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1、晚期非小细胞肺癌整体治疗策略美国临床肿瘤学协会(ASCO)临床实践指南更新解读,上海市肺部肿瘤临床医学中心上海交通大学附属胸科医院陆舜,1997,2003,2009,ASCO Guideline,NCCN Guideline,alliance of 21 of the world leading cancer center,is dedicated to improving the quality and effectiveness of care provided to patients with cancer.Through the leadership and expertise of
2、clinical professionals at NCCN Member Institutions,NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system.As the arbiter of high-quality cancer care,NCCN promotes the importance of continuous quality improvement and recognizes the si
3、gnificance of creating clinical practice guidelines appropriate for use by patients,clinicians,and other health care decision-makers.The primary goal of all NCCN initiatives is to improve the quality,effectiveness,and efficiency of oncology practice so patients can live better lives.,与NCCN Guideline
4、相比，ASCO Guideline更有权威性,背景介绍,ASCO最初于1997年公布无法手术切除的NSCLC治疗的临床实践指南并于2003年进行了更新ASCO指南的更新是一个连续过程，自2003年以来，发表了大量与本指南相关的研究文献本次指南的更新基于2002年1月至2009年5月间所发表的文献主要基于OS改变有显著性统计学意义的前瞻性随机对照研究仅有PFS显著改善的研究结果仍需得到进一步验证毒性生活质量,Azzoli CG,et al.J Clin Oncol 2009;27(36):6251-66,研究方法的更新情况,文献评估时间：2002年2008年7月数据来源MEDLINEEMBASE
5、Cochrane数据库入组条件随机入组IV期NSCLC患者药物间的比较，药物与安慰剂的比较，药物与最佳支持治疗间的比较报告了疗效(OS/PFS/ORR)，毒性，QOL，症状缓解化疗药物仅限III期RCT；靶向药物包括II期、III期随机试验分子标志物研究包括II/III期试验，队列研究以及临床试验中的回顾性亚组分析,Azzoli CG,et al.J Clin Oncol 2009;27(36):6251-66.,研究方法的更新情况,文献评估结果至少与一个临床问题相关的190篇文献,Azzoli CG,et al.J Clin Oncol 2009;27(36):6251-66.,入组文献的局
6、限性,体力状态评分较差患者的研究入组数目有限(ECOG PS 2或者KPS65 岁或者 70岁)三线及以上治疗缺乏III期研究数据,Azzoli CG,et al.J Clin Oncol 2009;27(36):6251-66.,指南推荐更新-一线治疗,哪些IV期患者应接受药物治疗？2003年指南推荐：对于IV期的NSCLC患者进行药物治疗可延长生存期。药物治疗适用于ECOG/Zubrod PS 0-1以及PS 2的患者，并应在PS评分较好的时期开始治疗2009年指南推荐A1：ECOG PS 0-1以及PS 2的患者,Azzoli CG,et al.J Clin Oncol 2009;27(
7、36):6251-66.,化疗在晚期NSCLC治疗地位的确立,汇聚16项随机对照研究，2714例NSCLC患者的荟萃分析显示：化疗有显著生存获益，HR=0.77，p 0.0001；MST 增加1.5个月；1年生存率提高9%,NSCLC Meta-Analyses Collaborative Group.J Clin Oncol.2008;26(28):4617-25,OS,指南推荐更新-一线治疗,IV期患者最有效的一线治疗方案是什么？2003年指南推荐：晚期NSCLC一线治疗应为含铂双药化疗，一线非铂类化疗可替代含铂方案2009年指南推荐A2：对于PS 0-1的患者应选择两药联合化疗含铂两药联
