如何将不可切除的结直肠癌肝转移灶转为可手术切除

如何将不可切除的结直肠癌肝转移灶转为可手术切除 潘宏铭浙江大学附属邵逸夫医院肿瘤内科 内容 序言可切除肝转移灶的治疗不可切除肝转移灶的治疗总结 结肠癌肝转移发生率 肝脏是结肠癌转移的主要器官 首诊时约20 30 结肠癌患者发生仅有肝脏转移复发时大约30 40 结肠癌患者发生仅有肝脏转移 结肠癌肝转移的治疗 结直肠癌肝转移后若不治疗 中位生存期仅8月 5年生存率几乎为0 手术切除肝转移灶已经成为结直肠癌肝转移治疗的金标准 是肝转移患者目前唯一能达到治愈的治疗手段 结直肠癌可手术切除肝转移灶患者的5年生存率达30 40 中位生存期达28 46个月 DEFINITIONS ASCO2006LIVERTHINKTANK NeoadjuvantTherapy Preoperativesystemictherapyforresectablehepaticmetastasesfollowedbypostresectiontherapy AdjuvantTherapy Systemic regionaltherapyposthepaticresection ConversionTherapy Systemic regionaltherapyutilizedforpatientswithunresectablehepaticmetastasesinanattempttomakethemetastasesresectable 内容 序言可切除肝转移灶的治疗不可切除肝转移灶的治疗总结 结直肠癌肝转移的切除指征 既往 异时性肝转移 转移灶局限于单个肝叶 数量少于4个 肿块小于5cm的患者 这样只有不到10 的患者可以获得手术机会 2006年美国肝胆胰协会大会讨论认为 只要转移灶能够完全切除 相邻的肝段可以共用足够的血流和胆汁通道 剩余的肝脏能够维持正常功能 那么转移灶就被认为是可切除的 切缘距离 切缘距离是患者总生存率 P 0 003 和无病生存率 P 0 001 的唯一独立预后因素 切缘 5mm的患者切缘复发率大大增加 总生存率和无病生存率明显下降 切缘1cm以上是结直肠癌肝转移灶切除的追求标准 但是切缘1cm以内也不是肝转移灶切除的手术禁忌 Peri operativeFOLFOX4chemotherapyandsurgeryforresectablelivermetastasesfromcolorectalcancerFinalefficacyresultsoftheEORTCIntergroupphaseIIIstudy40983 B Nordlinger H Sorbye B Glimelius G J Poston P M Schlag P Rougier W O Bechstein J Primrose E T Walpole T GruenbergerStatisticalanalysisL ColletteFortheEORTCGIGroup CRUK ALMCAO AGITGandFFCD TrialDesignandObjectives R FOLFOX4x6cycles Surgery FOLFOX4x6cycles Surgery 364patientsPotentiallyresectable 1 4 livermetastasesGoal Improveprogression freesurvivaltodemonstratea40 increaseinmedianPFS HR 0 71 with80 powerand2 sidedsignificancelevel5 Pre OperativeAssessment OutcomeinchemotherapyarmCR 3 3 PR 35 2 Stable 33 5 Progression7 7 Notevaluable 20 3 Progression freesurvivalineligiblepatients HR 0 77 CI 0 60 1 00 p 0 041 PeriopCT 28 1 36 2 8 1 At3years years 0 1 2 3 4 5 6 0 10 20 30 40 50 60 70 80 90 100 O N Numberofpatientsatrisk 125 171 83 57 37 22 8 115 171 115 74 43 21 5 Surgeryonly AdjuvantChemotherapy CurrentandFutureStudiesC 09 MetastasectomyfollowedbywithOxaliplatinandCapecitabine FUDR Resectionoflivermetastases 1 6 Capecitabine Oxaliplatin Capecitabine OxaliplatinalternatingwithHAIFUDR Randomize Open PlannedAccrual400 Trial40051 BOS 内容 序言可切除肝转移灶的治疗不可切除肝转移灶的治疗总结 LIVERMETASTASES RESECTABLE20 25 NONRESECTABLE75 80 SURVIVALBENEFIT30 40 AT5YEARS RESECTABLE10 20 Downsizing size location number OncoSurgicalstrategiesinlivermetastasesfrompalliativetocurative Palliative Curative Survival Time HepaticArteryInfusion HAI forUnresectableLiverMetastases