非小细胞肺癌放射治疗进展.ppt

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1、非小非小细胞肺癌放射治胞肺癌放射治疗进展展影像技术和计算机技术的进步为准确放射治疗的实现提供可能2021/11/1422021/11/1432021/11/144屏气技术举例:Elekta ABC2021/11/145四维CT影像技术呼气吸气螺旋开场时相时相由吸转呼呼气末由呼转吸由吸转呼呼气吸气螺旋开场呼吸曲线呼吸曲线床位床位2021/11/146影像引导放射治疗技术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2021/11/147在线校正在线校正影像匹配影像匹配2021/11/148一、放射治疗在肺癌治疗中的地位一、放射治疗在肺癌治疗中的地位

2、二、早期二、早期NSCL的放射治疗的放射治疗三、局部晚期三、局部晚期NSCL的放疗的放疗/化疗化疗 综合治疗综合治疗 四、四、3DCRT提高提高NSCLC的生存率的生存率五、术后放射治疗五、术后放射治疗2021/11/149一、放射治疗在肺癌治疗中的一、放射治疗在肺癌治疗中的地位地位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。2021/11/14102021/11/1411RT 在在 SCLC治疗中的地位治疗中的地位l53.6%3.3%SCLC 病例在其疾病的不同时期需要承受放射治疗 45.4%4.3%为首程治疗l in the initial treatment.8.2%1.5%为复

3、发和进展病例的治疗later for recurrence or progression2021/11/1412 RT 在在 NSCLC 治疗中的地位治疗中的地位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 illness2021/11/1413二、二、早期非小细胞肺癌的放射治疗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 2021/11/1414Japanese StudiesI I期期期期NSCLCNS

4、CLC大剂量分割大剂量分割大剂量分割大剂量分割SRTSRT获得满意的局部控制率获得满意的局部控制率获得满意的局部控制率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,20042021/11/1415Summary of Japanes

5、e 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 20042021/11/1416Local Control and ComplicationlFo

6、llow-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 20042021/11/1417Local Fa

7、ilure 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 20042021/11/1418Mountain*JCOG*JNCCH*Stage IAStage IB67%57%80%63%74%53%STI*90%84%*S

8、urgery*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,ASC

9、O 20042021/11/1419I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年龄年龄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/长春花碱长春花碱PE:顺铂顺铂/oral 足叶乙甙足叶乙

10、甙RT:放疗放疗;QD:每日一次每日一次;HFRT:超分隔放疗超分隔放疗Curran:ASCO,2000;updated IASLC 2000;ASTRO 2001,2003RANDOMIZE2021/11/1434二二.同时化放疗同时化放疗 vs 序贯化放疗序贯化放疗(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%G3急性和晚期非血液系统毒性：急性和晚期非血液系统毒性：30%，48%，62%和和 14%，15%，16%。Curran W et al.Pro.Am Soc Clin Oncol.J.Cl

11、in.Oncol.2003;(abstract 2499)2021/11/14352021/11/14362021/11/1437结论：结论：同步放化疗优于序贯放化同步放化疗优于序贯放化疗，但是，急性毒性反响疗，但是，急性毒性反响增加增加2021/11/1438同步放化疗同步放化疗？诱导化疗？诱导化疗?稳固化疗稳固化疗2021/11/1439同步放化疗同步放化疗诱导化疗诱导化疗2021/11/1440Induction Chemotherapy Followed by Chemoradiotherapy With Induction Chemotherapy Followed by Chemo

12、radiotherapy 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.E

13、pub 2007Apr 2021/11/1441CALGB 39801 study designlJuly 1998 and was closed in May 2002,Totally 366 patients registered2021/11/1442Survival intent to treat2021/11/1443Survival of eligible patients with a weight loss of 5%2021/11/1444Discussion 增加毒性增加毒性 induction chemotherapy increases neutropenia and

14、overall maximal toxicity 没有生存优势没有生存优势 No survival benefit over concurrent therapy alone同期放化疗是标准的治疗模式同期放化疗是标准的治疗模式 Concomitant chemoradiotherapy is current standard therapy for unresectable stage IIIB NSCLC2021/11/1445Simultaneous Chemoradiotherapy Compared With Radiotherapy Alone After Induction Che

15、motherapy 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,Joch

16、en Willner,and Kurt UlmKurt UlmPC x 3诱导化疗诱导化疗RandomizeRT aloneRT+Paclitaxel 60mg/m2 weekly2021/11/1446paclitaxel 200 mg/m2 carboplatin AUC=6every 3 weeks X 2 cyclespaclitaxel 60 mg/m2 weeklyRadiotherapy alone2021/11/14472021/11/1448Survival after induction chemotherapy for Survival after induction c

