非小细胞肺癌(NSCLC)目前治疗进展及未来发展方向.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Chandra P.Belani MD,Professor of Medicine,University of Pittsburgh School of Medicine,Co-Director,Lung&Thoracic Cancer Program,University of Pittsburgh Cancer Institute,非小细胞肺癌,(NSCLC),目前治疗进展及未来发展方向,NSCLC:,诊断时分期及生存,Mountain.,Chest,.1997;1710-1717.,Stage I,Stage II,Stage III,Stage IV,0,20,40,60,80,100,生存比例,诊断时分期,St I,St II,St IIIA,St IIIB,St IV,两药方案一线治疗晚期,NSCLC,的合理性,Good PS,患者,1990s:,含铂方案是治疗标准,NSCLC Collaborative Group BMJ.1995;311:899-909,目前,ASCO,指南,:,含铂两药方案或非铂两药方案是具有较佳,PS,晚期,NSCLC,的治疗标准,Pfister,et al.,J Clin Oncol,.2004;22:330-353,ECOG 1594:,研究,设计,分层,:,分期,:IIIB vs IV,PS:01 vs 2,体重降低,:,5%vs,5%,CNS,转移,:no vs yes,Arm A,:,顺铂,+,泰素,泰素,:135 mg/m,2,/24 h Day 1,顺铂,:75 mg/m,2,day 2,q3wk,Arm D,:,卡铂,+,泰素,泰素,:225 mg/m,2,/3 h Day 1,卡铂,:AUC 6 Day 1,Arm C,:,顺铂,+,多西他赛,多西他赛,:75 mg/m,2,Day 1,顺铂,:75 mg/m,2,Day 1,Arm B,:,顺铂,+,双氟胞苷,双氟胞苷,:1000 mg/m,2,Days 1,8,15,顺铂,:100 mg/m,2,Day 1,q4wk,q3wk,q3wk,Schiller JH,et al.,Proc ASCO 36th Annual Meeting.,2000;19:abstr 2.,Schiller JH,et al.,N Engl J Med,.2002;346:92-98.,R,A,N,D,O,M,I,Z,E,TAX326,研究设计,RANDOMIZE,分层因素,:,疾病分期,IIIB,vs,.IV,和,区域,US/Canada,South America,Europe/Lebanon,Israel,SouthAfrica/AustraliaNew Zealand,Response assessment every 2 cycles,多西他赛,75mg/m,2,IV,卡铂,AUC 6,IV,Q 3 wks,去甲长春花碱,25mg/m,2,IV D 1,8,15&22,顺铂,100mg/m,2,IV,D 1Q 4 wks,多西他赛,75mg/m,2,IV,顺铂,75mg/m,2,IV,Q 3 wks,vs.,or,TAX 326,总生存,Fossella et al.,J Clin.Oncol.,2003;21:3016-3024.,100,80,60,40,20,0,Survival(%),0,3,6,9,12,15,18,21,24,27,30,33,Time(months),TC,VC,100,80,60,40,20,0,Survival(%),0,3,6,9,12,15,18,21,24,27,30,33,Time(months),P,=.657,adjustedlog-rank test,TCb,VC,1-y survival 46%vs 41%with VC,2-y survival 21%vs 14%with VC,Median survival:11.3 vs 10.1 mo,P,=.044,adjusted log-rank test,1-y survival 38%vs 40%with VC,2-y survival 18%vs 14%with VC,R,A,N,D,O,M,I,Z,E,方案设计,分层,前,6,个月体重降低,:,5%vs 