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1、同步放化療在同步放化療在NSCLC的進(jìn)展的進(jìn)展主要內(nèi)容主要內(nèi)容放療在早期NSCLC的進(jìn)展同步放化療與靶向藥物治療NSCLC的進(jìn)展同步放化療聯(lián)合培美曲塞治療NSCLC的研究進(jìn)展同步放化療在晚期NSCLC的進(jìn)展放療在早期NSCLC的進(jìn)展同步放化療與靶向藥物治療NSCLC的進(jìn)展同步放化療聯(lián)合培美曲塞治療NSCLC的研究進(jìn)展同步放化療在晚期NSCLC的進(jìn)展Stereotactic ablative radiotherapy(SABR)in potentially operable Stage I non-small cell lung cancer patients立體定向消融放療治療潛在可手術(shù)的I期

2、非小細(xì)胞肺癌患者Frank J.LagerwaardDept.of Radiation Oncology VUmc Cancer Center AmsterdamI期期NSCLC經(jīng)經(jīng)SABR治療后的局部控制情況治療后的局部控制情況不選擇手術(shù)的原因不選擇手術(shù)的原因心血管心血管整體狀態(tài)整體狀態(tài)肺功能肺功能偏好偏好拒絕拒絕合并癌癥合并癌癥SABR對潛在科手術(shù)病人的基線特征對潛在科手術(shù)病人的基線特征those with prior high-dose(chemo-)radiotherapy or pneumonectomy(N=23)GOLD Class 3(N=216)WHO performance

3、 score 3(N=23)因共患心血管疾病排除手術(shù)的(N=94)并發(fā)其他腫瘤的(N=50)因主要共患病除外手術(shù)的,e.g.新發(fā)冠心病,腎衰(N=68)SABR的治療劑量選擇的治療劑量選擇Performed at VUmc since April 2003T1 tumors(3 cm),腫瘤未達(dá)縱膈和胸壁腫瘤未達(dá)縱膈和胸壁3 x 18 Gy 80%;3 fx/week(BED 134 Gy)T1 tumors 達(dá)胸壁和縱膈達(dá)胸壁和縱膈,and T2 tumors5 x 11 Gy 80%;3 fx/week(BED 116 Gy)Tumors 臨近心包，臂叢神經(jīng)或肺門臨近心包，臂叢神經(jīng)或肺門8

4、 x 7.5 Gy 80%;3 fx/week(BED 105 Gy)SABR的主要的主要 毒性毒性早期不良反應(yīng)早期不良反應(yīng)疲乏疲乏25%咳嗽咳嗽14%胸壁痛胸壁痛11%呼吸困難呼吸困難10%晚期不良反應(yīng)放射性肺炎2%肋骨骨折3%胸壁痛3%SABR治療治療117例潛在可手術(shù)患者的結(jié)果例潛在可手術(shù)患者的結(jié)果Operable pts時(shí)間時(shí)間中位生存5.1年2年生存88%3年生存85%5年生存51%結(jié)論結(jié)論應(yīng)用SABR是可行的治療后30天死亡率為0%，對比該群患者術(shù)后死亡率為2.6%盡管多數(shù)老年病人共患病率很高，經(jīng)SABR治療后中位生存仍超過5年鼓勵(lì)內(nèi)鏡分期Nakajima T,2010;Harle

5、y D,2010SABR數(shù)據(jù)支持隨機(jī)入組放療在早期NSCLC的進(jìn)展同步放化療與靶向藥物治療NSCLC的進(jìn)展同步放化療聯(lián)合培美曲塞治療NSCLC的研究進(jìn)展同步放化療在晚期NSCLC的進(jìn)展LCCC 0511:Phase I/II Trial of Induction Carboplatin/Paclitaxel plus Bevacizumab followed by Concurrent Thoracic Conformal Radiotherapy with Carboplatin/Paclitaxel,Bevacizumab and Erlotinib in Stage IIIA/B NSC

6、LC卡鉑紫杉醇聯(lián)合貝伐單抗行誘導(dǎo)治療繼之以同步胸部適型放療聯(lián)合卡鉑紫杉醇，貝伐單抗和厄羅替尼治療IIIA/B期NSCLC的I/II期臨床研究MA Socinski on behalf of the co-authorsUniversity of North Carolina,Yale University,Wake Forest University and Northeast Medical Center實(shí)驗(yàn)設(shè)計(jì)實(shí)驗(yàn)設(shè)計(jì)入組病人基線特征入組病人基線特征Age(yrs),median(range)61(34-74)Sex(M:F)23(51%):18(49%)Stage(IIIA:IIIB)2

