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1、临床肿瘤学的新时代 诊疗规范化和个体化,孙 燕 中国医学科学院北京协和医学院肿瘤医院 2008 - 8 - 28 上海,内 容,1、2008年临床肿瘤学的新概念 2、肿瘤治疗的里程碑 3、分子靶向治疗的进展 4、我国在靶向治疗中的实践 5、总结和展望,2008年7月29日，世界卫生组织(WHO)更新了有关全球癌症状况的数据。其中指出，2007年癌症死亡人数达790万，约占所有死亡人数的13%；而30%的癌症死亡是可以避免的。 据联合国网站报道，导致死亡的主要癌症种类为：肺癌(140万人)；胃癌(86.6万人)；肝癌(65.3万人)；结肠癌(67.7万人)和乳腺癌(54.8万人)。2007年，大
2、约80%的癌症导致的死亡发生在低收入和中等收入国家。预计全世界癌症导致的死亡人数将继续增加，2030年估计将达1200万。,WHO表示，通过改变或避免主要危险因素以及及早发现和治疗，很多癌症可以得到预防和控制。人们应大力避免以下危险因素：体重超重或肥胖；水果和蔬菜摄入量低；久坐不动；烟草使用；酒精使用；不安全的性行为；城市空气污染；家庭使用固体燃料产生的室内烟雾；卫生保健设施中被乙型肝炎病毒或丙型肝炎病毒污染的注射。此外，还应针对人类乳头瘤病毒和乙型肝炎病毒感染接种疫苗、控制职业危害以及减少暴露在阳光下的时间。 人们应对一些最常见的癌症种类，例如乳腺癌、宫颈癌和结肠直肠癌，在得到及早发现和根据
3、最佳做法治疗时，有很高的治愈率。此外，姑息治疗可帮助90%以上的癌症患者可以缓解疼痛和其他问题。,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CML 2、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
4、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,2008年临床肿瘤学的一些新概念 1、癌症的形成是一漫长过程可以早期干预、 早期发现、早期治疗和治愈； 2、分子靶向治疗和细胞毒药物不同治疗癌 变过程； 3、在循证
5、医学资料的基础上制定诊疗规范使 诊疗规范； 4、治疗的个体化是进一步提高的途径之一； 5、以人为本的综合治疗成为主流。,二、肿瘤内科治疗的里程碑,1940s 氮芥治疗淋巴瘤 1950s 环磷酰氨、氟尿嘧啶 1970s 阿霉素、顺铂 1980s 紫杉醇、 CPT-11 2000s 靶向治疗 治疗癌变过程中的分子事件 使癌症成为慢性病,当前重要的目标诊疗的规范化和个体化,1、进入21世纪以来通过靶向治疗更多参加国 际多中心临床试验，提高了我国同道的国际 地位； 2、CSCO和ASCO/ESMO/ACOS建立平等， 互相承认会员的协议； 3、2000年开始国家人事部和卫生部开始专业 医生考试； 4、
6、2006年开始和美国NCCN合作共同制定常 见肿瘤的中国版； 5、中西医结合同病异治、异病同治,三、分子靶向治疗的成绩（2008）, 药物 近期疗效 延长生存 辅助应用 伊马替尼 CML,GIST CML,GIST GIST? 美罗华 B细胞淋巴瘤 B细胞淋巴瘤 吉非替尼 NSCLC NSCLC? NSCLC? 厄罗替尼 NSCLC、胰腺癌 赫赛汀 乳腺癌 乳腺癌 乳腺癌 索拉芬尼 肾癌 肝癌 索拉芬尼 肾癌、肠癌？ 西妥昔单抗 NSCLC，大肠癌 贝伐单抗 NSCLC，大肠癌 恩度 NSCLC NSCLC 参一胶囊 NSCLC NSCLC ,抗肿瘤抗体靶向治疗,2007年重大研究进展,肾癌,
7、Everolimus治疗肾癌的临床研究,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） Sutentinib（Sutent，苏尼替尼） Zact
8、ima(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）,INTEREST Study,amodified Hochberg procedure applied to control for multiple testing CT, chemotherapy; PS, performance status; EGFR, epidermal growth factor receptor,Patients Age 18 years Life expectancy 8 weeks P
9、rogressive or recurrent disease following CT Considered candidates for further CT with docetaxel 1 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 copy number) Secondary Progression
10、-free survival Objective response rate Quality of life Disease related symptoms Safety and tolerability Exploratory Biomarkers,Endpoints,Objective tumor response (RECIST) (EFR population),RECIST, response evaluation criteria in solid tumors; EFR, evaluable for response; OR, odds ratio; CI, confidenc
11、e interval,Patients (%),(n=659),(n=657),OR 1 implies a greater chance of response on gefitinib OR and p-value from logistic regression with covariates,Overall survival in overall PP population,96% of historical docetaxel advantage over BSC from TAX-317 retained by gefitinib (96% CI: 52%, 129%) Indir
12、ect comparison of gefitinib to BSC: HR (96% CI) = 0.63 (0.42, 0.92), p=0.0137 PP, 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) = 1.154,723,336,225,131,83,50,3
13、1,14,0,0,710,339,228,139,89,46,24,7,0,0,518,503,0,4,8,12,16,20,24,28,32,36,40,0.0,0.2,0.4,0.6,0.8,1.0,Months,Probability of survival,At risk :,Gefitinib,Docetaxel,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
