非小细胞肺癌放射治疗进展授课课件

1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234屏气技术举例:ElektaABC5四维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6影像引导放射治疗技术

IGRT

40对叶片MLCKV级X射线球管KV级探测器阵列MV级探测器阵列7在线校正—影像匹配108–116,2006Histology: Sqamous:122Birdas,2006SWOG9504:总生存3year

survivalrateASCO2005.是选择手术还是选择放疗？3yLRFSur.pN0pN1有害3、NormalTissueProtection：CurranWetal.Abstract7014.757(P=0.LocalFailureRates8一、放射治疗在肺癌治疗中的地位二、早期NSCL的放射治疗三、局部晚期NSCL的放疗/化疗综合治疗四、3DCRT提高NSCLC的生存率五、术后放射治疗9一、放射治疗在肺癌治疗中的地位应用循证医学的方法评价放射治疗在肺癌治疗中的地位。1011RT在SCLC治疗中的地位53.6%±3.3%SCLC病例在其疾病的不同时期需要接受放射治疗

45.4%±4.3%

为首程治疗（intheinitialtreatment）.

8.2%±1.5%

为复发和进展病例的治疗（laterforrecurrenceorprogression）12RT在NSCLC治疗中的地位64.3%±4.7%ofNSCLCcasesrequireRT.

45.9%±4.3%intheirinitialtreatment.

18.3%±1.8%laterinthecouseoftheillness13二、早期非小细胞肺癌的放射治疗

放射治疗能够使早期NSCLC获得治愈

14JapaneseStudies

I期NSCLC大剂量分割SRT获得满意的局部控制率

Institute Dose/fx/OTT

LC/Follow-up Uematsu 50-60/5-10/5d94%

(47/50)36M Kyoto 48Gy/4fr/12d96%

(49/51)20M

Arimoto 60Gy/8fr/11d92%

(22/24)24M Onimaru

60Gy/8fr/11d:88%

(50/57)18MNagataY,KyotoUniv,IASLC,200415SummaryofJapaneseStudies

Totalcases： 281Age: 39-92(median76)yearsPulmonarydisease: Positive:172,Negative:109Histology: Sqamous:122 Adeno:131, Others:28Stage: IA:178, IB:103Tumordiameter: 7-58(median23)mmMedicalOperability:

Inoperable:177, Operable:

104OnishiH,ASCO200416LocalControlandComplicationFollow-upperiod 2-128(median30)monthsLocalresponse CR26.9% PR59.1% NC14.0%Pneumonitis(NCI-CTC) Grade0:33.7% Grade1:59.9% Grade2:4.0% Grade3:1.2% Grage4:1.2%Esophagitis(Grade3) 1.2%Pleuraleffusion(transient) 1.6%Ribfracture 1.2%Bonemarrowsuppression 0.0%OnishiH,ASCO200417LocalFailureRatesTotalcases 38/281(13.5%) BED<100Gy 21/70(30.0%) BED>100Gy 17/211(8.1%)StageIA 17/177(9.6%)

BED<100Gy 8/41(19.5%) BED>100Gy 9/136(6.6%)StageIB 21/102(20.6%) BED<100Gy 13/29(44.8%) BED>100Gy 8/73(11.0%)Adenocarcinoma 17/122(14.0%)Squamouscellca. 18/131(13.7%)OnishiH,ASCO200418Mountain*JCOG*JNCCH*StageIAStageIB67%57%80%63%74%53%STI**90%

84%*Surgery**StereotacticIrradiationComparisonof5-YrOverallSurvivalBetweenSurgery&STISurvivalcurvesofoperableptsirradiated

withBEDof100GyormoreaccordingtoStagestageIA(n=47)stageIB(n=16)p=0.2OverallSurvivalTime(years)SummaryofJapaneseStudiesOnishiH,ASCO200419I期非小细胞肺癌立体定向放射治疗或楔形切除后的转归SRBT(n=55)楔形切除(n=69)P肺功能（FEV-1）1.39(0.86-2.37)1.31(0.52-3.0)NSCharlson合并症指数

3(1-4)4(3-6)<0.01年龄74(69-78)78(55-89)<0.01分期T1-T2T1-T2NS病变最大直径GTV:2.3(1-5.3)手术标本：1.7(0.4-4.7)-纵隔淋巴结转移0(PET,纵隔镜)0(手术)NS化疗16%10%NSGrillsetal:VP-1650mg/m2d1-5,29-33Hannaetal.HOGLUN01-24PhaseIIIStudyDesign108–116,20063Dvs2DinMEDICALLYINOPERABLELocalresponse CR26.9%Landreneau,1997JapaneseStudies

