肝癌规范化治疗ppt课件

1、1 HCC 数据 HCC 占肝脏原发肿瘤首位 : 90%1 男性肿瘤第五位, 女性肿瘤第九位2。 恶性肿瘤死亡率第三位3 是肝硬化患者死亡的主要原因4 年新发病例 (560,000) 年死亡病例 (550,000)51. Perz JF, et al. J Hepatol. 2006;45:529-38. 2. Jelic S. Ann Oncol. 2009;Suppl 4:iv41-5. 3. Garcia M, et al. American Cancer Society. 2007. . Accessed Jan 2010.4. Llovet J, J He

2、patol. 2000;33:423-9. 5. Marrero CR, Marrero JA. Arch Med Res. 2007;38:612-20.Subject to PATH Program Disclaimer 2男女数据来源：数据来源：(中国2014年肿瘤登记年报)3HCC流行病学HCC发病率不同的地域性时间相关性 (不同地域有不同的时间相关性 )种族差异性性别和社会地位差异性 高危因素 ( 已知)与肝硬化相关性 (6095% 的病例)致癌机理:- 非正常肝脏- 继发于慢性肝炎炎症性癌症El-Serag HB. Clin Liver Dis. 2001;5:87-107.Sub

3、ject to PATH Program Disclaimer 4El-Serag HB, Rudolph KL. Gastro. 2007;132:2557-76. HCC地域死亡率 (每100,000人 ) 50% of HCCAnnual mortality per region: Europe: 54,000 USA: 19,000 ChinaKoreaJapan: 390,000Subject to PATH Program Disclaimer 5 HCC高危因素和发病率 80% HCC 与HBV或 HCV相关Llovet JM, et al. Lancet. 2003;362:1

4、907-7.Pisani et al. Cancer Epidemiol Biomarkers Prev. 1997 ;6:387-400.Subject to PATH Program Disclaimer 67回顾性研究: 173,463糖尿病病例对比650,620 非糖尿病病例. 患者无因急性或慢性肝脏疾病近一年内住院治疗 El-Serag HB, et al. Gastroenterology. 2004;26:460-8.824,263 住院治疗 美国退伍军人 (19851990):肝细胞肝癌: 317 diabetes (2.39 x 105 person-years)515 co

5、ntrols (0.87 x 105 person-years) 肝细胞高位因素: 糖尿病Subject to PATH Program Disclaimer 8肝细胞肝癌: 男性多于女性 24 倍 400,000 例/年 160,000 例/年Database ITA.LI.CA, 2008.Subject to PATH Program Disclaimer 9肝细胞肝癌: 人种差别 (USA)2 倍2 倍遗传多态性: 免疫应答 (i.e. HCV) 炎症反应 酒精代谢, 环境致癌胰岛素抗药性治疗反应(IFN)高危因素经济文化因素: 传播 暴露Thorgeirsson SS, et al.

6、 Hepatology. 2006;43(2 Suppl 1):S145-50.Avila MA, et al. Oncogene. 2006;25:3866-84.Subject to PATH Program Disclaimer 10 HBV HCV 酒精 黄曲霉毒素B1损伤干细胞增殖停止星形细胞活化慢性肝病Liver cirrhosisAbnormal livernodulesExtensive scarring(collagen)染色体不稳定染色体重度不稳定和P53缺失Hepatocellularcarcinoma幼稚细胞结节Hyperplasticnodule分化好的中等分化的分化

7、差的增殖坏死Farazi PA, DePinho RA. Nat Rev Cancer. 2006;6:674-87.肝细胞肝癌的组织病理学和分子病理学特征Subject to PATH Program Disclaimer 肝硬化广泛瘢痕形成肝脏结节形成结节增生肝细胞肝癌112 +ve for arterial hypervascularization among: Angiography CT MRI Doppler USor 1 +ve plus AFP 400 ng/mLBruix J, et al. J Hepatol. 2001;35:421-30.Subject to PATH