8、合化疗疗效好于非铂类两药联合化疗对不适合铂类治疗的患者，可考虑非铂类两药联合化疗,Azzoli CG,et al.J Clin Oncol 2009;27(36):6251-66.,对于PS 0-1的患者应选择两药联合化疗,汇聚65项随机对照研究，13601例NSCLC患者的荟萃分析显示：两药联合化疗的疗效优于单药化疗或三药化疗,Delbaldo C.et al.,JAMA 2004;292:470-484,两药/三药联合化疗vs.单药化疗,对于PS 0-1的患者应选择含铂两药联合化疗,多项荟萃分析的结果显示：含铂两药联合化疗疗效好于非铂类两药联合化疗,Hotta K.et al.,Ann O
9、ncol 2004;15:1782-1789DAddario G,et al.,J Clin Oncol 2005;23(13):2926-2936Rajeswaran A,et al.,Lung Cancer 2008;59(1):1-11,*partial response,非铂类两药联合化疗,健择+紫杉醇用于NSCLC治疗的研究研究设计：,健择 1000 mg/m2 d 1,8+紫杉醇 200 mg/m2 d1 q 3 weeks,紫杉醇200 mg/m2 d1 q 3 wks+卡铂 AUC 6 d1 q 3 weeks,RANDOMIZE,Kosmidis,ASCO 2000 Abst
10、ract#1908,非铂类两药联合化疗,健择+紫杉醇用于NSCLC治疗的研究研究结果：,Kosmidis,ASCO 2000 Abstract#1908,非铂类两药联合化疗,健择+紫杉醇用于NSCLC治疗的研究研究结果：,Kosmidis,ASCO 2000 Abstract#1908,指南推荐更新-一线治疗,IV期PS2 患者的最佳治疗方案是什么？2003年指南推荐：对于老年患者或ECOG/Zubrod PS 2的患者，证据支持单药治疗2009年指南推荐A3：现有证据支持PS 2的患者应接受单药治疗尚无充分证据推荐PS 2的患者应/不应接受两药联合化疗,Azzoli CG,et al.J C
11、lin Oncol 2009;27(36):6251-66.,Gridelli C,et al.Ann Oncol.2004;15(3):419-26.,单药治疗,指南推荐更新-一线治疗,IV期老年患者的最佳治疗方案是什么？2003年指南推荐：对于老年患者或ECOG/Zubrod PS 2的患者，证据支持单药治疗2009年指南推荐A4：没有证据支持仅根据年龄来选择某特定一线单药或联合化疗,Azzoli CG,et al.J Clin Oncol 2009;27(36):6251-66.,单药治疗,WJTOG9904研究证实，多西他赛用于老年晚期NSCLC患者的mPFS优于诺维本(5.5m vs
12、.3.1m)，mOS无差别(14.3m vs.9.9m),Kudoh S,et al.J Clin Oncol 2006;24(22):3657-63.,P0.001,P=0.138,单药治疗,Gridelli C,et al.J Clin Oncol.2005;23(13):3125-37.,联合化疗,Gridelli C,et al.J Clin Oncol.2005;23(13):3125-37.,指南推荐更新-一线治疗,IV期患者的一线治疗，顺铂比卡铂更有效吗？2003年指南推荐：没有明确推荐2009年指南推荐A5：选择顺铂或卡铂都是可以接受的顺铂与卡铂可分别联合第三代化疗药物(多西他
13、赛、吉西它滨、伊立替康、紫杉醇、培美曲赛和长春瑞滨)相比卡铂，顺铂联合第三代化疗药物的缓解率更高，能延长生存期卡铂引起恶心、肾毒性和神经毒性的风险低于顺铂，但更容易发生血小板减少,Azzoli CG,et al.J Clin Oncol 2009;27(36):6251-66.,顺铂与卡铂的疗效比较,三项荟萃分析的结果显示：与卡铂相比，含顺铂方案化疗的缓解率更高,Hotta K.et al.,J Clin Oncol 2004;22(19):3852-9Ardizzoni A,et al.,J Natl Cancer Inst.2007;99(11):847-57Jiang J,et al.,
14、Lung Cancer 2007;57(3):348-58,顺铂与卡铂的疗效比较,对汇聚8项随机对照研究，2948例NSCLC患者的荟萃分析的亚组分析(联合第三代化疗药的方案)显示：与卡铂相比，含顺铂联合化疗可使生存期延长11%(HR=1.106，P=0.039)对汇聚9项随机对照研究，2968例NSCLC患者的荟萃分析的亚组分析显示：卡铂联合三代化疗药可引起死亡风险显著增加(HR=1.11)；对非鳞癌患者，含卡铂方案引起死亡风险显著增加(HR=1.12),Hotta K.et al.,J Clin Oncol 2004;22(19):3852-9Ardizzoni A,et al.,J Na