17、hemotherapy for patients with complete or partial responsepatients with complete or partial response2021/11/1449同步放化疗同步放化疗稳固化疗稳固化疗2021/11/1450SWOG 9504:同步放化疗后应用泰索帝同步放化疗后应用泰索帝 稳固化疗治疗稳固化疗治疗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)

18、,16Gy 缩野缩野(2Gy/fx)泰索帝泰索帝:75mg/m2 cycle 1 -100mg/m2 cycle 2-3 2021/11/1451SWOG 9504:总生存总生存%0 02 20 04 40 06 60 08 80 01 10 00 0%0 01 12 22 24 43 36 64 48 8入组时间月入组时间月入组时间月入组时间月 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%2021/11/1452 SWOG 9

19、504 和 SWOG 9019比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%CI2021/11/1453SWAG 0023Concurrent Chemo/RadioDDP+Vp16/RTConsolidation ChemoDocetaxel MaintenanceGEFITINIB orPLACEBO2021/11/14542021/11/1455同步放化疗同步放化疗

20、稳固化疗稳固化疗Results of ASCO 20072021/11/1456HOG 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 b

21、aseline 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,toxicity2021/11/1457HOG LUN 01-24:OS(ITT)Randomized Patients

22、(n=147)Hanna et al.ASCO 2007:Abstract 7512.Months Since Registration0102030405060Percent of patients surviving0%25%50%75%100%Median3 yearsurvival rateObservation18.0-34.227.6%Taxotere17-34.827.2%2021/11/1458Comparison of Grade 3-5 ToxicitiesToxicitySWOG 9504SWOG 0023HOG 01-24Febrile Neutropenia PE/X

23、RT 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 2021/11/1459Hog LUGN o1-20/USO-023 The MST with EP/XRT was higher than historical controls;Consolidation D does not further improve survival,is associat

24、ed with significant toxicity including an increased rate of hospitalization and premature death,And should no longer be used for pts with unresectable stage III NSCLCConclusions2021/11/1460术前同时化放疗的临床研究术前同时化放疗的临床研究2021/11/1461可手术可手术Operable A(N2)放放/化疗化疗 vs 放化疗放化疗+手术手术 RTOG 93-09 INT：0139 2021/11/1462

25、CT/RT/S 145/202CT/RT 155/194危险比危险比=0.87(0.70,1.10)存活率存活率%0255075100从随机分组开场后的月数从随机分组开场后的月数01224364860死亡死亡/总数总数INT0139试验试验:总生存总生存中位中位FU 81 个月个月Albain et al.ASCO 2005.Abstract 7014.2021/11/1463随机分组后的月数随机分组后的月数 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

26、/S38/51CT/RT42/51Log rank p=NSINT0139试验试验:肺切除亚组和相应化疗肺切除亚组和相应化疗/放疗亚组的总生存的比较放疗亚组的总生存的比较Albain et al.ASCO 2005.Abstract 7014.2021/11/1464Logrank 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随机分组后的月数随机分组后的月数01224364860/MS 34月月 22 月月5 yr OS 36%18%CT/RT/SCT/RTINT0139试验试验:肺叶切除亚组和相应化疗肺叶切除亚组和相应化疗

27、/放疗亚组的放疗亚组的总生存的比较总生存的比较Albain et al.ASCO 2005.Abstract 7014.2021/11/14652021/11/1466 EORTC 08941 A：Unresectable pN2不能手术的不能手术的ApN2病例病例通过诱导化疗后成为可手术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？是选择手术还是选择放疗？2021/11/14672021/11/14682021/11/14692021/11/14702021/11/1471四、四、NSCLC术后放射治疗术后放射治疗New data supports PORT in N2 cases

28、2021/11/14721998 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,2005.47:81-32021/11/1473New Data 1回忆分析回忆分析PORTSEER 1988年年2001年年、期期NSCLC 7465例例根治性术后根治性术后PORT 3508例例47%SEER J Clin Oncol,2006.24:2998-3006 预后多因素分析预后多因素分析

29、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 nodes1.0431.027-1.0600.0001PORT1.0480.987-1.1130.12692021/11/1474PORT在N2中的作用N0N1N2SSRSSRSSR5yOS41%31%34%30%20%27%DSS53%39%44%38%27%36%P0.04350.01960.0077PO

30、RT既能既能够够提高提高OS也能也能够够提高提高DSSN0N1N22021/11/1475New 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,J

31、Y Douillard on behalf of the A Adjuvant N Navelbine I International T Trial A Association2021/11/1476CT RTCTRTOBSPORT in N1 PatientsRT is better than OBS.For patient who can not tolerate CT,RT would be recommended.2021/11/1477CT RTCTRTOBSPORT in N2 PatientsDURATION OF SURVIVAL(MONTHS)020406080100120

