非小细胞肺癌的放射治疗.ppt

非小细胞肺癌非小细胞肺癌-放射治疗放射治疗Lung Cancer ScreeningLung Cancer ScreeningFrom Presentation at:2011 ASCO Annual MeetingFrom Presentation at:2011 ASCO Annual MeetingStageStageIncidenceIncidenceTreatmentTreatment5-YrSurvival5-YrSurvivalI15-20%Surgery or SBRT60-80%II5-10%SurgeryChemotherapy40-50%III30-35%Combined-Modality Tr15-40%IV35-40%ChemoRT5%rSBRT vs.手术rSBRT靶区勾画rSBRT毒副反应I I期期NSCLC-NSCLC-放射治疗放射治疗SBRT-Inoperable stage I NSCLCSBRT-Inoperable stage I NSCLCSBRTSBRT是无法耐受手术的外周型是无法耐受手术的外周型I I期期NSCLCNSCLC的首选治疗的首选治疗JAMA.2010;303:1070-6JAMA.2010;303:1070-6.Phase II trial of SBRT for medically Phase II trial of SBRT for medically inoperable stage I/II NSCLC-RTOG 0236inoperable stage I/II NSCLC-RTOG 023655 patients 55 patients T 5 cm,N0,M0 T 5 cm,N0,M0 20 Gy in 3 fractions 20 Gy in 3 fractions over 1.5 to 2 weeksover 1.5 to 2 weeksrResultsResults3-year primary tumor control rate:97.6%3-year primary tumor control rate:97.6%Disease-free survival at 3 years:48.3%Disease-free survival at 3 years:48.3%Overall survival Overall survival at 3 years:at 3 years:55.8%55.8%Median overall survival:48.1 monthsMedian overall survival:48.1 months2012201220122012SBRT vs 3DCRT SBRT-Operable stage I NSCLCInt J Radiat Oncol Biol Phys.2011;81:1352-8.rSBRT is safe and promising treatment for operable Stage I NSCLC rThe survival rate for SBRT is potentially comparable to that for surgery Retrospective AnalysisSBRT VS.Surgery TrialsSBRT VS.Surgery TrialsClosed prematurelySlowly accruingSBRT vs Surgery RTOG foundation study 3502 is kicking off soonRTOG foundation study 3502 is kicking off soon 中方中方PI 于金明于金明，山东省肿瘤防治研究院，山东省肿瘤防治研究院美国美国PIFeng-Ming(Spring)Kong，美国密西根大学肿瘤中心，美国密西根大学肿瘤中心A Randomized Trial in Patients with Operable Stage I Non-Small Cell Lung Cancer:Radical Resection Vs Ablative Stereotacitic Radiotherapy(POSITLV)I I期期NSCLC-NSCLC-中心型中心型中心型中心型NSCLCNSCLC（距离支气管树（距离支气管树2cm2cm内）可能对临近气管、食管及大血内）可能对临近气管、食管及大血管造成损伤管造成损伤RTOG 0813 I/IIRTOG 0813 I/II期研究剂量爬坡期研究剂量爬坡(50Gy/5f(50Gy/5f）研究适合中心型）研究适合中心型NSCLCNSCLC的分割模式及最大耐受剂量的分割模式及最大耐受剂量靶区勾画靶区勾画-SBRT-SBRTGTVGTV在肺窗进行勾画，纵膈窗可区分邻近血管或胸壁结构在肺窗进行勾画，纵膈窗可区分邻近血管或胸壁结构GTVGTV不外扩，不外扩，GTV=CTVGTV=CTVGTVGTV在水平面上外扩在水平面上外扩0.5cm0.5cm，在头尾方向外扩，在头尾方向外扩1cm1cm为为PTVPTV4D CT4D CT设备的中心使用呼气或吸气图像或最大密度投影设备的中心使用呼气或吸气图像或最大密度投影(MIP)(MIP)时可能会产生一个内靶区（时可能会产生一个内靶区（IGTVIGTV）无无4D-CT4D-CT，GTVGTV勾画应建立在慢勾画应建立在慢CTCT扫描的基础上扫描的基础上PTV=IGTV+PTV=IGTV+摆位摆位 误差误差(根据各肿瘤中心而定）根据各肿瘤中心而定）SBRTSBRT毒副反应毒副反应55 inoperable patients with T1-2N0M0 peripheral NSCLC55 inoperable patients with T1-2N0M0 peripheral