobethedetectionofoccultextrahepaticdisease.1.1年内结肠镜检查，判断是否有同时或异时原发癌，以及是否有局部复发，尤其是直肠癌患者。2.腹+盆高分辨CT平扫，判断是否有肝外转移。3.PET应该作为常规。因为能发现20-50%的复发，从而影响治疗策略。PET的优势就在于能够发现隐匿的肝外病变。CEAlevelshouldalsobedrawn,andservesasabaselinetofollowaftertheconclusionoftherapeuticinterventions.High-qualityimagingoftheliverisessentialindeterminingbulkofdiseaseandresectability.CTscan.RoutineCTscanscannowevaluatetheliverincombinationwithCTangiographyortriphasicimagingoftheparenchymathroughvariousphasesofintravenouscontrastcirculation.ThemostsensitiveCTtechniqueisCTportography,whichisaCTscanperformedafterinjectionofcontrastintothesuperiormesentericartery.Wheninjectedcontrastenterstheportalcirculation,metastasesappearlikefillingdefects.evaluatingthenumberofhepatictumors,itoftenfailstodefinetheanatomicrelationshipsoftumortohepaticvasculature,itrequiresaninvasiveprocedure,anditiscostly.4.检测CEA水平的变化。5.肝脏的高清影像，如CT。现在对肝脏的评估常采用常规CT联合CT血管造影以及注射对比剂之后的三相摄片。敏感度最高的是CT门静脉造影，向肠系膜上动脉内注射对比剂，当对比剂经过门脉循环时转移灶会呈现充盈缺损。缺点是难以分辨肿瘤与肝脏血管的解剖关系、有创、价格高昂。UltrasoundandMRIareadditionalimagingtechniquesthatcanbeusefulinspecificcircumstances.Ultrasoundisnotanaccuratemethodforaddressingextrahepaticdisease,oftencannotvisualizetheentireliver.Distinguishingneoplastictumorsfrombenignlesionssuchascysts,focalnodularhyperplasia,orhemangiomata.Additionally,ultrasoundcanspecificallyevaluatetherelationshipofspecificlesionstomajorvascularstructuresandthebiliarytree.MRIisanexcellentmethodforcharacterizingliverlesions.Particularlyiftherearemultiplehepaticlesions.MRIisalsoanexcellentmodalityforevaluatingrelationshipsoftumortothebiliarytree(viamagneticresonancecholangiopancreatographyMRCP)andtohepaticvasculature.High-qualityMRIandCTareprobablyequivalent.6.超声和MRI腹部超声对肝外病变的确定稍差，而且常常不能检查到整个肝脏。但是能用于鉴别肿瘤与良性疾病，如囊肿、局部增生结节、肝血管瘤等。另外还有助于确定肿瘤与肝血管及胆管结构的关系。MRI可以很好的明确肝转移。尤其是肝内多处转移灶，以及转移灶与血管、胆管的关系。Inanypatientbeingconsideredforhepaticresection,acompletemedicalworkupshouldbeperformedtoassessthepatientsfitnessforundergoingamajorabdominaloperation.Anypotentialforliverdysfunction;Pulmonaryfunction;Cardiacdisease.所有需要行开腹肝切除的患者都应完善上述检查，并评估是否适合手术。除此之外，还应考虑患者的全身情况，是否存在肝功能不全，肺功能障碍及心脏疾患。Untilrecently,chemotherapywasconsideredlargelyineffectiveastreatmentofunresectablemetastaticcolorectalcancer.However,withthedevelopmentofirinotecan,oxaliplatin,hepaticarterialinfusionalchemotherapywithfluorodeoxyuridine(FUDR),andnewermolecular-basedtherapies,therearenowmoreeffectivechemotherapeuticoptionsforthesepatients.Irinotecan(CPT-11)inconjunctionwith5-FU/LVhasbeenrecentlyshowntobemoreeffectivethan5-FU/LValonefortreatmentofmetastaticcolorectalcancer.Theadditionofoxaliplatinhasbeenparticularlyexcitingbecauseoftheinvitrosensitivityseenincisplatin-resistantcelllines,aswellasitssynergywith5-FU.截至近期，对于不可切除的转移性结直肠癌，化疗是无效的。但是随着伊立替康、奥沙利铂、肝血管灌注脱氧氟脲苷化疗以及靶向治疗的发展，提供了更有效的化疗方案。伊立替康联合5-FU/LV比单纯5-FU/LV有更好的疗效。奥沙利铂对顺铂耐药的细胞有效，而且与5-FU有协同作用。Asthesetrialsmature,andmodernsystemicchemotherapyregimensarerefined,wearenowseeingmediansurvivalsinexcessof20months.随着现代化疗方案的改善，结直肠癌肝转移患者的中位生存时间已经超过20个月。Regionalhepatictherapyviahepaticarteryinfusional(HAI)chemotherapyhasbeenstudiedsincethe1970s.Thistreatmenttakesadvantageofthefactthathepaticmetastasesderivetheirbloodsupplyfromhepaticarterialbranches.Additionally,onlyasmallproportionofsystemicallyadministeredchemotherapyreachestheliver.ThemostfrequentlyusedagentforHAIisFUDR,whichhasa90%hepaticextractionratio.Thispermitsmaximaltreatmentoflivermetastasesandminimizationofsystemicsideeffects.However,HAIwithFUDRlimitstreatmentofoccultextrahepaticdisease.Thiscanbeaddressedbygivingadditionalsystemicagents,orbyusing5-FUviathehepaticarterywithahigher”spillover”effectintothesystemiccirculation.