非小细胞肺癌放射治疗进展-王绿化.ppt

肺癌的放射治肺癌的放射治疗进疗进展展中国医学科学院中国医学科学院协协和医科大学和医科大学肿肿瘤医院瘤医院 王王绿绿化化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2.3.4.屏气技术举例:Elekta ABC5.四维CT影像技术呼气吸气螺旋开始时时相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呼吸曲线线床位床位6.影像引影像引导导放射治放射治疗疗技技术术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.在在线线校正校正影像匹配影像匹配8.一、放射治一、放射治疗疗在肺癌治在肺癌治疗疗中的地位中的地位二、早期二、早期NSCL的放射治的放射治疗疗三、局部晚期三、局部晚期NSCL的放的放疗疗/化化疗疗 综综合治合治疗疗 四、四、3DCRT提高提高NSCLC的生存率的生存率五、五、术术后放射治后放射治疗疗9.一、放射治一、放射治疗疗在肺癌治在肺癌治疗疗中的中的地位地位l应用循证医学的方法评价放射治疗在肺癌治疗中的地位。10.11.RT 在在 SCLC治治疗疗中的地位中的地位l53.6%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 （in the initial treatment）.8.2%1.5%为复发和进展病例的治疗（later for recurrence or progression）12.RT 在在 NSCLC 治治疗疗中的地位中的地位l64.3%4.7%of NSCLC cases require RT.45.9%4.3%in their initial treatment.18.3%1.8%later in the couse of the illness13.二、二、早期非小早期非小细细胞肺癌的放射治胞肺癌的放射治疗疗 放射治疗能够使 早期NSCLC获得治愈 14.Japanese StudiesI I期期期期NSCLCNSCLC大大大大剂剂剂剂量分割量分割量分割量分割SRTSRT获获获获得得得得满满满满意的局部控制率意的局部控制率意的局部控制率意的局部控制率Institute Dose/fx/OTT LC/Follow-upUematsu 50-60/5-10/5d 94%(47/50)36MKyoto 48Gy/4fr/12d 96%(49/51)20M Arimoto 60Gy/8fr/11d 92%(22/24)24MOnimaru 60Gy/8fr/11d:88%(50/57)18M Nagata Y,Kyoto Univ,IASLC,200415.Summary of Japanese StudieslTotal cases：281lAge:39-92(median 76)yearslPulmonary disease:Positive:172,Negative:109lHistology:Sqamous:122Adeno:131,Others:28lStage:IA:178,IB:103lTumor diameter:7-58(median 23)mmlMedical Operability:Inoperable:177,Operable:104Onishi H,ASCO 200416.Local Control and ComplicationlFollow-up period 2-128(median 30)monthslLocal responseCR 26.9%PR 59.1%NC 14.0%lPneumonitis(NCI-CTC)Grade 0:33.7%Grade 1:59.9%Grade 2:4.0%Grade 3:1.2%Grage 4:1.2%lEsophagitis(Grade 3)1.2%lPleural effusion(transient)1.6%lRib fracture1.2%lBone marrow suppression 0.0%Onishi H,ASCO 200417.Local Failure RateslTotal cases38/281(13.5%)BED 100 Gy17/211(8.1%)lStage IA17/177(9.6%)BED 100 Gy 9/136(6.6%)lStage IB21/102(20.6%)BED 100 Gy 8/73(11.0%)lAdenocarcinoma17/122(14.0%)lSquamous cell ca.18/131(13.7%)Onishi H,ASCO 200418.Mountain*JCOG*JNCCH*Stage IAStage IB67%57%80%63%74%53%STI*90%84%*Surgery*Stereotactic IrradiationComparison of 5-Yr Overall Survival Between Surgery&STISurvival curves of operable pts irradiated with BED of 100 Gy or more according to Stagestage IA(n=47)stage IB(n=16)p=0.2Overall SurvivalOverall SurvivalTime(years)Time(years)Summary of Japanese StudiesOnishi H,ASCO 200419.I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)楔形切除楔形切除(n=69)P肺功能（肺功能（FEV-1）1.39(0.86-2.37)1.31(0.52-3.0)NSCharlson合并症指数合并症指数 3(1-4)4(3-6)0.01年年龄龄74(69-78)78(55-89)RT(60 Gy,2Gy QD)day 50 同步同步:PV/RT(60 Gy,2Gy QD)day 1 同步同步/HFRT:PE/HFRT(69.2 Gy,1.2Gy BID)day 1PV:顺铂顺铂/长长春花碱春花碱PE:顺铂顺铂/oral 足叶乙足叶乙甙甙RT:放放疗疗;QD:每日一次每日一次;HFRT:超分隔放超分隔放疗疗Curran:ASCO,2000;updated IASLC 2000;ASTRO 2001,2003RANDOMIZE34.