CALGB9481 HAIFUDRversusSystemic5FUandLeucovorin EligibilityLiver only unresectablemetastasesfromCRCNopriortherapyformetastaticCRC HAIFUDR0 18mg kg DEX25mgover14daysEvery28days N 68 5 FU425mg m2 LV20mg m2Dailyx5every4weeks N 67 R KemenyNEetal JClinOncol24 1395 1403 2006 CALGB9481 OverallSurvival HAI5FU LVMedOS months 24 420 0 p 0 034 THP months 9 87 3 p 0 034 TEP months 7 714 8 p 0 029 RR47 24 HAI 5FU LV CALGB9481 HepaticvsNonhepaticDiseaseProgression Kemenyetal JClinOncol 2006 24 1395 Hepatic Nonhepatic HAI Systemic P 0 034 Yearsfromtrialentry Proportionhepaticprogression free HAI Systemic P 0 029 Proportionnonhepaticprogression free Yearsfromtrialentry HAIasNeoadjuvantTherapyforInitiallyUnresectableDisease PotentialLimitationsInvasivePercutaneouslyplacedcathetershaveahighrateofcomplicationsSurgicalplacementmaydelaysystemictherapyLackoftreatmentforpotentialextrahepaticdiseaseLimitedstudies RoleofNeoadjuvantSystemicChemotherapyforLiver onlyMetastases Resectionofnon resectablelivermetastasesaftersystemicchemotherapyPublishedseries AuthorsLeviFowlerBismuthGiachettiAdamWeinRivoire Year1992199219961999200120012002 NoPts98 33038970153131 TypeChemoFu Fol OxaliFu FolFu Fol OxaliFu Fol Oxali Fu Fol OxaliFu FolFu Fol Oxali NoResect18 19 1153 16 77 20 95 14 6 11 57 43 5 yrSurv 40 50 39 Fu Fol Oxali Chronomodulated Liveronlymetastases SurvivalafterLiverResectionofColorectalMetastasesPaulBrousseHospital 473patients Apr 88 Jul 99 91 48 30 66 33 23 52 P 0 01 AdamRetal AnnSurg2004 NoSurgery Resectable 335Initiallynonresectable 138 Collaboration Oncologists SurgeonsForNonResectableMetastases 1 Currentchemotherapyallowsatleast20 ofpatientstoberescuedbyliversurgery2 Thesurvivalbenefitofthesepatientsissubstantial 30 and20 rateat5and10years 3 Resectability anewendpointfortreatmentstrategy NeoadjuvantOxaliplatinPaulBrousseHospitalStudy AdamR etal Ann Surg Oncol 2001 8 347 353 Chemo 701 80 14 900 800 700 600 500 400 300 200 100 0 Resection 266 31 86 36 64 95 171 872patients1988 1996 Initiallynon resectableNon resectableResectable 14 of701CT treatedpatientsachievedaresponsepermittingresection 171 Chemotherapy RoleofNeoadjuvantTreatment Patientstatusatameanfollow upof4 2years 56dead 59 Survivalafterprimaryorsecondaryresectionoflivermetastases C225 FOLFIRI用于mCRC一线治疗 Peetersetal EurJCancer2005 Supplement3 Abstract664 PhaseIIITrialofFOLFOXIRIvsFOLFIRIasFirst LineTherapyofAdvancedColorectalCancerG O N O StudyDesign StratificationCenterPS0 1vs2Adj