局部晚期非小細(xì)胞肺癌的同期放化療進(jìn)展協(xié)和王綠化

1、1,局部晚期非小細(xì)胞肺癌的同期放化療進(jìn)展,中國(guó)醫(yī)學(xué)科學(xué)院協(xié)和醫(yī)科大學(xué)腫瘤醫(yī)院 王綠化,2,一、影像技術(shù)和計(jì)算機(jī)技術(shù)的進(jìn)步為精確放射治療的實(shí)現(xiàn)提供可能,3,腫瘤功能顯像,4,5,肺灌注功能顯像,,,腫瘤壓迫相關(guān)灌注減低病例特征p右肺鱗癌 T2a N2 M0 IIIA期 右肺上葉下葉各一結(jié)節(jié)伴阻塞性炎癥右肺門(mén)、縱膈2R、4R淋巴結(jié)轉(zhuǎn)移右肺上葉、右肺中葉灌注減低,6,屏氣技術(shù)舉例: Elekta ABC,7,四

2、維CT影像技術(shù),,呼氣,,吸氣,,,,螺旋開(kāi)始,,,,,,時(shí)相,,由吸轉(zhuǎn)呼,,呼氣末,,由呼轉(zhuǎn)吸,,由吸轉(zhuǎn)呼,,呼氣,,吸氣,,,,螺旋開(kāi)始,,呼吸曲線,,床位,8,影像引導(dǎo)放射治療技術(shù)IGRT,,40對(duì)葉片MLC,KV級(jí)X射線球管,KV級(jí)探測(cè)器陣列,MV級(jí)探測(cè)器陣列,9,在線校正—影像匹配,10,二、同期放化療是局部晚期NSCL的標(biāo)準(zhǔn)治療模式,局部晚期NSCLC,Evolution of Treatment Strategy

3、 Operable：,Surgery Surgery ± RT Surgery ± RT ± CT,,,CT + Surgery RT/CT + Surge

4、ry RT/CT ± Surgery RT/CT,,,,,局部晚期NSCLC,Evolution of Treatment Strategy Inoperable :,RT CT + RT Sequential CT/RT Concurrent ?Induction CT CT/RT CT/RT

5、 Consolidation?,,,,,,,,,,,,,Inoperable序貫放化綜合治療同步放化綜合治療Operable Ⅲa-N2RT/CT + Surgery vs RT/CT CT + Surgery vs CT / RT,序貫化放療薈萃（META）分析,22trails 3033cases Favor Gr HR benefit% sur%

6、 2y 5y 2y 5y Chemo 0.90 3 2 R+DDP 0.87 4 2 15 19 5 7

7、 p=0.005 DDP 40-120mg/m2/cycle, total dose 120-800mg/m2radiation dose 50Gy/20f- 65Gy/ 30f,,,結(jié)論：序貫放療/化療優(yōu)于單純放射治療,同時(shí)化放療 vs 序貫化放療,同時(shí)化放療 vs 序貫化放療(1)

8、 序貫化放療 同時(shí)化放療5年生存率 8.9% 15.8% P=0.04。中位生存期（月） 13.3 16.5 3y LRF Sur. 21.1% 33.9% 同時(shí)化放療: 提高局部控制率和生存率Furuse K, et al. J Clin. Oncol. 1999; 17:2

9、692-2699,RTOG 9410:III期NSCLC 同步放化療 vs 序貫放化療,序貫: PV --> RT (60 Gy, 2Gy QD) day 50 同步: PV/RT (60 Gy, 2Gy QD) day 1 同步/HFRT: PE/HFRT (69.2 Gy, 1.2Gy BID) day 1PV: 順鉑/長(zhǎng)春花堿PE: 順鉑/oral 足葉乙甙RT: 放療;

10、 QD: 每日一次; HFRT: 超分隔放療,Curran: ASCO, 2000; updated IASLC 2000; ASTRO 2001,2003,,RANDOMIZE,,,,,同時(shí)化放療 vs 序貫化放療(2) SEQ CON-QD CON-BID 中位生存期： 14.6

11、 17 15.6（月） 4 年生存率： 12% 21% 17% p=0.046 G3急性和晚期非血液系統(tǒng)毒性： 30%，48%，62% 和 14%，15%，16%。Curran W et al. P