二二.同同时时化放化放疗疗 vs 序序贯贯化放化放疗疗(2)SEQ CON-QD CON-BID 中位生存期：中位生存期：14.6 17 15.6（月）（月）4 年生存率：年生存率：12%21%17%p=0.046 G3急性和晚期非血液系急性和晚期非血液系统统毒性：毒性：30%，48%，62%和和 14%，15%，16%。Curran W et al.Pro.Am Soc Clin Oncol.J.Clin.Oncol.2003;(abstract 2499)35.36.37.结论结论：同步放化同步放化疗优疗优于序于序贯贯放化放化疗疗，但但是，急性毒性反是，急性毒性反应应增加增加38.同步放化同步放化疗疗？诱导诱导化化疗疗?巩固化巩固化疗疗39.同步放化同步放化疗疗诱导诱导化化疗疗40.Induction Chemotherapy Followed by Chemoradiotherapy With Induction Chemotherapy Followed by Chemoradiotherapy With Chemoradio-therapy Alone for Regionally Advanced Chemoradio-therapy Alone for Regionally Advanced Unresectable StageIII NonSmall-CellUnresectable StageIII NonSmall-CellLung:Cancer and Leukemia GroupBLung:Cancer and Leukemia GroupBCALGB 39801J Clin Oncol.2007 May 1;25(13):1698-704.Epub 2007Apr 41.CALGB 39801 study designlJuly 1998 and was closed in May 2002,Totally 366 patients registered42.Survival intent to treat43.Survival of eligible patients with a weight loss of 5%44.Discussion 增加毒性增加毒性 induction chemotherapy increases neutropenia and overall maximal toxicity 没有生存没有生存优势优势 No survival benefit over concurrent therapy alone同期放化同期放化疗疗是是标标准的治准的治疗疗模式模式 Concomitant chemoradiotherapy is current standard therapy for unresectable stage IIIB NSCLC45.Simultaneous Chemoradiotherapy Compared With Radiotherapy Alone After Induction Chemotherapy in Inoperable Stage IIIA or IIIB NonSmall-Cell Lung Cancer:Study CTRT99/97 by the Bronchial Carcinoma Therapy GroupRudolf M.Huber,Michael Flentje,Michael Schmidt,Rudolf M.Huber,Michael Flentje,Michael Schmidt,Barbara Pllinger,Helga Gosse,Jochen Willner,and Barbara Pllinger,Helga Gosse,Jochen Willner,and Kurt UlmKurt UlmPC x 3诱导诱导化化疗疗RandomizeRT aloneRT+Paclitaxel 60mg/m2 weekly46.paclitaxel 200 mg/m2 carboplatin AUC=6every 3 weeks X 2 cyclespaclitaxel 60 mg/m2 weeklyRadiotherapy alone47.48.Survival after induction chemotherapy for Survival after induction chemotherapy for patients with complete or partial responsepatients with complete or partial response49.同步放化同步放化疗疗巩固化巩固化疗疗50.SWOG 9504:同步放化同步放化疗疗后后应应用泰索帝用泰索帝 巩固化巩固化疗疗治治疗疗IIIb 期期NSCLC顺铂顺铂/VP-16 X XRT泰索帝泰索帝 X X X 顺铂顺铂 50mg/m2 d 1,8,29,36 VP-16 50mg/m2 d1-5,29-33RT:61 Gy:45Gy(1.8Gy/fx),16Gy 缩缩野野(2Gy/fx)泰索帝泰索帝:75mg/m2 cycle 1 -100mg/m2 cycle 2-3 51.SWOG 9504:总总生存生存%0 02 20 04 40 06 60 08 80 01 10 00 0%0 01 12 22 24 43 36 64 48 8入入入入组时间组时间组时间组时间（月）（月）（月）（月）N EventsN Events中位生存中位生存中位生存中位生存83834545 26 26月月月月2 2 年生存率年生存率年生存率年生存率:54%:54%3 3 年生存率年生存率年生存率年生存率:37%:37%52.SWOG 9504 和和 SWOG 9019比比较较研究研究病例病例MST(月)2 年生存年生存3 年生存年生存S9019(PE/RT PE)5015(10-22)*34%(21-47)*17%(7-27)*S9504(PE/RT 泰索帝泰索帝)8326(18-35)*54%(43-65)*37%(22-52)*95%CI53.SWAG 0023Concurrent Chemo/RadioDDP+Vp16/RTConsolidation ChemoDocetaxel MaintenanceGEFITINIB orPLACEBO54.55.