放療與TKI在局晚NSCLC中的應(yīng)用課件

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

2、%J Natl Canc Instit. 83: p. 417-423, 1991Advance of RT in NSCLCRT techniques CT, PET3D-CRT, IMRT, ProtonCBCT, GatingRT fieldOmission of ENI Involved-Field Radiation Therapy for Inoperable NonSmall-Cell Lung Cancer - Rosenzweig，JCO 2007RT doseMichigan experience5-OS 4%, 22%, and 28% for patients rece

3、iving 63-69, 74-84, and 92-103 Gy - Spring Kong，IJROBP 2005RTOG 06-17 negative resultsRTOG 0617544 patients assessed for eligibilityRT techniqueZubrod PSPET stagingHistology166 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 ce

4、tuximabStratified 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 pat

5、ient deathBradley JD, 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 spaceR

6、adiation sensitivityDifferent 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 cancerRad

7、iation-induced EGFR autophosphorylation Radiation resistanceNSCLC drive geneCaucasianAsianWu YL, et al. 2011.Bruce E Johnson, et al. 2015 WCLC MINI09.06741 patientsDrugMonoclonal antibodiesSmall-molecule tyrosine kinase inhibitorsEffects of Cetuximab combined with RTEGFR-positiveEGFR-negativeClin Ca

8、ncer Res 2005;11:795-805 Tumor Growth Inhibition with Cetuximab and Chemotherapy in Non Small 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-H19

9、75 (L858R,T790M) EGFR-expressing xenografts. Clin Cancer Res 2007;13:1540-1551 Effect of Epidermal Growth 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 mo

10、lecule tyrosine kinase inhibitor)? Clin Cancer Res 2007;13:2512-2518 Cetuximab showed a benefit in patients 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-induce

11、d activation of epidermalgrowth factor receptor.In vivo activity of erlotinib +/- radiationin tumor xenografts.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

12、Factor Receptor Are Sensitive to Ionizing Radiation Cancer Res 2006;66:9601-9608 Antitumor Activity of EGFR 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 R

13、adait Oncol, 2004, 59(2): Suppl 11-20CALGB30106Between May 2002 and April 2005, 63 patients were entered before the 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 los

14、s and/or performance status 2) received radiotherapy 200 cGy for 33 fractions (6600 cGy) and gefitinib 250 mg daily. Good-risk 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 g

15、efitinib until progression was started after all toxicities were grade or =2RESULTS: Acute high-grade infield toxicities were not 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 mon

16、ths 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 had KRAS mutations. There was no apparent survival difference with EGFR-activating mutations versus wild type or KRAS mutation versus wild type.CONCLUSIONS: S

17、urvival of poor-risk patients with wild type or mutated EGFR receiving sequential CRT with gefitinib was promising. Survival for good-risk patients receiving concurrent CRT plus gefitinib was disappointing even for tumors with activating EGFR mutations.J Thorac Oncol. 2010;5(9):1382-90一項(xiàng)前瞻性、開放、隨機(jī)對照、

18、多中心期臨床研究評估同期厄洛替尼聯(lián)合放療對比同期依托泊甙順鉑（EP）方案聯(lián)合放療用于伴有表皮生長因子受體19或21外顯子活化突變的不可切除期非小細(xì)胞肺癌（NSCLC）的療效及安全性(ML 28545)A multicenter, randomized, open-label, phase II trial of Erlotinib versus Etoposide plus Cisplatin with concurrent radiotherapy in unresectable stage III non-small cell lung cancer (NSCLC) with activa

19、ting mutation of epidermal growth factor receptor (EGFR) in exon 19 or 21PI:于金明院士不可切除IIIA/IIIB NSCLC未行任何治療EGFR 19或21外顯子突變(+) 18歲， 75歲ECOG PS 01 n100RPD同步放化療（8周）順鉑 50mg/m2 d1,8,29,36依托泊甙 50mg/m2 d1-5,29-33同期RT 60Gy/30fr同步治療(8周)厄洛替尼 150mg/day同期 RT 60Gy/30frPD厄洛替尼 150mg/day最長2年研究設(shè)計(jì)主要終點(diǎn)： PFS（progression

20、 free survival rate） 次要終點(diǎn)：ORR (objective response rate);LCR (local control rate) OS (overall survival, OS);安全性(NCI CTCAE 4.0版);采用FACT-LC及LCSS量表比較兩組的生活質(zhì)量;探索性分子標(biāo)志物分析分層因素：分期：IIIA vs. IIIB組織病理學(xué)：腺癌 vs. 非腺癌EGFR突變類型：19號 外顯子vs. 21號外顯子 凱美納開展的IIIA/IIIB期EGFR突變的NSCLC研究設(shè)計(jì)初治的IIIA/IIIB期NSCLC患者；不可手術(shù)切除；EGFR 19/21突變；

21、N=120?？颂婺崧?lián)合放療依托泊苷/順鉑聯(lián)合放療2周期PD1:1隨機(jī)含鉑兩藥聯(lián)合化療?？颂婺嵘骐S訪?？颂婺峋S持PDPI：王綠化教授Proposal of TKI and RT in lung cancerEGFR mutation positiveSpecial setting, olderWide typeNeoadjuvent chemotherapy and Concurrent TKI Concurrent TKI and adjuvant chemotherapypaclitaxel 100mg/m2 d 1,8,15carboplatin AUC=5 d1 21-day cycl

22、e 2RT 66 Gy/33F/7WErlotinib 150mg qd從 d43 開始到放療結(jié)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月啟動） ECOG PS =2 or PS=0-1 and 10% weight loss Primary endpoint: OS Secondary e

23、ndpoint: 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 16 and 19 months, compared to 9 and

24、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 patients with EGFR mut

25、ation 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. However, as per the sta

26、tistical 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 thoracic radiotherapy and TKI in EGFR wild-type patients who refused to or unsuitable for concurrent chemoradiotherapy. TKI was administrated c