NSCLCRTRT：20Gy 20Gy3 3（RTOG 0236RTOG 0236）Logistic regression to investigate relationship between Logistic regression to investigate relationship between Pulmonary Function(PF)and pulmonary toxicity.Pulmonary Function(PF)and pulmonary toxicity.Cox proportional hazards models to evaluated between PF Cox proportional hazards models to evaluated between PF test and OStest and OS2012Results&ConclusionsResults&ConclusionsBaseline PF was not predictive of radiation pneumonitis or any Baseline PF was not predictive of radiation pneumonitis or any pulmonary toxicity following SBRTpulmonary toxicity following SBRTThere did not appear to be a relationship between the There did not appear to be a relationship between the occurrence of radiation pneumonitis and normal lung tissue occurrence of radiation pneumonitis and normal lung tissue dosedosePoor baseline PF alone did not appear to predict decreased OSPoor baseline PF alone did not appear to predict decreased OSPoor baseline PF alone within the range defining trial eligibility Poor baseline PF alone within the range defining trial eligibility should not be used to exclude early stage NSCLC pts from SBRTshould not be used to exclude early stage NSCLC pts from SBRTII期期NSCLC-放射治放射治疗II II期期NSCLCNSCLCII期NSCLC术后不推荐给予术后放疗不可手术切除或患者，首选治疗为根治性放疗同步放化疗的应用尚无明确定论不可手术患者，根治性同步放化疗(60-74Gy)，5年OS 15-23%肺上沟瘤易侵犯临近结构如臂丛、胸膜或肋骨，通常分期为T3-T4同步放化疗联合手术是可切除肺上沟瘤的首选治疗，45Gy 常规分割，5年生存率44-59%r术后放疗的价值r术后化放疗顺序r术后靶区的勾画AA期期NSCLC-NSCLC-放射治疗放射治疗AA期期NSCLCNSCLCA期NSCLC单纯完全切除术后5年生存率约为20-35%，术后复发率、死亡率高术后辅助化疗已有I类循证证据显示其明确的临床获益A期NSCLC包括T1-4或N0-3，异质性很大，对于A(N2)患者，仅行手术/化疗的局部复发率达30%-60%对于切除状态不完全或不确定的A(N2)患者，需要进行术后辅助放疗和化疗手术完全切除后是否需要辅助辅助放疗是目前争论的焦点IIIaIIIa不同预后亚群及治疗选择不同预后亚群及治疗选择Ruckdeschel Ruckdeschel 将将N2N2分为四种预后显著不同亚型分为四种预后显著不同亚型 亚型亚型 描描 述述 治疗选择治疗选择IIIa-1IIIa-1术前和术中未发现而术后病术前和术中未发现而术后病理确诊有理确诊有 N2 N2 淋巴结转移淋巴结转移手术手术+术后辅助化疗、放疗术后辅助化疗、放疗IIIa-2IIIa-2术中发现术中发现N2N2单组淋巴结转移单组淋巴结转移 手术手术+术后辅助化疗、放疗术后辅助化疗、放疗IIIa-3IIIa-3术前检查术前检查N2N2淋巴结有单组或淋巴结有单组或多组转移，多组转移，但融合无固定但融合无固定新辅助放化疗新辅助放化疗-如有效如有效-手术手术或或同步放化疗同步放化疗巩固化疗巩固化疗IIIa-4IIIa-4N2N2呈大块状或多组转移表现，呈大块状或多组转移表现，转移的淋巴结固定转移的淋巴结固定不可手术切除不可手术切除 同步放化疗同步放化疗巩固化疗巩固化疗A-术后放疗:Evidence-Based研究（年代）研究（年代）病例（病例（AA期）期）主要结论主要结论Mayo ClinicMayo Clinic（19971997）224224（224224）PORTPORT能显著提高患者的局控率（能显著提高患者的局控率（17%vs 60%,17%vs 60%,p p0.00010.0001）和生存率）和生存率22%vs 43%,p=0.00522%vs 43%,p=0.005）MRC MRC（1999)1999)308(113)308(113)亚组分析显示亚组分析显示PORTPORT能降低局部复发和远处转移，能降低局部复发和远处转移，延长生存期延长生存期 SEER DatabaseSEER Database（20062006）7465(2738)7465(2738)PORTPORT显著提高了显著提高了N2N2阳性患者的生存获益阳性患者的生存获益 (5-yr(5-yr 20%vs27%,HR=0.855;95%CI,0.762-20%vs27%,HR=0.855;95%CI,0.762-0.959;p=.0077)0.959;p=.0077)ANITA ANITA（20082008）840(294)840(294)亚组分析显示亚组分析显示PORTPORT提高了提高了N2N2患者的患者的5-ys(34%5-ys(34%vs 47%)vs 47%)卢铀等（2010）183与术后辅助化疗相比，术后辅助化疗、放疗提与术后辅助化疗相比，术后辅助化疗、放疗提高了患者的生存期（高了患者的生存期（p=0.007p=0.007）王绿化等（2011）221术后放疗显著改善OS（P=0.046）和无病生存（P=0.009）术后放疗Meta分析结果及缺陷结论：结论：术后放疗对生存率的降低与分期相 关。