12、ro. Am Soc Clin Oncol. J. Clin. Oncol. 2003; (abstract 2499),結(jié)論：同步放化療優(yōu)于序貫放化療，但是，急性毒性反應(yīng)增加,三、誘導(dǎo)化療+同期放化療 或同期放化療+鞏固化療 未能提高同期放化療的療效,Induction Chemotherapy Followed by Chemoradiotherapy With Chemoradio-therapy Alon

13、e for Regionally Advanced Unresectable StageIII Non–Small-CellLung:Cancer and Leukemia GroupBCALGB 39801,J Clin Oncol. 2007 May 1;25(13):1698-704. Epub 2007Apr,CALGB 39801 study design,July 1998 and was closed in May

14、 2002, Totally 366 patients registered,Survival intent to treat,Survival of eligible patients with a 　weight loss of ≤ 5%,Discussion,增加毒性 induction chemotherapy increases neutropenia and overall maximal toxicity

15、沒(méi)有生存優(yōu)勢(shì) No survival benefit over concurrent therapy alone同期放化療是標(biāo)準(zhǔn)的治療模式 Concomitant chemoradiotherapy is current standard therapy for unresectable stage IIIB NSCLC,,,SWOG 9504: 同步放化療后應(yīng)用泰索帝 鞏固化療治

16、療IIIb 期NSCLC,順鉑/VP-16 X XRT泰索帝 X X X,順鉑 50mg/m2 d 1, 8, 29, 36 VP-16 50mg/m2 d1-5, 29-33RT: 61 Gy: 45Gy(1.8Gy/fx), 16Gy 縮野 (2Gy/fx)泰索帝: 75mg/m2 cycle 1 --> 100mg/m2 cycle 2-3,SWOG

17、9504: 總生存-Promising,,,,,,,,,,,,,,,,,,,,,,,,,,,%,%,%,%,%,%,,,0,,,,,,,,,,,,,,,,,4,8,入組時(shí)間（月）,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

18、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,N Events中位生存8345 26月,2 年生存率: 54%3 年生存率: 37%,SWOG 9504 和 SWOG 9019比較,*95% CI,HOG LUN 01-24 Ph

19、ase III Study Design,Hanna et al. ASCO 2007:Abstract 7512.,ChemoRTCisplatin 50 mg/m2 IV d 1,8,29,36Etoposide 50 mg/m2 IV d 1-5 & 29-33Concurrent RT 59.4 Gy (1.8 Gy/fr),Stratificationat randomization PS 0-1 vs 2

20、 IIIA vs IIIB CR vs non-CR,,Inclusion at baseline Unresectable stage IIIA or IIIBNSCLC ECOG PS 0-1 at study entry(+PS2 at random) FEV-1 > 1 liter at study entry,203 patients,147 patients,73 patients,74 patien

21、ts,Taxotere75 mg/m2 q 3 wk ? 3,,Observation,,Primary endpoint: OS,,,HOG LUN 01-24: OS (ITT)Randomized Patients (n=147),,Hanna et al. ASCO 2007:Abstract 7512.,Months Since Registration,,0,10,20,30,40,50,60,Percent of pa

22、tients surviving,,,,,,0%,25%,50%,75%,100%,,,P-value: 0.940,Comparison of Grade 3-5 Toxicities,,*reported as “infection with neutropenia”,Hog LUGN o1-20/USO-023,The MST with EP/XRT was higher than historical controls;

23、 Consolidation D does not further improve survival, is associated with significant toxicity including an increased rate of hospitalization and premature death, And should no longer be used for pts with unresectable

24、 stage III NSCLC,Conclusions,局部晚期NSCLC同步放化療后鞏固化療能否帶來(lái)獲益？Meta analysis,Yamamoto S, et al. 2012 ASCO Abstract 7000.,研究方法與結(jié)果,研究方法：通過(guò)Pubmed系統(tǒng)檢索1995年1月1日-2011年10月31日上發(fā)表的評(píng)價(jià)同步放化療治療局部晚期NSCLC生存的II/III期試驗(yàn)研究結(jié)果：共檢索到41項(xiàng)研究：III期研究7項(xiàng)

