从近年来临床肿瘤学进展看内科治疗的发展前景孙燕课件

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1、从近年来临床肿瘤学进展看内科从近年来临床肿瘤学进展看内科治疗的发展前景治疗的发展前景近年来临床肿瘤学的重要进展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将肿瘤定位为慢性可控疾病 分子靶向治疗分子靶向治疗肿瘤内科治疗的新时代肿瘤内科治疗的新时代中医理论和靶向治疗融合中医理论和靶向治疗融合结语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

2、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 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

3、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 DNA DNA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

4、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HBV、HPV疫苗 EGF/VEGF疫苗EGFEGFRSIGNALThe Epidermal Growth Factor receptor (EGFR)is over-expressed in Cancer Cells.This EGF system is deregulated.CELL PROLIFERATIONCancer(Solid Tumour)TKTKTKerbB1HER1EGFRerbB2HER2neuerbB3HER3erbB4H

5、ER4No specific ligands-often acts as dimer partnerHeregulinsNRG2NRG3Heregulins-cellulinEGF,TGFa,b CellulinAmphiregulin,HB-EGFHuman Epidermal Growth Factor Receptor Family抗肿瘤抗体靶向治疗抗肿瘤抗体靶向治疗Cancer Types Percentage of EGFR Expressin （%）Head and Neck 80-100Renal 50-90Breast 14-91Lung 40-80Colon 25-77Ova

6、rian 35-70Prostate 39-47Glioma 40-63Pancreas 30-50Bladder 31-48EGFR expression in the various cancer typesCancer 2002;94:1593-1611已经进入我国的EGFR 抑制剂n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）n单克隆抗体(MAbs)Cetuximab（C

7、225，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）Sutentinib（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 malignancyEGFR-TKEGFRLigandSurvival(anti-apoptosis)Proliferation/maturationC

8、hemotherapy/radiotherapy/hormonal resistanceAngiogenesisMetastasisGene transcriptionCell-cycle progressionDNAMycMycCyclin D1JunFosP PCyclin D1PI3-KRAS RAFSOSGRB2PTENAktSTAT3MEKMAPKpYpYpYPharmacokinetics of IRESSA IRESSA is given as a once-daily tablet peak plasma concentration within 3-7 h mean term

9、inal half-life of 41 h in cancer patients steady-state concentrations achieved within 7-10 days of daily dosing in cancer patients The large volume of distribution in cancer patients indicates extensive distribution into tissueSwaisland et al 2001;Swaisland et al 2005;Ranson et al 2002;Wolf et al 20

10、04Gefitinib250 mg/dayDocetaxel75 mg/m2 every3 weeks1:1 randomizationStudy designamodified Hochberg procedure applied to control for multiple testingCT,chemotherapy;PS,performance status;EGFR,epidermal growth factor receptorPatientsAge 18 years Life expectancy 8 weeksProgressive or recurrent disease

11、following CTConsidered candidates for further CT with docetaxel1 or 2 CT regimens(1 platinum)PS 0-2Primary Overall survival(co-primary analysesa of non-inferiority in all patients and superiority in patients with high EGFR gene copy number)Secondary Progression-free survival Objective response rate

12、Quality of life Disease related symptoms Safety and tolerabilityExploratory BiomarkersEndpointsDocetaxelGefitinibPost-discontinuation treatments(ITT population)Nothing apart from further EGFR TKI 54%(Nothing 49%,gefitinib 4%,erlotinib 1%)Docetaxel at any pointa 31%Nothing apart from further docetaxe

13、l 53%(Nothing 52%,docetaxel 1%)EGFR TKI at any pointa 37%(15%gefitinib,22%erlotinib)aPatients may have also received other chemotherapy and/or erlotinib during the studyRadiotherapy,surgery,medical procedures and other treatment excludedITT,intent-to-treat;EGFR TKI,EGFR tyrosine kinase inhibitorOthe

14、r chemotherapy without docetaxel 15%Other chemotherapy without EGFR TKI 10%Objective tumor response(RECIST)(EFR population)OR(95%CI)=1.22(0.82,1.84)p=0.3257RECIST,response evaluation criteria in solid tumors;EFR,evaluable for response;OR,odds ratio;CI,confidence interval Patients(%)(n=659)(n=657)OR