同步放化同步放化疗疗巩固化巩固化疗疗Results of ASCO 200756.HOG LUN 01-24 Phase III Study DesignHanna 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 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 entry203 patients147 patients73 patients74 patientsTaxotere75 mg/m2 q 3 wk 3ObservationPrimary endpoint:OSSecondary endpoints:PFS,toxicity57.HOG LUN 01-24:OS(ITT)Randomized Patients(n=147)Hanna et al.ASCO 2007:Abstract 7512.Months Since Registration0102030405060Percent of patients surviving0%25%50%75%100%P-value:0.940Median3 yearsurvival rateObservation18.0-34.227.6%Taxotere17-34.827.2%58.Comparison of Grade 3-5 ToxicitiesToxicitySWOG 9504SWOG 0023HOG 01-24Febrile Neutropenia PE/XRT Docetaxel NR 9%5%*5%*9.9%10.9%Esophagitis17%14%17.2%Pneumonitis 7%7%8.2%Docetaxel-related death4.8%4%5.5%*reported as“infection with neutropenia”59.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 an increased rate of hospitalization and premature death,And should no longer be used for pts with unresectable stage III NSCLCConclusions60.术术前同前同时时化放化放疗疗的的临临床研究床研究61.可手可手术术（Operable）A(N2)放放/化化疗疗 vs 放化放化疗疗+手手术术 RTOG 93-09 INT：0139 62.CT/RT/S 145/202CT/RT 155/194Logrank p=0.24危危险险比比=0.87(0.70,1.10)存活率存活率%0255075100从随机分从随机分组组开始后的月数开始后的月数01224364860死亡死亡/总总数数INT0139试验试验:总总生存生存中位中位FU 81 个月个月Albain et al.ASCO 2005.Abstract 7014.63.随机分随机分组组后的月数后的月数 MS3 yr OS5 yr OS19月月 36%22%CT/RT/SCT/RT存活率存活率%025507510001224364860/29月月 45%24%死亡死亡/总计总计CT/RT/S38/51CT/RT42/51Log rank p=NSINT0139试验试验:肺切除肺切除亚组亚组和相和相应应化化疗疗/放放疗亚组疗亚组的的总总生存的比生存的比较较Albain et al.ASCO 2005.Abstract 7014.64.Logrank p=0.002CT/RT/S 57/90CT/RT 74/90死亡死亡/总计总计存活率存活率%0255075100随机分随机分组组后的月数后的月数01224364860/MS 34月月 22 月月5 yr OS 36%18%CT/RT/SCT/RTINT0139试验试验:肺叶切除肺叶切除亚组亚组和相和相应应化化疗疗/放放疗亚组疗亚组的的总总生存的比生存的比较较Albain et al.ASCO 2005.Abstract 7014.65.66.EORTC 08941 A：Unresectable pN2不能手不能手术术的的ApN2病例病例通通过诱导过诱导化化疗疗后成后成为为可手可手术术病例病例是是选择选择手手术还术还是是选择选择放放疗疗？67.68.69.70.71.四、四、NSCLC术术后放射治后放射治疗疗New data supports PORT in N2 cases72.1998 PORTl死亡风险增加 21%l2年OS 下降7 55%-48%lpN0 pN1 有害lpN2 降低局部复发 对OS无明确结论PORT Meta-analysis Lancet,1998.352:257-63Update of PORT Lung Cancer,2005.47:81-373.New Data 1回回顾顾分析分析PORTSEER 1988年年2001年年、期期NSCLC 7465例例根治性根治性术术后后PORT 3508例（例（47%）SEER J Clin Oncol,2006.24:2998-3006 预预后多因素分析后多因素分析HR95%CI Polder age1.0251.022-1.0280.0001T3-4 disease1.2881.117-1.4840.0005N2 nodal disease1.2811.101-1.4900.0014greater number of involved lymph