早期NSCLC术后辅助治疗规范与展望.pptx

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,早期,NSCLC,术后辅助治疗：规范与展望,PP-PM-CN-0202,北京朝,阳医院,王洋,目录,辅助化疗的回顾,2015,辅助治疗新进展及展望,IB,期患者是否需要接受辅助治疗,(2015 ASCO 7520),辅助化疗是否需要联合抗血管生成药物,(2015 WCLC PLEN04.03),EGFR-TKI,辅助治疗的价值,(2015 ASCO 7540),目录,辅助化疗的回顾,2015,辅助治疗新进展及展望,IB,期患者是否需要接受辅助治疗,(2015 ASCO 7520),辅助化疗是否需要联合抗血管生成药物,(2015 WCLC PLEN04.03),EGFR-TKI,辅助治疗的价值,(2015 ASCO 7540),外科治疗,NSCLC 5,年生存率（,1997,年）,分期,临床分期,(%),病理分期,(%),早期,IA(T1N0M0),61,67,IB(T2N0M0),38,57,IIA(T1N0M0),34,55,IIB(T2N1M0),(T3N0M0),22-24,38-39,III,期,IIIA(,T3N1M0)(T1-3N2M0),9-13,23-25,IIIB(,T4N0-2M0),(,T1-3N3M0),3-7,NA,Mountain CF.Chest 1997;111:1710-7.,手术治疗,NSCLC,的术后复发率,淋巴结状态,局部复发,远处复发,N0,6-17%,18-30%,N1,9-28%,22-64%,c,N2,14-54%,38-55%,pN2,17-41%,70%,远处复发较局部复发多,Bogart JA.Clin Cancer Res.2005;11(13 Pt 2):5004s-5010s.,分期,患者数,5,年复发,%,Ia,560,26.4,Ib,644,31.2,IIa,415,42.0,IIb,292,46.6,IIIa,499,70.1,IIIb,39,71.2,Peters S,et al.2013 ASCO,Poster Discussion,Abstract 7514.,外科治疗,NSCLC 5,年生存率（,2013,年）,局部,+,全身综合治疗是提高疗效的根本,早期,NSCLC,治疗：辅助化疗的关键临床,ALPI,HR=0.96,N=1207,NSCLCCG-Meta-analysis,1995,年,2003,年,2004,年,IALT,HR=0.86,N=467,BLT,HR=1.02,N=1207,2005,年,JBR.10,HR=0.69,N=482,CALGB 9633,HR=0.83,N=344,2008,年,2008,年,LACE-Pooled Analysis,2010,年,NSCLCCG-Adjuvant,Meta-analysis,2006,年,ANITA,HR=0.76,N=840,2009,年,CALGB9633,HR=0.8,N=344,NSCLC,术后辅助化疗得到确认,1995,年：,NSCLC,合作组荟萃分析：,52,项研究，,9387,例患者,顺铂为基础的方案有获益趋势,药物,(,研究数,/,例数,),HR,95%CI,P,5YS,(%),烷化剂,(5/2145),1.15,1.04-1.27,0.005,5,其他药物,(3/818),0.89,0.72-1.11,0.30,4,顺铂为基础,(8/1394),0.87,0.74-1.02,0.08,5,生存概率,(%),100,80,6040,20,0,0,12,24,36,48,60,手术,+,化疗,单纯手术,时间,(,月,),顺铂为基础的辅助化疗,HR=0.87,95%CI 0.74-1.02,P=0.08,NSCLC collaborative group,.,BMJ,1995,;,311:899-909,.,NSCLC,辅助化疗可延长患者生存,研究,n,分期,化疗方案,5,年生存率,化疗组,观察组,p,值,ALPI,1088,I,II,IIIA,MVP,+1%,-,0.59,IALT,1867,I,II,III,CBC,44%,40%,0.03,BLT,381,I,II,IIIA,CBC,58%(2,年,),60%(2,年,),0.90,JBR.10,482,IB,II,CV,69%,54%,0.002,ANITA,840,IB,II,IIIA,CV,51%,43%,0.013,Belani