mpm治療進(jìn)展

1、惡性胸膜間皮瘤(MPM)的治療進(jìn)展,北京協(xié)和醫(yī)院呼吸內(nèi)科 王孟昭,MPM的定義和分類,定義是包繞肺臟和被覆在胸膜腔的間皮細(xì)胞所發(fā)生的癌癥分類上皮樣間皮瘤肉瘤樣間皮瘤雙相性間皮瘤或混合性間皮瘤,MPM的流行病學(xué),美國每年新診斷的發(fā)病人數(shù)為2500例日本每年新診斷的發(fā)病人數(shù)為1000例我國大城市胸膜間皮瘤發(fā)病率約為0.3/10萬～0.5/10萬惡性胸膜間皮瘤的發(fā)病多與石棉暴露有關(guān)，美國已過發(fā)病高峰期，但歐洲、澳大利亞、日本及

2、中國等國家發(fā)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曲宸緒等, 肺癌研究與臨床 2004; 16(2): 143-144,間皮瘤與腺癌的鑒別診斷,MPM的治療,內(nèi)科化療治療放射治療外科治療多學(xué)科治療,MPM- 化療治療,在力比泰®未研發(fā)前

3、，順鉑單藥治療的療效較好,Ong and Vogelzang, J Clin Oncol 1996,,唯一被FDA批準(zhǔn)的治療MPM一線化療藥物—力比泰®,JMCH研究：迄今為止MPM治療領(lǐng)域最大樣本的隨機(jī)、多中心、Ⅲ期臨床研究,Vogelzang NJ, et al. J Clin Oncol 2003; 21(14):2636-2644,JMCH研究：力比泰®/順鉑方案顯著延長MPM患者生命,Vogelzang N

4、J, et al. J Clin Oncol 2003; 21(14):2636-2644,唯一被FDA批準(zhǔn)的治療MPM一線化療藥物—力比泰®,JMCH研究：力比泰® /順鉑方案的緩解率是順鉑單藥的兩倍,Vogelzang NJ, et al. J Clin Oncol 2003; 21(14):2636-2644,唯一被FDA批準(zhǔn)的治療MPM一線化療藥物—力比泰®,JMCH研究：力比泰®/順鉑方

5、案顯著改善MPM患者生活質(zhì)量,Gralla RJ. et al. Proc Am Soc Clin Oncol. 2003; 22:621(abstract 2496),唯一被FDA批準(zhǔn)的治療MPM一線化療藥物—力比泰®,大型臨床研究證明，力比泰® /順鉑方案無論在生存期、緩解率還是生活質(zhì)量方面，都顯著優(yōu)于順鉑單藥方案，是目前治療MPM的標(biāo)準(zhǔn)一線方案,唯一被FDA批準(zhǔn)的治療MPM一線化療藥物—力比泰®,Ja

6、ssem, J. et al. J Clin Oncol; 26:1698-1704 2008,培美曲塞單藥二線治療晚期惡性間皮瘤,Jassem, J. et al. J Clin Oncol; 26:1698-1704 2008,培美曲塞單藥二線治療晚期惡性間皮瘤,®,MPM-A,NCCN,Practice Guidelinesin Oncology – v.1.2010,Guidelines IndexMPM Tab

7、le of ContentsStaging, Discussion, References,化療的原則,一線化療聯(lián)合方案力比泰 500 mg/m2 day 1順鉑 75 mg/m2 day 1每3 周1次 (1類推薦) 1,二線化療力比泰 (如果未用于一線) 8諾維本9吉西他濱,力比泰 500 mg/m2 day 1卡鉑 AUC 5 day 1每3 周1次 2,3吉西他濱 1000

8、-1250 mg/m2 day 1, 8, 15順鉑80-100 mg/m2 day 1每3-4 week 1個(gè)周期 4,5 力比泰 500 mg/m2 每3周1次6 諾維本 25-30 mg/m2 每周1次71 Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of

9、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 co

10、mbination 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 meso

11、thelioma. 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,

12、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 a

13、nd 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 wi

14、thout 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

15、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 e

16、fficacy 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

17、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 ri

18、ghts reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.,MPM的化療,一線治療方法的比較,,二線化療方案的比較,®,MPM-B,NCCN,Practice Guidelinesin Oncology – v.1.

19、2010,Guidelines IndexMPM Table of ContentsStaging, Discussion, References,外科切除原則· 應(yīng)由獲得認(rèn)證的胸外科醫(yī)師對(duì)已仔細(xì)評(píng)估的病人進(jìn)行手術(shù)切除，· 手術(shù)的目的是減滅腫瘤細(xì)胞，在這種情況下，如果不能多個(gè)位點(diǎn)切除，手術(shù)應(yīng)停止.· 手術(shù)的選擇是：（1）胸膜切除術(shù)/剝脫術(shù)(P/D)，完整切除胸膜和所有腫瘤;（2）胸膜肺切除術(shù)