7、9(64%):16(36%)PS 0:1 26(71%):13(29%HistologyAdeno 27(60%)Squamous 12(27%)Lg Cell 4(9%)NSCLC NOS 2(4%)RaceCaucasian（高加索）（高加索）34(78%)Black （黑人）（黑人）9(20%)Asian 2(4%)FEV1(),median(range)2.4(0.8-3.9)發(fā)生率多于等于發(fā)生率多于等于1個(gè)病人且大于等于個(gè)病人且大于等于3級的毒性統(tǒng)計(jì)級的毒性統(tǒng)計(jì)誘導(dǎo)期誘導(dǎo)期同步期同步期毒性毒性血液學(xué)毒性貧血粒細(xì)胞缺乏血小板減少非血液學(xué)毒性腹瀉食管炎肺出血The following g

8、rade 3-4 toxicities occurred in 1 patient:dehydration,fatigue,hypertension,sensory neuropathy,chest pain,anorexia,dizziness,fever,ALT,hyponatremia,pneumonia,nausea,pneumonitis,tracheo-esophageal fistula反應(yīng)率反應(yīng)率RECIST(n=45)誘導(dǎo)期誘導(dǎo)期整體反應(yīng)率整體反應(yīng)率Induction RR 39%(95%CI,24-55%)ORR 60%(95%CI,44-75%)*Judged 2-6 m

9、onths after completion of RTLCCC 生存結(jié)果生存結(jié)果首要終點(diǎn)是PFS 假設(shè)檢驗(yàn)=PFS at 1 year=50%排除值if PFS 70%LCCC高劑量同步放化療的相關(guān)臨床實(shí)驗(yàn)高劑量同步放化療的相關(guān)臨床實(shí)驗(yàn)Socinski MA et al Cancer 92:1213-23,2001,Marks L et al J Clin Oncol 22:4329-40,2004,Socinski MA et al J Clin Oncol 22:4341-50,2004,Stinchcombe TE et al J Thorac Oncol 3:250-7,2008,S

10、ocinski MA et al J Clin Oncol 26:2457-63,2008,Socinski MA et al J Clin Oncol 27:389s,2009LCCC 0511-結(jié)論結(jié)論誘導(dǎo)CbP+Bev 是可以耐受并有效的同步Erlotinib+Bev 繼之以強(qiáng)烈的同步放化療治療非鱗癌的NSCLC 的前提是.放療參數(shù)要預(yù)期設(shè)定對食管炎行最佳支持治療首要毒性是食管炎(經(jīng)常為遲發(fā)型)聯(lián)合Erlotinib+Bevacizumab 不可行This approach was associated with late PH in squamous histology patient

11、sPFS and OS 的結(jié)果相對于我們的歷史經(jīng)驗(yàn)不被看好基于實(shí)驗(yàn)中觀察到得毒性加倍,應(yīng)用Bev 和chemoRT 不被推薦MultimodAlity treatment with Radio-chemoTherapy and Erlotinib in advanced NSCLC(MARTE trial)進(jìn)展期進(jìn)展期NSCLC放化療聯(lián)合厄羅替尼的多模式治療放化療聯(lián)合厄羅替尼的多模式治療（MARTE實(shí)驗(yàn)實(shí)驗(yàn)）Sara RamellaRadiation Oncology Campus Bio-Medico University,Rome(Italy)材料和方法材料和方法之前經(jīng)過化療目前正在行放化

12、療的病人包括局限野放療(IF RT)中值升高至59.4 Gy,標(biāo)準(zhǔn)分割(1.8Gy/day)Erlotinib(E)150 mg/dayChemotherapy:Gemcitabine(GEM)300 mg/m2/week(E-GEM group)Pemetrexed(PEM)500mg/m2 every 3 weeks(E-PEM group)病人基線特征和治療相關(guān)毒性病人基線特征和治療相關(guān)毒性G3 血液學(xué)毒性血液學(xué)毒性:30%WBC,5%HB;12%PLTG3 非血液學(xué)毒性非血液學(xué)毒性:Esophagus 2%;Lung 8%*,Diarrhea 5%*2 致死性肺炎致死性肺炎E-PEM