15、tl Cancer Inst.2007;99(11):847-57,铂类联合三代化疗药物治疗晚期NSCLC,以铂类为基础的三代化疗药仍是晚期NSCLC一线治疗基石,NSCLC:Pivotal Phase III Trials in Stage IIIB/IV-1st-line Treatment-,铂类联合三代化疗药物治疗晚期NSCLC,JMDB:一线对照健择/顺铂治疗晚期NSCLC的III期研究,Scagliotti GV,et al.J Clin Oncol.2008;26(21):3543-51,迄今样本最大且唯一入组1600例晚期NSCLC一线治疗的前瞻性、随机、双盲、全球多中心的II
16、I期研究,铂类联合三代化疗药物治疗晚期NSCLC,JMDB研究研究设计随机、III期、非劣效性设计试验IIIB/IV期NSCLC一线治疗每3周方案，最多6个周期特定的组织学亚组分析随机因素ECOG PS 分期 脑转移史 性别病理学类型组织学 Vs.细胞学,Scagliotti GV,et al.J Clin Oncol.2008;26(21):3543-51,铂类联合三代化疗药物治疗晚期NSCLC,JMDB研究总生存时间：力比泰/顺铂OS与健择/顺铂相似,Scagliotti GV,et al.J Clin Oncol.2008;26(21):3543-51,铂类联合三代化疗药物治疗晚期NSC
17、LC,JMDB研究力比泰顺铂对非鳞癌患者的疗效更优,Scagliotti GV,et al.J Clin Oncol.2008;26(21):3543-51,优效性检验 P=0.005,13.5%,铂类联合三代化疗药物治疗晚期NSCLC,JMDB研究力比泰顺铂的安全性更好,Scagliotti GV,et al.J Clin Oncol.2008;26(21):3543-51,Summary of Progression-free survivalfor All of the Patients and the East Asian Subgroup,*Chih-Hsin Yang,et al
18、J Thorac Oncol.2010;5,Summary of Median Survival Times for All of the Patients and the East Asian Subgroup,*Chih-Hsin Yang,et al J Thorac Oncol.2010;5:),Survival time in all patients from Taiwan/Korea,*Chih-Hsin Yang,et al J Thorac Oncol.2010;5:),Survival time in all non-squamous patients from Taiwa
19、n/Korea(Months),*Chih-Hsin Yang,et al J Thorac Oncol.2010;5:),Survival time in all squamous patients from Taiwan/Korea(Months),*Chih-Hsin Yang,et al J Thorac Oncol.2010;5:),Conclusions,The NSCLC histology effect on treatment outcomes for pemetrexedtreated patients seen in the entire study population
20、 was also apparent in the EA subgroupThe potential prognostic influence of race,histology subtype,and smoking status should be assessed in future NSCLC studies,*Chih-Hsin Yang,et al J Thorac Oncol.2010;5,指南推荐更新-一线治疗,一线治疗的最佳持续时间是多久？2003年指南推荐：对于IV期NSCLC患者，4个周期治疗后未缓解应停药，最长治疗时间不应超过6个周期2009年指南推荐A6：4周期细胞毒
21、药物化疗后出现疾病进展或未缓解时，应停药不应给予患者超过6周期的细胞毒药物双药化疗方案一线治疗后稳定或缓解的患者，不推荐继续化疗直至进展或在疾病进展前给予不同的化疗*,*注：本指南完稿印刷时，美国FDA于2009年7月批准了力比泰维持治疗晚期NSCLC，全文也于2009年9月发表于Lancet，该数据尚未列入本指南的文献评估中。有关维持治疗的推荐会根据近期发表的数据进行更新,Azzoli CG,et al.J Clin Oncol 2009;27(36):6251-66.,一线治疗持续的时间,Socinski MA,et al.J Clin Oncol 2002;20(5):13351343.