8、Program Disclaimer 非转移早期肝癌的诊断标准12肝功能分期- Child-Pugh 分级肿瘤大小分期-TNM-Vauthey (改良的TNM )-Izumi (改良的TNM )-JS (日本分期)联合分期(肝功能和肿瘤) -Okuda-Cancer of the Liver Italian Program (CLIP)-Chinese University Prognostic Index (CUPI)-Japanese integrated staging score (JIS)-Barcelona Clinic Liver Cancer (BCLC)Subject to

9、PATH Program Disclaimer HCC 分期Kudo M, et al. J Gastroenterol. 2003;38:207-15;Wildi S, et al. Br J Surg. 2004;91:400-8;Dohmen K, et al. J Gastroenterol Hepatol. 2004;19:1227-32;Marrero JA, et al. Hepatology. 2005;41:707-16.13 HCC不同分期包含变量指标 (1)肿瘤大小病变数量血管侵犯病变累及程度远处转移肝硬化Child-Pugh 分级实验室检查其他 (门静脉血栓, AFP,

10、 腹水等.)Subject to PATH Program Disclaimer Kudo M, et al. J Gastroenterol. 2003;38:207-15;Wildi S, et al. Br J Surg. 2004;91:400-8;Dohmen K, et al. J Gastroenterol Hepatol. 2004;19:1227-32;Marrero JA, et al. Hepatology. 2005;41:707-16.14Subject to PATH Program Disclaimer HCC不同分期包含变量指标(2)Wildi S, et al

11、. Br J Surg. 2004;91:400-8.15日本分期 (JS)UICC 2002 TNM分期Subject to PATH Program Disclaimer Wildi S, et al. Br J Surg. 2004;91:400-8.16T1期评定中的问题 (1)定义太宽：符合肿瘤大小1 cm 肝功能分级Child-Pugh A (5年无治疗预期生存期 50%) ，而一个大小11 cm肿瘤,肝功能分级Child-Pugh B (5年无治疗预期生存期 5%) 两者均属同期肿瘤。Subject to PATH Program Disclaimer TNM stage acc

12、ording to UICC 2002Wildi S, et al. Br J Surg. 2004;91:400-8.1718 Child-Pugh 评分评分123总胆红素 3 mg/dl国际标准化比值INR 2.2白蛋白 3.5 gr/dl3.52.8 gr/dl 50%的肝脏2甲胎蛋白 400 ng/ml0 400 ng/ml1门静脉血栓形成No0Yes1 21 早期HCC在多种分期中的判定早期肝癌诊断在不同分期标准中均不够准确 TNM 分期 (独立病灶, 5 cm, 未限定肝功能状态)Child-Pugh 评分 (未限定肿瘤大小)OKUDA 和 CLIP (涉及瘤负荷占肝脏体积 50%

13、 )JIS 分期较好; 定义了较早期肝癌 (JIS 评分 = 0) 较准确判定早期肝细胞肝癌 (JIS评分 = 1） 包括了门静脉血栓, 或 Child-Pugh B 或10 cm的大肝癌)最好的确定早期肝癌分期为 BCLC 分期标准Subject to PATH Program Disclaimer Kudo M, et al. J Gastroenterol. 2003;38:207-15;Llovet JM, et al. Semin Liver Dis. 1999;19:329-38.22BCLC 分期预后和治疗分配体系 *Grieco A, et al. Gut. 2005;54:4

14、11-18;Llovet JM, et al. Semin Liver Dis. 1999;19:329-38.Subject to PATH Program Disclaimer 肿瘤伴随特征肝脏特征 中位生存 (月)* A期 (早期 HCC)A1 PST 0单一无门静脉高血压, 胆红素无异常43A2 PST 0单一门静脉高血压, 胆红素无异常29A3 PST 0单一门静脉高血压, 胆红素异常25A4 PST 03 个肿瘤均 3 cmChild Pugh AB22 Stage B ( 中期 HCC)PST 0多个大结节Child-Pugh AB 18Stage C (晚期 HCC)PST 1