13、組組Compliance RT-CT:54/60(90%);3/6 pts Tox;3/6 PD during RTMedian weekly GEM:5 weeksMedian PEM:2 cycles病人基線特征和毒性統(tǒng)計(jì)數(shù)據(jù)病人基線特征和毒性統(tǒng)計(jì)數(shù)據(jù)有效性有效性隨訪范圍6-45 months整體人群:中位生存23.3 mPFS 4.7 m27.9 vs 19.3 months;p=0.0217.5 vs 3.7 months;p=0.0527.9 vs 18.2 months;p=0.00423.1 vs 22 months;p=0.791非鱗癌總生存鱗癌總生存結(jié)論結(jié)論臨床前期數(shù)據(jù)證實(shí)厄

14、羅替尼的靶向治療有放射增敏作用之前經(jīng)過多次化療的病人行厄羅替尼聯(lián)合同步放化療治療是可行的有效的臨床生物學(xué)標(biāo)志物保障了放射治療的效應(yīng)Determination of standard dose cetuximab together with concurrent individualised,isotoxic accelerated radiotherapy and cisplatin-vinorelbine for patients with stage III non-small cell lung cancer:A phase I study(NCT00522886)測定標(biāo)放療準(zhǔn)計(jì)量的西妥

15、昔單抗聯(lián)合同步個(gè)體化，同毒性加速放療聯(lián)合順鉑長春瑞賓治療III期非小細(xì)胞肺癌的I期臨床研究Anne-Marie C.Dingemans Gerben Bootsma Angela van Baardwijk Bart Reijmen Rinus Wanders Monique Hochstenbag Arne van Belle Ruud Houben Philippe Lambin Dirk de Ruysscher治療流程表治療流程表*Vinorelbine:step 1 10 mg/m2d 1-8,8 mg/m2 d22-29 step 2 20 mg/m2d 1-8,8 mg/m2 d

16、22-29 step3 20 mg/m2d 1-8,15 mg/m2 d 22-29毒性毒性治療治療3個(gè)月后經(jīng)個(gè)月后經(jīng)FDG-PET測定代謝反應(yīng)測定代謝反應(yīng)(N=22)CR:8 PR:11 PD:3結(jié)論 同步放化療聯(lián)合順鉑，長春瑞賓及西妥昔單抗時(shí)可行的 長春瑞賓不能選擇最大劑量 毒性在預(yù)期內(nèi) 3月后治療結(jié)果令人鼓舞放療在早期NSCLC的進(jìn)展同步放化療與靶向藥物治療NSCLC的進(jìn)展同步放化療聯(lián)合培美曲塞治療NSCLC的研究進(jìn)展同步放化療在晚期NSCLC的進(jìn)展力比泰卡鉑同步力比泰卡鉑同步3D適形放療后以力比泰卡鉑鞏適形放療后以力比泰卡鉑鞏固化療治療中國局部晚期固化療治療中國局部晚期NSCLC患者患

17、者M(jìn)a S,et al.ASCO 2009 abstract e18502.摘要摘要e18502：研究設(shè)計(jì)：研究設(shè)計(jì)力比泰500mg/m2 卡鉑 AUC 5放療 62Gy*Q3W2周期入組(N=10)IIIA/IIIB未接受同步放化療的NSCLC無胸水KPS80力比泰500mg/m2 卡鉑 AUC 5Q3W3周期摘要摘要e18502：研究結(jié)果：研究結(jié)果 緩解情況緩解情況摘要摘要e18502：研究結(jié)果：研究結(jié)果 不良反應(yīng)不良反應(yīng)放療在早期NSCLC的進(jìn)展同步放化療與靶向藥物治療NSCLC的進(jìn)展同步放化療聯(lián)合培美曲塞治療NSCLC的研究進(jìn)展同步放化療在晚期NSCLC的進(jìn)展15-year(very)

18、long-term survival(VLTS)and competing risks(CR)analysis of induction(IND)chemotherapy(CTx)with three cycles cisplatin(P)/etoposide(E)followed by concurrent(cc)chemoradiation(CTx/RTx)PE/45 Gy(1.5 Gy bid)plus surgery(S)=TRIMODALITY phase-II West German Cancer Centre(WGCC)trial(JCO 98).R.Hepp1,T.C.Gaul