15、1 implies a greater chance of response on gefitinibOR and p-value from logistic regression with covariatesQuality of life and symptom improvement rates(EFQ population)p 0.0001p=0.0026 p=0.1329EFQ,evaluable for quality of life,FACT-L,Functional Assessment of Cancer Therapy-Lung;TOI,Trial Outcome Inde

16、x;LCS,Lung Cancer Subscale%patients with sustained clinically relevant improvementGefitinib(n=490)Docetaxel(n=476)p-values from logistic regression with covariates.Clinically relevant improvement pre-defined as6 point improvement for FACT-L and TOI;2 point improvement for LCS,maintained for at least

17、 21 daysOverall survival in overall PP population96%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)=0.63(0.42,0.92),p=0.0137PP,per-protocol;NI,non-inferiority;HR,hazard ratio;OS,overall survival;BSC,best s

18、upportive carePre-specified NI limit in HR terms(translates to 50%effect retention Rothmann 2003)=1.154723593(82.0%)710576(81.1%)NEventsPrimary Cox analysis without covariatesHR(96%CI)=1.020(0.905,1.150)Median OS(months)1-year survival7.632%8.034%GefitinibDocetaxelConclude non-inferiorityin the over

19、all PP population723336225131835031140071033922813989462470051850304812162024283236400.00.20.40.60.81.0MonthsProbabilityof survivalAt risk:GefitinibDocetaxelOverall survival in patients with highEGFR gene copy number(ITT population)Probabilityof survival8572(84.7%)8971(79.8%)NEventsCox analysis with

20、out covariatesHR(95%CI)=1.09(0.78,1.51),p=0.6199Median OS(months)1-year survival8.432%7.535%Conclude no statistical superiorityin EGFR FISH+patientsGefitinibDocetaxel854426131064300894231221474100666304812162024283236400.00.20.40.60.81.0MonthsAt risk:GefitinibDocetaxelFISH,fluorescence in situ hybri

21、dizationThatcher 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 2004IRESSA:1-year survival rates in Asian patients1-yearsurvival(%)ISEL(all)ISEL(Asian)IDEAL 1(all)IDEAL 1(Japanese)Park et alGuan et alWu et alTakano et al

22、2741355744444537IRESSA(250 mg/day)+BSCPrimary end pointl Survival overall population adenocarcinomaSecondary end pointsl TTFl ORRl QoL,symptomsl SafetyExploratory end pointl Tumour biomarker analysis(eg EGFR)ISEL trial design1692 patients in 210 centres across 28 countriesStratified for histology,se

23、x,intolerant/refractory,PS and smoking historyPlacebo+BSCRandomisation(2:1 ratio)BSC,best supportive care;CT,chemotherapy;ISEL,IRESSA Survival Evaluation in Lung cancer;ORR,objective response rate;PS,performance status;QoL,quality of life;TTF,time to treatment failure Patientsl Locally advanced or m

24、etastatic NSCLCl 1 or 2 prior CT regimensl Intolerant to most recent CT regimen or progression 90 days of last CT cycleThatcher et al 2005ISEL:survival in the overall population0246810121416Time(months)At risk:1692134787748525210431Median,months1-year survival,%Log-rank HR 0.89;95%CI 0.77,1.02;p=0.0

25、87Cox analysis,p=0.030IRESSA5.627Placebo5.1210.00.20.40.60.81.0ProportionsurvivingIRESSAPlaceboMedian follow-up:7 months(range 3-15);58%deathsThatcher et al 2005HR,hazard ratioMedian,months1-year survival,%Log-rank HR 0.84;95%CI 0.68,1.03;p=0.089Cox analysis,p=0.033IRESSA6.330Placebo5.418ISEL:surviv

26、al in the adenocarcinoma populationTime(months)At risk:8126694462621456618IRESSAPlacebo02468101214160.00.20.40.60.81.0ProportionsurvivingThatcher et al 2005ISEL:significant improvement in TTF and ORR169210515392781294917IRESSAPlaceboIRESSAPlaceboCox analysis(95%CI)Log rankOdds ratio(95%CI)Median TTF

27、,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)p0.0001TTF(months)At risk:02468101214160.00.20.40.60.81.0Proportionwithout treatment failureThatcher et al 2005SurvivalHR and 95%CI0.40.6 0.8 1.01.5AdenocarcinomaAll patientsFemalePS 0,11 prior lineRefractoryNeve