25、；II期研究34項(xiàng)；共45組有鞏固化療25組(N=1707)；無(wú)鞏固化療20組(N=1740)兩組臨床分期、體力狀態(tài)、組織學(xué)類(lèi)型、性別、中位年齡可比,Yamamoto S, et al. 2012 ASCO Abstract 7000.,基線特征,Yamamoto S, et al. 2012 ASCO Abstract 7000.,治療情況,兩組計(jì)劃TRT劑量可比同步階段，兩組均有80%-90%的患者完成化療/放療,Yamamo

26、to S, et al. 2012 ASCO Abstract 7000.,TRT=胸部放療；CCT=鞏固化療,影響中位生存的因素,Yamamoto S, et al. 2012 ASCO Abstract 7000.,上表中各變量的分布情況在兩組間沒(méi)有顯著性差異 (P?0.182),研究結(jié)果：中位OS,Yamamoto S, et al. 2012 ASCO Abstract 7000.,CCT-:無(wú)鞏固化療CCT+:有鞏固化療,亞

27、組分析：有鞏固化療 vs. 無(wú)鞏固化療,Yamamoto S, et al. 2012 ASCO Abstract 7000.,研究結(jié)果：毒性,Yamamoto S, et al. 2012 ASCO Abstract 7000.,研究討論與結(jié)論,本項(xiàng)基于發(fā)表文獻(xiàn)的匯總分析未能證明鞏固化療能夠改善局部晚期NSCLC的總生存除了臨床研究外，不應(yīng)推薦同步放化療后的鞏固化療出乎意料的是，整個(gè)治療過(guò)程中兩組的毒性可比，可能的解釋是實(shí)際鞏固

28、化療的周期數(shù)低于預(yù)計(jì)根據(jù)基因改變，將分子靶向治療結(jié)合到該治療模式中可能是未來(lái)臨床研究的方向需要評(píng)估鞏固化療影響的臨床研究,Yamamoto S, et al. 2012 ASCO Abstract 7000.,GILT研究：比較口服長(zhǎng)春瑞濱與順鉑聯(lián)合同步放療后口服長(zhǎng)春瑞濱順鉑聯(lián)合BSC與BSC鞏固治療III期NSCLC的一項(xiàng)III期研究的最終結(jié)果,Huber RM, et al. 2012 ASCO Abstract 7001.

29、,GILT* CT-RT：研究背景*German InterGroup Lung Trial group,同步放化療（CT-RT）是身體狀況好的III期不可手術(shù)的NSCLC患者的標(biāo)準(zhǔn)治療常見(jiàn)CT-RT后的全身復(fù)發(fā)加上鞏固化療是否能對(duì)所有或某些亞組的同步化放療患者帶來(lái)獲益尚不清楚*German InterGroup Lung Trial group,GILT：研究設(shè)計(jì),Huber RM, et al. 2012 ASCO Ab

30、stract 7001.,主要終點(diǎn)：PFS,根據(jù)分期分層,GILT：主要入組標(biāo)準(zhǔn),既往未經(jīng)治療的組織學(xué)或細(xì)胞學(xué)確診的NSCLC不可手術(shù)的IIIA(N2)或IIIB期適合接受66Gy根治性放療(TNM第六版)18-75歲生存預(yù)期?12周KPS?80%既往3個(gè)月內(nèi)體重減輕?10%足夠肺、骨髓、肝腎功能至少1個(gè)可測(cè)量病灶,Huber RM, et al. 2012 ASCO Abstract 7001.,GILT：基線特征,Hu

31、ber RM, et al. 2012 ASCO Abstract 7001.,GILT：研究結(jié)果 – 療效,Huber RM, et al. 2012 ASCO Abstract 7001.,*HR=0.93; 95%CI=0.69-1.26,GILT：研究結(jié)果 – PFS與OS,Huber RM, et al. 2012 ASCO Abstract 7001.,GILT：研究結(jié)果 – 3/4級(jí)毒性,Huber RM, et al.

