1、Radiotherapy and TKI in the treatment of LA-NSCLCShi Xiu Wu Hangzhou Cancer Hospital&InstituteAJCC Staging SystemRT alone in NSCLC60 Gy became the standard dose for advanced NSCLC after this trial was publishedRTOG 73-01Conventional RT,pathological local regional failure rates of approximately 80%J
2、Natl Canc Instit.83:p.417-423,1991Advance of RT in NSCLC RT techniques CT,PET 3D-CRT,IMRT,Proton CBCT,Gating RT field Omission of ENI Involved-Field Radiation Therapy for Inoperable NonSmall-Cell Lung Cancer -Rosenzweig，JCO 2007 RT doseMichigan experience5-OS 4%,22%,and 28%for patients receiving 63-
3、69,74-84,and 92-103 Gy -Spring Kong，IJROBP 2005RTOG 06-17 negative resultsRTOG 0617544 patients assessed for eligibility166 to standard dose(60 Gy)121 to high dose(74 Gy)147 to standard dose(60 Gy)plus cetuximab110 to high dose(74 Gy)plus cetuximabRT techniqueZubrod PSPET stagingHistologyStratified
4、byTreatment-related deaths were more common in the high-dose groupConcurrent chemotherapy more difficult to completeRadiation therapy planning more likely to be non-compliantPlanning target volume coverage by the 95%isodose line poorerHeart V5 and heart V30 being predictors of patient deathBradley J
5、D,et al.Lancet Oncology 2015History of RT combined with chemotherapyPROCLAIMPresented By Suresh Senan at 2015 ASCO Annual MeetingSlide 11Presented By Suresh Senan at 2015 ASCO Annual MeetingMerits and Demerits of concurrent chemoradiotherapySynergic effect in temporal and spaceRadiation sensitivityD
6、ifferent mechanism of actionSuperior to sequentialHigh toxicitiesOptimal drug?Dosage?Optimal method of using drug?Optimal RT dose and fractionation?Rational for blockage of EGFR signaling during RTLiang k.Int J Radiat Oncol,2003,57:246 High EGFR expression in lung cancerRadiation-induced EGFR autoph
7、osphorylation Radiation resistanceNSCLC drive geneCaucasianAsianWu YL,et al.2011.Bruce E Johnson,et al.2015 WCLC MINI09.06741 patientsDrugEffects of Cetuximab combined with RTEGFR-positiveEGFR-negativeClin Cancer Res 2005;11:795-805 Tumor Growth Inhibition with Cetuximab and Chemotherapy in Non Smal
8、l Cell Lung Cancer Xenografts Expressing Wild-type and Mutated Epidermal Growth Factor Receptor Cetuximab showed antitumor activity in wt(A549,NCI-H358,NCI-H292)and mutated HCC-827(delE746-A750),NCI-H1975(L858R,T790M)EGFR-expressing xenografts.Clin Cancer Res 2007;13:1540-1551 Effect of Epidermal Gr
9、owth Factor Receptor Inhibitor Class in the Treatment of Head and Neck Cancer with Concurrent Radiochemotherapy In vivo which method of inhibiting EGFR is superior(an EGFR antibody versus a small molecule tyrosine kinase inhibitor)?Clin Cancer Res 2007;13:2512-2518 Cetuximab showed a benefit in pati
10、ents with an H score of 200 or more Bradley JD,et al.2015 Lancet OncologyRTOG 0617 subgroup analysisEffects of TKI combined with RTCancer Res 2005;65:3328-3335 Erlotinib inhibits radiation-induced activation of epidermalgrowth factor receptor.In vivo activity of erlotinib+/-radiationin tumor xenogra
11、fts.TKI radiosensitizes NSCLC cells by suppressing cellular DNA repair capacityClin Cancer Res 2008;14:1266-1273.NonSmall Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation Cancer Res 2006;66:9601-9608 Antitumor Activity of EGFR
12、 TKI Gefitinib(ZD1839,Iressa)in NonSmall Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels Clin Cancer Res 2006;12:7117-7125 Int J Radait Oncol,2004,59(2):Suppl 11-20CALGB30106 Between May 2002 and April 2005,63 patients were entered before t
13、he study closing early.All received two cycles paclitaxel 200 mg/m and carboplatin area under the curve 6 intravenous plus gefitinib 250 mg daily.Poor risk stratum 1(or=5%weight loss and/or performance status 2)received radiotherapy 200 cGy for 33 fractions(6600 cGy)and gefitinib 250 mg daily.Good-r
14、isk stratum 2(performance status:0-1 weight loss and 5%)received the same RT with gefitinib 250 mg daily and weekly paclitaxel 50 mg/m plus carboplatin AUC 2.Consolidation gefitinib until progression was started after all toxicities were grade or=2RESULTS:Acute high-grade infield toxicities were not
15、 clearly increased compared with historical CRT data.Poor-risk(N=21)median PFS was 13.4 months and median OS was 19.0 months.Good-risk(N=39)median PFS was 9.2 months and median OS was 13 months.Thirteen of 45 tumors analyzed had activating EGFR,and 2 of 13 also had T790M mutations.Seven tumors of 45