C.P.,Semin Oncol 32(suppl 2):S9-S15,MVP,：顺铂,/,丝裂霉素,/,长春地,辛,CBC,：顺铂为基础的,化疗,CV,：顺铂,/,长春瑞,滨,CbP,：卡铂,/,紫杉,醇,Arriagada R,et al.N Engl J Med.2004;350:351-360.,IALT,：总生存的获益主要来自,III,期患者,I,期,II,期,III,期,全组,化疗更优,对照组更优,1.00,0.86,HR,JBR.10,长期随访：,II,期患者获益更大,长期生存数据显示，患者接受辅助化疗后生存获益,Butts CA,et al.J Clin Oncol 2010;28(1):29-34.,OS(,辅助化疗,vs.,对照,),HR=0.78,95%CI=0.61-0.99,P=0.04,绝对获益：,11%,HR=1.03,95%CI=0.70-1.52,P=0.87,(11,年,vs.9.8,年,),II,期,IB,期,HR=0.68,95%CI=0.50-0.92,P=0.01,(6.8,年,vs.3.6,年,),交互检验,P=0.09,中位随访,9.3,年,(N=482),JBR.10,：,IB,期肿瘤直径,4cm,的患者,辅助化疗有,获益,趋势,IB,期肿瘤直径,4cm,Survival rate,(%),100,80,60,40,20,Log rank:P=.056,HR 1.73(95%CI,0.98-3.04),Survival rate,(%),100,80,60,40,20,0,3,6,9,12,15,Log rank:P=.133,HR 0.66(95%CI,0.39-1.14),Time,(,y,),IB,期肿瘤直,径,4cm,0,3,6,9,12,15,Time,(,y,),Observation,Treatment,Observation,Treatment,Butts CA,et al.J Clin Oncol 2010;28(1):29-34.,CALGB 9633,：肿瘤,4cm,的,IB,期患者可从辅助化疗获益,Strauss GM,et al.J Clin Oncol 2008;26:5043-5051.,1.0,0.8,0.6,0.4,0.2,0,20,40,60,80,100,120,时间,(,月,),生存概率,(%),化疗,(n=99),不化疗,(n=97),HR=0.69,90%CI=0.48-0.99,P=0.043,1.0,0.8,0.6,0.4,0.2,0,20,40,60,80,100,120,时间,(,月,),生存概率,(%),化疗,(n=63),不化疗,(n=71),HR=1.12,90%CI=0.75-1.07,P=0.32,肿瘤,4cm,的,IB,期亚组,肿瘤,4cm,的,IB,期亚组,LACE,荟萃分析：辅助化疗显著延长总生存期与无病生存期,Pignon JP,et al.J Clin Oncol 2008;26:3552-3559.,HR=0.89,95%CI=0.82-0.96,P=0.005,100,80,60,40,20,0,1,2,3,4,5,6,随机入组后时间,(,年,),总体生存,(%),随机入组后时间,(,年,),100,80,60,40,20,0,1,2,3,4,56,无病生存,(%),HR=0.84,95%CI=0.78-0.91,P4cm,、楔形切除等,目录,辅助化疗的回顾,2015,辅助治疗新进展及展望,IB,期患者是否需要接受辅助治疗,(2015 ASCO 7520),辅助化疗是否需要联合抗血管生成药物,(2015 WCLC PLEN04.03),EGFR-TKI,辅助治疗的价值,(2015 ASCO 7540),T2N0M0,期,NSCLC,患者的辅助化疗,研究背景与目的：,辅助化疗能改善完全切除的,II-III,期,NSCLC,患者,OS,，但对,IB,期患者的作用仍不明确,本研究旨在评价辅助化疗对完全切除的,T2N0M0,期,NSCLC,患者的作用,研究设计,运用,Cox,比例风险模型评价辅助化疗能否独立预测每个肿瘤体积组患者的生存,校正性别，年龄、种族、组织学及手术类型,Morgenszttern D,et al.2015 ASCO Abstract 7520.,NCDB,：美国国家癌症数据库,根据化疗状态进行,Kaplan-Meier,生存分析,log-rank,检验比较,肿瘤体积分组,3-3.9 cm,4-4.9 cm,5-5.9 cm,6-7 