1、1,局部晚期非小细胞肺癌的同期放化疗进展,中国医学科学院协和医科大学肿瘤医院 王绿化,2,一、影像技术和计算机技术的进步为精确放射治疗的实现提供可能,3,肿瘤功能显像,4,5,肺灌注功能显像,肿瘤压迫相关灌注减低病例特征p右肺鳞癌 T2a N2 M0 IIIA期 右肺上叶下叶各一结节伴阻塞性炎症右肺门、纵膈2R、4R淋巴结转移右肺上叶、右肺中叶灌注减低,6,屏气技术举例: Elekta ABC,7,四维CT影像技术,呼气,吸气,螺旋开始,时相,由吸转呼,呼气末,由呼转吸,由吸转呼,呼气,吸气,螺旋开始,呼吸曲线,床位,8,影像引导放射治疗技术IGRT,40对叶片MLC,KV级X射线球管,KV级
2、探测器阵列,MV级探测器阵列,9,在线校正影像匹配,10,二、同期放化疗是局部晚期NSCL的标准治疗模式,局部晚期NSCLC,Evolution of Treatment Strategy Operable：,Surgery Surgery RT Surgery RT CT,CT + Surgery RT/CT + Surgery 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
3、 CT/RT Consolidation?,Inoperable序贯放化综合治疗同步放化综合治疗Operable a-N2RT/CT + Surgery vs RT/CT CT + Surgery vs CT / RT,序贯化放疗荟萃（META）分析,22trails 3033cases Favor Gr HR benefit% sur% 2y 5y 2y 5y Chemo 0.90 3 2 R+DDP 0.87 4 2 15 19 5 7 p=0.005 DDP 40-120mg/m2/cycle, total dose 120-800mg/m2radiation dose 50Gy/20f
4、- 65Gy/ 30f,结论：序贯放疗/化疗优于单纯放射治疗,同时化放疗 vs 序贯化放疗,同时化放疗 vs 序贯化放疗(1) 序贯化放疗 同时化放疗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% 同时化放疗: 提高局部控制率和生存率Furuse K, et al. J Clin. Oncol. 1999; 17:2692-2699,RTOG 9410:III期NSCLC 同步放化疗 vs 序贯放化疗,序贯: PV - RT (60 Gy, 2Gy QD) day 50 同步: PV/RT (60 Gy, 2
5、Gy QD) day 1 同步/HFRT: PE/HFRT (69.2 Gy, 1.2Gy BID) day 1PV: 顺铂/长春花碱PE: 顺铂/oral 足叶乙甙RT: 放疗; QD: 每日一次; HFRT: 超分隔放疗,Curran: ASCO, 2000; updated IASLC 2000; ASTRO 2001,2003,RANDOMIZE,同时化放疗 vs 序贯化放疗(2) SEQ CON-QD CON-BID 中位生存期： 14.6 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统毒性： 30%，48%，62% 和 14%
6、，15%，16%。Curran W et al. Pro. Am Soc Clin Oncol. J. Clin. Oncol. 2003; (abstract 2499),结论：同步放化疗优于序贯放化疗，但是，急性毒性反应增加,三、诱导化疗+同期放化疗 或同期放化疗+巩固化疗 未能提高同期放化疗的疗效,Induction Chemotherapy Followed by Chemoradiotherapy With Chemoradio-therapy Alone for Regionally Advanced Unresectable StageIII NonSmall-CellLung:
7、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 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 chemot
8、herapy increases neutropenia and overall maximal toxicity 没有生存优势 No survival benefit over concurrent therapy alone同期放化疗是标准的治疗模式 Concomitant chemoradiotherapy is current standard therapy for unresectable stage IIIB NSCLC,SWOG 9504: 同步放化疗后应用泰索帝 巩固化疗治疗IIIb 期NSCLC,顺铂/VP-16 X XRT泰索帝 X X X,顺铂 50mg/m2 d 1,
9、 8, 29, 36 VP-16 50mg/m2 d1-5, 29-33RT: 61 Gy: 45Gy(1.8Gy/fx), 16Gy 缩野 (2Gy/fx)泰索帝: 75mg/m2 cycle 1 - 100mg/m2 cycle 2-3,SWOG 9504: 总生存-Promising,%,%,%,%,%,%,0,4,8,入组时间（月）,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比较,*95% CI,HOG LUN 01-24 Phase III Study Design,Hanna et al. AS
10、CO 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 IIIA vs IIIB CR vs non-CR,Inclusion at baseline Unresectable stage IIIA or IIIBNSCLC ECOG PS 0-1 at study entry(+PS2 at rando
11、m) FEV-1 1 liter at study entry,203 patients,147 patients,73 patients,74 patients,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 patients surv
12、iving,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; Consolidation D does not further improve survival, is associated with significant toxicity including a