32、2012 ASCO Abstract 7001.,GILT：研究結(jié)論,在這項(xiàng)III期研究中，同步口服長(zhǎng)春瑞濱與順鉑聯(lián)合放療后行鞏固治療高度有效毒性較低，是不可切除III期NSCLC的有效治療選擇放化療階段：ORR 55.6%，DCR 78.5% (ITT)毒性資料與其他方案相比有優(yōu)勢(shì)口服長(zhǎng)春瑞濱可能減少放化療期間計(jì)劃中的約束長(zhǎng)春瑞濱聯(lián)合順鉑鞏固治療顯著提高DCR (P=0.0084)延長(zhǎng)放化療后SD患者的PFS目前，在未經(jīng)

33、選擇患者中，沒(méi)有顯著的生存獲益總生存期與既往公布的結(jié)果一致,Huber RM, et al. 2012 ASCO Abstract 7001.,四、同期放化療 化療方案的選擇,化放療方案,* 隨機(jī)研究資料支持含順鉑的方案優(yōu)于含卡鉑的方案，并且順鉑應(yīng)予全量，含卡鉑的方案尚待研究。,Cisplatin/etoposide (EP) vs. weekly paclitaxol/carboplatin (PC) with r

34、adiotherapy for patients with locally advanced non-small cell lung cancer,Phase II study,Oral presentation in ASTRO 2010Lung Cancer 77 (2012) 89– 96,Treatment,Legend:,Chemotherapy,EPCisplatin: 50mg/m2, day 1, 8, 29, 36

35、VP-16: 50mg/m2, day 1 to 5 and 29 to 33Hydration and polyantiemeticPC (day 1, 8, 15, 22, 28)Carboplatin AUC 2Paclitaxol 45mg/m2Antiemetic drugsConsolidation treatment,Radiotherapy,GTVThe primary diseaseLymph nod

36、es involved CTVPrimary tumor plus a 0.7cm marginRegion of ipsilateral hilum, subcarina, and ipsilateral mediastinal to the highest lymph node stations involvedContralateral mediastinal if contralateral mediastinal ly

37、mph nodes were involvedPTVextended from CTV by motion and system errorTotal dose: 60-66Gy,The characteristics of 65 patients,Treatment delivery,Follow-up,Follow-up until 20 Dec 2009Median follow-up time for alive pat

38、ients 37.2mMST: 15.5m; 1, 2, 3 yr OS: 61.5%, 26.2%, 22.9%,Response,Overall survival,P=0.037,EP arm,PC arm,Progress Free Survival,Treatment-related toxicities,,Conclusion,This trial shows(1) A favorable survival and (2)

39、 a different toxicity profile of the PE-based ChRT program comparing to that of weekly PC-based ChRT program,培美曲塞與卡鉑或順鉑聯(lián)合同步放療后以培美曲塞鞏固治療預(yù)后良好的不可手術(shù)IIIA/B期NSCLC患者的II期研究,Choy H, et al. 2012 ASCO Abstract 7002.,研究設(shè)計(jì),Choy H,

40、et al. 2012 ASCO Abstract 7002.,主要終點(diǎn)：2年OS率次要終點(diǎn)：OSTTPORR毒性,研究結(jié)果：劑量與療效,Choy H, et al. 2012 ASCO Abstract 7002.,*P=0.270; **P=0.057,研究結(jié)果：4級(jí)毒性,Choy H, et al. 2012 ASCO Abstract 7002.,沒(méi)有發(fā)生藥物相關(guān)死亡研究結(jié)論：雖然受到樣本量的限制，本研究提示培美曲

41、塞聯(lián)合順鉑的OS與TTP有優(yōu)勢(shì)，兩種同步放化療方案的耐受性都較好,比較標(biāo)準(zhǔn)胸部放療聯(lián)合或不聯(lián)合每日低劑量卡鉑同步治療老年局部晚期NSCLC的III期研究的更新結(jié)果：JCOG0301,Okamoto H, et al. 2012 ASCO Abstract 7017.Lancet Oncol 2012 May 21,JCOG0301：研究設(shè)計(jì),主要終點(diǎn)：OS期望中位OS從RT組的10個(gè)月提高到CRT組的15個(gè)月（計(jì)劃樣本量?jī)山M各1

