恶性胸膜间皮瘤(MPM)治疗进展

MPM的定义和分类定义是包绕肺脏和被覆在胸膜腔的间皮细胞所发生的癌症分类上皮样间皮瘤肉瘤样间皮瘤双相性间皮瘤或混合性间皮瘤第一页，共31页。MPM的流行病学美国每年新诊断的发病人数为2500例日本每年新诊断的发病人数为1000例我国大城市胸膜间皮瘤发病率约为0.3/10万～0.5/10万恶性胸膜间皮瘤的发病多与石棉暴露有关，美国已过发病高峰期，但欧洲、澳大利亚、日本及中国等国家发病率正逐年增加GoudarRK,TheraClinRiskManag2008;4(1):205-211NakanoT,EnvironHealthPrevMed2008;13(2):75-83曲宸绪等,肺癌研究与临床2004;16(2):143-144第二页，共31页。间皮瘤与腺癌的鉴别诊断项目腺癌间皮瘤发病率>30/10万0.3/10万主要高危因素吸烟石棉症状多样胸痛、胸闷影像学淋巴转移、肺内病灶胸膜结节血清学CA指标间皮素、骨桥蛋白胸水细胞学电镜表现组织病理学免疫组织化学第三页，共31页。MPM的治疗内科化疗治疗放射治疗外科治疗多学科治疗第四页，共31页。MPM-化疗治疗在力比泰®未研发前，顺铂单药治疗的疗效较好

OngandVogelzang,JClinOncol1996药物病人数研究数缓解率（％）阿霉素66211表阿霉素69212米托蒽醌6225顺铂59214卡铂88311泰素3519环磷酰胺1610第五页，共31页。唯一被FDA批准的治疗MPM一线化疗药物—力比泰®JMCH研究：迄今为止MPM治疗领域最大样本的随机、多中心、Ⅲ期临床研究VogelzangNJ,etal.JClinOncol2003;21(14):2636-2644第六页，共31页。JMCH研究：力比泰®/顺铂方案显著延长MPM患者生命VogelzangNJ,etal.JClinOncol2003;21(14):2636-2644唯一被FDA批准的治疗MPM一线化疗药物—力比泰®第七页，共31页。JMCH研究：力比泰®/顺铂方案的缓解率是顺铂单药的两倍VogelzangNJ,etal.JClinOncol2003;21(14):2636-2644唯一被FDA批准的治疗MPM一线化疗药物—力比泰®第八页，共31页。JMCH研究：力比泰®/顺铂方案显著改善MPM患者生活质量GrallaRJ.etal.ProcAmSocClinOncol.2003;22:621(abstract2496)唯一被FDA批准的治疗MPM一线化疗药物—力比泰®第九页，共31页。大型临床研究证明，力比泰®/顺铂方案无论在生存期、缓解率还是生活质量方面，都显著优于顺铂单药方案，是目前治疗MPM的标准一线方案唯一被FDA批准的治疗MPM一线化疗药物—力比泰®第十页，共31页。Jassem,J.etal.JClinOncol;26:1698-17042008培美曲塞单药二线治疗晚期恶性间皮瘤第十一页，共31页。Jassem,J.etal.JClinOncol;26:1698-17042008培美曲塞单药二线治疗晚期恶性间皮瘤第十二页，共31页。®MPM-ANCCNPracticeGuidelines

GuidelinesIndex MPMTableofContentsStaging,Discussion,References化疗的原则一线化疗联合方案力比泰500mg/m2day1顺铂75mg/m2day1每3周1次(1类推荐)1二线化疗力比泰(如果未用于一线)8诺维本9吉西他滨