I、期明显，期病例术后放期病例术后放疗对生存率没有明显影响疗对生存率没有明显影响 缺陷：缺陷：3/9随机研究是未发表资料 每组样本量偏小 时间跨度大 分期不明确 入选标准差异大 放疗技术特点：放疗技术特点：大多数接受Co60 线照射 部分患者采用单野照射 4/9个临床试验的单次剂量2Gy 4/9个研究的总剂量=60Gy该Meta分析，入组了自1965年以来符合标准的手术联合化疗放疗13项临床研究 9项临床试验采用先化疗后放疗模式4项临床试验采用同步放化疗模式序贯化、放疗和同步放化疗之间无显著性差异（P=0.28）A术后化疗、放疗顺序2013 NCCN：化疗、放疗顺序尚无定论，但可优先选择先化疗后放疗模式关于a完全切除术后辅助化疗、放疗顺序有待随机临床试验证明A术后化疗、放疗顺序A术后放疗靶区目前术后放疗靶区勾画各肿瘤中心存在分歧荷兰研究分析了来自不同肿瘤中心的17位胸部肿瘤放疗专家勾画A（N2）NSCLC术后靶区:不同医生之间术后放疗靶区勾画存在着较大差异前瞻性临床试验的研究方案统一确定的靶区勾画能降低这种差异Int J Radiat Oncol Biol Phys,2010,76:1106-1113.A术后放疗靶区 不同肿瘤中心放疗靶区University of Michigan Cancer Center支气管残端+同侧肺门+隆突下+阳性区域淋巴结同侧上下一站纵隔区域淋巴结MD Anderson Cancer Center支气管残端+阳性区域淋巴结同侧肺门、隆突下（根据肿瘤位置和淋巴结清扫程度）中科院肿瘤医院支气管残端+同侧肺门、同侧纵隔区域淋巴结、隆突下山东省肿瘤医院支气管残端+阳性区域淋巴结+同侧肺门+隆突下Handbook of Evidence Based Radiation Oncology Second Editionr同步化疗方案r同步放疗剂量r放疗靶区勾画r靶向联合放疗BB期期NSCLC-NSCLC-放射治疗放射治疗同步化疗方案同步放化疗为首选标准治疗同步放化疗优于序贯放化疗和单纯放疗同步化疗方案：2013NCCN增加了培美曲塞联合顺铂或卡铂方案同步化疗方案之间目前无孰优孰劣顺铂为主的同步化疗方案优于卡铂（王绿化等，III期临床试验-NCT01494558待发表）同步放疗剂量Carbo/Taxol WeeklyRadiation to 60GyCarbo/Taxol2-3 wk cyclesStage III NSCLC N=512 ptsCarbo/Taxol Weekly+Weekly ErbituxRadiation to 60GyCarbo/Taxol2-3 wk cycles+Weekly ErbituxCarbo/Taxol WeeklyRadiation to 74GyCarbo/Taxol2-3 wk cyclesCarbo/Taxol Weekly+Weekly ErbituxRadiation to 74GyCarbo/Taxol2-3 wk cycles+Weekly ErbituxJeffery Bradley et al.2011 ASTRO Annual MeetingJeffery Bradley et al.2011 ASTRO Annual Meeting Overall survivalOverall survival根治性放化疗通常推荐的放疗剂量仍是60Gy放疗靶区勾画放疗靶区勾画-IFI-IFISTDSTDF FIFIFStage III NSCLC:ChT/RT;200 Pts RandomizedStage III NSCLC:ChT/RT;200 Pts RandomizedParameterParameter2Yr LF2Yr LF1Yr OS1Yr OS2Yr OS2Yr OS3Yr OS3Yr OSENI4959.725.619.2IFRT4167.238.727.3P=0.048Am J Cli Oncol 2007;30:239-244放疗靶区勾画放疗靶区勾画-IFI-IFINSCLCNSCLC累及野照射较预防照射提高了疗效并降低了放射损伤累及野照射较预防照射提高了疗效并降低了放射损伤2 2年生存率由常规放疗的年生存率由常规放疗的25.6%25.6%提高到提高到39.4%39.4%放射性肺损伤由常规放疗的放射性肺损伤由常规放疗的29%29%降低到降低到17%17%预防照射预防照射累及野照射累及野照射美国国家癌症治疗协作网最新修订美国国家癌症治疗协作网最新修订的的肿瘤治疗指南肿瘤治疗指南采用了我们的采用了我们的研究：将肺癌放疗靶区的定义由预研究：将肺癌放疗靶区的定义由预防性淋巴结照射改为累及野照射防性淋巴结照射改为累及野照射美国美国RTOG-0617临床试验临床试验的参照的参照The Phase II Trial Of Erlotinib-RT After Chemo-RT For The Phase II Trial Of Erlotinib-RT After Chemo-RT For Patients With Stage