22、von Plessen C et al.Br J Cancer 2006;95(8):966-73.Park JO,et al.J Clin Oncol 2007;25(33):52335239.,一线两药化疗直到4-6个周期后，将导致毒性累积，但没有确切的疗效优势,JMEN研究,研究设计：多中心、双盲、安慰剂对照期临床研究,B/期NSCLC患者ECOG PS 0-1既往接受4周期含铂诱导化疗未进展,2:1比例随机化,力比泰 500 mg/m2(d1,q21d)+BSC*N=441,安慰剂(d1,q21d)+BSCN=222,*BSC:所有患者均接受VB12、叶酸和地塞米松,Ciuleanu
23、T et al.,Lancet 2009;374(9699):1432-40,JMEN研究,研究结果：力比泰维持治疗可显著延长ITT人群的OS,Ciuleanu T et al.,Lancet 2009;374(9699):1432-40,JMEN研究,研究结果：力比泰维持治疗对非鳞癌患者的OS改善更显著,Ciuleanu T et al.,Lancet 2009;374(9699):1432-40,毒性反应,P0.05 for grade 3/4 rates of neutropenia and fatigue,JMEN研究,Ciuleanu T et al.,Lancet 2009;374
24、(9699):1432-40,JMEN研究,研究结论：这是第一项证明维持治疗可显著延长NSCLC患者OS的随机、双盲、安慰剂对照研究，也证明了力比泰维持治疗的疗效再次证明：非鳞癌组织类型可作为力比泰治疗NSCLC疗效的预测指标力比泰在维持治疗应用中具有良好的安全性和耐受性,Ciuleanu T et al.,Lancet 2009;374(9699):1432-40,SATURN study design,Stratification factors:EGFR IHC(positive vs negative vs indeterminate)Stage(IIIB vs IV)ECOG PS(
25、0 vs 1)CT regimen(cis/gem vs carbo/doc vs others)Smoking history(current vs former vs never)Region,1:1,Chemonave advanced NSCLCn=1,949,Non-PDn=889,4 cycles of 1st-line platinum-based doublet*,Placebo,PD,Erlotinib150mg/day,PD,Mandatory tumour sampling,*Cisplatin/paclitaxel;cisplatin/gemcitabine;cispl
26、atin/docetaxel cisplatin/vinorelbine;carboplatin/gemcitabine;carboplatin/docetaxel carboplatin/paclitaxelEGFR=epidermal growth factor receptor;IHC=immunohistochemistry,Co-primary endpoints:PFS in all patientsPFS in patients with EGFR IHC+tumoursSecondary endpoints:Overall survival(OS)in all patients
27、 and those with EGFR IHC+tumours,OS and PFS in EGFR IHC tumours;biomarker analyses;safety;time to symptom progression;quality of life(QoL),F.Cappuzzo.et al,J Clin Oncol 27:7s,2009(suppl;abstr 8001),Efficacy and safety of erlotinib in Asian patients with advanced non-small-cell lung cancer Baseline c
28、haracteristics in the Asian population,Best response in Asian population,14%of patients in the erlotinib arm had an upgrade of response from SD to PR in the maintenance phase,versus 0%in the placebo arm,Patients(%),6050403020100,Erlotinib,Placebo,PFS in Asian population,1.00.80.60.40.20,Probability,
29、04812162024283236404448525660646872,768084889296100104,Time(weeks),636239282317131054432222221,11110000,595937312823191715151413131086432,00000000,n at riskPlaceboErlotinib,11.4,17.9,Placebo,Erlotinib,HR=0.57(0.370.86)Log-rank p=0.0067,OS in Asian population,1.00.80.60.40.20,Survival,Time(months),03
30、69121518212427303336,6561534642332116111060060575045373526191610310,n at riskPlaceboErlotinib,15.2,20.8,HR=0.67(0.421.07)Log-rank p=0.0931,Placebo,Erlotinib,Summary of Asian safety data,Only two patients had treatment-related interstitial lung disease(ILD);both were in the erlotinib arm,one was grad
31、e 3,化疗药物作为维持治疗的荟萃分析,A,较少争议;B1,少量争议;B2,中等争议;C,较大争议;NR:未报道,Soon YY et al,J Clin Oncol 2009;27(20):3277-83,维持化疗在一定程度上延长了生存期(HR 0.92；95%CI，0.86-0.99；P=0.03),同样维持化疗明显延长PFS(HR 0.75；95%CI，0.69-0.81；P=0.00001),Soon YY et al,J Clin Oncol 2009;27(20):3277-83,指南推荐更新-一线治疗,靶向药物对IV期患者的总生存期、无进展生存期、毒性和生活质量/症状改善的获益如