Ctx R FOLFIRICPT 11180mg m2d1LV100mg m2d1 25 FU400mg m2bolusd1 25 FU600mg m222hinfd1 2q2wksx12cycles FOLFOXIRICPT 11165mg m2d1Oxali85mg m2d1LV200mg m2d15 FU3200mg m248hinfd1q2wksx12cycles Falconeetal ASCO 4026 JCO2007 PhaseIIITrialofFOLFOXIRIvsFOLFIRIasFirst LineTherapyofAdvancedCRC externallyreviewed 67 2ndlineFOLFOX Falcone ASCO 4026 JCO2007 CMHtest n 599 group n 599 group n 134 n 122 p 0 0034 oddsratio3 0 95 CI 1 4 6 5 Noresidualtumorinpatientswithlivermetastases ITTpopulation Liver limiteddiseasepopulation VanCutsemetal ASCO2007 CRYSTALTrial SurgerywithCurativeIntent SpecificChemotherapyAssociatedHepaticToxicity Irinotecan SteatohepatitisOxaliplatin Sinusoidal vascularinjuryAcute chronicclinicalsequelaeBiologics Bevacizumab 6to8wksbeforeresectionLiverregeneration hemorrhageMorbidityisincreasedwithprolongedcourseofchemotherapy Aloiaetal JClinOncol 2006 LiverToxicityofNeoadjuvantTherapy Patientswithsteatohepatitishadanincreased90 daymortalitycomparedwithpatientswhodidnothavesteatohepatitis P 0 001 Comparisonofeachgroupvsnochemotherapy Vautheyetal JClinOncol 2006 24 2065 Vasodilation Congestion Peliosis HemorrhagicCentrilobularNecrosis NodularRegenerativeHyperplasia VascularChangesinLiverPostSystemicChemotherapyAloiaetal JClinOncol24 4983 2006 Hepaticatrophy sinusoidalcongestion CollaborationOncologists SurgeonsforTimingofSurgeryafterChemotherapy Assoonasthemetastasesbecomeresectable Nottomissthe good therapeuticwindow Tumoralprogression Surgeryevenpotentiallycurative haspoorresultsNotto overtreat thepatientCompleteresponse amajorproblemforthesurgeonwithhoweveraminorityofpathology provennecrosisHepatotoxicity aclinicalimpactrelatedtoduration FolprechtG etal AnnOncol2005 16 1311 1319 Responserate 0 9 0 8 0 7 0 6 0 5 0 4 0 3 Resectionrate 0 6 0 5 0 4 0 3 0 2 0 1 0 ImpactofIncreasingResponseRates N014A ResectionofUnresectableCRCLimitedtotheLiverUsingFOLFOX6 Cetuximab CR PRresectable O R CTx2PR unresectable RxtoProg TolerabilityProg OffStudy RxperM D Endpoints Resectability ResponseRate Survival Evaluation Oxaliplatin 5 FU LV FOLFOX6 C225 射频消融 RFA 操作简单易行 创伤小 既可治疗原发灶又可治疗转移灶 耗时短并发症少 安全可靠 病人易耐受 可重复治疗 适用于多个病灶 缩短住院时间 术后1 2天可出院 尤其适用于不能耐受手术者 部分肿瘤可达到根治目的 潘宏铭 金伟 中国癌症杂志 2006 16 10 781 784 射频消融 RFA RFA对于直径大于3cm的病灶疗效不佳 局部复发率高 因此多数情况下 局部消融只可作为姑息性治疗或辅助性治疗 RFA在提高手术切除率上得到了很好的应用 多被用于那些转移灶双叶分布 靠近切缘和无法切除的肝内复发的患者 9MH 患者 男 43岁 2004年8月6日肠镜诊为 直肠癌 8月10日行 直肠癌根治术 术后病理示 高分化腺癌 侵出浆膜外 LNs9 19 CT示3个肝转移灶 患者于04 8 26行肝转移灶射频治疗 后行 MOSAIC 方案化疗12次 根治 RFA术后辅