力比泰500mg/m2day1

卡铂AUC5day1

每3周1次2,3

吉西他滨1000-1250mg/m2day1,8,15

顺铂80-100mg/m2day1

每3-4week1个周期4,5

力比泰500mg/m2

每3周1次6

诺维本25-30mg/m2

每周1次71VogelzangNJ,RusthovenJJ,SymanowskiJ,etal.PhaseIIIstudyofpemetrexedincombinationwithcisplatinversuscisplatinaloneinpatientswithmalignantpleural mesothelioma.JClinOncol2003;21:2636-44.2CastagnetoB,BottaM,AitiniE,etal.PhaseIIstudyofpemetrexedincombinationwithcarboplatininpatientswithmalignantpleuralmesothelioma.AnnOncol 2008;19:370-3.3CeresoliGL,ZucaliPA,FavarettoAG,etal.PhaseIIstudyofpemetrexedpluscarboplatininmalignantpleuralmesothelioma.JClinOncol2006;24:1443-8.4NowakAK,ByrneMJ,WilliansonR,etal.AmulticentrephaseIIstudyofcisplatinandgemcitabineformalignantmesothelioma.BrJCancer2002;87:491-6.5VanHaarstJM,BaasJ,ManegoldCH,etal.MulticentrephaseIIstudyofgemcitabineandcisplatininmalignantpleuralmesothelioma.BrJCancer2002;86:342-5.6TaylorP,CastagnetoB,DarkG,etal.Single-agentpemetrexedforchemonaiveandpretreatedpatientswithmalignantpleuralmesothelioma:resultsofanInternational ExpandedAccessProgram.JThoracOncol2008;3:764-771.7MuersMF,StephensRJ,FisherP,etal.Activesymptomcontrolwithorwithoutchemotherapyinthetreatmentofpatientswithmalignantpleuralmesothelioma(MS01): amulticentrerandomisedtrial.Lancet2008;371:1685-94.8JassemJ,RamlauR,SantoroA,etal.PhaseIIItrialofpemetrexedplusbestsupportivecarecomparedwithbestsupportivecareinpreviouslytreatedpatientswith advancedmalignantpleuralmesothelioma.JClinOncol2008;26:1698-1704.9StebbingJ,PowlesT,McPhersonK,etal.Theefficacyandsafetyofweeklyvinorelbineinrelapsedmalignantpleuralmesothelioma.LungCancer2009;63:94-7.

Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.

ClinicalTrials:NCCNbelievesthatthebestmanagementofanycancerpatientisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.

Version1.2010,01/26/10©2010NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.TheseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MPM的化疗第十三页，共31页。一线治疗方法的比较方法试验例数ORRPFSOS文献PEM+DDPIII226/22241.3%12.1JClinOncol2003PEM+CBPII6229%714Clinlungcancer2010PEM+CBPII7621%814AnnOncol2008PEM+CBPII10218.6%6.512.7JClinOncol2006GEM+DDPII5026%10Cancer2003GEM+DDPII5333%6.411.2BrJCancer2002GEM+DDPII2516%69BrJCancer2002PEMEAP31910.5%6.114.1JThoracOncol2008NVBIII13616%6.29.5Lancet2008第十四页，共31页。二线化疗方案的比较方法试验例数ORRPFSOS文献PEMIII123/12018.1%8.4JClinOncol2008PEMEAP49312.1%4.9JThoracOncol2008NVBII6316%9.6Lungcancer2009第十五页，共31页。®MPM-BNCCNPracticeGuidelines

GuidelinesIndex MPMTableofContentsStaging,Discussion,References

外科切除原则·应由获得认证的胸外科医师对已仔细评估的病人进行手术切除，·手术的目的是减灭肿瘤细胞，在这种情况下，如果不能多个位点切除，手术应停止.·手术的选择是：（1）胸膜切除术/剥脱术(P/D)，完整切除胸膜和所有肿瘤;（2）胸膜肺切除术(EPP)，

切除整块胸膜，肺，膈肌和心包。并进行纵隔淋巴结清扫;·对于早期疾病(病变限于胸膜)，组织学类型为上皮型的低风险患者，EPP是最好的选择。对进展期(局部进展),组织学类型为混合型和/或高风险患者，胸膜切除术/剥脱术(P/D)是较好的选择。·从手术恢复后，病人应进行包括化疗和放疗在内的辅助治疗，采用哪种治疗取决于术前治疗情况和手术

样本的组织学分析。Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanycancerpatientisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2010,01/26/10©2010NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.TheseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MPM的外科治疗第十六页，共31页。外科治疗是目前唯一可能获得根治性疗效的手段分为姑息性和相对根治性方法因MPM常呈弥漫性生长并易于复发，外科治疗的实际效果往往不尽如人意，仅极少数较局限的病例可彻底切除第十七页，共31页。外科治疗-姑息性胸腔置管引流术患者胸穿后胸腔积液反复出现或增长极快，则需要彻底的胸腔引流胸膜固定术使用化学制剂造成无菌性粘连性胸膜炎，继而产生胸膜表面的永久性粘连，胸膜腔消失对原发疾病不会产生影响，但可缓解症状滑石粉目前仍是最有效的胸膜粘连剂第十八页，共31页。外科治疗-根治性胸膜切除术(剥脱术)胸膜外全肺切除术(EPP)手术范围应将胸膜连同肿瘤整块切除(包括一侧胸膜、全肺、同侧膈肌、通常包括心包，同时行淋巴结清扫)如何选择：对于早期疾病(病变限于胸膜)，组织学类型为上皮型的低风险患者，EPP是最好的选择。对进展期(局部进展),组织学类型为混合型和/或高风险患者，胸膜切除术/剥脱术(P/D)是较好的选择。第十九页，共31页。外科治疗胸膜切除术(剥脱术)治疗效果对Ⅰ期或选择性Ⅱ期的患者，如将肿瘤基本完整切除(剥脱)，中位生存约为13.4个月年份作者病例数中位生存期(月)2年生存率1996Rush5118.340%1994Allen5698.9%1984Law282032%MPM胸膜切除(剥脱)术治疗效果第二十页，共31页。外科治疗胸膜外全肺切除术(EPP)疗效几个多中心研究表明，单纯EPP并不能显著延长MPM患者的生存期，联合其他治疗措施则更有可能清除所有肿瘤并发症两种多见且威胁生命的并发症是支气管残端瘘和ARDS术后患者室上性心律失常的发生率高达25%~40%，但一般均能以适当的药物控制第二十一页，共31页。®1of3NCCNPracticeGuidelines