5%,疾病分期,:,湿性,IIIB,IV,是否脑转移,:,双氟胞苷,1000 mg/m,2,d 1,8,泰素,200 mg/m,2,d 1,q 21 days,双氟胞苷,1000 mg/m,2,d 1,8,卡铂,AUC 5.5 d 1,q 21 days,Arm A,:,双氟胞苷,+,卡铂,Arm B,:,双氟胞苷,+,泰素,Arm C,:,泰素,+,卡铂,泰素,225 mg/m,2,d 1,卡铂,AUC 6.0 d 1,q 21 days,非铂方案,ASCO Abstract#7025,Arm 3,Arm 2,Arm 1,泰素,150 mg/m,2,+,卡铂,AUC=2 (,连用,6,周,休,2,周,),then,泰素,100 mg/m,2,+,卡铂,AUC=2(,连用,6,周,休,2,周,)*,泰素,100 mg/m,2,+,卡铂,AUC=2,(,连用,3,周,休,1,周,)*,泰素,100 mg/m,2,(,连用,3,周,休,1,周,),+,卡铂,AUC=6(d1)*,SCHEMA,Belani et al,JCO 21:2933-39,2003,泰素每周方案联合卡铂初始化疗后泰素每周方案维持治疗晚期,NSCLC,随机,II,期临床试验,*,泰素,/,卡铂初始化疗后取得,CR,PR or SD,的患者随机接受泰素,70 mg/m,2,/wk,维持治疗或观察,疗效,/,毒性,Arm 1 Arm 2 Arm 3,中位生存时间,49 wks 31 wks 40 wks,(p=0.077,vs,1)(p0.45,vs,1),中位,TTP 30 wks 21 wks 27 wks,(p=0.01,vs,1)(p0.73,vs,1),1-,年生存率,47%31%41%,(p0.01,vs,1)(p0.20,vs,1),中性粒细胞减少,(grade 4)22%8%19%,血小板减少,(grade 4)5%2%1%,神经病变,(grade 3)5%3%13%,Belani et al,JCO 21:2933-39,2003,泰素每周方案联合卡铂初始化疗后泰素每周方案维持治疗晚期,NSCLC,随机,II,期临床试验,Taxmen 12:Kaplan-Meier,评估,患者生存,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,8,16,24,32,40,48,56,64,72,80,88,96,104,112,120,128,136,144,152,160,Weekly,Standard,Proportion of Patients Who Survived,Time(Weeks),最后,泰素每周方案维持治疗可明显改善生存,(76.6,周,vs.49.6,周,P=0.016)-,扮演什么角色,?,这个概念能通过应用其它药物得到验证吗,?,转移性肺癌,贝伐单抗,+,化疗,靶向药物联合化疗治疗晚期非小细胞肺癌,向前飞跃的一大步,患者特征,(,入组患者,),90%,91%,白种人,50%,58%,男性,40%,38%,ECOG PS 0,43%,44%,年龄,65,28%,28%,既往体重下降,5%,91%,91%,可测量疾病,13%,14%,Stage IIIB,N,=424,N,=431,PCB,PC,非血液学毒性,PC(%n)PCB(%n),Grade 3,Grade 3 p-value,出血,3(0.7)19(4.5).001,咳血,1(0.2)8(1.9)0.04,CNS04(1.0)0.03,GI2(0.5)5(1.2)NS,Other1(0.2)4(1.0)NS,高血压,3(0.7)25(6.0).001,静脉血栓,13(3.0)16(3.8)NS,动脉血栓,4(1.0)8(1.9)NS,6 mo.1 yr,33%6%,55%15%,缓解,(,病例,),PC,(383),PCB,(391),CR,0.3%,1.3%,PR,9%,24%,CR/PR,9%,25%*,*,p0.0001,Sandler:abstract#ASCO 05,ECOG Trial(E4599):rhuMab VEGF(,贝伐单抗,),联合化疗治疗非鳞型,NSCLC,0.0,0.2,0.4,0.6,0.8,1.0,无进展生存,Probability,PC,PCB,P 