I期NSCLC大剂量分割SRT获得满意的局部控制率9032序贯化放疗同时化放疗*Surgery3、NormalTissueProtection：NagataY,KyotoUniv,IASLC,2004Birdas,200620I期非小细胞肺癌立体定向放射治疗或楔形切除后的转归21作者患者MFUTRRorLRDMOSCSSGinsberg,19951225417-6175Landreneau,1997422924-5838*602416-6538*Sienel,2007495416--67Sienel,200856451618-713145556-48Keenan,200454271196274El-Sherif,20062073171540-Lee,200335516304761Voynov,2005110414818-Birdas,200641255-54-27250---142514---I期非小细胞肺癌局部切除后的转归22作者患者MFUTRRorLRDMOSCSSOnisi,2007257388-14206590Negata,20054536216-3183-Uematsu,200150306146688Zimmerman,2006681712165173Fakiris,2009705012134382RTOG,0236552561572-I期非小细胞肺癌立体定向放射治疗后的转归232425早期非小细胞肺癌的放射治疗

放射治疗成为早期NSCLC的另一根治性治疗手段放射治疗在早期NSCLC治疗中的地位的确立，是肺癌治疗进展中的一个里程碑三、局部晚期NSCLC的治疗局部晚期NSCLC

EvolutionofTreatmentStrategy

Operable：

Surgery

Surgery±RTSurgery±RT±CT

CT+Surgery

RT/CT+SurgeryRT/CT±Surgery

RT/CT局部晚期NSCLC

EvolutionofTreatmentStrategy

Inoperable:

RT

CT+RTSequential

CT/RTConcurrent?InductionCTCT/RTCT/RTConsolidation?

Inoperable序贯放化综合治疗同步放化综合治疗OperableⅢa-N2RT/CT+SurgeryvsRT/CTCT+SurgeryvsCT/RT序贯化放疗荟萃（META）分析22trails3033cases

FavorGrHRbenefit%sur%

2y5y2y5yChemo0.9032R+DDP0.8742151957

p=0.005

DDP40-120mg/m2/cycle,totaldose120-800mg/m2

radiationdose50Gy/20f-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）13.316.53yLRFSur.21.1%33.9%同时化放疗:提高局部控制率和生存率FuruseK,etal.JClin.Oncol.1999;17:2692-2699RTOG9410:III期NSCLC

同步放化疗vs序贯放化疗

序贯:PV-->RT(60Gy,2GyQD)day50

同步:PV/RT(60Gy,2GyQD)day1

同步/HFRT:PE/HFRT(69.2Gy,1.2GyBID)day1 PV: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;updatedIASLC2000;ASTRO2001,2003RANDOMIZE二.同时化放疗vs序贯化放疗(2)SEQCON-QDCON-BID

中位生存期：14.61715.6（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%，15%，16%。CurranWetal.Pro.AmSocClinOncol.J.Clin.Oncol.2003;(abstract2499)

结论：

同步放化疗优于序贯放化疗，但是，急性毒性反应增加SurvivalafterinductionchemotherapyforpatientswithcompleteorpartialresponseP-value:0.ForpatientwhocannottolerateCT,Grage4:1.1%33.paclitaxel200mg/m260mg/m2weeklyPORT在N2中的作用四、NSCLC术后放射治疗PORTcanbesafelyusedwith3DCRT3Dvs2DinMEDICALLYINOPERABLELocalFailureRates?InductionCTCT/RTCT/RTConsolidation?结论：

同步放化疗优于序贯放化疗，但是，急性毒性反应增加二、早期NSCL的放射治疗同步放化疗？诱导化疗?巩固化疗同步放化疗诱导化疗InductionChemotherapyFollowedbyChemoradiotherapyWithChemoradio-therapyAloneforRegionallyAdvanced