13、n increased rate of hospitalization and premature death, And should no longer be used for pts with unresectable stage III NSCLC,Conclusions,局部晚期NSCLC同步放化疗后巩固化疗能否带来获益？Meta analysis,Yamamoto S, et al. 2012 ASCO Abstract 7000.,研究方法与结果,研究方法：通过Pubmed系统检索1995年1月1日-2011年10月31日上发表的评价同步放化疗治疗局部晚期NSCLC生存的II/II
14、I期试验研究结果：共检索到41项研究：III期研究7项；II期研究34项；共45组有巩固化疗25组(N=1707)；无巩固化疗20组(N=1740)两组临床分期、体力状态、组织学类型、性别、中位年龄可比,Yamamoto S, et al. 2012 ASCO Abstract 7000.,基线特征,Yamamoto S, et al. 2012 ASCO Abstract 7000.,治疗情况,两组计划TRT剂量可比同步阶段，两组均有80%-90%的患者完成化疗/放疗,Yamamoto S, et al. 2012 ASCO Abstract 7000.,TRT=胸部放疗；CCT=巩固化疗,
15、影响中位生存的因素,Yamamoto S, et al. 2012 ASCO Abstract 7000.,上表中各变量的分布情况在两组间没有显著性差异 (P0.182),研究结果：中位OS,Yamamoto S, et al. 2012 ASCO Abstract 7000.,CCT-:无巩固化疗CCT+:有巩固化疗,亚组分析：有巩固化疗 vs. 无巩固化疗,Yamamoto S, et al. 2012 ASCO Abstract 7000.,研究结果：毒性,Yamamoto S, et al. 2012 ASCO Abstract 7000.,研究讨论与结论,本项基于发表文献的汇总分析未
16、能证明巩固化疗能够改善局部晚期NSCLC的总生存除了临床研究外，不应推荐同步放化疗后的巩固化疗出乎意料的是，整个治疗过程中两组的毒性可比，可能的解释是实际巩固化疗的周期数低于预计根据基因改变，将分子靶向治疗结合到该治疗模式中可能是未来临床研究的方向需要评估巩固化疗影响的临床研究,Yamamoto S, et al. 2012 ASCO Abstract 7000.,GILT研究：比较口服长春瑞滨与顺铂联合同步放疗后口服长春瑞滨顺铂联合BSC与BSC巩固治疗III期NSCLC的一项III期研究的最终结果,Huber RM, et al. 2012 ASCO Abstract 7001.,GILT
17、* CT-RT：研究背景*German InterGroup Lung Trial group,同步放化疗（CT-RT）是身体状况好的III期不可手术的NSCLC患者的标准治疗常见CT-RT后的全身复发加上巩固化疗是否能对所有或某些亚组的同步化放疗患者带来获益尚不清楚*German InterGroup Lung Trial group,GILT：研究设计,Huber RM, et al. 2012 ASCO Abstract 7001.,主要终点：PFS,根据分期分层,GILT：主要入组标准,既往未经治疗的组织学或细胞学确诊的NSCLC不可手术的IIIA(N2)或IIIB期适合接受66Gy根
18、治性放疗(TNM第六版)18-75岁生存预期12周KPS80%既往3个月内体重减轻10%足够肺、骨髓、肝肾功能至少1个可测量病灶,Huber RM, et al. 2012 ASCO Abstract 7001.,GILT：基线特征,Huber RM, et al. 2012 ASCO Abstract 7001.,GILT：研究结果 疗效,Huber RM, et al. 2012 ASCO Abstract 7001.,*HR=0.93; 95%CI=0.69-1.26,GILT：研究结果 PFS与OS,Huber RM, et al. 2012 ASCO Abstract 7001.,G
19、ILT：研究结果 3/4级毒性,Huber RM, et al. 2012 ASCO Abstract 7001.,GILT：研究结论,在这项III期研究中，同步口服长春瑞滨与顺铂联合放疗后行巩固治疗高度有效毒性较低，是不可切除III期NSCLC的有效治疗选择放化疗阶段：ORR 55.6%，DCR 78.5% (ITT)毒性资料与其他方案相比有优势口服长春瑞滨可能减少放化疗期间计划中的约束长春瑞滨联合顺铂巩固治疗显著提高DCR (P=0.0084)延长放化疗后SD患者的PFS目前，在未经选择患者中，没有显著的生存获益总生存期与既往公布的结果一致,Huber RM, et al. 2012 AS
20、CO Abstract 7001.,四、同期放化疗 化疗方案的选择,化放疗方案,* 随机研究资料支持含顺铂的方案优于含卡铂的方案，并且顺铂应予全量，含卡铂的方案尚待研究。,Cisplatin/etoposide (EP) vs. weekly paclitaxol/carboplatin (PC) with radiotherapy for patients with locally advanced non-small cell lung cancer,Phase II study,Oral presentation in ASTRO 2010Lung Cancer 77 (2012) 89
21、 96,Treatment,Legend:,Chemotherapy,EPCisplatin: 50mg/m2, day 1, 8, 29, 36VP-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 nodes involved CTVP
22、rimary tumor plus a 0.7cm marginRegion of ipsilateral hilum, subcarina, and ipsilateral mediastinal to the highest lymph node stations involvedContralateral mediastinal if contralateral mediastinal lymph nodes were involvedPTVextended from CTV by motion and system errorTotal dose: 60-66Gy,The charac
23、teristics of 65 patients,Treatment delivery,Follow-up,Follow-up until 20 Dec 2009Median follow-up time for alive patients 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 show