28、r smokedNon-adenocarcinomaEver smokedIntolerant2 prior linesPS 2,3Male11.98.014.78.87.67.918.14.85.39.48.46.65.1ORR,%ISEL:survival and ORR in subsets(1)Favours IRESSAFavours placeboThatcher et al 2005ISEL:survival and ORR in subsets(2)11.18.012.47.46.99.06.87.510.17.76.47.210.2Prior docetaxelAll pat

29、ientsAsian ethnicity65 yearsNon-Asian ethnicityPrior CT response:PD/NEPrior CT response:CR/PRPrior CT response:SDTime since Dx:12 monthsFavours IRESSAFavours placebo0.40.6 0.8 1.01.5HR and 95%CICR,complete response;PR,partial response;SD,stable disease;PD,progressive disease;NE,non-evaluableThatcher

30、 et al 2005SurvivalORR,%ISEL:survival and ORR in subsets(2)11.18.012.47.46.99.06.87.510.17.76.47.210.2Prior docetaxelAll patientsAsian ethnicity65 yearsNon-Asian ethnicityPrior CT response:PD/NEPrior CT response:CR/PRPrior CT response:SDTime since Dx:12 monthsFavours IRESSAFavours placebo0.40.6 0.8

31、1.01.5HR and 95%CICR,complete response;PR,partial response;SD,stable disease;PD,progressive disease;NE,non-evaluableThatcher et al 2005SurvivalORR,%ISEL:survival by smoking history and racial originIRESSAPlaceboProportion surviving0246810 12 14 160.01.00.80.60.40.20246810 12 14 16Time(months)Never s

32、moked(n=375)Ever smoked(n=1317)HR 0.92;95%CI 0.79,1.06;p=0.242HR 0.67;95%CI 0.49,0.92;p=0.012Proportion surviving0.01.00.80.60.40.20246810 12 14 160246810 12 14 16Asian origin(n=342)Non-Asian origin(n=1350)HR 0.92;95%CI 0.80,1.07;p=0.294HR 0.66;95%CI 0.48,0.91;p=0.010Cox regression analysisThatcher

33、et al 2005TALENT and TRIBUTE:study designPatients with HER1/EGFR-positive or-negative,stage IIIB/IV NSCLC Primary objective overall survival(80%power to detect a 25%survival benefit and a 33%1-year survival benefit,a=0.05)Secondary objectives time to disease progression response rate/duration of res

34、ponse time to symptomatic progression safety150mg/day Tarceva p.o.+six cycles of chemotherapy Placebo+six cycles of chemotherapyDaily oral Tarceva alonePlacebo aloneTALENT=gemcitabine and cisplatin(n=1,172)TRIBUTE=carboplatin and paclitaxel(n=1,079)TALENT and TRIBUTE:resultsTALENTTRIBUTETarcevaPlace

35、boTarcevaPlaceboResponse rate(%)31.529.921.519.3Median survival(months)9.910.210.810.61-year survival rate(%)41 42 47 44l 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

36、 ApoptosisTarceva induces G1 arrest,which can block the M-phase activity of docetaxelTarceva DocetaxelDocetaxel TarcevaG1MSG2Cell CycleApoptosisG1MSG2Cell CycleApoptosisSequence effects of docetaxel plus Tarceva:a model of responseGumerlock,UC DavisTALENT:survival and rash(Tarceva)Proportion event-f

37、ree 1.00.80.60.40.20 0100200300400500600Study dayLog-rank testp=0.0001Median survival(months)Grade 110.7Grade 210.4Grade 312.9No AE7.6Grade 1Grade 2Grade 3No AEGatzemeier U,et al.J Clin Oncol 2004;23(Suppl.14):617(Abs.7010)TRIBUTE:carboplatin+paclitaxel plus continuous Tarceva improved survival in n

38、ever smokersMiller V,et al.J Clin Oncol 2004;22(Suppl.14S):628(Abs.7061)1.00.80.60.40.200510152025Survival rateTarcevaPlaceboMonths on studyMedian survival(months)No.of patientsTarceva22.564Placebop value10.1410.01Avastin在非小细胞肺癌的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