19、er2,C.Poettgen1,S.Korfee2,S.Bildat2,G.Stamatis3,S.Seeber4,H.Wilke4,V.Budach5,M.Stuschke1,W.E.E.Eberhardt2西德癌癥中心TRIMODALITY II期臨床試驗(yàn)：三周期EP誘導(dǎo)化療繼以同步放化療聯(lián)合手術(shù)治療的一項(xiàng)15年長期生存和競爭風(fēng)險(xiǎn)分析試驗(yàn)設(shè)計(jì)試驗(yàn)設(shè)計(jì)OS(stage),OS(R0)and OS(R0:pCR vs no pCR)Fig.2.OS(stage)Fig.3.OS(R0)Fig.4.OS(R0:pCR)LTS/VLTS 在選擇性亞群的在選擇性亞群的CR分析分析Tab.1.VLTS

20、 in selected subgroupsFig.5.Competing Risk-analysis結(jié)論結(jié)論LTS/VLTSontheWGCC-trialJCO98定義為第一個(gè)選擇性定義為第一個(gè)選擇性可切除可切除IIIA期期NSCLC患者的隨機(jī)對照多中心臨床試驗(yàn)患者的隨機(jī)對照多中心臨床試驗(yàn)探索性分析顯示前期治療對15年長期結(jié)果無影響基于選擇性的R0-可切除的可切除的IIIA和和IIIB期患者繼以誘導(dǎo)治療期患者繼以誘導(dǎo)治療手長期隨訪結(jié)果優(yōu)手長期隨訪結(jié)果優(yōu)60個(gè)月的競爭性風(fēng)險(xiǎn)分析提示(心血管，肺疾病，再發(fā)肺心血管，肺疾病，再發(fā)肺癌和再發(fā)腫瘤是香港風(fēng)險(xiǎn)癌和再發(fā)腫瘤是香港風(fēng)險(xiǎn)(5yrs)SOCCAR

21、 trial results:Comparing toxicity and efficacy ofhypofractionated concurrentchemoradiation to published regimensCancer Research UK&UCL Cancer Trials CentreN ORourke,J Maguire,R McMenamin,C Peedell,M SneeSOCCAR試驗(yàn)結(jié)果：對比已公開發(fā)表的超分割同步試驗(yàn)結(jié)果：對比已公開發(fā)表的超分割同步放化療方案的毒性和有效性放化療方案的毒性和有效性Funding:CRUKSponsor:University

22、CollegeLondonTrial administration:UCLcancer trials centreSupported by BritishThoracic Oncology GroupORourke,N:support for meetingRocheMaguire,J:research support andspeakers honoraria:Pierre Fabre,Astra Zeneca;advisory boards:Eli LillyMcMenamin,R:speakers honoraria:Pfizer;advisory boards:Bayer,GSK;su

23、pport for meetings:GSK,Ibt,Ferring,BoeringerSnee,M:nilCancer Research UK&UCL Cancer Trials CentreTrial funding and Disclosure3CONCURRENT ARM55Gy/20f/4weekscisplatinum 80mg/m2 weeks 1,4vinorelbine 15mgs/m2 weekly4 weekscisplatinum 80mg/m2 day 1vinorelbine 25mg/m2 d 1,d 82 cyclesSEQUENTIAL ARMcisplati

24、num 80mg/m2 day 1vinorelbine 25mg/m2 day 1,84 cycles4 weeks55Gy/20f/4weeksSOCCARTrial Design病理學(xué)確診NSCLC stage III,PS 0-1,CT mediastinoscopy,PET-CTunsuitable for surgerySOCCARNSCLC Stage III PS 0-1CONSEQnmedian1 year2 year3 year5 yearLocal PD6727.4 m73.1%54%38%33.6%10%5918.6 m83.1%42%27%NR22%ConSeqMon

25、thsCancer Research UK&UCL Cancer Trials CentreConcurrent Schedules ComparedTrialno.%2ysRTCT%TRMG3/4oespatientsGy/fSOCCAR 2010705455/20cis/vin417%Jeremic 1996654369.6/58/6w carbo/etop08Belderbos 2006Fournel 2005Curran 2003Huber 2006Furuse 1999Zatloukal 2004Belani 2005Vokes 200466100201991565192182393