14、-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: Iressa 5.0月,A组: TXT 3.0月,生存率,A组: Iressa 7.0月,B组: TXT 4.0月,生存率,Iressa : 6.0月,TXT : 4.0月,p =0.0383,p =0.017,p =0.046,TXT,Iressa,Gefitinib in China,Thatcher et al 2005; Chang et al 2006
15、; 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-year survival (%),ISEL (all),ISEL (Asian),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
16、,37,IRESSA (250 mg/day) + BSC,Primary end point Survival overall population adenocarcinoma Secondary end points TTF ORR QoL, symptoms Safety Exploratory end point Tumour biomarker analysis (eg EGFR),ISEL trial design,1692 patients in 210 centres across 28 countries Stratified for histology, sex, int
17、olerant / 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; QoL, quality of life; TTF, time to treatment failure,Patients Local
18、ly advanced or metastatic NSCLC 1 or 2 prior CT regimens Intolerant 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:,1692,1347,877,485,252,104,31,Median, months 1-year survival,
19、 % Log-rank HR 0.89; 95% CI 0.77, 1.02; p=0.087 Cox analysis, p=0.030,IRESSA 5.6 27,Placebo 5.1 21,0.0,0.2,0.4,0.6,0.8,1.0,Proportion surviving,IRESSA,Placebo,Median follow-up: 7 months (range 3-15); 58% deaths,Thatcher et al 2005,HR, hazard ratio,Median, months 1-year survival, % Log-rank HR 0.84;
20、95% CI 0.68, 1.03; p=0.089 Cox analysis, p=0.033,IRESSA 6.3 30,Placebo 5.4 18,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,Proportion surviving,Thatcher et al 2005,ISEL: significant improvement in TTF a
21、nd ORR,1692,1051,539,278,129,49,17,IRESSA,Placebo,IRESSA Placebo Cox analysis (95% CI) Log rank Odds ratio (95% CI),Median TTF, months 3.0 2.6 0.82 (0.73, 0.92) p=0.0006 p=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
22、,0.4,0.6,0.8,1.0,Proportion without 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 an
23、d 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 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 m
24、onths,Time since Dx: 12 months,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,
25、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,Favours IRES
26、SA,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 by smoking history and racial origin,IRESSA,Placebo,Proportion surviving,0,2,4,6,8,10,12
27、,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),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
28、 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=0.010,Cox regression analysis,Thatcher et al 2005,TALENT and TRIBUTE: study design,Patients with HER1/EGFR-positive or -negative, stage IIIB/IV NSCLC,Primary objective overall survival (80% power to detect a 25% survi
29、val benefit and a 33% 1-year survival benefit, =0.05) Secondary objectives time to disease progression response rate/duration of response time to symptomatic progression safety,150mg/day Tarceva p.o. + six cycles of chemotherapy,Placebo + six cycles of chemotherapy,Daily oral Tarceva alone,Placebo a
30、lone,TALENT = gemcitabine and cisplatin (n=1,172) TRIBUTE = carboplatin and paclitaxel (n=1,079),TALENT and TRIBUTE: 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 Ta