UnresectableStageIIINon–Small-Cell

Lung:CancerandLeukemiaGroupB

CALGB39801JClinOncol.2007May1;25(13):1698-704.Epub2007AprCALGB39801studydesignJuly1998andwasclosedinMay2002,Totally366patientsregisteredSurvival

intent

to

treatSurvivalofeligiblepatientswitha

weightlossof≤5%Discussion

增加毒性

inductionchemotherapyincreasesneutropeniaandoverallmaximaltoxicity

没有生存优势

Nosurvivalbenefitoverconcurrenttherapyalone同期放化疗是标准的治疗模式

Concomitantchemoradiotherapyiscurrentstandard

therapyforunresectablestageIIIBNSCLCSimultaneousChemoradiotherapyComparedWithRadiotherapyAloneAfterInductionChemotherapyinInoperableStageIIIAorIIIBNon–Small-CellLungCancer:StudyCTRT99/97bytheBronchialCarcinomaTherapyGroupRudolfM.Huber,MichaelFlentje,MichaelSchmidt,BarbaraPöllinger,HelgaGosse,JochenWillner,andKurtUlmPCx3诱导化疗RandomizeRTaloneRT+Paclitaxel60mg/m2weeklypaclitaxel200mg/m2carboplatinAUC=6every3weeksX2cyclespaclitaxel60mg/m2weeklyRadiotherapyaloneSurvivalafterinductionchemotherapyforpatientswithcompleteorpartialresponse同步放化疗巩固化疗SWOG9504: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 XXX

顺铂50mg/m2d1,8,29,36VP-1650mg/m2d1-5,29-33RT:61Gy:45Gy(1.8Gy/fx),16Gy缩野(2Gy/fx)泰索帝:75mg/m2cycle1-->100mg/m2cycle2-3

SWOG9504:总生存%%%%%020406080100%012243648入组时间（月）

NEvents 中位生存83 45 26月2年生存率:54%3年生存率:37%

SWOG9504和SWOG9019比较研究病例MST(月)2年生存3年生存S9019(PE/RTPE)5015(10-22)*

34%(21-47)*17%(7-27)*S9504(PE/RT泰索帝)8326(18-35)*54%(43-65)*37%(22-52)**95%CISWAG0023ConcurrentChemo/RadioDDP+Vp16/RTConsolidationChemoDocetaxelMaintenanceGEFITINIBorPLACEBO同步放化疗巩固化疗ResultsofASCO2007HOGLUN01-24PhaseIIIStudyDesignHannaetal.ASCO2007:Abstract7512.ChemoRTCisplatin50mg/m2IVd1,8,29,36

Etoposide50mg/m2IVd1-5&29-33

ConcurrentRT59.4Gy(1.8Gy/fr)Stratification

atrandomization

PS0-1vs2IIIAvsIIIBCRvsnon-CR

InclusionatbaselineUnresectablestageIIIAorIIIB

NSCLCECOGPS0-1atstudyentry

(+PS2atrandom)FEV-1>1literatstudyentry203patients147patients73patients74patientsTaxotere

75mg/m2q3wk3ObservationPrimaryendpoint:OSSecondaryendpoints:PFS,toxicityHOGLUN01-24:OS(ITT)

RandomizedPatients(n=147)Hannaetal.ASCO2007:Abstract7512.MonthsSinceRegistration0102030405060Percentofpatientssurviving0%25%50%75%100%P-value:0.940Median3year

survivalrateObservation18.0-34.227.6%Taxotere17-34.827.2%ComparisonofGrade3-5ToxicitiesToxicitySWOG9504SWOG0023HOG01-24FebrileNeutropenia

PE/XRT

Docetaxel

NR9%~5%*~5%*9.9%10.9%Esophagitis17%~14%17.2%Pneumonitis7%7%8.2%Docetaxel-relateddeath4.8%4%5.5%*reportedas“infectionwithneutropenia”

HogLUGNo1-20/USO-023

TheMSTwithEP/XRTwashigherthanhistoricalcontrols;

ConsolidationDdoesnotfurtherimprovesurvival,isassociatedwithsignificanttoxicityincludinganincreasedrateofhospitalizationandprematuredeath,AndshouldnolongerbeusedforptswithunresectablestageIIINSCLCConclusions60术前同时化放疗的临床研究61可手术（Operable）ⅢA(N2)

放/化疗vs放化疗+手术

RTOG93-09INT：0139

62CT/RT/S

145/202CT/RT

155/194Logrankp=0.24危险比=0.87(0.70,1.10)存活率%0255075100从随机分组开始后的月数01224364860死亡/总数INT0139试验:总生存中位FU81个月Albainetal.

ASCO2005.Abstract7014.63随机分组后的月数

MS3yrOS5yrOS19月

36%22%CT/RT/SCT/RT存活率%025507510001224364860//////////29月

45%24%死亡/总计CT/RT/S38/51CT/RT42/51Logrankp=NSINT0139试验:肺切除亚组和相应化疗/放疗亚组的总生存的比较Albainetal.