39、 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 permittedAvastin 每三周直至进展Sandler A,et al.N Engl J Med 2006;355:254250E4599 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 0612182

40、4303642MonthsProbabilityHR=0.79(0.670.92);p=0.00310.312.3生存期(%)12 月24 月化疗+Avastin5123化疗4415Sandler A,et al.N Engl J Med 2006;355:254250E4599试验:一线治疗中加入Avastin 能改善PFS1.00.80.60.40.200612182430时间(月)Probability化疗+Avastin化疗HR=0.66(0.570.77);p0.0014.56.2Sandler A,et al.N Engl J Med 2006;355:254250E4599 试验

41、: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 0.001 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Sa

42、ndler A,et al.N Engl J Med 2006;355:254250E4599 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 who had a grade 5 AE was considered to be ineligible because of undocumented advanced disease;dat

43、a on this patient are not included in the table(but were included in the analysis of AEs)NR=not reportedSandler A,et al.N Engl J Med 2006;355:254250E4599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

44、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1 Avastin 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)1 E4599试验是Avastin进入美国的基础。2006年10月，美国FDA批准 Avastin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,

45、version 1 2007.Available at:http:/www.nccn.org/professionals/physician_gls/PDF/nscl.pdfNSCLCFirst or 2nd lines 493ptsPS 0-2期期NVB25mg/m2NVB25mg/m2Rndoistar 7.5mg/m2+NS 250ml IV gttd1d2,3,4d5d1-14d21RNVB25mg/m2CDDP30mg/m2NVB25mg/m2d21d1d2,3,4d5Placebo NS 3.5ml)+NS250ml IV gtt 24 Centers24 CentersR R、d

46、ouble blind double blind、placebo controlplacebo control、multicentermulticenterfirstfirst：2nd line=22nd line=2：1 1T T：C=2C=2：1 1CDDP30mg/m2d1-14Phase III Clinical TrialClinical ResponseClinical ResponseNPEndostarNP+PlaceboPCR+PR(%)35.419.50.0003First line40.023.90.0032nd line23.98.50.03CR+PR+SD(%)73.

47、364.00.035First line76.565.00.022nd line65.261.70.68TTP(m)6.33.60.0000First line6.63.70.00002nd line5.73.20.0002Survival Time（m）14.879.900.0000First line15.169.770.00002nd line14.6710.000.01861year survival（）（）62.7531.460.0000First line64.0831.830.00002nd lin59.4529.870.0186Phase III Clinical Trial复

48、治病人的生存情况疗效例数有效率(RR)临床收益率(CBR)CR523.8%(129/543)III期总有效率35.4%82.7%(449/543)III期总临床收益率73.3%PR124SD320PD94病例例数有效率（RR）临床受益率（CBR）初治27230.9%(84/272)87.5%（238/272）复治27116.6%(45/271)77.9%(211/271)病理分型例数有效率（RR）临床受益率（CBR）腺癌32019.4%(62/320)83.4%（266/320）鳞癌16732.3%(54/167)83.2%(139/167)其他5623.2%(13/56)60.7%(34/5

49、6)不良反应比较不良反应发生率III期临床粒细胞减少28.97%52.4%血红蛋白下降35.2932.2血小板减少30.0515.6恶心呕吐37.13%50.6%出血1.69%0.6腹泻4.31%3.7便秘10.02%16.9皮疹3.7%0.6%发热2.16%1.8%心律失常7.4%6.38%Gefitinib in China NResponse rateDisease Control RateMedian PFS1-year SurvivalRateMedianOS(mo)Registration Trial in China15927%54.1%97days10PUMCHCAMS&PUM

50、C9836%67.3%7.0mo53.1%12CI/HCAMS&PUMC9126.4%53.9%3.6mo48.1%11Beijing CancerHospital9120.9%63.7%5.0mo56.4%吉非替尼治疗最佳疗效的单因素分析 有效率(%)P值疾病控制率(%)P值性别男22.3%P=0.02175.0%P=0.227女36.0%81.3%年龄65岁33.5%P=0.03475.0%P=0.03365岁22.1%87.0%病理类型腺癌33.0%P=0.00780.9%P=0.035非腺癌9.4%62.5%腺癌肺泡癌48.3%P=0.08986.2%P=0.614非肺泡癌30.8%8

