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1、从近年来临床肿瘤学进展看内科治疗的发展前景,近年来临床肿瘤学的重要进展WHO将肿瘤定位为慢性可控疾病 分子靶向治疗肿瘤内科治疗的新时代中医理论和靶向治疗融合结语孙燕中国医学科学院北京协和医学院肿瘤医院2008-7-25,ASCO 2006年临床肿瘤研究的主要进展,1、Dasatinib可有效治疗伊 马替尼耐药的CML2、Lapatinib改善晚期 乳腺癌疗效3、预测少突胶质细胞瘤患 者预后的分子标志物4、奥沙利铂加吉西他滨对 胰腺癌治疗无优势5、肾癌一线和二线治疗 均有新药问世6、人乳头瘤病毒（HPV)疫苗 能预防子宫颈癌和外阴癌,7、腹腔化疗可延长卵巢癌 患者生存期8、大剂量化疗治疗睾丸癌
2、疗效不优于常规化疗9、西妥昔单抗加放疗能延 长头颈部癌患者生存期10、肺癌预后可预测11、FDA批准了两种治疗儿 童血液系统癌症的药物12、黑色素瘤患者应常规接 受前哨淋巴结活检,ASCO 2007年临床肿瘤研究进展,24大进展涵盖肿瘤预防、筛查、治疗和患者生存状态6大重要进展：4项涉及肿瘤预防和筛查；2项为分子靶向治疗18大显著进展,MRI用于乳腺癌高危人群筛查肾癌治疗又添新靶向药物PCI有效降低肺癌脑转移危险HPV感染与头颈部肿瘤相关索拉非尼改善肝癌患者生存 乳腺癌发病率降低与HRT应用减少相关,2007年临床肿瘤研究6大重要进展,2006年WHO将癌症定位为可控慢性病,1、发生发展慢性过
3、程预防、干预、早期 发现、早期治疗；2、改变以前“根治”治疗的概念，如果超越可 能根治范畴，可以和其他慢性病一样控 制、保持正常生活和工作，“和平共处”；3、内科治疗的地位提高和任务加重。,近十年来分子靶向治疗进入临床,为实现个体化前进一步同病异治、异病同治调控和病理生理治疗,肿瘤治疗的靶点,传统靶点DNADNA合成的前体细胞分类 微管蛋白内分泌腺受体 ER/PR,新靶点信号转导 TK酶抑制剂格列卫、吉非替尼、厄罗替尼、索拉芬尼、苏尼替尼 新生血管VEGF 小分子化合-恩度 单克隆抗体-贝伐单抗调控基因-曲妥珠单抗EGF受体 小分子化合物 单克隆抗体西妥昔单 抗、尼莫珠单抗表面受体美罗华疫苗H
4、BV、HPV疫苗 EGF/VEGF疫苗,Deregulation of EGF System in Cancer,erbB1HER1EGFR,erbB2HER2neu,erbB3HER3,erbB4HER4,No specific ligands-often acts as dimer partner,Heregulins,NRG2NRG3Heregulins-cellulin,EGF,TGFa,b CellulinAmphiregulin,HB-EGF,Human Epidermal Growth Factor Receptor Family,抗肿瘤抗体靶向治疗,EGFR expressio
5、n in the various cancer types,Cancer 2002;94:1593-1611,已经进入我国的EGFR 抑制剂,酪氨酸激酶抑制剂(TKIs)Gefitinib（Iressa,吉非替尼，易瑞沙）Erlotinib（Tarceva,厄罗替尼,特罗凯）Sorafinib（索拉非尼，多吉美）Sutentinib（Sutent，索坦）Zactima(Vandetanib,凡德他尼）单克隆抗体(MAbs)Cetuximab（C225，西妥昔单抗）Nimotuzumab(h-R3，泰新生）,已经来到我国的VEGF抑制剂,TKIs Sorafinib（索拉非尼，多吉美）Suten
6、tinib（Sutent，苏尼替尼）Zactima(Vandetanib,凡德他尼）单克隆抗体 Bevacizumab(Avastin,贝发单抗)血管内皮抑素 恩度（Endostar)中药成分 参一胶囊（Rg3）,Activation of the EGFR:a pivotal driver of malignancy,EGFR-TK,EGFR,Ligand,Gene transcriptionCell-cycle progression,DNA,Myc,Myc,Cyclin D1,JunFos,P P,Cyclin D1,PI3-K,RAS,RAF,SOS,GRB2,PTEN,Akt,STA
7、T3,MEK,MAPK,pY,pY,pY,Pharmacokinetics of IRESSA,IRESSA is given as a once-daily tablet peak plasma concentration within 3-7 hmean terminal half-life of 41 h in cancer patientssteady-state concentrations achieved within 7-10 days of daily dosing in cancer patients The large volume of distribution in
8、cancer patients indicates extensive distribution into tissue,Swaisland et al 2001;Swaisland et al 2005;Ranson et al 2002;Wolf et al 2004,Study design,amodified Hochberg procedure applied to control for multiple testingCT,chemotherapy;PS,performance status;EGFR,epidermal growth factor receptor,Patien
9、tsAge 18 years Life expectancy 8 weeksProgressive or recurrent disease following CTConsidered candidates for further CT with docetaxel1 or 2 CT regimens(1 platinum)PS 0-2,Primary Overall survival(co-primary analysesa of non-inferiority in all patients and superiority in patients with high EGFR gene