26、9373634.634312966/2466/3360/3060/3056/28split60/3063/3466/33daily ciscis/etopcis/vblwkly taxolcis/vindcis/vincarbo/taxcarbo/tax1.510300.602?173225133182831ConclusionsCancer Research UK&UCL Cancer Trials Centre 55Gy/20f/26-28d 同步順鉑聯(lián)合長春瑞賓治療III NSCLC,PS 0-1高度有效 2 year survival 同步放化療組 50%相比于16 RCTs,1733

27、 患者經(jīng)同步CTRT治療后的總生存最高且耐受性良好Randomized phase II trial of uracil/tegafur(UFT)and cisplatinversus vinorelbine and cisplatin with concurrent thoracicradiotherapy for locally advanced unresectable stage IIInon-small-cell lung cancerNJLCG 0601試驗(yàn)?zāi)繕?biāo)試驗(yàn)?zāi)繕?biāo)尿嘧啶替加氟尿嘧啶替加氟(UFT)聯(lián)合順鉑聯(lián)合順鉑(UP arm)對比長春瑞賓聯(lián)合順鉑輔以同對比長春瑞賓聯(lián)合順鉑輔

28、以同步胸部放療步胸部放療,治療進(jìn)展期不可切除的治療進(jìn)展期不可切除的stage III NSCLC 的有效性和安全性的有效性和安全性.首要終點(diǎn)整體有效率整體有效率(ORR)次要終點(diǎn)Progression free survival(PFS)Overall survival(OS)Toxicity profileRANDOMIZATIONStratified factorAgeGenderHistologyStage59/6064/6569/7075Male/FemaleAdeno./Sq./Large/OthersIIIA/IIIBENROLLMENT(n=70)UP arm(n=36)(35

29、patients were evaluable)UFT:400mg/m2,day 1-14,29-42CDDP:80mg/m2,day 8,36RT :2Gy x 5days/week,day 1-40,60Gy試驗(yàn)設(shè)計(jì)試驗(yàn)設(shè)計(jì)NP arm(n=34)(31 patients were evaluable)VNR:20mg/m2,day 1,8,29,36CDDP:80mg/m2,day 1,29RT :2Gy x 5days/week,day 1-40,60Gy 組織學(xué)或細(xì)胞學(xué)確診為NSCLC 不可切除的 stage IIIA or IIIB disease 無胸部放療，胸部外科手術(shù)和化療史

30、 ECOG 評分0 or 1 年齡介于20 and 75 yearsPatients Recruitment:Between February 2006 and May 2009UP armNP armNo.(%)No.(%)白細(xì)胞減少白細(xì)胞減少8231961中性粒細(xì)胞減少中性粒細(xì)胞減少7201858發(fā)熱性嗜中性粒細(xì)胞減少00413腹瀉腹瀉2600肺炎肺炎262*6UP armNP armn3531ORR80%71%PFS8.8 months6.8 monthsOS26.9 months21.8months2-year survival rate51.0%46.9%反應(yīng)和生存數(shù)據(jù)反應(yīng)和生存數(shù)據(jù)

31、毒性數(shù)據(jù)毒性數(shù)據(jù)(Grade3)*Two patients died of radiation pneumonitis.中位隨訪時(shí)間:20.2 monthsNCI-CTC ver.3.0SummeryORRs 為80%and 71%在UP 組 和NP 組.中位隨訪時(shí)間是20.2 months,median PFS 和中位生存在UP組是組是8.8months和和26.9months，在，在NP組為組為6.8months和和21.8months2-年生存率兩組分別是UP 51.0%，NP 46.9%Grade 3/4 血液學(xué)毒性兩組分別是UP 20%和 NP58%發(fā)熱性嗜中性粒細(xì)胞減少僅見于NP組兩組肺炎發(fā)生率都是6%，但在NP 組2例病人死于放射性肺炎Conclusion聯(lián)合同步放療，UP組更顯優(yōu)勢，可作為局晚期NSCLC的候選方案進(jìn)一步評估UP 聯(lián)合 c-TRT 的有效性有待于在將來的以順鉑為基礎(chǔ)的第三代化療聯(lián)合c-TRT 的 III期臨床研究中證實(shí)謝謝 謝謝