MPM治疗进展wangmengzhao

恶性胸膜间皮瘤(MPM)的治疗进展,北京协和医院呼吸内科 王孟昭,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,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,Goudar RK, Thera Clin Risk Manag 2008; 4(1):205-211Nakano T, Environ Health Prev Med 2008; 13(2): 75-83曲宸绪等, 肺癌研究与临床 2004; 16(2): 143-144,间皮瘤与腺癌的鉴别诊断,MPM的治疗,内科化疗治疗放射治疗外科治疗多学科治疗,MPM- 化疗治疗,在力比泰未研发前，顺铂单药治疗的疗效较好,Ong and Vogelzang, J Clin Oncol 1996,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、期临床研究,Vogelzang NJ, et al. J Clin Oncol 2003; 21(14):2636-2644,JMCH研究：力比泰/顺铂方案显著延长MPM患者生命,Vogelzang NJ, et al. J Clin Oncol 2003; 21(14):2636-2644,唯一被FDA批准的治疗MPM一线化疗药物力比泰,JMCH研究：力比泰 /顺铂方案的缓解率是顺铂单药的两倍,Vogelzang NJ, et al. J Clin Oncol 2003; 21(14):2636-2644,唯一被FDA批准的治疗MPM一线化疗药物力比泰,JMCH研究：力比泰/顺铂方案显著改善MPM患者生活质量,Gralla RJ. et al. Proc Am Soc Clin Oncol. 2003; 22:621(abstract 2496),唯一被FDA批准的治疗MPM一线化疗药物力比泰,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,Jassem, J. et al. J Clin Oncol; 26:1698-1704 2008,培美曲塞单药二线治疗晚期恶性间皮瘤,Jassem, J. et al. J Clin Oncol; 26:1698-1704 2008,培美曲塞单药二线治疗晚期恶性间皮瘤,MPM-A,NCCN,Practice Guidelinesin Oncology v.1.2010,Guidelines IndexMPM Table of ContentsStaging, Discussion, References,化疗的原则,一线化疗联合方案力比泰 500 mg/m2 day 1顺铂 75 mg/m2 day 1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 500 mg/m2 day 1卡铂 AUC 5 day 1每3 周1次 2,3吉西他滨 1000-1250 mg/m2 day 1, 8, 15顺铂80-100 mg/m2 day 1每3-4 week 1个周期 4,5 力比泰 500 mg/m2 每3周1次6 诺维本 25-30 mg/m2 每周1次71 Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleuralmesothelioma. J Clin Oncol 2003;21:2636-44.2 Castagneto B, Botta M, Aitini E, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma. Ann Oncol2008;19:370-3.3 Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006;24:1443-8.4 Nowak AK, Byrne MJ, Willianson R, et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002;87:491-6.5 Van Haarst JM, Baas J, Manegold CH, et al. Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma. Br J Cancer 2002; 86:342-5.6 Taylor P, Castagneto B, Dark G, et al. Single-agent pemetrexed for chemonaive and pretreated patients with malignant pleural mesothelioma: results of an InternationalExpanded Access Program. J Thorac Oncol 2008;3:764-771.7 Muers MF, Stephens RJ, Fisher P, et al. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01):a multicentre randomised trial. Lancet 2008;371:1685-94.8 Jassem J, Ramlau R, Santoro A, et al. Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients withadvanced malignant pleural mesothelioma. J Clin Oncol 2008;26:1698-1704.9 Stebbing J, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 2009;63:94-7.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2010, 01/26/10 2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.,MPM的化疗,一线治疗方法的比较,二线化疗方案的比较,MPM-B,NCCN,Practice Guidelinesin Oncology v.1.2010,Guidelines IndexMPM Table of ContentsStaging, 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: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2010, 01/26/10 2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.,MPM的外科治疗,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,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,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。,外科治疗,胸膜切除术(剥脱术)治疗效果对期或选择性期的患者，如将肿瘤基本完整切除(剥脱)，中位生存约为13.4个月,MPM胸膜切除(剥脱)术治疗效果,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,1 of 3,NCCN,Practice Guidelinesin Oncology v.1.2010,Guidelines IndexMPM Table of ContentsStaging, Discussion, References,放疗的原则 (1 of 3)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. See NCCN Non-Small Cell Lung Cancer Guidelines.放疗剂量和范围 放疗的剂量应以治疗为目的. See Recommended Doses for Conventionally FractionatedRadiation Therapy MPM-C 2 of 3.辅助放疗的剂量为50-60 Gy,放疗剂量为54 Gy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40 Gy治疗的患者生存期显著长于低于40 Gy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 60 Gy，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. 7-94 Gy/天的分割剂量对缓解胸痛的疗效优于 4 Gy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21 Gy (3 x 7 Gy)。 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。