24、s(1) A favorable survival and (2) a different toxicity profile of the PE-based ChRT program comparing to that of weekly PC-based ChRT program,培美曲塞与卡铂或顺铂联合同步放疗后以培美曲塞巩固治疗预后良好的不可手术IIIA/B期NSCLC患者的II期研究,Choy H, et al. 2012 ASCO Abstract 7002.,研究设计,Choy H, et al. 2012 ASCO Abstract 7002.,主要终点：2年OS率次要终点：OS
25、TTPORR毒性,研究结果：剂量与疗效,Choy H, et al. 2012 ASCO Abstract 7002.,*P=0.270; *P=0.057,研究结果：4级毒性,Choy H, et al. 2012 ASCO Abstract 7002.,没有发生药物相关死亡研究结论：虽然受到样本量的限制，本研究提示培美曲塞联合顺铂的OS与TTP有优势，两种同步放化疗方案的耐受性都较好,比较标准胸部放疗联合或不联合每日低剂量卡铂同步治疗老年局部晚期NSCLC的III期研究的更新结果：JCOG0301,Okamoto H, et al. 2012 ASCO Abstract 7017.Lanc
26、et Oncol 2012 May 21,JCOG0301：研究设计,主要终点：OS期望中位OS从RT组的10个月提高到CRT组的15个月（计划样本量两组各100例，一侧值为5%，把握度80%）,Okamoto H, et al. 2012 ASCO Abstract 7017. Lancet Oncol 2012 May 21,JCOG0301：OS (主要终点),Okamoto H, et al. 2012 ASCO Abstract 7017.,研究结果： 3年生存率,Okamoto H, et al. 2012 ASCO Abstract 7017.,研究结果： ORR,Okamoto
27、 H, et al. 2012 ASCO Abstract 7017.,研究结果： PFS,Okamoto H, et al. 2012 ASCO Abstract 7017.,研究结果： 3/4级不良事件,Okamoto H, et al. 2012 ASCO Abstract 7017.,两组间复发部位与方案制定后的治疗情况相似通过Cox回归分析对6个变量(分期、PS、性别、年龄、组织学、吸烟状态)调整后，CRT组仍显示出更好的生存 (HR=0.71; P=0.038)研究结论： 每日卡铂的同步放化疗是老年局部晚期NSCLC的标准治疗,五、同期放化疗 与放射性肺炎,Received Mar
28、 8, 2012, and in revised form Apr 19, 2012. Accepted for publication Apr 29, 2012,化疗方案，V20 是放射性肺炎独立的相关因素,Conclusion,Patients 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 as
29、sociated with large doses per fraction, 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 Radiation Induced Lung Toxicity,Jingbo Wang
30、, 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.; Luhua Wang, M.D.; Feng-Ming (Spring) Kong, M.D., Ph.D.Accepted by International Journal of Radiation Oncology*Biology*Physics
31、,Purpose: Poor pulmonary function (PF) is often considered a contraindication for definitive radiotherapy 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 rad
32、iation therapy (CRT).,Correlation between PFTs and G2 SRILT,Logistic regression for analytical variables,非小细胞癌患者2级放射性肺损伤综合参数的多因素分析-北京单中心分析结果,Multivariate analysis including MLD and PF parameters as continuous variables-联合分析结果,Multivariate analysis including MLD and PF parameters as categorical varia
33、bles,Individual based scatter plot indicates no linear correlation between MLD and FEV1.,Based on 247 patients with complete data, ROC curves in figure 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 com
34、bination of age and the dichotomized MLD (17.4 Gy split) and FEV1 (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 did not increase th
35、e 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 predicting the risk for SRILT.,94,Three Clinical Research Topics in Radiotherapy of Locally Advanced NSCLC,1、Combined Treatment： Concurrent Chemoradiotherapy同时放化疗中化疗方案的选择诱导化疗或巩固化疗的必要性和化疗方案放射治疗与生物靶向治疗的联合应用,95,Three Clinical Research Topics in Radiotherapy of Locally Advanced NSCLC,2、New Radiation Techniques: 3DRT，IMRT, IGRT, 4D RT3、Normal Tissue Protection： Radiation Pneumonitis and Esophagitis,96,谢谢,