51、0.1%吸烟否35.3%P=0.00582.4%P=0.029是17.3%69.3%紫杉类耐药否33.0%P=0.04079.2%P=0.701是18.0%76.0%脑转移否29.4%P=0.63474.1%P=0.001是32.8%93.4%治疗方式1线治疗40.9%P=0.07286.4%P=0.226客观疗效：logistic多因素回归分析 协变量Odds Ratio95.0%C.p 1表明左侧一栏因素有效的机率大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：234.2%17.065%2

52、9.39.035.7%P值P=0.001P=0.000疗效预测模型评分对应的RR和DCRCut-off value（界值）（界值）=2，每增加，每增加1分，疗效增加分，疗效增加1倍。倍。A A组组:第一阶段第一阶段第二阶段第二阶段B B组组:PDPDPDPD吉非替尼吉非替尼:250mg/天天,口服至疾病进展口服至疾病进展单药多西紫杉醇单药多西紫杉醇60mg/m2-75mg/m2，d1,；或多西紫杉醇；或多西紫杉醇35mg/m2,d1，d8，顺铂，顺铂30mg/m2第第2，3，4天，每天，每21天重复天重复X3-6个周期。个周期。吉非替尼吉非替尼/多西紫杉醇二线治疗晚期多西紫杉醇二线治疗晚期NS

53、CLC的用药顺序比较的用药顺序比较吉吉非非替替尼尼吉非替尼吉非替尼/多西紫杉醇二线治疗晚期多西紫杉醇二线治疗晚期NSCLC的疗效的疗效吉吉非非替替尼尼吉吉非非替替尼尼第一、第二阶段及调整后两组的 PFS第一阶段TTP(月)403020100百分比（%）1.0.8.6.4.20.0-.2A组：TXTB组:Iressa生存率B组组:Iressa5.0月月A组组:TXT3.0月月第二阶段TTP（月）3020100百分比（%）1.21.0.8.6.4.20.0-.2B组：TXTA组：Iressa生存率A组组:Iressa 7.0月月B组组:TXT4.0月月调整后TTP（月）403020100百分比（%

54、）1.21.0.8.6.4.20.0-.2TXTIressa生存率Iressa:6.0月月TXT:4.0月月p=0.0383 p=0.017 p=0.046 TXTIressa皮皮 疹疹指甲改变指甲改变皮肤干燥皮肤干燥靶向治疗的不良反应需要处理人参（人参（Ginsing Radix）人参甙的结构人参甙的结构CAM实验0.9%N.SCAM实验Rg3组（500ug/ml）Rg3抑制人体肺癌新生血管形成Multi-center Treatment Plan Arm B：Chemotherapy+Rg3。20mg P.O.BID Arm A:Chemotherapy+Placebo 20 mg P.O

55、.BID Cycles：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 1cyclePreliminary Results of a double-blind randomized trial of advanced NSCLC treated with NP or NP+Rg3 Arm A Arm B N=61 N=54

56、 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 12The results of survival analyses：Arm B(NP+Rg3)are longer than Arm A(NP+placebo)in Median survival and Mean Survival TimearmarmcasecaseSurvival TimeSE95%CIA619.681.097.55，11.82B5415.261.7611.80，18.71Kap

57、lan-Meier法，Log Rank统计量=6.86，P=0.0088。Mean of Survival Time(month)(month)0.00 10.00 20.00 30.00 40.00 时时 间间 0.0 0.2 0.4 0.6 0.8 1.0 1.00 2.00 1.00-censored 2.00-censored Survival Functions 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

58、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

59、with Possible Angiogenesis inhibition effect Rg3 人参皂甙-Basic fibroblastic growth factor(bFGF)Turmeric 姜黄素-Human umbilical vein endothelial cell Artesunate 青蒿琥酯-HUVEC,VEGF Tripterine 红素-HUVEC,bFGF Laminarin 昆布硫酸多糖-bFGF Ursolic acid 熊果酸-Matrine 苦参碱-VEGF,bFGF Epigallocatechin-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 化），异病同治应当在我国得到体现和做出成 绩；4、靶向治疗带来的新问题：调控使肿瘤变成慢性过程；调控导致的不良反应（超敏反应、副作用、毒性反应等）值得注意、学习、避免。