GuidelinesIndex MPMTableofContentsStaging,Discussion,References放疗的原则

(1of3)总体原则应由放射科医生、外科医生、肿瘤科医生、影像诊断医生和胸科医生对所有患者进行评估，给予多学科综合治疗的建议.多学科综合小组应对术后放疗和或联合化疗的最佳时间进行讨论.对于可切除的MPM患者，建议给予辅助放疗.1-6辅助放治疗的目的是改善局部控制.放疗可预防胸膜术后的种植性播散.放疗是有效缓解胸痛的姑息治疗手段.胸膜外肺切除术后，辅助放疗可显著降低局部复发.当无法进行进行手术时，高剂量放疗不会改善生存，并且发生放射损伤.1,5,6有关放疗的首字母和缩写同非小细胞肺癌的放疗.SeeNCCNNon-SmallCellLungCancerGuidelines.放疗剂量和范围·放疗的剂量应以治疗为目的.SeeRecommendedDosesforConventionallyFractionated RadiationTherapyMPM-C2of3.辅助放疗的剂量为50-60Gy,放疗剂量为54Gy用于半胸放疗、开胸手术切口和引流口都可以耐受，辅助放疗的剂量可限制影响预后，接受超过40Gy治疗的患者生存期显著长于低于40Gy的生存(P=0.001).1受临近正常组织的照射剂量所限，对于残存微病灶，剂量60Gy，除手术床外，

术后放疗的范围还应包括手术疤痕和胸壁活检区域.7-94Gy/天的分割剂量对缓解胸痛的疗效优于<4Gy的剂量，8,10虽然用于姑息治疗的放疗的最佳每日剂量和总剂量仍不明确。对于术后的预防性放疗，推荐总剂量为21Gy(3x7Gy)。7,11对于有残瘤的患者，一些有经验的医生可进行近距离放疗或术中体内放疗。

SeeRadiationTechniquesMPM-C2of3 SeeReferencesMPM-C3of3Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanycancerpatientisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.

MPM-CVersion1.2010,01/26/10©2010NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.TheseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MPM的放疗第二十二页，共31页。放疗指征胸膜外肺切除术后或胸膜切除术后的辅助治疗胸膜外肺切除术后或胸膜切除术后残留病灶治疗姑息治疗:疼痛、骨转移、脑转移预防介入操作引起的沿通道转移第二十三页，共31页。放疗剂量选择治疗选择总剂量分割剂量时间术前40-501.8-24-5周术后辅助50-541.8-24-5周术后残留54-601.8-25-6周姑息止痛20-40≥41-2周多发骨或脑转移3032周介入通道预防2171-2周第二十四页，共31页。其他治疗疗效有待于进一步研究证实免疫治疗：通过触发机体特有的防御机制，作用于肿瘤并使之消退的过程光动力治疗：特定波长的光照射在一定的光敏物质后产生的一系列化学、物理、生物等反应，可用以诊断和治疗肿瘤的一种方法基因治疗：指DNA/RNA水平上对疾病的控制与治疗，将对肿瘤有治疗作用的外源基因转移到靶细胞，通过外源基因的表达，达到治疗目的第二十五页，共31页。®MPM-1NCCNPracticeGuidelinesMPM的诊断

GuidelinesIndex MPMTableofContentsStaging,Discussion,References初步评估复发性胸膜积液和/或胸膜增厚·胸部增强CT·胸部穿刺的细胞学评估·胸膜活检（例如，Abrahm‘s针，CT引导下活检，胸腔镜活检[首选]，或开胸活检)·如果需要的话，用滑石粉胸膜或胸腔导管对胸腔积液进行处理确诊MPM推荐多学科综合治疗MPMSeePretreatmentEvaluation(MPM-2)