对于肝脏血管内灌注化疗的研究始于19世纪70年代。肝脏转移灶的血供来源于肝脏血管是该治疗手段的依据。另外，全身性化疗中只有一小部分化疗药物能够到达肝脏。HAI最常用的药物是FUDR脱氧氟脲苷，在肝脏中吸收率达90%，使对转移灶的治疗最大化，全身的副反应最小化。然而HAI对肝脏外病变作用有限，这可以通过额外的全身性化疗解决，或使用5-FU灌注，通过肝动脉与更多的“外溢”到全身血液循环的效果。Thedevelopmentoftargetedmolecular-basedtherapyprovidesevengreaterhopeformoreeffectivesystemictreatments.Anti-angiogenictherapywithanti-vascularendothelialgrowthfactorantibodies(bevacizumab)arealsocurrentlybeingevaluated.Inhibitorsofthereceptorforepidermalgrowthfactor,atyrosinekinasereceptor,hasalsoshownpromisingresults,anddrugssuchascetuximab(C225),ZD1839(Iressa),andOSI774(Tarceva)areactivelybeingstudied.Resultsofcurrentclinicaltrialsareanxiouslyawaitedtoseewherethesemolecular-basedtargetedtherapieswillultimatelyfitinamongthearmamentariumofsystemictherapyforcolorectalcancer.分子靶向治疗的发展提供了更有效的治疗手段，前景被业界看好。抗血管内皮生长因子抗体（贝伐单抗），酪氨酸激酶受体，表皮生长因子受体抑制剂，也有着可喜的进展，以及药物，如西妥昔单抗（C225），ZD1839（易瑞沙），OSI774（特罗凯）正在积极研究。大家都在焦急的等待这些临床研究的结果，期待最终能有效治疗大肠癌。Althoughresponseratestochemotherapeuticregimensareimproving,theonlytherapyevershowntobepotentiallycurativeforhepaticcolorectalmetastasesiscompleteresection.Liverresectionperformedinthe1970sand1980swasassociatedwithhighmorbidityandmortality,makingitsroleinthetreatmentofadvancedcancersuspectatthattime.Overthelast20years,largeserieshavedemonstratedthatliversurgerycannowbepracticedwithacceptablesafety,andthatpatientswithisolatedandresectablehepaticmetastaseshavethepotentialforlong-termsurvival.Inmodernseries,mortalityratesforhepatectomyformetastaticcolorectalcancerareuniformly5%orless.虽然化疗的反应率在提高，但是对于结直肠癌肝转移的患者唯一可能达到治愈目的的手段就是手术切除。在19世纪70-80年代，肝切除有着高并发症率及死亡率，使其治疗作用遭到质疑。在过去的20年中，大宗的研究表明随着手术技术的进步肝脏手术已经安全许多，并使孤立的（转移灶）和可切除肝转移患者有了长期生存的可能性。研究显示肝转移癌肝叶切除术的死亡率为5%或更低。Morbidityfortheseoperationsremainssubstantial,andisusuallyreportedbetween20%and50%.Themostominouscomplications,suchasliverfailureandsignificanthemorrhage,arenowdistinctlyuncommon,thankstobettersurgicaltechniqueandpostoperativecare.inthe1970s,thefirsttime,documented5-yearsurvivalratesof25%.Majorinstitutionalandmulti-institutionalreviewsofpatientsundergoinghepatectomyformetastaticcolorectalcancerhavenowclearlydocumentedthat,inwell-selectedpatients,5-yearsurvivalrangesfrom25%to40%,10-yearsurvivalrangesfrom20%to26%,andmediansurvivalsrangefrom24to46months肝切除的并发症发病率在20-50%最恶性的并发症如肝衰竭及严重出血现在已非常罕见，这也得益于手术技术的进步和术后护理的发展。19世纪70年代研究中首次发表的5年生存率为25%。现如今，大量单中心及多中心研究，病例选择恰当的条件下，5年生存率在25-40%，10年生存率在20-26%，中位生存时间在24-46个月。Despiterecentimprovementsinchemotherapyresultinginmediansurvivalsashighas20months,completeresectionstillprovidesthebestoutcomes.Truelong-termcurefromchemotherapyisextraordinarilyrare,whereasatleasthalfofthelong-termsurvivorsafterliverresectionaredisease-freeandpresumablycured.Forthesereasons,notrialhasevercomparedhepatectomytonotreatmentorchemotherapyalone.Liverresectionforresectablehepaticcolorectalmetastasesisthetreatmentofchoice.Thetwomostconsistentnegativeprognosticfactorsarethepresenceofextrahepaticdiseaseandtheinabilitytoresectalltumor;thesetwofactorsremaincontraindicationstohepatectomy.虽然接受化疗中位生存时间达到20个月，但是要想达到最佳的预后还是需要完整的切除。经过化疗治愈的患者极为罕见，而接受肝切除术的患者中至少有一半能长期生存，并且无瘤生存。所以没有研究去对比肝切除和不治疗以及仅化疗的疗效。两个预后不良的因素：肝外病变和不能切除全部转移灶。这两点也是肝切除的禁忌症。Althoughtherearemanyinconsistenciesinthemajorreportedseries,alistofoth