32、CT&RT is the bestRT is better than OBS 2021/11/1478New Data 3 from Cancer Hospital&Institute of CAMS根治性切除根治性切除NSCLCT1-3,N2具备完整治疗信息具备完整治疗信息 一般临床资料一般临床资料 术中所见及术后病理术中所见及术后病理 治疗模式及参数治疗模式及参数 随访资料随访资料2021/11/1479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术后手术后3个月内死亡的患者个月内死亡的患者手术后手术后3个月内肿瘤进展者个月内肿瘤进展者单纯探查术或纵隔镜活检术单

33、纯探查术或纵隔镜活检术2021/11/1480材料与方法全组全组例数例数PORT无无PORT术式术式肺叶切除肺叶切除19784113全肺切除全肺切除241212清扫淋巴结数目清扫淋巴结数目总数（枚）总数（枚）1-603-601-60中位数（枚）中位数（枚）2119222021/11/1481OS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 2021/11/1482DFS 1年年3年年5年年2P值值无无PORT 56.428.216.56.8910.009PORT 76

34、.139.832.1DFS2021/11/1483治疗模式与生存率治疗模式与生存率 项目项目例数例数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%2021/11/1484非肿瘤死亡非肿瘤死亡项目项目 例数例数无术后放疗无术后放疗术后放疗组术后放疗组 心功能衰竭心功能衰竭10心肌梗死心肌梗死10小脑萎缩小脑萎缩10急性胰腺炎急性胰腺炎10脓胸脓胸10脑血管意外脑血管意外11肺部感染肺部感染21气管食管瘘气管

35、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合计合计107u有无术后放疗组的非肿瘤死亡率并无差异有无术后放疗组的非肿瘤死亡率并无差异p=0.493 2021/11/1485S+C+R S+CS+RS5yOS%34.0%16.6%5yOS%33.7%23.1%MSTMMSTMANITA的结果的结果医科院肿瘤医医科院肿瘤医院的结果院的结果完全切除的完全切除的AN2 NCSLC推荐术后化疗推荐术后化疗+放疗放疗2021/11/1486Absolute Volume of lung received 30GyRP(%)NO RP(%)P 340 cm329.2(7

36、/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

37、 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

38、 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 2021 BostonConclusion：It was safe fo

39、r patients with NSCLC to receive postoperative 3DCRT，if irradiation dose to lung tissue was well defined.2021/11/14873DCRT能够提高能够提高NSCLC的治疗疗效的治疗疗效 2021/11/1488Int.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 MEDICA

40、LLY INOPERABLE STAGE I NONSMALL-CELL LUNG CANCER(a)Overall survival(b)Disease-specific survival2021/11/1489Int.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 CANCERLoc

41、al-regional control2021/11/14903 DCRT vs 常规放疗常规放疗 中国医学科学院肿瘤医院中国医学科学院肿瘤医院 2001-20062021/11/1491期期NSCLC适形放疗适形放疗 vs 常规放疗常规放疗2021/11/1492局部晚期局部晚期NSCLCNSCLCA/BA/B3DCRT vs 3DCRT vs 常规放疗常规放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-DCRT21873.373.326.126.114.414.420.120.1

42、5 5年年OS 6.4%OS 6.4%2021/11/1493局部晚期局部晚期NSCLCNSCLCA/BA/B3DCRT vs 3DCRT vs 常规放疗常规放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-DCRT21879.079.033.333.320.820.82021/11/1494OSOS单因素及多因素单因素及多因素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

43、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(12

44、0 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+PD1.6071.6070.0000.0001.5711.571

45、0.0010.0012021/11/1495局部晚期局部晚期NSCLCNSCLCA/BA/B3DCRT vs 3DCRT vs 常规放疗常规放疗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)1.0550.3

46、633疾25(11.5)24(8.7)2021/11/1496结论结论与常规放射治疗技术相比与常规放射治疗技术相比3DCRT 能够提能够提高高NSCLC的生存率的生存率推荐推荐3DCRT作为非小细胞肺癌的标准治作为非小细胞肺癌的标准治疗技术疗技术2021/11/1497Three Clinical Research Topics in Radiotherapy of Locally Advanced NSCLC1、Combined Treatment：Concurrent Chemoradiotherapy同时放化疗中化疗方案的选择同时放化疗中化疗方案的选择诱导化疗或稳固化疗的必要性和化疗方案诱导化疗或稳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放射治疗与生物靶向治疗的联合应用2021/11/1498Three Clinical Research Topics in Radiotherapy of Locally Advanced NSCLC2、New Radiation Techniques:3DRT，IMRT,IGRT,4D RT3、Normal Tissue Protection：Radiation Pneumonitis and Esophagitis 2021/11/1499