15、2血管侵犯或肝外转移 Child-Pugh AB 7Stage D (终末期 HCC)PST 34任何情况Child-Pugh C 无法肝移植-23PEI/RFASorafenibStage 0PST 0, Child-Pugh AVery early stage (0) 1 HCC 2 cmcarcinoma in situEarly stage (A)1 HCC or 3 nodules 2, Child-Pugh CHCCIntermediate stage (B)multinodular,PST 0Stage ACPST 02, Child-Pugh ABBCLC staging sy

16、stem and treatment strategySubject to PATH Program Disclaimer 24a Presence of vascular invasion or extrahepatic metastasis to be indicated separatelyb Selected when the severity of liver damage is class B and the tumor diameter is 2 cmc Tumor diameter 5 cm, when there is only one tumorJapanese HCC g

17、uidelines (ctd)Subject to PATH Program Disclaimer Kokudo N, Makuuchi MJ. Gastroenterology. 2009;44 Suppl XIX:119-21.HCC and percutaneous ablation (ctd)Hasegawa K, et al. J Hepatol. 2008;49:589-94.Subject to PATH Program Disclaimer Surgical resection vs percutaneous ablation for hepatocellular carcin

18、oma: a preliminary report of the Japanese nationwide surveySubject to PATH Program Disclaimer Hasegawa K, et al. J Hepatol. 2008;49:589-94.Surgical resection vs percutaneous ablationfor hepatocellular carcinoma: a preliminary report of the Japanese nationwide surveySubject to PATH Program Disclaimer

19、 Hasegawa K, et al. J Hepatol. 2008;49:589-94.PEI/RFASorafenibStage 0PST 0, Child-Pugh AVery early stage (0) 1 HCC 2 cmcarcinoma in situEarly stage (A)1 HCC or 3 nodules 2, Child-Pugh CHCCIntermediate stage (B)multinodular,PST 0Stage ACPST 02, Child-Pugh ABBCLC staging system and treatment strategyS

20、ubject to PATH Program Disclaimer 292930Liver transplantation for HCC Results of liver transplantation: ELTR data31Single HCC 5 cm23 HCCs 3 cm32Single HCC 5 cm3 HCCs 3 cm扩大肝脏移植适应症的原则: 生存延长：5年生存率50 移植获益：移植生存获益优于非移植 等待肝源的死亡风险3334Subject to PATH Program Disclaimer 名额等待与切除的危害和效益之间的平衡取决于一）肝癌的候选人比例b）肝切除术至

21、转移c）预期移植时间Cucchetti A, et al. Am J Transplant.2010;Jan 29 Epub ahead of print.35PEI/RFASorafenibStage 0PST 0, Child-Pugh AVery early stage (0) 1 HCC 2 cmcarcinoma in situEarly stage (A)1 HCC or 3 nodules 2, Child-Pugh CHCCIntermediate stage (B)multinodular,PST 0Stage ACPST 02, Child-Pugh ABBCLC stag

22、ing system and treatment strategySubject to PATH Program Disclaimer 36细胞热效应Subject to PATH Program Disclaimer 沸腾，汽化和炭化瞬时蛋白质凝固不可逆的损害增加对化疗药物的敏感性和辐射细胞动态平衡37Expandable needle (Radiotherapeutics RITA)Single needle cooled tip (Radionics) Catheter needle (Miras)Cluster needle (Radionics) Subject to PATH Pr

23、ogram Disclaimer 38小肝癌研究 (13 cm)PEI组: pCR 48/60 (80%)RF组: pCR 47/52 (80%) 2 cm HCC 完全消融率 RF = 97%早期肝硬化肝癌射频治疗的完全缓解时间和完全缓解率: 外科手术切除是否还是治疗首选? 21. Livraghi T, et al. Radiology. 1999;210:655-61. 2. Livraghi T, et al. Hepatology. 2008;47:82-9. 1Subject to PATH Program Disclaimer 39Alcohol胞质蛋白的脱水和由此产生的肿瘤细胞

24、凝固性坏死内皮细胞，血小板聚集和血管血栓形成，导致肿瘤组织缺血坏死经皮无水酒精消融作用Germani G, et al. J Hepatol. 2009;doi:10.1016.Subject to PATH Program Disclaimer 40 PEI-治疗的生存结果(回顾性研究)Author and yearShiina S, et al.1Livraghi T, et al.2 Child A, single 5 cm Child B, single 5 cmLencioni R, et al.3 Child A, single/multiple 3 cm Child B, sin