20、(EPP)， 切除整塊胸膜，肺，膈肌和心包。并進(jìn)行縱隔淋巴結(jié)清掃;· 對(duì)于早期疾病(病變限于胸膜)，組織學(xué)類型為上皮型的低風(fēng)險(xiǎn)患者，EPP是最好的選擇。對(duì)進(jìn)展期 (局部進(jìn)展),組織學(xué)類型為混合型和/或高風(fēng)險(xiǎn)患者，胸膜切除術(shù)/剝脫術(shù)(P/D)是較好的選擇。· 從手術(shù)恢復(fù)后，病人應(yīng)進(jìn)行包括化療和放療在內(nèi)的輔助治療，采用哪種治療取決于術(shù)前治療情況和手術(shù) 樣本的組織學(xué)分析。

21、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

22、 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

23、written permission of NCCN.,MPM的外科治療,外科治療,是目前唯一可能獲得根治性療效的手段分為姑息性和相對(duì)根治性方法因MPM常呈彌漫性生長并易于復(fù)發(fā)，外科治療的實(shí)際效果往往不盡如人意，僅極少數(shù)較局限的病例可徹底切除,外科治療-姑息性,胸腔置管引流術(shù)患者胸穿后胸腔積液反復(fù)出現(xiàn)或增長極快，則需要徹底的胸腔引流胸膜固定術(shù)使用化學(xué)制劑造成無菌性粘連性胸膜炎，繼而產(chǎn)生胸膜表面的永久性粘連，胸膜腔消失對(duì)原發(fā)疾

24、病不會(huì)產(chǎn)生影響，但可緩解癥狀滑石粉目前仍是最有效的胸膜粘連劑,外科治療-根治性,胸膜切除術(shù)(剝脫術(shù))胸膜外全肺切除術(shù)(EPP)手術(shù)范圍應(yīng)將胸膜連同腫瘤整塊切除(包括一側(cè)胸膜、全肺、同側(cè)膈肌、通常包括心包，同時(shí)行淋巴結(jié)清掃)如何選擇：對(duì)于早期疾病(病變限于胸膜)，組織學(xué)類型為上皮型的低風(fēng)險(xiǎn)患者，EPP是最好的選擇。對(duì)進(jìn)展期 (局部進(jìn)展),組織學(xué)類型為混合型和/或高風(fēng)險(xiǎn)患者，胸膜切除術(shù)/剝脫術(shù)(P/D)是較好的選擇。,外科治療,胸

25、膜切除術(shù)(剝脫術(shù))治療效果對(duì)Ⅰ期或選擇性Ⅱ期的患者，如將腫瘤基本完整切除(剝脫)，中位生存約為13.4個(gè)月,MPM胸膜切除(剝脫)術(shù)治療效果,外科治療,胸膜外全肺切除術(shù)(EPP)療效幾個(gè)多中心研究表明，單純EPP并不能顯著延長MPM患者的生存期，聯(lián)合其他治療措施則更有可能清除所有腫瘤并發(fā)癥兩種多見且威脅生命的并發(fā)癥是支氣管殘端瘺和ARDS術(shù)后患者室上性心律失常的發(fā)生率高達(dá)25%~40%，但一般均能以適當(dāng)?shù)乃幬锟刂?®

26、;,1 of 3,NCCN,Practice Guidelinesin Oncology – v.1.2010,Guidelines IndexMPM Table of ContentsStaging, Discussion, References,放療的原則 (1 of 3)總體原則應(yīng)由放射科醫(yī)生、外科醫(yī)生、腫瘤科醫(yī)生、影像診斷醫(yī)生和胸科醫(yī)生對(duì)所有患者進(jìn)行評(píng)估，給予多學(xué)科綜合治療的建議.多學(xué)科綜合小組應(yīng)對(duì)術(shù)后放療和或聯(lián)

27、合化療的最佳時(shí)間進(jìn)行討論.對(duì)于可切除的MPM患者，建議給予輔助放療.1-6輔助放治療的目的是改善局部控制.放療可預(yù)防胸膜術(shù)后的種植性播散.放療是有效緩解胸痛的姑息治療手段.胸膜外肺切除術(shù)后，輔助放療可顯著降低局部復(fù)發(fā). 當(dāng)無法進(jìn)行進(jìn)行手術(shù)時(shí)，高劑量放療不會(huì)改善生存，并且發(fā)生放射損傷. 1,5,6有關(guān)放療的首字母和縮寫同非小細(xì)胞肺癌的放療. See NCCN Non-Small Cell Lung Cancer Guidel

28、ines.放療劑量和范圍· 放療的劑量應(yīng)以治療為目的. See Recommended Doses for Conventionally FractionatedRadiation Therapy MPM-C 2 of 3.輔助放療的劑量為50-60 Gy,放療劑量為54 Gy用于半胸放療、開胸手術(shù)切口和引流口都可以耐受， 輔助放療的劑量可限制影響預(yù)后，接受超過40 Gy治療的患者生存期顯著長于低于40 Gy的