32、何？2003年指南推荐：如果IV期NSCLC患者2个周期治疗无效，可选择性的让患者参加临床研究进行治疗2009年指南推荐A7：不推荐厄洛替尼或吉非替尼联合化疗一线治疗未经选择的患者没有充分证据推荐厄洛替尼或吉非替尼一线单药治疗未经选择的患者对于EGFR突变的患者，一线使用吉非替尼可能是一种选择如果患者EGFR突变阴性或状态未知，应首选化疗,Azzoli CG,et al.J Clin Oncol 2009;27(36):6251-66.,phase III,randomized,open-label,first-line study of gefitinib vs carboplatin/pa
33、clitaxel in clinically selected patients with advanced non-small cell lung cancer in Asia(IPASS),*Never smokers,100 cigarettes in lifetime;ex-light smokers,stopped 15 years ago and smoked 10 pack years;#limited to a maximum of 6 cycles.,Carboplatin(AUC 5 or 6)/paclitaxel(200 mg/m2)3 weekly#,1:1 rand
34、omization,PatientsChemo-naveAge 18 years Adenocarcinoma histologyNever or ex-light smokers*Life expectancy12 weeksWHO PS 0-2Measurable stage IIIB/IV disease,Primary Progression-free survival(non-inferiority)Secondary Objective response rate Overall survival Quality of life Disease-related symptoms S
35、afety and tolerabilityExploratory BiomarkersEGFR mutationEGFR-gene-copy numberEGFR protein expression,End points,Conducted in China,Japan,Thailand,Taiwan,Indonesia,Malaysia,Philippines,Hong Kong and Singapore,Mok et al N Engl J Med 2009;361.,Gefitinib(250 mg/day),Progression-free survival,609453(74.
36、4%),608497(81.7%),NEvents,HR(95%CI)=0.74(0.65,0.85)p0.0001,Gefitinib,Gefitinib demonstrated superiority relative to carboplatin/paclitaxel in terms of PFS,Primary Cox analysis with covariates;HR 1 implies a lower risk of progression on gefitinib;ITT populationPFS,progression-free survival;ITT,intent
37、-to-treat;HR,hazard ratio;CI,confidence interval;C/P,carboplatin/paclitaxel,Carboplatin/paclitaxel,C/P,Gefitinib,Median PFS(months)4 months progression-free6 months progression-free12 months progression-free,5.761%48%25%,5.874%48%7%,609,212,76,24,5,0,608,118,22,3,1,0,363,412,0,4,8,12,16,20,24,Months
38、,0.0,0.2,0.4,0.6,0.8,1.0,Probabilityof PFS,Patients at risk:,Mok et al N Engl J Med 2009;361.,TKI药物需用于EGFR突变的人群,IPASS研究显示：吉非替尼的疗效随EGFR突变的不同而有显著差异；而EGFR突变状态对化疗的疗效影响不明显,Mok et al,N Engl J Med 2009;361(3):947-57.,TKI药物需用于EGFR突变的人群,IPASS研究显示:EGFR突变野生型的患者缓解率只有1.1%，和安慰剂没有区别,Gefitinib Carboplatin/paclitaxe
39、lEGFR M+odds ratio(95%CI)=2.75(1.65,4.60),p=0.0001 EGFR M-odds ratio(95%CI)=0.04(0.01,0.27),p=0.0013,总体反应率(%),(n=132),(n=129),(n=91),(n=85),71.2%,47.3%,1.1%,23.5%,Mok et al,N Engl J Med 2009;361(3):947-57.,First-SIGNAL：study design,2009 WCLC,Primary endpoint:Overall survival Secondary endpoint:Progr
40、ession free survival,First-SIGNAL：Overall survival and Progression-free survival,2009 WCLC,First-SIGNAL:PFS by EGFR mutation status within treatment arm,2009 WCLC,First-SIGNAL：Conclusion,EGFR mutations is a strong predictive marker for overall response and PFS with GefitinibGefitinib did not improve