10、copy number)Secondary Progression-free survival Objective response rate Quality of life Disease related symptoms Safety and tolerabilityExploratory Biomarkers,Endpoints,Docetaxel,Gefitinib,Post-discontinuation treatments(ITT population),aPatients may have also received other chemotherapy and/or erlo
11、tinib during the studyRadiotherapy,surgery,medical procedures and other treatment excludedITT,intent-to-treat;EGFR TKI,EGFR tyrosine kinase inhibitor,Other chemotherapy without docetaxel 15%,Other chemotherapy without EGFR TKI 10%,Objective tumor response(RECIST)(EFR population),RECIST,response eval
12、uation criteria in solid tumors;EFR,evaluable for response;OR,odds ratio;CI,confidence interval,Patients(%),(n=659),(n=657),OR 1 implies a greater chance of response on gefitinibOR and p-value from logistic regression with covariates,Quality of life and symptom improvement rates(EFQ population),p 0.
13、0001,p=0.0026,p=0.1329,EFQ,evaluable for quality of life,FACT-L,Functional Assessment of Cancer Therapy-Lung;TOI,Trial Outcome Index;LCS,Lung Cancer Subscale,%patients with sustained clinically relevant improvement,p-values from logistic regression with covariates.Clinically relevant improvement pre
14、-defined as6 point improvement for FACT-L and TOI;2 point improvement for LCS,maintained for at least 21 days,Overall survival in overall PP population,96%of historical docetaxel advantage over BSC from TAX-317 retained by gefitinib(96%CI:52%,129%)Indirect comparison of gefitinib to BSC:HR(96%CI)=0.
15、63(0.42,0.92),p=0.0137PP,per-protocol;NI,non-inferiority;HR,hazard ratio;OS,overall survival;BSC,best supportive care,Pre-specified NI limit in HR terms(translates to 50%effect retention Rothmann 2003)=1.154,723,336,225,131,83,50,31,14,0,0,710,339,228,139,89,46,24,7,0,0,518,503,0,4,8,12,16,20,24,28,
16、32,36,40,0.0,0.2,0.4,0.6,0.8,1.0,Months,Probabilityof survival,At risk:,Gefitinib,Docetaxel,Overall survival in patients with highEGFR gene copy number(ITT population),Probabilityof survival,85,44,26,13,10,6,4,3,0,0,89,42,31,22,14,7,4,1,0,0,66,63,0,4,8,12,16,20,24,28,32,36,40,0.0,0.2,0.4,0.6,0.8,1.0
17、,Months,At risk:,Gefitinib,Docetaxel,FISH,fluorescence in situ hybridization,Thatcher et al 2005;Chang et al 2006;Fukuoka et al 2003;Nishiwaki et al 2004;Park et al 2004;Guan et al 2005;Wu et al 2004;Takano et al 2004,IRESSA:1-year survival rates in Asian patients,1-yearsurvival(%),ISEL(all),ISEL(As
18、ian),IDEAL 1(all),IDEAL 1(Japanese),Park et al,Guan et al,Wu et al,Takano et al,27,41,35,57,44,44,45,37,IRESSA(250 mg/day)+BSC,Primary end pointSurvival overall population adenocarcinomaSecondary end pointsTTFORRQoL,symptomsSafetyExploratory end pointTumour biomarker analysis(eg EGFR),ISEL trial des