See Radiation Techniques MPM-C 2 of 3See References MPM-C 3 of 3Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.MPM-CVersion 1.2010, 01/26/10 2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.,MPM的放疗,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,放疗剂量选择,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,MPM-1,NCCN,Practice Guidelinesin Oncology v.1.2010,MPM的诊断,Guidelines IndexMPM Table of ContentsStaging, 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，Abrahms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MPMSee Pretreatment Evaluation (MPM-2),可选择性检测血清间皮蛋白和骨桥 蛋白水平Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2010, 01/26/10 2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.,MPM-2,NCCN病理评估,Practice Guidelinesin Oncology v.1.2010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,Guidelines IndexMPM Table of ContentsStaging, 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),a See, 胸部MRI(可选) 如果怀疑对侧异常， 考虑胸腔镜Principles of Chemotherapy (MPM-A).,临床分期 IV 或组织学类型为肉瘤性,化疗 a,Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2010, 01/26/10 2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.,T,N,TX,NX,T0,N0,T1,N1,N2,T1a,T1b,N3,T2,M,M0,M1,ST-1,NCCN,Practice Guidelinesin Oncology v.1.2010,Guidelines IndexMPM Table of ContentsStaging, Discussion, References,分期Table 1.IMIG Staging System for Diffuse Malignant Pleural Mesothelioma*,Primary TumorPrimary tumor cannot be assessedNo evidence of primary tumorTumor limited to the ipsilateral parietal pleura with orwithout mediastinal pleura and with or withoutdiaphragmatic pleural involvementNo involvement of the visceral pleuraTumor also involving the visceral pleuraTumor involving each of the ipsilateral pleural surfaces(parietal, mediastinal, diaphragmatic, and visceral pleura)with a least one of the following:-Involvement of the diaphragmatic muscle-Extension of tumor from visceral pleura into the underlying,Regional Lymph NodesRegional lymph nodes cannot be assessedNo regional lymph node metastasisMetastasis to the ipsilateral bronchpulmonary or hilar lymph nodesMetastases in the subcarinal lymph node or the ipsilateral mediastinallymph nodes including the ipsilateral internal mammary andperidiaphragmatic nodesMetastasis in contralateral mediastinal, contralateral internalmammary, ipsilateral or contralateral supraclavicular lymph nodesDistant MetastasisNo distant metastasisDistant metastasisStage Grouping,pulmonary parenchyma,Stage,T,N,M,T3T4,Locally advanced but potentially resectable tumorTumor involving all of the ipsilateral pleural surfaces(parietal, mediastinal, diaphragmatic, and visceral pleura),with at least one of the following:-Involvement of the endothoracic fascia-Extension into the mediastinal fat-Solitary, completely resectable focus of tumor extendinginto the soft tissues of the chest wall-Nontransmural involvement of the pericardiumLocally advanced technically unresectable tumorTumor involving all of the ipsilateral pleural surfaces(parietal, mediastinal, diaphragmatic, and visceral pleura)with at least one of the following:-Diffuse extension or multifocal masses of tumor in thechest wall, with or without associated rib destruction-Direct transdiaphragmatic extension of the tumor to the,IIAIBIIIIIIV,T1T1aT1bT2T1, T2T1, T2T3T4Any TAny T,N0N0N0N0N1N2N0, N1, N2Any NN3Any N,M0M0M0M0M0M0M0M0M0M1,-Direct extension of tumor to the contralateral pleura-Direct extension of the tumor to mediastinal organs-Direct extension of tumor into the spine-Tumor extending through to the internal surface of thepericardium with or without a pericardial effusion or tumorinvolving the myocardium,*Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago Illinois.The original and primary source for this information is the AJCC Cancer Staging Manual,Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (Forcomplete information and data supporting the staging tables, visit .) Anycitation or quotation of this material must be credited to the AJCC as its primary source. Theinclusion of this information herein does not authorize any reuse or further distribution withoutthe expressed, written permission of Springer SBM, on behalf of the AJCC.,Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2010, 01/26/10 2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.,MPM的分期,MPM-3,NCCN,Practice Guidelinesin Oncology v.1.2010,MPM的治疗,Guidelines IndexMPM Table of ContentsStaging, Discussion, References,临床分期临床分期 I临床分期 II-III,手术评估 肺功能 肺通气/灌注 定量分析 心脏压力测试 肺功能 肺通气/灌注 定量分析 心脏压力测试,临床评估可手术无法手术可手术无法手术,治疗手术切除观察进展情况见初始治疗MPM-4化疗a