cm,化疗组,N=5209,(17.4%),观察组,N=24699,(82.6%),(NCDB,数据库筛选,),2003-2010,经,R0,切除,T2N0M0,NSCLC,患者N=29908,T2N0M0,期,NSCLC,患者,无论肿瘤体积，辅助化疗均能改善患者,OS,Morgenszttern D,et al.2015 ASCO Abstract 7520.,1.0,0.0,24,0.8,0.6,0.4,0.2,0,48,72,96,120,1.0,0.0,24,0.8,0.6,0.4,0.2,0,48,72,96,120,OS,时间,(,月,),OS,时间,(,月,),无化疗,化疗后,无化疗,化疗后,肿瘤大小,3-3.9cm,P0.0001,肿瘤大小,4-4.9cm,P0.0001,1.0,0.0,24,0.8,0.6,0.4,0.2,0,48,72,96,120,OS,时间,(,月,),无化疗,化疗后,肿瘤大小,6-7cm,P0.0001,1.0,0.0,24,0.8,0.6,0.4,0.2,0,48,72,96,120,OS,时间,(,月,),无化疗,化疗后,肿瘤大小,5-5.9cm,P0.0001,辅助化疗是否需要联合抗血管生成药物,？,辅助化疗联合或不联合贝伐珠单抗治疗术,后,NSCLC,的随机,III,期临床研究：,E1505,主要,入,组,标准,完全,切除,足够的淋巴结取样,术后,6-,12,周,(,42,+,天,),ECOG PS 0-1,可,抗凝,(,INR,3,),足够的器官,功能,(,实验室检查,),既往未化疗,5,年内无其他肿瘤病史,12,个月内无动脉血栓栓塞,既往无,CVA,、,TIA,无未控制的,HTN,(,150/90,),无活动性出血,无计划性术后放疗,主要,终点,：,总,生存期,85,%,权重检出,OS HR,为,0.79,(,单侧，显著性水平,2.5%,),中位,OS,从,66,个月提到高,83.,5,个月,次要终点,无病生存期,(DFS),CTCAE4.0,版本评估的毒性,(2011,),入,组,标准,：,手术切除,IB,(,4,cm,),-,IIIA,期,术后,6-,12,周,(,AJCC,第,6,版,),分层因素：,1,),顺,铂双,药,2,),分期,3,),组织学,4,),性别,A,组：,化疗,4,周期,B,组：,化疗,4,周期,+,贝伐珠单抗,1,年,每,21,天为一周期，均含顺铂，,75mg/m2,，第,1,天给药,贝伐珠单抗，,15mg/kg,，,IV,，每,3,周给药达,1,年,生存,/,复发随访,2,年内每,3,个月,CXR/,体检，,之后每,6,个月直到,5,年，,之后每年直到,10,年,随,机,Wakelee HA,et al.2015 WCLC Abstract PLEN04.03.,E1505,：化疗,+,贝伐辅助治疗，患者依从性差,化疗,(%),化疗,+,贝伐珠单抗,(%),按研究方案完成治疗,82,37,不良事件,8,28,退出,/,拒绝,7,24,研究期间死亡1,1,进展,1,5,其他,2,6,Wakelee HA,et al.2015 WCLC Abstract PLEN04.03.,E1505,辅助化疗联合贝伐未改善早期,NSCLC,术后总生存,1.0,0.8,0.6,0.4,0.2,0.0,0,12,24,36,48,60,72,84,时间,(,月,),OS,化疗,(n=749),化疗,+,贝伐珠单抗,(n=752),OS,HR*,：,0.99,95%CI,：,(0.81-1.21),P=0.93,OS,DFS,1.0,0.8,0.6,0.4,0.2,0.0,0,12,24,36,48,60,72,84,时间,(,月,),DFS,DFS,HR*,：,0.98,95%CI,：,(0.84-1.14),P=0.75,化疗,(n=749),化疗,+,贝伐珠单抗,(n=752),*HR,为贝伐珠单抗,vs.,对照组的数值,结论：对于,手术切除的早期NSCLC，辅助化疗联合贝伐珠单抗未改善生存,Wakelee HA,et al.2015 WCLC Abstract PLEN04.03.,是否需要辅助靶向治疗？