III Non-Small Cell Lung Cancer Has Patients With Stage III Non-Small Cell Lung Cancer Has Shown A Favorable ResponseShown A Favorable Response NCI Trial Identifier:NCI-2012-01761NCI Trial Identifier:NCI-2012-01761Ritsuko Komaki,M.D.FACR,FASTRO Ritsuko Komaki,M.D.FACR,FASTRO The University of Texas MD Anderson Cancer The University of Texas MD Anderson Cancer Center,Houston,TXCenter,Houston,TX靶向联合放疗-Erlotinib2012Week1Week2Week3Week4Week5Week6Week7Days1234567123456712345671234567123456712345671234567RT12345123451234512345123451234512345Paclitaxel1111111Carboplatin1111111Erlotinib 234567 234567 234567 234567 234567 234567 234567XRT:63Gy/35FX/7weeks;1.8Gy/daily5;Paclitaxel:45mg/m2,Carboplatin:AUC=2 ConsolidationChemotherapy(Every 3 weeks;Two cyclesPaclitaxel:200mg/m2Carboplatin:AUC=6 Concurrent ChemoRT+Tarceva(150mg PO)48 Stage III NSCLC2012ResultsResultsTumor Responses by RECIST 3.0Tumor Responses by RECIST 3.0CRCRPRPRSD or PDSD or PDNot Not Available*Available*All 46 casesAll 46 cases14/46(30%)14/46(30%)23/46(50%)23/46(50%)8/46(18%)8/46(18%)1/46(2%)1/46(2%)EGFR mutationEGFR mutation(EGRR-M)(EGRR-M)3/4(75%)3/4(75%)0(0%)0(0%)0(0%)0(0%)1/4(25%)1/4(25%)EGFR wild typeEGFR wild type11/36(30%)11/36(30%)19/36(53%)19/36(53%)6/36(17%)6/36(17%)0(0%)0(0%)No dataNo data0(0%)0(0%)4/5(80%)4/5(80%)1/5(20%)1/5(20%)0(0%)0(0%)*One patient was not evaluable for tumor response due to no follow-up image p=0.0720122012ConclusionsConclusionsChemoradiotherapy F/B erlotinib/RT well toleratedChemoradiotherapy F/B erlotinib/RT well toleratedExcellent 2-year OS 67.7%and median survival time 34.1 monthsExcellent 2-year OS 67.7%and median survival time 34.1 monthsGrade 3 pneumonitis rate was 6.5%Grade 3 pneumonitis rate was 6.5%Erlotinib seemed to demonstrate a radiosensitization effect in Erlotinib seemed to demonstrate a radiosensitization effect in combination with chemoradiotherapycombination with chemoradiotherapyEGFR mutated patients might need maintenance EGFR-TKI to reduce EGFR mutated patients might need maintenance EGFR-TKI to reduce DMDMNeed to validate with a larger number of patients or in a randomized Need to validate with a larger number of patients or in a randomized prospective trialprospective trial2012Phase II Study of Nimotuzumab in Combination With Phase II Study of Nimotuzumab in Combination With Concurrent Chemoradiation Therapy in Patients With Concurrent Chemoradiation Therapy in Patients With Locally Advanced Non-small Cell Lung CancerLocally Advanced Non-small