42、00例，一側(cè)α值為5%，把握度80%）,Okamoto H, et al. 2012 ASCO Abstract 7017. Lancet Oncol 2012 May 21,JCOG0301：OS (主要終點(diǎn)),Okamoto H, et al. 2012 ASCO Abstract 7017.,研究結(jié)果： 3年生存率,Okamoto H, et al. 2012 ASCO Abstract 7017.,研究結(jié)果： ORR,Okam

43、oto H, et al. 2012 ASCO Abstract 7017.,研究結(jié)果： PFS,Okamoto H, et al. 2012 ASCO Abstract 7017.,研究結(jié)果： 3/4級(jí)不良事件,Okamoto H, et al. 2012 ASCO Abstract 7017.,兩組間復(fù)發(fā)部位與方案制定后的治療情況相似通過(guò)Cox回歸分析對(duì)6個(gè)變量(分期、PS、性別、年齡、組織學(xué)、吸煙狀態(tài))調(diào)整后，CRT組仍顯示出更

44、好的生存 (HR=0.71; P=0.038)研究結(jié)論： 每日卡鉑的同步放化療是老年局部晚期NSCLC的標(biāo)準(zhǔn)治療,五、同期放化療 與放射性肺炎,Received Mar 8, 2012, and in revised form Apr 19, 2012. Accepted for publication Apr 29, 2012,化療方案，V20 是放射性肺炎獨(dú)立的相關(guān)因素,,Conclusion,Pati

45、ents undergoing CCRT for NSCLC, pneumonitis risk is associated with the type of chemotherapy regimen, dosimetric parameters, and patient age.Fatal pneumonitis is uncommon but is associated with large doses per fraction,

46、 large V20, and lower-lobe tumors. Further research is needed to evaluate methods to mitigate pneumonitis risk in patients undergoing curative-intent CCRT.,Poor Baseline Pulmonary Function May Not Increase the Risk of Ra

47、diation Induced Lung Toxicity,Jingbo Wang, M.D.; Jianzhong Cao, M.D. ; Shuanghu Yuan, M.D.; Wei Ji, M.D.; Douglas Arenberg, M.D.; Jianrong Dai, Ph. D.; Paul Stanton, B.A. ; Daniel Tatro; Randall K Ten Haken, Ph. D.; Luhu

48、a Wang, M.D.; Feng-Ming (Spring) Kong, M.D., Ph.D.Accepted by International Journal of Radiation Oncology*Biology*Physics,Purpose: Poor pulmonary function (PF) is often considered a contraindication for definitive rad

49、iotherapy for lung cancer. This study investigates whether baseline PF is associated with radiation induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC) receiving conformal radiation thera

50、py (CRT).,Correlation between PFTs and ≥ G2 SRILT,Logistic regression for analytical variables,非小細(xì)胞癌患者≥2級(jí)放射性肺損傷綜合參數(shù)的多因素分析--北京單中心分析結(jié)果,,Multivariate analysis including MLD and PF parameters as continuous variables-聯(lián)合分析結(jié)果,

51、Multivariate analysis including MLD and PF parameters as categorical variables,Individual based scatter plot indicates no linear correlation between MLD and FEV1.,Based on 247 patients with complete data, ROC curves in f

52、igure 2 displayed that the addition of age to MLD based model did not enhance the predictability for SRILT (AUC 0.63 vs. 0.64, p = 0.65). However, the combination of age and the dichotomized MLD (17.4 Gy split) and FEV1

53、(65% split) can marginally improve the predictive efficacy of SRITL than that of MLD alone (AUC = 0.70, p = 0.088).,Conclusion,Age and MLD were independently correlated with SRILT. Lower baseline pulmonary function

54、did not increase the risk of SRILT and might even be associated with lower probability of SRILT, Which suggests that poor PFTs should not be a contraindication to definitive radiation therapy. FEV1 may help p

55、redicting the risk for SRILT.,,94,Three Clinical Research Topics in Radiotherapy of Locally Advanced NSCLC,1、Combined Treatment： Concurrent Chemoradiotherapy同時(shí)放化療中化療方案的選擇誘導(dǎo)化療或鞏固化療的必要性和化療方案放射治療與生物靶向治療的聯(lián)合應(yīng)用,95,Thr