25、gle/multiple 3 cm8598 93 100 91627963 8753No. of patients982931496441Survival (%)3 years 5 years1 year524729 55131. Shinna S, Am J Roentgenol. 1993;160:1023-8.2. Livraghi T, et al. Radiology. 1995;197:101-8.3. Lencioni R, et al. Cancer. 1995;76:1737-46.Subject to PATH Program Disclaimer 41Long-term

26、survival of HCC patientsafter microwave ablationLiang P, et al. Radiology. 2005;235:299-307.Subject to PATH Program Disclaimer 42PEI/RFASorafenibStage 0PST 0, Child-Pugh AVery early stage (0) 1 HCC 2 cmcarcinoma in situEarly stage (A)1 HCC or 3 nodules 2, Child-Pugh CHCCIntermediate stage (B)multino

27、dular,PST 0Stage ACPST 02, Child-Pugh ABBCLC staging system and treatment strategySubject to PATH Program Disclaimer 43药物+离子载体+栓塞剂 = 明胶海绵聚乙烯醇微球的N-异氰基丙烯酸酯Subject to PATH Program Disclaimer TACE 原理 明胶海绵聚乙烯醇微球的N-异氰基丙烯酸酯44nsingle HCC 5 cm44n多发 HCC 3个肿瘤, 肿瘤大小 3 cm无肿瘤相关症状无血管侵犯和/或肝外转移Child-Pugh class ABTAC

28、E理想选择ORR: 30%60%死亡率 4%12% HCCKudo M, et al. Oncology. 2007;72 Suppl 1:2-15.Llovet JM, et al. J Nat Cancer Inst. 2008;100:698-711.Subject to PATH Program Disclaimer 45射频消融或无水酒精注射后的巩固治疗术前新辅助治疗术后辅助治疗肝移植手术等待期治疗4546RCTTACE vs TAE vs 保守治疗112 patients with HCC 84% anti-HCV+Class Child-Pugh: A and BStage Ok

29、uda: I and II No portal thrombosis (even segmentary)79 patients wtih HCC80% HBsAg+Stage Okuda: I and IILlovet, Lancet 2002Lo, Hepatology 2002RCTTACE vs 保守治疗Randomized studies from 2002 (intermediate stage HCC)Llovet JM, et al. Lancet. 2002;359:1734-9. Lo CM, et al. Hepatology. 2002;35:1164-71.Subjec

30、t to PATH Program Disclaimer 47不能手术切除的肝癌的标准治疗: 与对照组相比TACE提高患者2年生存率 客观率反应率约35（16-61）TACE与顺铂或阿霉素联合较单纯TAE带给患者生存获益 Llovet JM, Bruix J. Hepatology. 2003;37:429-42.The response of randomized studies from 2002 (intermediate stage HCC)Subject to PATH Program Disclaimer 48PEI/RFASorafenibStage 0PST 0, Child-

31、Pugh AVery early stage (0) 1 HCC 2 cmcarcinoma in situEarly stage (A)1 HCC or 3 nodules 2, Child-Pugh CHCCIntermediate stage (B)multinodular,PST 0Stage ACPST 02, Child-Pugh ABBCLC staging system and treatment strategySubject to PATH Program Disclaimer 49 不能切除的HCC “不能切除的”患者并不代表晚期 HCCTerminalstagePST

32、0-2, ChildPugh ABMultinodular, PST 0 N1, M1, PST 12Intermediate stagePST 2,ChildPugh CVery early stageSingle 2 cmEarly stageSingle or 3 nodulesAdvanced stagePortal invasion,PST 0, ChildPugh ABCLC stage 0ASurvival 36 monthsBCLC stage BSurvival 16 monthsBCLC stage CSurvival 6 (48) monthsBCLC stage DSu