nodes1.0431.027-1.0600.0001PORT1.0480.987-1.1130.126974.PORT在N2中的作用N0N1N2SSRSSRSSR5yOS41%31%34%30%20%27%DSS53%39%44%38%27%36%P0.04350.01960.0077PORT既能既能够够提高提高OS也能也能够够提高提高DSSN0N1N275.New Data 2Results from ANITA:Phase III Adjuvant Vinorelbine and Cisplatin versus Observation in Completely Resected Non-Small-Cell Lung Cancer PatientsR Rosell,M De Lena,F Carpagnano,R Ramlau,JL Gonzalez-Larriba,T Grodzki,A Le Groumelec,D Aubert,J Gasmi,JY Douillard on behalf of the A Adjuvant N Navelbine I International T Trial A Association76.CT RTCTRTOBSPORT in N1 PatientsRT is better than OBS.For patient who can not tolerate CT,RT would be recommended.77.CT RTCTRTOBSPORT in N2 Patients0.000.250.500.751.00DURATION OF SURVIVAL(MONTHS)020406080100120CT&RT is the bestRT is better than OBS 78.New Data 3 from Cancer Hospital&Institute of CAMS2003.01.01-2005.12.30根治性切除根治性切除NSCLCT1-3,N2具具备备完整治完整治疗疗信息信息 一般一般临临床床资资料料 术术中所中所见见及及术术后病理后病理 治治疗疗模式及参数模式及参数 随随访资访资料料79.材料与方法排除标准T4N2者者pN3病例及病例及N分期不明者分期不明者手手术术后后3个月内死亡的患者个月内死亡的患者手手术术后后3个月内个月内肿肿瘤瘤进进展者展者单纯单纯探探查术查术或或纵纵隔隔镜镜活活检术检术80.材料与方法全全组组例数例数PORT无无PORT术术式式肺叶切除肺叶切除19784113全肺切除全肺切除241212清清扫扫淋巴淋巴结结数目数目总总数（枚）数（枚）1-603-601-60中位数（枚）中位数（枚）21192281.OS例数例数MST(月月)1年年3年年5年年2P值值无无PORT 12531.977.645.430.65.2350.046PORT 9643.994.859.134.3生存率 82.DFS 1年年3年年5年年2P值值无无PORT 56.428.216.56.8910.009PORT 76.139.832.1DFS83.治治疗疗模式与生存率模式与生存率 项项目目例数例数MST(月月)1年年OS3年年OS5年年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%84.非非肿肿瘤死亡瘤死亡项项目目 例数例数无无术术后放后放疗疗术术后放后放疗组疗组 心功能衰竭心功能衰竭10心肌梗死心肌梗死10小小脑脑萎萎缩缩10急性胰腺炎急性胰腺炎10脓脓胸胸10脑脑血管意外血管意外11肺部感染肺部感染21气管食管瘘气管食管瘘01肺栓塞肺栓塞01不明原因消瘦不明原因消瘦01死亡原因不明死亡原因不明22合合计计107u有无有无术术后放后放疗组疗组的非的非肿肿瘤死亡率并无差异瘤死亡率并无差异（p=0.493）85.S+C+R S+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的的结结果果医科院医科院肿肿瘤医瘤医院的院的结结果果完全切除的完全切除的AN2 NCSLC推荐推荐术术后化后化疗疗+放放疗疗86.Absolute Volume of lung received 30GyRP(%)NO RP(%)P 340 cm329.2(7/24)70.8(17/24)0.003340 cm32.5(1/40)97.5(39/40)PORT can be safely used with 3DCRTGraph 1.&Table 4.ROC curse:The area under curve in receiver operating characteristic curves based on the relationship between incidence of RP and the value of Vipsi-dose was 0.757(P=0.020).Graph 1.&Table 4.ROC curse:The area under curve in receiver operating characteristic curves based on the relationship between incidence of RP and the value of Vipsi-dose was 0.757(P=0.020).Graph 1.&Table 4.ROC curse:The area under curve in receiver operating characteristic curves based on the relationship between incidence of RP and the value of Vipsi-dose was 0.757(P=0.020).Graph 1.