Cell Lung CancerKinki University Faculty Of medicine,JapanKinki University Faculty Of medicine,JapanShizuoka Cancer Center,JapanShizuoka Cancer Center,JapanHyogo Cancer Center,JapanHyogo Cancer Center,JapanThe Cancer Institute Hospital,JapanThe Cancer Institute Hospital,Japan2012靶向联合放疗-NimotuzumabMaterials/MethodsMaterials/MethodsMulticenter phase II study evaluated tolerability and efficacy Multicenter phase II study evaluated tolerability and efficacy of nimotuzumab in combination with concurrent CRT in pts of nimotuzumab in combination with concurrent CRT in pts with unresectable locally advanced NSCLCwith unresectable locally advanced NSCLCPts receive concurrent RT(60Gy/30F)and 4 cycles of Pts receive concurrent RT(60Gy/30F)and 4 cycles of Chemo(NP)Chemo(NP)Nimotuzumab(200mg)was administrated once a week from Nimotuzumab(200mg)was administrated once a week from cycle 1 to 4cycle 1 to 42012ResultsResults39 pts were eligible from 7 institutions39 pts were eligible from 7 institutions34 Pts(87%)met criteria for treatment tolerability34 Pts(87%)met criteria for treatment tolerabilitygrade 3 skin rash,grade 3 skin rash,grade 3 radiation pneumonitis or grade 3 radiation pneumonitis or grade 4 nonhematological toxicity were not observedgrade 4 nonhematological toxicity were not observedThe 2 Yr OS rate was 76%;The median PFS was 16.7 monthsThe 2 Yr OS rate was 76%;The median PFS was 16.7 monthsIn-field relapse rates were low for Sq(19%)and non-Sq(13%)In-field relapse rates were low for Sq(19%)and non-Sq(13%)2012ConclusionsConclusionsAddition of nimotuzumab to concurrent CRT was Addition of nimotuzumab to concurrent CRT was well tolerated with clinical benefitwell tolerated with clinical benefitThe low in field relapse rates may be attributed to The low in field relapse rates may be attributed to radio-sensitizing effect of nimotuzumabradio-sensitizing effect of nimotuzumabThe finds warrant further clinical evaluation in a The finds warrant further clinical evaluation in a phase III trialphase III trial2012Meta-analysis of toxicities in Phase I or II trials studying the use of target therapy combined with radiation therapy in patients with locally advanced non-small cell lung cancer M.Santos,D.Lefeuvre,G.Le Teuff,et al.M.Santos,D.Lefeuvre,G.Le Teuff,et al.Institute Gustave Roussy,Paris,France.Institute Gustave Roussy,Paris,France.