19、ign,1692 patients in 210 centres across 28 countriesStratified for histology,sex,intolerant/refractory,PS and smoking history,Placebo+BSC,Randomisation(2:1 ratio),BSC,best supportive care;CT,chemotherapy;ISEL,IRESSA Survival Evaluation in Lung cancer;ORR,objective response rate;PS,performance status
20、;QoL,quality of life;TTF,time to treatment failure,PatientsLocally advanced or metastatic NSCLC1 or 2 prior CT regimensIntolerant to most recent CT regimen or progression 90 days of last CT cycle,Thatcher et al 2005,ISEL:survival in the overall population,0,2,4,6,8,10,12,14,16,Time(months),At risk:,
21、1692,1347,877,485,252,104,31,Median,months1-year survival,%Log-rank HR 0.89;95%CI 0.77,1.02;p=0.087Cox analysis,p=0.030,IRESSA5.627,Placebo5.121,0.0,0.2,0.4,0.6,0.8,1.0,Proportionsurviving,IRESSA,Placebo,Median follow-up:7 months(range 3-15);58%deaths,Thatcher et al 2005,HR,hazard ratio,Median,month
22、s1-year survival,%Log-rank HR 0.84;95%CI 0.68,1.03;p=0.089Cox analysis,p=0.033,IRESSA6.330,Placebo5.418,ISEL:survival in the adenocarcinoma population,Time(months),At risk:,812,669,446,262,145,66,18,0,2,4,6,8,10,12,14,16,0.0,0.2,0.4,0.6,0.8,1.0,Proportionsurviving,Thatcher et al 2005,ISEL:significan
23、t improvement in TTF and ORR,1692,1051,539,278,129,49,17,IRESSA,Placebo,IRESSAPlaceboCox analysis(95%CI)Log rankOdds ratio(95%CI),Median TTF,months3.02.60.82(0.73,0.92)p=0.0006p=0.002-,ORR,%(n)8.0(77/959)1.3(6/480)-7.28(3.1,16.9)p0.0001,TTF(months),At risk:,0,2,4,6,8,10,12,14,16,0.0,0.2,0.4,0.6,0.8,
24、1.0,Proportionwithout treatment failure,Thatcher et al 2005,Survival,HR and 95%CI,0.4,0.6,0.8,1.0,1.5,Adenocarcinoma,11.9,8.0,14.7,8.8,7.6,7.9,18.1,4.8,5.3,9.4,8.4,6.6,5.1,ORR,%,ISEL:survival and ORR in subsets(1),Favours IRESSA,Favours placebo,Thatcher et al 2005,ISEL:survival and ORR in subsets(2)
25、,11.1,8.0,12.4,7.4,6.9,9.0,6.8,7.5,10.1,7.7,6.4,7.2,10.2,Prior docetaxel,All patients,Asian ethnicity,65 years,No prior docetaxel,65 years,Non-Asian ethnicity,Prior CT response:PD/NE,Prior CT response:CR/PR,Prior CT response:SD,Time since Dx:6 months,Time since Dx:6-12 months,Time since Dx:12 months
26、,Favours IRESSA,Favours placebo,0.4,0.6,0.8,1.0,1.5,HR and 95%CI,CR,complete response;PR,partial response;SD,stable disease;PD,progressive disease;NE,non-evaluable,Thatcher et al 2005,Survival,ORR,%,ISEL:survival and ORR in subsets(2),11.1,8.0,12.4,7.4,6.9,9.0,6.8,7.5,10.1,7.7,6.4,7.2,10.2,Prior doc
27、etaxel,All patients,Asian ethnicity,65 years,No prior docetaxel,65 years,Non-Asian ethnicity,Prior CT response:PD/NE,Prior CT response:CR/PR,Prior CT response:SD,Time since Dx:6 months,Time since Dx:6-12 months,Time since Dx:12 months,Favours IRESSA,Favours placebo,0.4,0.6,0.8,1.0,1.5,HR and 95%CI,C