&Table 4.ROC curse:The area under curve in receiver operating characteristic curves based on the relationship between incidence of RP and the value of Vipsi-dose was 0.757(P=0.020).Ji Wei et al:ASTRO meeting 2008 BostonConclusion：It was safe for patients with NSCLC to receive postoperative 3DCRT，if irradiation dose to lung tissue was well defined.87.3DCRT能能够够提高提高NSCLC的治的治疗疗疗疗效效 88.Int.J.Radiation Oncology Biol.Phys.,Vol.66,No.1,pp.108116,2006Int.J.Radiation Oncology Biol.Phys.,Vol.66,No.1,pp.108116,20063D vs 2D in MEDICALLY INOPERABLE STAGE I NONSMALL-CELL LUNG CANCER(a)Overall survival(b)Disease-specific survival89.Int.J.Radiation Oncology Biol.Phys.,Vol.66,No.1,pp.108116,2006Int.J.Radiation Oncology Biol.Phys.,Vol.66,No.1,pp.108116,20063D vs 2D in MEDICALLY INOPERABLE STAGE I NONSMALL-CELL LUNG CANCERLocal-regional control90.3 DCRT vs 常常规规放放疗疗 中国医学科学院中国医学科学院肿肿瘤医院瘤医院 2001-200691.期期NSCLC适形放适形放疗疗 vs 常常规规放放疗疗92.局部晚期局部晚期NSCLCNSCLC（A/B）3DCRT vs 3DCRT vs 常常规规放放疗疗分分组组例数例数1 1年年3 3年年5 5年年MSTMST常常规规放放疗疗27561.061.013.813.88.08.015.615.63-DCRT3-DCRT21873.373.326.126.114.414.420.120.15 5年年OS 6.4%OS 6.4%MST 4.5MST 4.5月月93.局部晚期局部晚期NSCLCNSCLC（A/B）3DCRT vs 3DCRT vs 常常规规放放疗疗分分组组例数例数1 1年年3 3年年5 5年年常常规规放放疗疗27565.165.116.716.711.211.23-DCRT3-DCRT21879.079.033.333.320.820.894.OSOS单单因素及多因素因素及多因素COXCOX分析分析变变量量单单因素因素多因素多因素危危险险比比P P 值值危危险险比比P P 值值70 vs 7070 vs 70岁岁1.0351.0350.7440.744-女性女性 vs vs 男性男性1.0751.0750.5520.552-体重下降体重下降(5%vs 5%)5%vs 5%)1.1221.1220.3700.370-吸烟吸烟(无无 vs vs 有有)1.0741.0740.5220.522-KPS(80 vs KPS(80 vs 80)80)1.6711.6710.0000.0001.5631.5630.0010.001IIIa vs IIIbIIIa vs IIIb1.2641.2640.0310.0311.2161.2160.0890.089非非鳞鳞癌癌 vs vs 鳞鳞癌癌1.0511.0510.6190.619-Hb(120 vs Hb(120 vs 120 g/L)120 g/L)1.6251.6250.0000.0001.4221.4220.0080.008化学治化学治疗 (无无 vs vs 有有)0.8660.8660.1380.138-50-60 vs 60 vs 50-60 vs 60 vs 60 Gy60 Gy0.7850.7850.0010.0010.8520.8520.0460.046常常规放放疗vs vs 三三维适形适形0.7370.7370.0020.0020.7620.7620.0090.009CR+PR vs SD+PDCR+PR vs SD+PD1.6071.6070.0000.0001.5711.5710.0010.00195.局部晚期局部晚期NSCLCNSCLC（A/B）3DCRT vs 3DCRT vs 常常规规放放疗疗2 D3 DX2P值值例数（比例例数（比例%）例数（比例例数（比例%）食管炎2级135（61.9）180（65.5）0.6560.4502疾83（38.1）95（34.5）放射性放射性肺炎肺炎2级级148（67.9）202（73.5)1.8290.1942疾疾70（32.1）73(26.5)食管炎3级207（95.0）264（96.0）0.3120.6623疾11（5.0）11（4.0）放射性肺炎3级192(88.5)251(91.3)1.0550.3633疾25(11.5)24(8.7)96.结论结论与常与常规规放射治放射治疗疗技技术术相比相比3DCRT 能能够够提提高高NSCLC的生存率的生存率推荐推荐3DCRT作作为为非小非小细细胞肺癌的胞肺癌的标标准治准治疗疗技技术术97.Three Clinical Research Topics in Radiotherapy of Locally Advanced NSCLC1、Combined Treatment：Concurrent Chemoradiotherapy同同时时放化放化疗疗中化中化疗疗方案的方案的选择选择诱导诱导化化疗疗或巩固化或巩固化疗疗的必要性和化的必要性和化疗疗方案方案放射治放射治疗疗与生物靶向治与生物靶向治疗疗的的联联合合应应用用98.Three Clinical Research Topics in Radiotherapy of Locally Advanced NSCLC2、New Radiation Techniques:3DRT，IMRT,IGRT,4D RT3、Normal Tissue Protection：Radiation Pneumonitis and Esophagitis 99.谢谢谢谢100.