33、rvival 3 monthsSubject to PATH Program Disclaimer 50中期或晚期肝癌患者的预后不佳1 7080% 肝癌患者在确诊时已为中晚期 , 失去根治机会1 102 肝癌患者生存分析2 患者中不包括接受过根治性治疗* 或 终末期患者 OS (%)Disease stage1 year2 years3 yearsIntermediate806550Advanced2916 8*Surgical resection, liver transplantation or ethanol injectionOkuda stage 3 or performance s

34、tatus 31. Llovet JM. Gastroenterology. 2005;40:225-35. 2. Llovet JM. Hepatology.1999;29:62-7.HCC = hepatocellular carcinoma; OS = overall survivalSubject to PATH Program Disclaimer 51化学治疗或内分泌治疗: 晚期肝癌几乎无效研究期别N客观有效率化学治疗Doxorubicin 单药1,2II/III20310%Doxorubicin 联合 (PIAF)1,3II/III14424%Cisplatin4II2815%E

35、pirubicin5,6II6211%Mitoxantrone7II2227%Irinotecan8, paclitaxel9, gemcitabine10,5-FU11 II/III10%Anti-androgen (flutamide + leuproline)12III376No benefit vs controlInterferon13III3010%Octreotide14III355%Seocalcitol15III7462,Child-Pugh CVery early stage (0)Single 2 cmcarcinoma in situEarly stage (A)13

36、nodules 3 cm,PS 0Intermediate stage (B)Multinodular,PS 0Advanced stage (C)Portal invasion, N1, M1, PS 12End stage (D)Single3 nodules 3 cmPortal pressure/bilirubinIncreasedAssociated diseasesNormalNoYesResectionLiver transplantation(CLT/LDLT)PEI/RFAChemoembolizationSorafenibCurative treatmentsRandomi

37、zed controlled trialsSymptomatictreatmentRFA = radiofrequency ablation;PEI = percutaneous ethanol injection.Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. Subject to PATH Program Disclaimer 54NCCN Guidelines (2009)NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer. V2.2009;

38、 Available at: . Accessed February 2010. Subject to PATH Program Disclaimer 55Japan Society of Hepatology:consensus-based treatment algorithm for HCCKudo M. Oncology. 2009;75 Suppl 1:1-12.Subject to PATH Program Disclaimer 56Extrahepatic metastasis Main portal vein tumor thrombus Resecta

39、bleSorafenib or systemic therapy trial Resection / RFA (for 5 cm 3 tumorsInvasion of hepatic / portal vein branches Yes NoChild Pugh A / B Child-Pugh COmata M et al., APASL working committee meeting consensus on HCC, APASL February 1316, 2009, Hong KongSubject to PATH Program Disclaimer 57肝细胞肝癌的发病机制

40、与多个信号传导通路相关 细胞膜 c-MYCc-JUNWnt 受体BcL-XLBADERK1/2MEK1/2-cateninGSK3GBPDSHHBxAktmTORRafPKCNF-BRasNF-BPLCSHCGrB2GEFPI3KPTENp53生存l转录和翻译-cateninHBxRTK: FGFR EGFRIGF-IRc-MET受体rAdapted from Avila MA, et al. Oncogene. 2006;25:3866-84.Subject to PATH Program Disclaimer 58肝细胞肝癌的分子学发病机制 肝细胞肝癌的发病机制与多个信号传导通路相关 肝细

41、胞恶变是基于炎症、细胞再生、细胞增生、肝硬化、遗传、后天因素等 肝细胞肝癌多伴有细胞信号通路失调，主要包括：1,2 血管生成信号 Ras/Raf/MEK/ERK PI3K/Akt/mTOR Wnt/-catenin 分子治疗的主要靶点1. Thorgeirsson S, et al. Hepatology. 2006;43:S145-50.2. Avila MA, et al. Oncogene. 2006;25:3866-84.Subject to PATH Program Disclaimer 59肝细胞肝癌靶向治疗:临床研究 肝细胞肝癌临床研究全面展开 Sorafenib 的有效性，引发