·可选择性检测血清间皮蛋白和骨桥蛋白水平Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanycancerpatientisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2010,01/26/10©2010NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.TheseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.第二十六页，共31页。®MPM-2

NCCN病理评估PracticeGuidelines治疗前评估·胸腹部增强CT·FDG-PET检查·纵隔镜或支气管内超声MPM的评估

临床评估

临床分期I-III

GuidelinesIndex MPMTableofContentsStaging,Discussion,References

见手术评估

(MPM-3)纵隔淋巴结活检(可选)MPM·腹腔镜检查以排除经

膈肌转移(可选)aSee

·胸部MRI(可选) ·如果怀疑对侧异常，

考虑胸腔镜PrinciplesofChemotherapy(MPM-A).临床分期IV或组织学类型为肉瘤性化疗aNote:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanycancerpatientisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2010,01/26/10©2010NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.TheseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.第二十七页，共31页。®TNTXNXT0N0T1N1N2T1aT1bN3T2MM0M1ST-1NCCNPracticeGuidelines

GuidelinesIndex MPMTableofContentsStaging,Discussion,References分期Table1.IMIGStagingSystemforDiffuseMalignantPleuralMesothelioma*PrimaryTumorPrimarytumorcannotbeassessedNoevidenceofprimarytumorTumorlimitedtotheipsilateralparietalpleurawithorwithoutmediastinalpleuraandwithorwithoutdiaphragmaticpleuralinvolvementNoinvolvementofthevisceralpleuraTumoralsoinvolvingthevisceralpleuraTumorinvolvingeachoftheipsilateralpleuralsurfaces(parietal,mediastinal,diaphragmatic,andvisceralpleura)withaleastoneofthefollowing:-Involvementofthediaphragmaticmuscle-Extensionoftumorfromvisceralpleuraintotheunderlying

RegionalLymphNodes

Regionallymphnodescannotbeassessed Noregionallymphnodemetastasis Metastasistotheipsilateralbronchpulmonaryorhilarlymphnodes Metastasesinthesubcarinallymphnodeortheipsilateralmediastinal lymphnodesincludingtheipsilateralinternalmammaryand peridiaphragmaticnodes Metastasisincontralateralmediastinal,contralateralinternal mammary,ipsilateralorcontralateralsupraclavicularlymphnodes

DistantMetastasis

Nodistantmetastasis DistantmetastasisStageGroupingpulmonaryparenchymaStageTNMT3T4LocallyadvancedbutpotentiallyresectabletumorTumorinvolvingalloftheipsilateralpleuralsurfaces(parietal,mediastinal,diaphragmatic,andvisceralpleura),withatleastoneofthefollowing:-Involvementoftheendothoracicfascia-Extensionintothemediastinalfat-Solitary,completelyresectablefocusoftumorextendingintothesofttissuesofthechestwall-NontransmuralinvolvementofthepericardiumLocallyadvancedtechnicallyunresectabletumorTumorinvolvingalloftheipsilateralpleuralsurfaces(parietal,mediastinal,diaphragmatic,andvisceralpleura)withatleastoneofthefollowing:-Diffuseextensionormultifocalmassesoftumorinthechestwall,withorwithoutassociatedribdestruction-DirecttransdiaphragmaticextensionofthetumortotheIIAIBIIIIIIVT1T1aT1bT2T1,T2T1,T2T3T4AnyTAnyTN0N0N0N0N1N2N0,N1,N2AnyNN3AnyNM0M0M0M0M0M0M0M0M0M1-Directextensionoftumortothecontralateralpleura-Directextensionofthetumortomediastinalorgans-Directextensionoftumorintothespine-Tumorextendingthroughtotheinternalsurfaceofthepericardiumwithorwithoutapericardialeffusionortumorinvolvingthemyocardium*UsedwiththepermissionoftheAmericanJointCommitteeonCancer(AJCC),ChicagoIllinois.TheoriginalandprimarysourceforthisinformationistheAJCCCancerStagingManual,SeventhEdition(2010)publishedbySpringerScienceandBusinessMediaLLC(SBM).(Forcompleteinformationanddatasupportingthestagingtables,visit.)AnycitationorquotationofthismaterialmustbecreditedtotheAJCCasitsprimarysource.Theinclusionofthisinformationhereindoesnotauthorizeanyreuseorfurtherdistributionwithouttheexpressed,writtenpermissionofSpringerSBM,onbehalfoftheAJCC.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanycancerpatientisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2010,01/26/10©2010NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.TheseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MPM的分期第二十八页，共31页。®MPM-3NCCNPracticeGuidelinesMPM的治疗

GuidelinesIndex MPMTableofContentsStaging,Discussion,References临床分期临床分期I临床分期II-III手术评估·肺功能·