28、R,complete response;PR,partial response;SD,stable disease;PD,progressive disease;NE,non-evaluable,Thatcher et al 2005,Survival,ORR,%,ISEL:survival by smoking history and racial origin,IRESSA,Placebo,Proportion surviving,0,2,4,6,8,10,12,14,16,0.0,1.0,0.8,0.6,0.4,0.2,0,2,4,6,8,10,12,14,16,Time(months)
29、,Never smoked(n=375),Ever smoked(n=1317),HR 0.92;95%CI 0.79,1.06;p=0.242,HR 0.67;95%CI 0.49,0.92;p=0.012,Proportion surviving,0.0,1.0,0.8,0.6,0.4,0.2,0,2,4,6,8,10,12,14,16,0,2,4,6,8,10,12,14,16,Asian origin(n=342),Non-Asian origin(n=1350),HR 0.92;95%CI 0.80,1.07;p=0.294,HR 0.66;95%CI 0.48,0.91;p=0.0
30、10,Cox regression analysis,Thatcher et al 2005,TALENT and TRIBUTE:study design,Patients with HER1/EGFR-positive or-negative,stage IIIB/IV NSCLC,Primary objectiveoverall survival(80%power to detect a 25%survival benefit and a 33%1-year survival benefit,=0.05)Secondary objectivestime to disease progre
31、ssionresponse rate/duration of responsetime to symptomatic progressionsafety,150mg/day Tarceva p.o.+six cycles of chemotherapy,Placebo+six cycles of chemotherapy,Daily oral Tarceva alone,Placebo alone,TALENT=gemcitabine and cisplatin(n=1,172)TRIBUTE=carboplatin and paclitaxel(n=1,079),TALENT and TRI
32、BUTE:results,Two very similar negative studies with gefitinib(INTACT 1 and INTACT 2),Docetaxel induces M-phase arrest and apoptosis that is enhanced by the anti-cell survival effect of Tarceva,Apoptosis,Tarceva induces G1 arrest,which can block the M-phase activity of docetaxel,Tarceva Docetaxel,Doc
33、etaxel Tarceva,G1,M,S,G2,Cell Cycle,Apoptosis,G1,M,S,G2,Cell Cycle,Apoptosis,Sequence effects of docetaxel plus Tarceva:a model of response,Gumerlock,UC Davis,TALENT:survival and rash(Tarceva),Proportion event-free,1.00.80.60.40.20,0100200300400500600,Study day,Log-rank testp=0.0001,Median survival(
34、months)Grade 110.7Grade 210.4Grade 312.9No AE7.6,Grade 1Grade 2Grade 3No AE,Gatzemeier U,et al.J Clin Oncol 2004;23(Suppl.14):617(Abs.7010),TRIBUTE:carboplatin+paclitaxel plus continuous Tarceva improved survival in never smokers,Miller V,et al.J Clin Oncol 2004;22(Suppl.14S):628(Abs.7061),Avastin在非
35、小细胞肺癌的III期临床(E4599):试验设计,主要终点:总生存期Avastin 15mg/kg i.v.每三周卡铂 iv.AUC 6mg/mL和 紫杉醇 200mg/m2 i.v.每三周Avastin联合CP组患者接受 Avastin单药直至疾病进展,未经治疗 IIIB期/IV期非鳞癌非小细胞肺癌(n=878),CP 6(n=444),Avastin(15mg/kg)每三周+CP 6(n=434),PD*,PD,*No cross over permitted,Avastin 每三周直至进展,Sandler A,et al.N Engl J Med 2006;355:254250,E459
36、9 试验:一线治疗中加入Avastin 能改善生存期,在这个里程碑的试验中，Avastin为基础的治疗能延长中位生存期超过一年。,1.00.80.60.40.20,06121824303642,Months,Probability,HR=0.79(0.670.92);p=0.003,10.3,12.3,Sandler A,et al.N Engl J Med 2006;355:254250,E4599试验:一线治疗中加入Avastin 能改善PFS,1.00.80.60.40.20,0612182430,时间(月),Probability,化疗+Avastin化疗,HR=0.66(0.570.