31、rceva,Apoptosis,Tarceva induces G1 arrest, which can block the M-phase activity of docetaxel,Tarceva Docetaxel,Docetaxel 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
32、 (Tarceva),Proportion event-free,1.0 0.8 0.6 0.4 0.2 0,0 100 200 300 400 500 600,Study day,Log-rank test p=0.0001,Median survival (months) Grade 1 10.7 Grade 2 10.4 Grade 3 12.9 No AE 7.6,Grade 1 Grade 2 Grade 3 No AE,Gatzemeier U, et al. J Clin Oncol 2004;23(Suppl. 14):617 (Abs. 7010),TRIBUTE: carb
33、oplatin + paclitaxel plus continuous Tarceva improved survival in never smokers,Miller V, et al. J Clin Oncol 2004;22(Suppl. 14S):628 (Abs. 7061),四、我国在靶向治疗中的实践,1、积极参加国际多中心临床试验 2、主持开展多中心临床研究 恩度、参一胶囊、泰新生、 吉非替尼一线应用 恩度辅助应用 3、开展适当的实验研究中药作为新生血 管抑制剂 4、治疗个体化（同病异治）,有我国参加的重要临床试验,InterestPhaseIII临床试验比较吉非替尼和多西紫
34、杉醇二线应用治疗NSCLC的疗效 SharpPhaseIII临床试验索拉芬尼和安慰剂对比延长肝癌生存率 IPASS-吉非替尼与CP化疗一线治疗晚期亚洲NSCLC病人的III期对比研究 埃克替尼治疗NSCLC的I、II、III期临床试验,Efficacy and Safety of Sorafenib in Patients with Advanced Hepatocellular Carcinoma: Results of a Phase III Randomised, Double-Blind, Placebo-Controlled Trial Conducted in the Asia-P
35、acific Region Ann-Lii Cheng, MD, PhD1; Yoon-Koo Kang, MD2; Zhendong Chen, MD3; Chao-Jung Tsao, MD4; Shukui Qin, MD5; Jun Suk Kim, MD6; Rongcheng Luo, MD7; Jifeng Feng, MD8; Shenglong Ye, MD9; Tsai-Sheng Yang, MD10; Jianming Xu, MD11; Yan Sun, MD12; Houjie Liang, MD13; Jiwei Liu, MD14; Jiejun Wang, M
36、D15; Hongming Pan, MD17; Karin Burock, MS18; Jessie Zou, MD, PhD19; Dimitris Voliotis, MD, PhD20; Zhongzhen Guan, MD, PhD21 通讯作者：郑安理、管忠震 44th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, Illinois, USA, May 30-June 3, 2008 International Liver Congress (ILC), Hong Kong,
37、 China, June 12-15, 2008 2nd Annual International Liver Cancer Association (ILCA) Conference, Chicago, Illinois, USA, September 5-7, 2008 已经为Lancet 接受发表,NSCLC First or 2nd lines 493pts PS 0-2 期,NVB 25mg/m2,NVB 25mg/m2,Rndoistar 7.5mg/m2+NS 250ml IV gtt,d1,d2,3,4,d5,d1-14,d21,R,NVB 25mg/m2,CDDP 30mg/
38、m2,NVB 25mg/m2,d21,d1,d2,3,4,d5,Placebo NS 3.5ml)+NS250ml IV gtt,24 Centers R、double blind 、placebo control、multicenter first：2nd line = 2：1 T：C= 2：1,CDDP 30mg/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,分层分析-初/复治,分层分析-病理类型
39、,不良反应比较,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：Chemotherapy + Rg3 。20mg P.O. BID Arm A : Chemotherapy + Placebo 20 mg P.O. BID
40、 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 1cycle,Preliminary Results of a double-blind randomized trial of advanced NSCLC treated with NP or NP+ Rg3,Arm A Arm B N=61 N
41、=54 CR+PR 14.5% （8/55） 33.4%（17/51） Median survival（m ) 8.0 10.0 Mean ST （m） 9.68 15.26 Survival 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 Rank统计量=6.86，P=0.0088。,Mean of Survival Time
42、(month),TCM 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
43、茶多酚 Gabderma 云芝多糖 张芷旋，周清华，中国肺癌杂志 2006；9：9699,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-o
44、ff value（界值）=2，每增加1分，疗效增加1倍。,五、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。 5、诊疗规范化和个体化是当前的时尚；,诊疗规范化提高全国同道的水平,诊疗个体化辨证论治进一步提高疗效 医生的责任是向病人和家属提供最新最好的治疗方案,