,前瞻性,BR19,辅助靶向治疗未延长,DFS,和,OS,DFS,OS,Goss GD,et al.J Clin Oncol.2013;31:3320-6.,RADIANT,：研究设计,Kelly K,et al.2014 ASCO Abstract 7501.,影像学评估：治疗期间每三个月一次，长期随访中每年一次,主要终点：,DFS,次要终点：,OS,；,del19/L858R(EGFR,阳性,),患者的,DFS,和,OS,肿瘤样本,EGFRIHC+,和,/,或,EGFR FISH+,IB-IIIA,期,NSCLC,完全手术切除,无辅助化疗,4,周含铂两药,化疗方案,(n=973),分层,因素：,组织学,疾病分期,既往辅助化疗,EGFR FISH,状态,吸烟史,国家,(n=350),安慰剂,(n=623),厄洛替,尼,150mg/,天,90,天,180,天,2,：,1,治疗,2,年,OBrien MER,et al.2015 ASCO Abstract 7540.,1.0,12,0,0.8,0.6,0.4,0.2,24,36,48,60,72,0.0,84,DFS,DFS(,月,),安慰剂,(,168,个事件,),中位值：,56.2 m,厄洛替尼,(,280,个事件,),中位值：,55.0 m,Log-rank,检验,P,值：,0.5620,HR:0.94,95%CI:0.780,1.144,1.0,12,0,0.8,0.6,0.4,0.2,24,36,48,60,72,0.0,84,安慰,剂,(n=350),厄洛替,尼,(n=623),安慰,剂,(n=350),厄洛替,尼,(n=623),OS,OS(,月,),安慰剂,(,110,个事件,),中位值,：,未达到,厄洛替尼,(,209,个事件,),中位值,：未达到,Log-rank,检验,P,值：,0.3306,HR:1.12,95%CI:0.890,1.413,手术切除或辅助化疗后,给予厄洛替尼治疗,并未,延长总体人群的,DFS,及,OS,RADIANT,辅助,靶向治疗并未延长总体,人群的,OS,总体人群,OBrien MER,et al.2015 ASCO Abstract 7540.,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,6,12,18,24,30,36,42,48,54,60,66,7278,84,DFS,DFS(,月,),安慰剂,中位值：,28.5 m,厄洛替尼,中位值：,47.8 m,Log-rank,检验,P,值：,0.1906,HR:,0.75,95%CI:0.482,1.158,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,安慰剂,中位值,：,未达到,厄洛替尼,中位值,：未达到,Log-rank,检验,P,值：,0.6142,HR:,1.19,95%CI:0.609,2.310,OS,OS(,月,),安慰,剂,(n=59),厄洛替,尼,(n=102),安慰,剂,(n=59),厄洛替,尼,(n=102),del19,和,L858R,突变亚组人群中，以往观察到的获益趋势不再明显。,RADIANT,辅助,靶向治疗并未,延长,EGFR,突变阳性亚组人群的,OS,EGFR,突变阳性亚组,人群,EGFR-TKI,术后辅助治疗：问题与思考,合适的人群,突变、,II-III,期,治疗手段的优化,疗程,、,剂量,、与,化疗的关系？,不规范治疗的普遍存在,需要更多设计更好的前瞻性期随机对照研究来进一步评估临床获益与治疗风险，尤其是与标准化疗的对照。,EGFR-TKI,术后辅助价值：仍需等待,ADJUVANT,(C-TONG1104),中国,长春瑞滨,25mg/m,2,顺铂,75mg/m,2,*,4,周期,吉非替尼,250mg,PO,*,2,年,主要终点,DFS,次要终点,OS,IMPACT,(WJOG6401L),日本,R,1:1,随机,II-IIIA,期,EGFR,敏感突变阳性且无,T790M,突变的,NSCLC 230,例,II-IIIA,（,N1-N2,）期,EGFR,敏感突变的,NSCLC 220,例,吉非替尼,250mg,PO,*,2,年,长春瑞滨,25mg/m,2,顺铂,75mg/m,2,*,4,周期,R,1:1,随机,基于高选择人群,EGFR-TKI辅助治疗的中国AJUVANT研究和日本IMPACT研究设计相似，这两项研究竞争入组，但最终数据共享合并分析。,Aleksandar M,et al.Onco Targets and Therapy 2015:8 2915-2921,2015NSCLC,术后辅助治疗：规范与展望,含铂双药化疗仍然是,II-IIIA,期,NSCLC,术后辅助治疗的标准方案,IB,期,(4cm),患者能否从辅助化疗中获益有待前瞻性研究进一步证实,辅助化疗联合贝伐未改善患者生存,EGFR-TKI,辅助治疗目前仍只限于临床试验,Thanks!,