42、靶向治疗临床研究 主要在早期和晚期患者临床研究， 一线治疗、二线治疗及辅助治疗方面的研究 Llovet JM , Bruix J. J Clin Oncol. 2009;27:833-35.Subject to PATH Program Disclaimer 60Adapted from Tanaka S, Arii S. Cancer Sci. 2009;100:1-8.临床开发: 分子靶向药物和其主要靶点 Agent 抗血管生存抗增殖VEGFVEGFRPDGFREGFRRafmTORBevacizumabCediranibThalidomideErlotinibGefitinibABT-8

43、69SorafenibSubject to PATH Program Disclaimer 61Agent 抗生成血管抗增殖VEGFVEGFRPDGFREGFRRafmTORBevacizumabCediranibThalidomideErlotinibGefitinibABT-869SorafenibLapatinibSunitinibCetuximabBrivanib SU6668Everolimus62Sorafenib targets both tumor-cell proliferation and angiogenesis in vitroKIT/Flt-3/RETAngiogen

44、esisRafEndothelial cell or pericyteNucleusVEGFR-2PDGFR-MEKApoptosisTumor cellProliferationPDGFVEGFEGFSurvivalWilhelm SM, et al. Cancer Res. 2004;64:7099-109 .RasNucleusRasERKRafMEKApoptosisERKPDGF-VEGFParacrine stimulationSorafenibXXXXXXXXSubject to PATH Program Disclaimer 63Primary endpoints: OS, T

45、TSPSecondary endpoints: TTP, DCR, safetyPhase III SHARP and AsiaPacific studiesEligibility Advanced HCC, ECOG PS 02, Child-Pugh A, no prior systemic therapyStratification MVS and/or EHS, ECOG PS (0 vs 12), geographic regionRANDOMIZE1:1SHARP1AsiaPacific2RANDOMIZE2:1Sorafenib400 mg bidPlaceboSorafenib

46、400 mg bidPlaceboEndpoints: OS, TTSP, TTP, DCR, safety (no primary endpoint defined)n=299n=303n=150n=761. Llovet JM, et al. N Engl J Med 2008;359:378-90. 2. Cheng A-L, et al. Lancet Oncol 2009;10:25-34. Subject to PATH Program Disclaimer 64Sorafenib consistently increased overall survival in differe

47、nt global patient populationsHR = hazard ratio; OS = overall survival; SHARP = Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol.Llovet JM et al. N Engl J Med. 2008;359:378-90. Cheng A-L, et al. Lancet Oncol. 2009;10:25-34. Survival probability1.000.750.500.25Months04681012141620.00S

48、orafenib (n=299)Median OS: 10.7 monthsPlacebo (n=303)Median OS: 7.9 months18HR = 0.69Survival probability1.000.750.500.25Months04812220.00Sorafenib (n=150)Median OS: 6.5 monthsPlacebo (n=76)Median OS: 4.2 months261014161820HR = 0.68SHARP1AsiaPacific 2Subject to PATH Program Disclaimer 65Asia-Pacific

49、(N=226)SHARP(N=602)Median age (range), years51 (23-86)67 (21-89)Sex (male), %8587ECOG PS (0/1/2), %26/69/554/38/8MVI, %3538EHS, %6951BCLC stage (B/C), %4/9617/82Hepatitis virus status (HBV/HCV), %73/818/28No. of tumor sites, % 11144 23531 32012 43513Sites of disease, % Lung5021 Lymph node3226AsiaPac

50、ific trial1 vs SHARP2:baseline patient characteristics1. Cheng A, et al. J Clin Oncol. 2008;26. Abstract 4509. Updated from oral presentation at ASCO; Chicago, IL; June 2008.2. Llovet JM, et al. N Engl J Med. 2008;359:378-90. Subject to PATH Program Disclaimer 66SHARP: sorafenib prolongs OS by 44% a

51、nd TTP by 74% in patients with advanced HCCLlovet JM, et al. N Engl J Med. 2008;359:378-90.1.00Survival probability0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Sorafenib (n=299) = 10.7 monthsPlacebo (n=303) = 7.9 monthsTime from randomization (months)Probability of radiologic progression0 1 2 3 4 5 6

