非小细胞肺癌放射治疗进展-王绿化

1,肺癌的放射治疗进展,中国医学科学院协和医科大学肿瘤医院 王绿化,2,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,3,4,5,屏气技术举例: Elekta ABC,6,四维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,7,影像引导放射治疗技术IGRT,40对叶片MLC,KV级X射线球管,KV级探测器阵列,MV级探测器阵列,8,在线校正影像匹配,9,一、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,10,一、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。,11,12,RT 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 （in the initial treatment）. 8.2%1.5% 为复发和进展病例的治疗（later for recurrence or progression）,13,RT 在 NSCLC 治疗中的地位,64.3%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 illness,14,二、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,15,Japanese StudiesI期NSCLC大剂量分割SRT获得满意的局部控制率,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, 2004,16,Summary of Japanese Studies,Total cases： 281Age: 39-92 (median 76) yearsPulmonary disease: Positive:172, Negative:109Histology: Sqamous:122Adeno:131,Others:28Stage: IA:178, IB:103Tumor diameter: 7-58 (median 23) mmMedical Operability: Inoperable:177, Operable: 104Onishi H, ASCO 2004,17,Local Control and Complication,Follow-up period 2-128 (median 30) monthsLocal responseCR 26.9%PR 59.1%NC 14.0%Pneumonitis (NCI-CTC)Grade 0 : 33.7%Grade 1 : 59.9%Grade 2 : 4.0%Grade 3 : 1.2%Grage 4 : 1.2%Esophagitis (Grade 3)1.2%Pleural effusion (transient)1.6%Rib fracture1.2%Bone marrow suppression0.0%Onishi H, ASCO 2004,18,Local Failure Rates,Total cases38/281 (13.5%) BED 100 Gy17/211 (8.1%)Stage IA17/177 (9.6%) BED 100 Gy 9/136 (6.6%)Stage IB21/102 (20.6%) BED 100 Gy 8/73 (11.0%)Adenocarcinoma17/122 (14.0%)Squamous cell ca.18/131 (13.7%)Onishi H, ASCO 2004,19,Mountain *,JCOG*,JNCCH*,Stage IAStage IB,67%57%,80%63%,74%53%,STI*,90%,84%,* Surgery,* Stereotactic Irradiation,Comparison of 5-Yr Overall Survival Between Surgery & STI,Survival curves of operable pts irradiated with BED of 100 Gy or more according to Stage,Summary of Japanese Studies,Onishi H, ASCO 2004,20,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,Grills et al: JCO 2010 doi: 10.1200/JCO.2009.26.5157,21,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,22,I期非小细胞肺癌局部切除后的转归,23,I期非小细胞肺癌立体定向放射治疗后的转归,24,25,26,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,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 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- 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, 2Gy 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,二.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%，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,同步放化疗,？诱导化疗,? 巩固化疗,同步放化疗,诱导化疗,Induction Chemotherapy Followed by Chemoradiotherapy With Chemoradio-therapy Alone for Regionally Advanced Unresectable StageIII NonSmall-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 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 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,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, Barbara Pllinger, Helga Gosse, Jochen Willner, and Kurt Ulm,paclitaxel 200 mg/m2 carboplatin AUC=6every 3 weeks X 2 cycles,paclitaxel 60 mg/m2 weekly,Radiotherapy alone,Survival after induction chemotherapy for patients with complete or partial response,同步放化疗,巩固化疗,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, 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,%,%,%,%,%,%,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,SWAG 0023,Concurrent Chemo/RadioDDP+Vp16/RT,Consolidation ChemoDocetaxel,MaintenanceGEFITINIB orPLACEBO,同步放化疗,巩固化疗,Results of ASCO 2007,HOG LUN 01-24 Phase 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 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 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 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; 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 NSCLC,Conclusions,61,术前同时化放疗的临床研究,62,可手术（Operable） A(N2) 放/化疗 vs 放化疗+手术 RTOG 93-09 INT：0139,63,CT/RT/S 145/202CT/RT 155/194,Logrank p=0.24危险比 = 0.87 (0.70, 1.10),存活率%,0,25,50,75,100,从随机分组开始后的月数,0,12,24,36,48,60,死亡/总数,INT0139试验: 总生存,中位FU 81 个月,Albain et al. ASCO 2005. Abstract 7014.,64,随机分组后的月数,MS3 yr OS5 yr OS,19月 36% 22%,CT/RT/S,CT/RT,存活率%,0,25,50,75,100,0,12,24,36,48,60,/,/,/,/,/,/,/,/,/,/,29月 45% 24%,死亡/总计,CT/RT/S,38/51,CT/RT,42/51,Log rank p=NS,INT0139试验: 肺切除亚组和相应化疗/放疗亚组的总生存的比较,Albain et al. ASCO 2005. Abstract 7014.,65,INT0139试验: 肺叶切除亚组和相应化疗/放疗亚组的总生存的比较,Albain et al. ASCO 2005. Abstract 7014.,66,67,EORTC 08941 A：Unresectable pN2,不能手术的ApN2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？,68,69,70,71,72,四、NSCLC术后放射治疗,New data supports PORT in N2 cases,73,1998 PORT,死亡风险增加 21%2年OS 下降7 55% -48%pN0 pN1 有害pN2 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: 81-3,74,New Data 1回顾分析PORT,SEER 1988年2001年、期NSCLC 7465例根治性术后PORT 3508例（47%）,SEER J Clin Oncol, 2006. 24: 2998-3006,75,PORT在N2中的作用,PORT既能够提高OS也能够提高DSS,N0,N1,N2,76,New Data 2Results from ANITA: Phase III Adjuvant Vinorelbine and Cisplatin versus Observation in Completely Resected Non-Small-Cell Lung Cancer Patients,R 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 Adjuvant Navelbine International Trial Association,77,PORT in N1 Patients,RT is better than OBS. For patient who can not tolerate CT, RT would be recommended.,PORT in N2 Patients,0.00,0.25,0.50,0.75,1.00,DURATION OF SURVIVAL (MONTHS),0,20,40,60,80,100,120,CT & RT is the best,RT is better than OBS,79,New Data 3 from Cancer Hospital & Institute of CAMS,2003.01.01-2005.12.30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,80,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,81,材料与方法,生存率,DFS,治疗模式与生存率,非肿瘤死亡,有无术后放疗组的非肿瘤死亡率并无差异（p=0.493）,S+C+R S+CS+RS,5yOS47.0%34.0 %21.3 %16.6 %,5yOS38.2%31.9% 33.7 %23.1 %,MST（M）47.423.822.712.7,MST（M）48.333.138.321.6,ANITA的结果,医科院肿瘤医院的结果,完全切除的AN2 NCSLC推荐术后化疗+放疗,87,PORT can be safely used with 3DCRT,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).,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 Boston,Conclusion：It was safe for patients with NSCLC to receive postoperative 3DCRT， if irradiation