ASCO2005.Abstract7014.64Logrank

p=0.002CT/RT/S

57/90CT/RT

74/90死亡/总计存活率%0255075100随机分组后的月数01224364860///////////////////////MS34月22月5yrOS36%18%CT/RT/SCT/RTINT0139试验:

肺叶切除亚组和相应化疗/放疗亚组的总生存的比较Albainetal.

ASCO2005.Abstract7014.6566

EORTC08941ⅢA：UnresectablepN2不能手术的ⅢApN2病例通过诱导化疗后成为可手术病例是选择手术还是选择放疗？6768697071四、NSCLC术后放射治疗NewdatasupportsPORTinN2cases721998PORT死亡风险增加21%2年OS下降7％55%----48%pN0pN1有害pN2降低局部复发

对OS无明确结论PORTMeta-analysisLancet,1998.352:257-63UpdateofPORTLungCancer,2005.47:81-373NewData1

回顾分析PORTSEER1988年～2001年Ⅱ、Ⅲ期NSCLC7465例根治性术后PORT3508例（47%）SEERJClinOncol,2006.24:2998-3006

预后－多因素分析HR95%CIPolderage1.0251.022-1.0280.0001T3-4disease1.2881.117-1.4840.0005N2nodaldisease1.2811.101-1.4900.0014greaternumberofinvolvedlymphnodes1.0431.027-1.0600.0001PORT1.0480.987-1.1130.126974PORT在N2中的作用N0N1N2SSRSSRSSR5yOS41%31%34%30%20%27%DSS53%39%44%38%27%36%P0.04350.01960.0077PORT既能够提高OS也能够提高DSSN0N1N275NewData2ResultsfromANITA:PhaseIIIAdjuvantVinorelbineandCisplatinversusObservationinCompletelyResectedNon-Small-CellLungCancerPatientsRRosell,MDeLena,FCarpagnano,RRamlau,JLGonzalez-Larriba,TGrodzki,ALeGroumelec,DAubert,JGasmi,JYDouillard

onbehalfoftheAdjuvantNavelbineInternationalTrialAssociation76CTRTCTRTOBSPORTinN1PatientsRTisbetterthanOBS.ForpatientwhocannottolerateCT,RTwouldberecommended.CTRTCTRTOBSPORTinN2Patients0.000.250.500.751.00DURATIONOFSURVIVAL(MONTHS)020406080100120CT&RTisthebestRTisbetterthanOBS78NewData3from

CancerHospital&InstituteofCAMS根治性切除NSCLCT1-3,N2具备完整治疗信息一般临床资料术中所见及术后病理治疗模式及参数随访资料79材料与方法——排除标准T4N2者pN3病例及N分期不明者手术后3个月内死亡的患者手术后3个月内肿瘤进展者单纯探查术或纵隔镜活检术80材料与方法全组例数PORT无PORT术式肺叶切除19784113全肺切除241212清扫淋巴结数目总数（枚）1-603-601-60中位数（枚）211922OS例数MST(月)1年3年5年χ2P值无PORT12531.977.645.430.65.2350.046PORT9643.994.859.134.3生存率DFS1年3年5年χ2P值无PORT56.4910.009PORT76.139.832.1DFS治疗模式与生存率项目例数MST(月)1年OS3年OS5年OSS+C+R6148.396.7%63.9%38.2%S+R3538.391.4%51.0%33.7%S+C10033.182.0%46.7%31.9%S2521.661.5%38.5%23.1%非肿瘤死亡项目

例数无术后放疗术后放疗组

心功能衰竭10心肌梗死10小脑萎缩10急性胰腺炎10脓胸10脑血管意外11肺部感染21气管食管瘘01肺栓塞01不明原因消瘦01死亡原因不明22合计107有无术后放疗组的非肿瘤死亡率并无差异（p=0.493）