41、 OS over the standard GP chemotherapy,but have high ORR and better toxicity profiles.,2009 WCLC,First line Gefitinib versus Caboplatin plus paclitaxle in NSCLC patients with EGFR mutations:North East Japan(NEJ)002 Gefi tinib Study Group,CBDCA AUC 6 and TXL 200mg/m2N=99,1:1 randomization,Patientssens
42、itive EGFR mutations(PNA-LNA PCR clamp test)measurable site(s)ECOG PS 0-1,age of 20-75 years,No prior chemotherapy,Primary Progression-free survivalSecondary Qol Overall survival,End points,Gefitinib(250 mg/day)N=98,Balanced by institution;sex,stage,Kobayashi K,et al.2009 ASCO Abstract 8016,Response
43、,Conclusion,This is the first phase III study to compare first line gefitinib with first line chemotherapy for advanced NSCLC patients with EGFR mutationThere were several differences in toxicities between Gefitinib Arm and Chemotherapy Arm grade 4 neutropenia:1%vs.29%grade 3-4 liver dysfunction:24%
44、vs.1%grade 3 neuropathy:0%vs.5%,respectively,p0.01The independent safety committee has decided to stop accumulation patients up to 31st,May,2009,Gefitinib versus cisplatin plus docetaxel in patients with NSCLC harbouring EGFR mutations(WJTOG3405):an open label,randomised phase III trial,docetaxel(60
45、 mg/m2,D1)followed by cisplatin(80 mg/m2,D1,1:1 randomization,PatientsLocal advanced/metastatic(IIIB/IV disease)Chemo-nave(adjuvant OK)Age 20 years Evaluable diseasePS 0-1,Primary Progression-free survivalSecondary Objective response rate Overall survival Third DCRSafety,End points,Gefitinib(250 mg/
46、day),EGFR mutationExon 19 deletion or L858R,200 patients with mutation,Tetsuya Mitsudomi,et al.Lancet,December 21,2009,Demography,Tetsuya Mitsudomi,et al.Lancet,December 21,2009,Progression-free survival in the overall population,Tetsuya Mitsudomi,et al.Lancet,December 21,2009,Overall survival in th
47、e overall population,Tetsuya Mitsudomi,et al.Lancet,December 21,2009,CTC Grade Non-haematological toxicity,Tetsuya Mitsudomi,et al.Lancet,December 21,2009,CTC Grade haematological toxicity,Tetsuya Mitsudomi,et al.Lancet,December 21,2009,Summary,Conclusion,Gefitinib significantly prolonged the progre
48、ssion-free survival of patients with NSCLC who carry EGFR mutations compared with chemotheray,指南推荐更新-一线治疗,靶向药物对IV期患者的总生存期、无进展生存期、毒性和生活质量/症状改善的获益如何？2009年指南推荐A8：在选择性患者中推荐贝伐单抗15mg/kg每三周方案与卡铂紫杉醇的联合治疗选择性患者应排除：鳞癌、脑转移、有临床意义的咯血、器官功能不足、ECOG PS 1、接受治疗性抗凝血药物、伴临床显著性心血管疾病或控制不佳的高血压贝伐单抗可持续给药直至疾病进展或出现不可耐受的毒性,Azzoli
49、 CG,et al.J Clin Oncol 2009;27(36):6251-66.,Bevacizumab,Bevacizumab,AVAiL:Cis/Gem,PD,PD,PD,Bevacizumab15mg/kg+CG,Bevacizumab7.5mg/kg+CG,Placebo+CG,Previously untreated,stage IIIB,IV or recurrent non-squamous NSCLC,RANDOMISE,Placebo+CG,2,2,1,1,Previously untreated stage IIIB/IV non-squamous NSCLC,CP,
50、Avastin(15mg/kg)every 3 weeks+CP,PD,PD,Avastin every 3 weeks until progression,ECOG 4599:Carbo/Taxol,Bevacizumab studies-Design of ECOG 4599+AVAiL-,贝伐单抗的应用,ECOG4599显示卡铂紫杉醇联合贝伐单抗可改善PFS和OS,Sandler A,et al.N Engl J Med 2006,355(24):2542-50.,注：贝伐单抗在中国还未上市,AVAiL:Global versus Asian populations,*Includes