37、77);p0.001,4.5,6.2,Sandler A,et al.N Engl J Med 2006;355:254250,E4599 试验:客观缓解率(可测量疾病),化疗,(n=,392,),化疗+Avastin,(n=,381,),p,value,总的反应期,(%),15,35,0.0,01,Sandler A,et al.N Engl J Med 2006;355:254250,化疗,(n=440),化疗+Avastin,(n=427),Grade(%),Grade(%),3,4,5,3,4,5,p value,所有出血事件,0.7,4.4,0.001,中枢神经系统出血,0.7,鼻出
38、血,0.2,0.7,呕血,0.5,咯血,0.2,0.5,0.2,1.2,黑便/消化道出血,0.2,0.2,0.7,0.2,其他出血,0.2,0.2,E4599试验:出血事件,Sandler A,et al.N Engl J Med 2006;355:254250,E4599 试验:死亡原因,CP,(n=440),CP+Avastin,(n=427),p value,总死亡数,344,305,死因,肺癌,309,260,NR,毒性反应,2,14,*,p=0.001,合并情况,16,16,NR,未知原因,17,15,NR,*One patient in the CP+Avastin group w
39、ho had a grade 5 AE was considered to be ineligible because of undocumented advanced disease;data on this patient are not included in the table(but were included in the analysis of AEs)NR=not reported,Sandler A,et al.N Engl J Med 2006;355:254250,E4599试验:总结,PS评分好的非鳞癌的非小细胞肺癌，Avastin加上标准的以铂类为基础的化疗方案能显著
40、改善生存期，无进展生存期和客观缓解率。加入Avastin后，可增加一些毒副反应。研究中可发现有高血压，蛋白尿和头痛(与 Avastin相关的不良反应)，通常可处理，不需要长期停用Avastin。非小细胞肺癌标准治疗中加入Avastin取得生存获益时，必须考虑这些危险因素。,Avastin:改变美国的治疗现状,根据 E4599试验的阳性结果，Avastin联合CP 成为ECOG 对于非鳞癌的非小细胞肺癌一线治疗标准1Avastin 联合化疗也被NCCN推荐为非小细胞肺癌一线治疗的临床指南(v.1.2007)1E4599试验是Avastin进入美国的基础。2006年10月，美国FDA批准 Avas
41、tin联合CP作为非鳞癌的非小细胞肺癌一线治疗,1NCCN clinical practice guidelines in oncology.Non-small cell lung cancer,version 1 2007.Available at:http:/www.nccn.org/professionals/physician_gls/PDF/nscl.pdf,NSCLCFirst or 2nd lines 493ptsPS 0-2期,NVB25mg/m2,NVB25mg/m2,Rndoistar 7.5mg/m2+NS 250ml IV gtt,d1,d2,3,4,d5,d1-14,
42、d21,R,NVB25mg/m2,CDDP30mg/m2,NVB25mg/m2,d21,d1,d2,3,4,d5,Placebo NS 3.5ml)+NS250ml IV gtt,24 CentersR、double blind、placebo control、multicenterfirst：2nd line=2：1T：C=2：1,CDDP30mg/m2,d1-14,Phase III Clinical Trial,Clinical Response,Phase III Clinical Trial,复治病人的生存情况,恩度IV期阶段性总结结果分析,2008年7月25日,总的疗效分析,分层分
43、析-初/复治,分层分析-病理类型,不良反应比较,Gefitinib in China,吉非替尼治疗最佳疗效的单因素分析,客观疗效：logistic多因素回归分析,因素：性别，年龄，病理类型，吸烟，紫杉类耐药，EGFR基因突变；Odds Ratio值1表明左侧一栏因素有效的机率大,疗效预测模型方程式,方程式=2x病理类型+吸烟状况+年龄+EGFR基因突变病理类型：腺癌=1分，非腺癌=0分年龄：65岁=1分，65岁=0分吸烟状况：不吸烟=1分，吸烟=0分EGFR突变：有突变=1分，无突变=0分,界值上下两组人群的疗效,疗效预测模型评分对应的RR和DCR,Cut-off value（界值）=2，每增