S+C+RS+CS+RS5yOS47.0%34.0%21.3%16.6%5yOS38.2%31.9%

33.7%23.1%MST（M）47.423.822.712.7MST（M）48.333.138.321.6ANITA的结果医科院肿瘤医院的结果完全切除的ⅢAN2NCSLC推荐术后化疗+放疗86AbsoluteVolumeoflungreceived30GyRP(%)NORP(%)P≥340cm329.2(7/24)70.8(17/24)0.003<340cm32.5(1/40)97.5(39/40)PORTcanbesafelyusedwith3DCRTGraph1.&Table4.ROCcurse:TheareaundercurveinreceiveroperatingcharacteristiccurvesbasedontherelationshipbetweenincidenceofRPandthevalueofVipsi-dosewas0.757(P=0.020).Graph1.&Table4.ROCcurse:TheareaundercurveinreceiveroperatingcharacteristiccurvesbasedontherelationshipbetweenincidenceofRPandthevalueofVipsi-dosewas0.757(P=0.020).Graph1.&Table4.ROCcurse:TheareaundercurveinreceiveroperatingcharacteristiccurvesbasedontherelationshipbetweenincidenceofRPandthevalueofVipsi-dosewas0.757(P=0.020).Graph1.&Table4.ROCcurse:TheareaundercurveinreceiveroperatingcharacteristiccurvesbasedontherelationshipbetweenincidenceofRPandthevalueofVipsi-dosewas0.757(P=0.020).JiWeietal:ASTROmeeting2008BostonConclusion：ItwassafeforpatientswithNSCLCtoreceivepostoperative3DCRT，ifirradiationdosetolungtissuewaswelldefined.873DCRT能够提高NSCLC

的治疗疗效88Int.J.RadiationOncologyBiol.Phys.,Vol.66,No.1,pp.108–116,20063Dvs2DinMEDICALLYINOPERABLESTAGEINON–SMALL-CELLLUNGCANCER(a)Overallsurvival(b)Disease-specificsurvival89Int.J.RadiationOncologyBiol.Phys.,Vol.66,No.1,pp.108–116,20063Dvs2DinMEDICALLYINOPERABLESTAGEINON–SMALL-CELLLUNGCANCERLocal-regionalcontrol903DCRTvs常规放疗

中国医学科学院肿瘤医院

2001-2006

91ⅠⅡ期NSCLC

适形放疗vs常规放疗体重下降(＜5%vs≥5%)108–116,2006PE/XRTOperable：STAGEINON–SMALL-CELLLUNGCANCEROS单因素及多因素COX分析3、NormalTissueProtection：RTisbetterthanOBS同时化放疗vs序贯化放疗61715.SWOG9504:同步放化疗后应用泰索帝

巩固化疗治疗IIIb期NSCLCCRvsnon-CRLocalresponse CR26.Birdas,2006SWOG9504:总生存92局部晚期NSCLC（ⅢA/B）

3DCRTvs常规放疗分组例数1年3年5年MST常规放疗27561.013.88.015.63-DCRT21873.326.114.420.15年OS6.4%MST4.5月93局部晚期NSCLC（ⅢA/B）

3DCRTvs常规放疗分组例数1年3年5年常规放疗27565.116.711.23-DCRT21879.033.320.894OS单因素及多因素COX分析变量单因素多因素危险比P值危险比P

值＜70vs≥70岁1.0350.744------------女性vs男性1.0750.552------------体重下降(＜5%vs≥5%)1.1220.370------------吸烟(无vs有)1.0740.522------------KPS(≥80vs＜80)1.6710.0001.5630.001IIIavsIIIb1.2640.0311.2160.089非鳞癌vs鳞癌1.0510.619------------Hb(≥120vs＜120g/L)1.6250.0001.4220.008化学治疗(无vs有)0.8660.138------------50-60vs60vs＞60Gy0.7850.0010.8520.046常规放疗vs三维适形0.7370.0020.7620.009CR+PRvsSD+PD1.6070.0001.5710.00195局部晚期NSCLC（ⅢA/B）

3DCRTvs常规放疗2D3DX2P值例数（比例%）例数（比例%）食管炎＜2级135（61.9）180（65.5）0.6560.450≥2疾83（38.1）95（34.5）放射性肺炎＜2级148（67.9）202（73.5)1.8290.194≥2疾70（32.1）73(26.5)食管炎＜3级207（95.0）264（96.0）0.3120.662≥3疾11（5.0）11（4.0）放射性肺炎＜3级192(88.5)251(91.3)1.0550.363≥3疾25(11.5)24(8.7)96结论与常规放射治疗技术相比3DCRT能够提高NSCLC的生存率推荐3DCRT作为非小细胞肺癌的标准治疗技术97ThreeClinicalResearchTopicsinRadiotherapyofLocallyAdvancedNSCLC1、CombinedTreatment：

ConcurrentChemoradiotherapy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98ThreeClinicalResearchTopicsinRadiotherapyofLocallyAdvancedNSCLC2、NewRadiationTechniques:3DRT，IMRT,IGRT,4DRT3、NormalTissueProtection：

RadiationPneumonitisandEsophagitis

99谢谢100LocalControlandCompli