29、生存(P=0.001). 1受臨近正常組織的照射劑量所限，對(duì)于殘存微病灶，劑量 60 Gy，除手術(shù)床外， 術(shù)后放療的范圍還應(yīng)包括手術(shù)疤痕和胸壁活檢區(qū)域. 7-94 Gy/天的分割劑量對(duì)緩解胸痛的療效優(yōu)于< 4 Gy的劑量， 8,10 雖然用于姑息治療的放療的最佳每日劑量和總劑量仍不明確。對(duì)于術(shù)后的預(yù)防性放療，推薦總劑量為21 Gy (3 x 7 Gy)。 7,11 對(duì)于有殘瘤的患者，一些有經(jīng)驗(yàn)的醫(yī)生可進(jìn)行近距離

30、放療或術(shù)中體內(nèi)放療。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

31、 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 gu

32、idelines and this illustration may not be reproduced in any form without the express written permission of NCCN.,MPM的放療,放療指征,胸膜外肺切除術(shù)后或胸膜切除術(shù)后的輔助治療胸膜外肺切除術(shù)后或胸膜切除術(shù)后殘留病灶治療姑息治療:疼痛、骨轉(zhuǎn)移、腦轉(zhuǎn)移預(yù)防介入操作引起的沿通道轉(zhuǎn)移,放療劑量選擇,其他治療,療效有待于進(jìn)一步研

33、究證實(shí)免疫治療：通過觸發(fā)機(jī)體特有的防御機(jī)制，作用于腫瘤并使之消退的過程光動(dòng)力治療：特定波長的光照射在一定的光敏物質(zhì)后產(chǎn)生的一系列化學(xué)、物理、生物等反應(yīng)，可用以診斷和治療腫瘤的一種方法基因治療：指DNA/RNA水平上對(duì)疾病的控制與治療，將對(duì)腫瘤有治療作用的外源基因轉(zhuǎn)移到靶細(xì)胞，通過外源基因的表達(dá)，達(dá)到治療目的,®,MPM-1,NCCN,Practice Guidelinesin Oncology – v.1.2010,M

34、PM的診斷,Guidelines IndexMPM Table of ContentsStaging, Discussion, References,初步評(píng)估,復(fù)發(fā)性胸膜積液和/或胸膜增厚,· 胸部增強(qiáng)CT· 胸部穿刺的細(xì)胞學(xué)評(píng)估· 胸膜活檢（例如，Abrahm‘s針，CT引導(dǎo)下活檢，胸腔鏡活檢[首選]，或開胸活檢)·如果需要的話，用滑石粉胸膜或胸腔導(dǎo)管對(duì)胸腔積液進(jìn)行處理,確診MPM

35、,推薦多學(xué)科綜合治療MPMSee Pretreatment Evaluation (MPM-2),·可選擇性檢測血清間皮蛋白和骨橋 蛋白水平Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the b

36、est 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 reserve

37、d. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.,®,MPM-2,NCCN病理評(píng)估,Practice Guidelinesin Oncology – v.1.2010治療前評(píng)估· 胸腹

38、部增強(qiáng)CT· FDG-PET檢查· 縱隔鏡或支氣管內(nèi)超聲,MPM的評(píng)估臨床評(píng)估 臨床分期I-III,Guidelines IndexMPM Table of ContentsStaging, Discussion, References見手術(shù)評(píng)估(MPM-3),縱隔淋巴結(jié)活檢(可選),MPM,&

39、#183; 腹腔鏡檢查以排除經(jīng) 膈肌轉(zhuǎn)移(可選),a See,· 胸部MRI(可選)· 如果懷疑對(duì)側(cè)異常， 考慮胸腔鏡Principles of Chemotherapy (MPM-A).,臨床分期 IV 或組織學(xué)類型為肉瘤性,化療 a,Note: All recommendations are category 2A unless

40、 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

41、 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,T

42、1a,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

43、*,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 i

44、nvolvement 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 foll

45、owing:-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

46、 the ipsilateral bronchpulmonary or hilar lymph nodesMetastases in the subcarinal lymph node or the ipsilateral mediastinallymph nodes including the ipsilateral internal mammary andperidiaphragmatic nodesMetastas

47、is in contralateral mediastinal, contralateral internalmammary, ipsilateral or contralateral supraclavicular lymph nodesDistant MetastasisNo distant metastasisDistant metastasisStage Grouping,pulmonary parenchym

48、a,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

49、 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

50、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

51、 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

52、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 int

53、o 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

54、 (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 informat

55、ion and data supporting the staging tables, visit www.springer.com.) Anycitation or quotation of this material must be credited to the AJCC as its primary source. Theinclusion of this information herein does not author

56、ize 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 believe

57、s 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 ri

58、ghts 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的治療,Guideline

59、s IndexMPM Table of ContentsStaging, Discussion, References,臨床分期臨床分期 I臨床分期 II-III,手術(shù)評(píng)估· 肺功能· 肺通氣/灌注 定量分析· 心臟壓力測試· 肺功能· 肺通氣/灌注 定量分析· 心臟壓力測試,臨床評(píng)估

60、可手術(shù)無法手術(shù)可手術(shù)無法手術(shù),治療手術(shù)切除觀察進(jìn)展情況見初始治療MPM-4化療a,a Seeb See,Principles of Chemotherapy (MPM-A).Principles of Surgical Resection (MPM-B).,Note: All recommendations are category 2

61、A 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