靶向联合放疗-Meta analysis2012Materials/MethodsMaterials/MethodsPhase I,I/II and II trials published between 2000 Phase I,I/II and II trials published between 2000 and 2011 treated by targeted therapy(TT)with and 2011 treated by targeted therapy(TT)with Chemo-RTChemo-RTPooled incidence rates of all and specific AEs Pooled incidence rates of all and specific AEs were estimatedwere estimatedPooled medians of PFS and OS were studiedPooled medians of PFS and OS were studied2012ResultsResultsEight trials(4 phase I,4 phase II)including 242 pts Eight trials(4 phase I,4 phase II)including 242 pts testing 4 drugs(Bevacizumab,Cetuximab,Erlotinib and testing 4 drugs(Bevacizumab,Cetuximab,Erlotinib and Gefitinib)Gefitinib)The pooled incidence rates of AE in TT/Chemo-RT was The pooled incidence rates of AE in TT/Chemo-RT was statistically higher than that estimated in Chemo-RT statistically higher than that estimated in Chemo-RT groupgroupMedian PFS and OS were 10.0 and 18.4 months in Median PFS and OS were 10.0 and 18.4 months in TT/Chemo-RT and 9.9 and 16.2 months in Chemo-RT TT/Chemo-RT and 9.9 and 16.2 months in Chemo-RT(p=0.98 and P=0.37)(p=0.98 and P=0.37)2012ConclusionsConclusionsThe use of TT combined to Chemo-RT seemed to The use of TT combined to Chemo-RT seemed to increase significantly the rate of severe adverse increase significantly the rate of severe adverse events in NSCLC pts as compared to Chemo-RTevents in NSCLC pts as compared to Chemo-RTNo significant difference was observed in survial No significant difference was observed in survial endpointsendpointsHeterogeneity was observed between different Heterogeneity was observed between different trialstrials2012一项前瞻性、开放、随机对照、多中心一项前瞻性、开放、随机对照、多中心期临床研究评估同期期临床研究评估同期厄洛替尼联合放疗对比同期依托泊甙顺铂（厄洛替尼联合放疗对比同期依托泊甙顺铂（EPEP）方案联合放疗）方案联合放疗用于伴有表皮生长因子受体用于伴有表皮生长因子受体1919或或2121外显子活化突变的不可切除外显子活化突变的不可切除期非小细胞肺癌（期非小细胞肺癌（NSCLCNSCLC）的疗效及安全性）的疗效及安全性(RECEL ML 28545RECEL ML 28545)A multicenter,randomized,open-label,phase II trial of Erlotinib versus Etoposide plus Cisplatin with concurrent radiotherapy in unresectable stage III non-small cell lung cancer(NSCLC)with activating mutation of epidermal growth factor receptor(EGFR)in exon 19 or 21山东省肿瘤医院；中国医学科学院肿瘤医院复旦大学附属肿瘤医院；天津肿瘤医院河北省肿瘤医院；浙江省肿瘤医院北京肿瘤医院；四川华西医院中国人民解放军总医院；杭州市第一人民医院等l不可切除不可切除IIIA/IIIB NSCLCIIIA/IIIB NSCLCl未行任何治疗未行任何治疗lEGFR 19EGFR 19或或2121外显子突变外显子突变(+)(+)l1818岁，岁，7575岁岁lECOG PS 0ECOG PS 01 1 n n100100RPDPD同步放化疗（同步放化疗（8 8周）周）顺铂顺铂 50mg/m 50mg/m2 2 d1,8,29,36 d1,8,29,36依托泊甙依托泊甙 50mg/m 50mg/m2 2 d1-5,29-33 d1-5,29-33同期同期RT 60-66Gy/30-33frRT 60-66Gy/30-33fr同步治疗同步治疗(8(8周周)厄洛替尼厄洛替尼 150mg/day150mg/day同期同期 RT 60-66Gy/30-33frRT 60-66