16、 had KRAS mutations.There was no apparent survival difference with EGFR-activating mutations versus wild type or KRAS mutation versus wild type.CONCLUSIONS:Survival of poor-risk patients with wild type or mutated EGFR receiving sequential CRT with gefitinib was promising.Survival for good-risk patie
17、nts receiving concurrent CRT plus gefitinib was disappointing even for tumors with activating EGFR mutations.J Thorac Oncol.2010;5(9):1382-90一项前瞻性、开放、随机对照、多中心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（EP）方案联合放疗用于伴有表皮生长因子受体19或21外显子活化突变的不可切除期非小细胞肺癌（NSCLC）的疗效及安全性(ML 28545)A multicenter,randomized,open-label,phase II
18、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 21PI:于金明院士l不可切除不可切除IIIA/IIIB NSCLCl未行任何治疗未行任何治疗lEGFR 19或或21外显子突变外显子突变(+)l18岁，岁，75
19、岁岁lECOG PS 01 n100RPD同步放化疗（同步放化疗（8周）周）顺铂顺铂 50mg/m2 d1,8,29,36依托泊甙依托泊甙 50mg/m2 d1-5,29-33同期同期RT 60Gy/30fr同步治疗同步治疗(8周周)厄洛替尼厄洛替尼 150mg/day同期同期 RT 60Gy/30frPD厄洛替尼厄洛替尼 150mg/day最长最长2年年研究设计主要终点：主要终点：PFS（progression free survival rate）次要终点：次要终点：ORR(objective response rate);LCR(local control rate)OS(overall
20、 survival,OS);安全性安全性(NCI CTCAE 4.0版版);采用采用FACT-LC及及LCSS量表比较两组的生活质量量表比较两组的生活质量;探索性分子标志物分析探索性分子标志物分析分层因素：分层因素：分期：分期：IIIA vs.IIIB组织病理学：腺癌组织病理学：腺癌 vs.非腺癌非腺癌EGFR突变类型：突变类型：19号号 外显子外显子vs.21号外显子号外显子 凯美纳开展的IIIA/IIIB期EGFR突变的NSCLC研究设计初治的初治的IIIA/IIIA/IIIBIIIB期期NSCLCNSCLC患者；患者；不可手术切除；不可手术切除；EGFR 19/21EGFR 19/21突
21、变；突变；N=120N=120埃克替尼埃克替尼联合放疗联合放疗依托泊苷依托泊苷/顺铂顺铂联合联合放疗放疗2 2周期周期PD1:1随机含铂两药含铂两药联合化疗联合化疗埃克替尼埃克替尼生存随访生存随访埃克替尼维持埃克替尼维持PDPI：王绿化教授Proposal of TKI and RT in lung cancer EGFR mutation positive Special setting,older Wide type Neoadjuvent chemotherapy and Concurrent TKI Concurrent TKI and adjuvant chemotherapypac
22、litaxel 100mg/m2 d 1,8,15carboplatin AUC=5 d1 21-day cycle 2RT 66 Gy/33F/7WErlotinib 150mg qd从 d43 开始到放疗结束A Phase II Study of Induction Chemotherapy Followed by Thoracic Radiotherapy and Erlotinib in Poor-Risk Stage III Non-Small Cell Lung Cancer.CALGB 30605(RTOG 0972)（2008年3月启动）l ECOG PS=2 or PS=0-
23、1 and 10%weight lossl Primary endpoint:OSl Secondary endpoint:RR,PFSNeoadjuvent chemotherapy and Concurrent TKI J Thorac Oncol.2015;10:143147Median age was 68(39,88)32%were 75 years oldstage IIIA/B 49%/51%61%had PS 2 and 39%PS 0-1 with WL.8%had CR,59%PR,27%SD,7%PD.Median PFS and OS in IIIA patients
24、16 and 19 months,compared to 9 and 12 in IIIB patients(p=0.038 for PFS and p=0.302 for OS).Toxicity was mild with 19%Gr3-4 neutropenia,9%Gr 3 diarrhea and no Gr5 events.Gr3 esophagitis and pneumonitis were recorded in 5%and 1%of patients respectively.Molecular data were available for 31 patients.No
25、patients with EGFR mutation were identified;two patients had tumors with KRAS mutations.Conclusions:Patients with poor-risk stage III nonsmall-cell lung cancer had better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by thoracic radiotherapy and erlotinib.How
26、ever,as per the statistical design,the 12-month OS was not sufficiently high to warrant further studies.Concurrent thoracic radiotherapy and tyrosine kinase inhibitors for wild-type EGFR patients with locally advanced NSCLC-a phase II trialObjective:to investigate the efficacy and safety of combined
27、 thoracic radiotherapy and TKI in EGFR wild-type patients who refused to or unsuitable for concurrent chemoradiotherapy.TKI was administrated concurrently with thoracic radiotherapy.The primary endpoint was local-regional control.Presented at 2015 WCLCUntreated,non-metastasis NSCLCEGFR wild-typeECOG
28、 PS 0-2TRT 60-70GyIcotinib 125mg Po TidInvestigators choicePemetrexed-CisplatinDocetaxel-CispatinPaclitaxel-CarboplatinResultsBetween 2012.1 and 2015.6,17 eligible patients were recruited.Median age 65.3 years(47 82 years)，1 female and 16 males.Three were stage,two were stage and were stage.Two(11.8
29、%)patients developed grade radiation pneumonitis,1(5.9%)developed grade radiation pneumonitis and 10(58.8%)developed level hematological toxicity.Median follow-up time 11.9 months(138months).Project1-year survival rate(%)2-year survival rate(%)OS83.141.5LRFS77.851.9PFS71.328.5Presented at 2015 WCLCcase2012.12.27A 62 years old man with adenocarcinoma,EGFR M negative 2013.2.15Thanks for your attention