44、加1分，疗效增加1倍。,A组:,第一阶段,第二阶段,TXT,吉非替尼,B组:,吉非替尼,TXT,PD,PD,吉非替尼:250mg/天,口服至疾病进展单药多西紫杉醇60mg/m2-75mg/m2，d1,；或多西紫杉醇35mg/m2,d1，d8，顺铂30mg/m2第2，3，4天，每21天重复X3-6个周期。,吉非替尼/多西紫杉醇二线治疗晚期NSCLC的用药顺序比较,吉非替尼,吉非替尼/多西紫杉醇二线治疗晚期NSCLC的疗效,吉非替尼,吉非替尼,第一、第二阶段及调整后两组的 PFS,生存率,B组:Iressa5.0月,A组:TXT3.0月,生存率,A组:Iressa 7.0月,B组:TXT4.0月,
45、生存率,Iressa:6.0月,TXT:4.0月,p=0.0383,p=0.017,p=0.046,TXT,Iressa,皮 疹,指甲改变,皮肤干燥,靶向治疗的不良反应需要处理,人参（Ginsing Radix）,人参甙的结构,Rg3,CAM实验0.9%N.S,CAM实验Rg3组,（500ug/ml）,Rg3抑制人体肺癌新生血管形成,A double-blind,randomized,Multi-center clinical trial in advanced NSCLC treated with NP+placebo or NP+Rg3,Treatment Plan,Arm B：Chemo
46、therapy+Rg3。20mg P.O.BIDArm A:Chemotherapy+Placebo 20 mg P.O.BIDCycles：One of chemotherapy every 3 Wks，Rg3 or Placebo every day for more than 2 months,Chemotherapy,NP:PDD 6080mgm2 ivgtt dl(or intro23days)NVB 25mgm2 ivgtt dl、8 2l for 1cycle,Preliminary Results of a double-blind randomized trial of ad
47、vanced NSCLC treated with NP or NP+Rg3,Arm A Arm B N=61 N=54 CR+PR 14.5%（8/55）33.4%（17/51）Median survival（m)8.0 10.0 Mean ST（m）9.68 15.26Survival Patients 8 12,The results of survival analyses：Arm B(NP+Rg3)are longer than Arm A(NP+placebo)in Median survival and Mean Survival Time,Kaplan-Meier法，Log R
48、ank统计量=6.86，P=0.0088。,Mean of Survival Time(month),已发表论文：,1、孙燕、林洪生、朱允中，等，长春瑞滨合并顺铂（NP）加参一胶囊或安慰剂治疗晚期非小细胞肺癌的多中心双盲随机临床研究报告。中国肺癌杂志 2006；9：2542582、高勇、王杰军、许青，等，人参皂甙Rg3抑制肿瘤新生血管形成的研究。第二军医大学学报，2001，22：40423、王兵、高勇等.人参皂苷Rg3对肺癌诱导血管内皮细胞增值的抑制作用。中国新药杂志,2002,11:4、黄小兵、侯梅，化疗联合人参皂甙治疗肺癌的实验研究。中国中西医结合杂志，2005，25：5895、刘基崴、陈
49、俊霞、于丽华,等.人参皂甙Rg3和核糖核酸抑制因子转基因对小鼠黑色素瘤的抑制作用。中华肿瘤杂志,2004，26：72256、张培彤、朴炳奎等.爱康胶囊II期临床试药研究。中国新药杂志，1999，8：3283307、刘秀丽、张伟辉.人参皂苷Rg3治疗老年晚期恶性肿瘤46例临床观察。吉林大学学报（医学版）,2003,29:,TCM with Possible Angiogenesis inhibition effect,Rg3 人参皂甙-Basic fibroblastic growth factor(bFGF)Turmeric 姜黄素-Human umbilical vein endotheli
50、al cellArtesunate 青蒿琥酯-HUVEC,VEGFTripterine 红素-HUVEC,bFGFLaminarin 昆布硫酸多糖-bFGFUrsolic acid 熊果酸-Matrine 苦参碱-VEGF,bFGFEpigallocatechin-3-gallate 茶多酚Gabderma 云芝多糖张芷旋，周清华，中国肺癌杂志 2006；9：9699,结论和展望,1、以人为本的综合治疗仍然是基本处理肿瘤病人的基本策略；2、靶向治疗已经从临床试验到临床实践。开启了内科治疗的新时代。和化放疗综 合应用或序贯应用有可能提高治愈率和 改善生活质量；3、新一代的辨证论治，同病异治（个体