0.0001,0,6,12,18,24,30,36,Months,Medians:4.5,6.4,MST,1y 2 yr,10.2 44%17%,12.5 52%22%,Sandler:ASCO 05,ECOG Trial(E4599):rhuMab VEGF(,贝伐单抗,),联合化疗治疗非鳞型,NSCLC,根据性别分层的疗效结果,(,亚组分析,),男性,女性,OS(HR),0.69,p=0.003,0.96,P=0.80,PFS(HR),0.53,P=0.0001,0.68,P=0.002,RR(%),12.2 vs 23.5,p=0.006,7.4 vs 31.7,P0.0001,?chance,信息,:,含铂或,非铂,两药方案是具有较佳,PS,患者一线治疗的标准,Dilemmas:,谁将在较佳,PS,患者中转换应用非铂方案,!,在选择的非鳞癌患者中化疗联合贝伐单抗的,疗效优于标准化疗,转移性肺癌,FDA,批准的,NSCLC,二线治疗选择,多西他赛,培美曲塞,Erlotinib,局部晚期无法切除,NSCLC,综合治疗,Stage III,无法切除疾病,泰素每周方案联合卡铂同步放化疗,(+2-3,周期联合化疗或多西他赛,),是美国目前治疗,III,期,NSCLC,的常规方案,在欧洲和加拿大序贯放化疗仍然是治疗标准,靶向药物,-Cetuximab,吉非替尼和贝伐单抗等已经在临床试验中评估联合放疗的疗效,但数据不成熟,同步放化疗是治疗标准,SWOG 0023,初步结果,:EP,同步放化疗,多西他赛巩固化疗,吉非替尼或安慰剂维持治疗无法切除,Stage III NSCLC,CDDP 50 mg/2,d 1,8,29,36,VP-16 50 mg/m2,d1-5,29-33,XRT 1.8-2 Gy/d,61 Gy,多西他赛,75 mg/m2,x 3 cycles,安慰剂,吉非替尼,500 mg/day,250 mg/day,(5-1-03),放化疗,巩固化疗,维持治疗,Registration#1,Registration#2,Registration#3,计划,840,例患者,:,入组,642,例患者,(80%),入组,:620 pts,574 pts(74%),263 pts(64%),Kelly:abstract#ASCO 05,CT/RT/S,145/202,CT/RT,155/194,Logrank p=0.24,Hazard ratio=0.87(0.70,1.10),%Alive,0,25,50,75,100,Months from Randomization,0,12,24,36,48,60,Dead/Total,INT 0139 Update,总生存,中位随访,81,月,根据病理淋巴结状态分层的总生存,不手术,(n=38),病理,N0(n=76),病理,N1-3,unknown(n=88),p 2cm),IIA-IIB,T3N1,NATCH(,泰素联合卡铂新辅助,/,辅助临床研究,),未回答问题,化疗方案的选择,患者选择,(,老年和较差,PS?),Stage IA?,是否有一组患者不应该接受化疗,?,新辅助治疗显示出明确的角色,或许其优于辅助化疗,!,早期肺癌,GG,C,GGG,CC,AAA,C,T,G,C,T,GGG,T,G,C,G,100,EGFR,蛋白表达,(,免疫组化,),EGFR,基因拷贝数,(FISH),EGFR,突变状态,EGFR,抑制剂患者的选择,EGFR,生物标记研究结果的差异,研究患者的差异,患者特征,:,all NSCLC,BAC,患者数量,:,结果差异,:,缓解,或,生存,应用的方法学和阳性定义的差异,IHC:,评分系统差异,FISH:,阳性,=,高多体性,+,扩增,或,仅有扩增,突变,:,所有突变均是被相同产生的吗,?,孤立的,生物标记研究,vs,多基因分子特征,的预测基础,结论,:“The jury is still out”,Final Message,肺癌患者正生活的更长更好,!,其它研发的新药,SAHA,PXD101,GW570216,GARFT Inhibitor,PARP Inhibitor,HSP 90 agents,SU 11248,PTK 987,PS-341,Cetuximab,SU11248,PTK787,ZD6474,AEE788,AG01736,AMG-706,Oral Taxane,Abraxane,预言,“靶向治疗将使得肿瘤治疗产生革命性的变革,”,