52、7 8 9 10 11 12 Sorafenib (n=299) = 5.5 monthsPlacebo (n=303) = 2.8 monthsTime from randomization (months)1.000.750.500.250HR = 0.69 (95% CI: 0.550.87) p0.0010.750.500.250HR = 0.58 (95% CI: 0.450.74)p0.001Overall survivalTime to progression(independent central review)Subject to PATH Program Disclaime

53、r 67Sorafenib prolongs OS by 47% and TTP by 74% in AsiaPacific patients with advanced HCCCheng A-L, et al. Lancet Oncol. 2009;10:25-34.Overall survivalTime to progressionSorafenibMedian: 6.5 months(95% CI: 5.67.6)PlaceboMedian: 4.2 months(95% CI: 3.75.5SorafenibMedian: 2.8 months(95% CI: 2.63.6)Plac

54、eboMedian: 1.4 months(95% CI: 1.31.5HR (S/P): 0.57(95% CI: 0.420.79)p 0.001SorafenibSorafenibSorafenibSorafenibSubject to PATH Program Disclaimer 68AsiaPacific study1 vs SHARP2: efficacy similar in both patient populationsEndpointAsiaPacific SHARPHazard ratio (95% CI)P-valueHazard ratio (95% CI)P-va

55、lueOS0.680.0140.690.001(0.500.93)(0.550.88)TTSP0.900.4981.080.77(0.671.22)(0.881.31)TTP0.570.0010.580.001(0.420.79)(0.450.74)1. Cheng A, et al. J Clin Oncol. 2008;26. Abstract 4509. Updated from oral presentation at ASCO; Chicago, IL; June 2008.2. Llovet JM, et al. N Engl J Med. 2008;359:378-90. 3.

56、Llovet JM et al. Hepatology. 2008;48:1312-27.Subject to PATH Program Disclaimer 69Sorafenib在晚期肝细胞肝癌为标准治疗 Sorafenib 是第一个也是迄今为止唯一延长肝细胞肝癌患者生存的药物 在西方和东方不同人种、不同病因中得到验证 疗效和安全性得到验证 早期肝细胞肝癌的研究在进行中 Sorafenib 在肝细胞肝癌患者的安全性是在可控范围内的 不良反应多为中度 可预料和可管理的Llovet JM et al. N Engl J Med. 2008;359:378-90. Cheng A-L, et a

57、l. Lancet Oncol. 2009;10:25-34. Subject to PATH Program Disclaimer 70不同靶向药物治疗在实体瘤带来的获益Tumor type or randomized trial(s)EndpointHR (95% CI)Hepatocellular carcinoma (advanced)Sorafenib (n=299) vs placebo (n=303)1SurvivalTTP0.69 (0.550.87)0.58 (0.450.74)Renal cell carcinoma (advanced)Sorafenib (n=384)

58、vs placebo (n=385)8,9PFSSurvival0.44 (0.350.55) 0.78 (0.620.97)Colorectal cancer (metastatic)IFL + bevacizumab (n=402) vs IFL (n=411)2Cetuximab (n=287) vs best supportive care (n=285)3SurvivalSurvival 0.66 (NA)0.77 (0.640.92)Lung cancerPac/carbo + bevacizumab (n=434) vs pac/carbo (n=444)4Erlotinib (

59、n=488) vs placebo (n=243)5SurvivalSurvival0.79 (0.690.93)0.79 (0.580.85)Breast cancer (advanced, HER2+ve)Chemo + trastuzumab (n=235) vs chemo (n=234)6Paclitaxel + bevacizumab vs paclitaxel (n=326)7TTPPFS0.51 (0.390.59)0.60 (0.510.70)1. Llovet et al N Engl J Med. 2008;359:378-90. 2. Hurwitz et al N E

60、ngl J Med. 2004;350:2335-42. 3. Jonkers et al N Eng J Med 2007. 4. Sandler et al N Engl J Med. 2006;355:2542-50. 5. Shepherd et al N Engl J Med. 2005 Jul 14;353:123-32. 6. Slamon et al N Engl J Med. 2001;344:783-92. 7. Miller et al N Engl J Med. 2007;357:2666-76. 8. Escudier B, et al. N Engl J Med. 200