肝癌规范化治疗（精品ｐｐｔ）

肝癌 内科 依荷芭丽.迟 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)5 1. 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 Hepatol. 2000;33:423-9. 5. Marrero CR, Marrero JA. Arch Med Res. 2007;38:612-20. Subject to PATH Program Disclaimer HCC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: - 无正常肝脏 - 继发于慢性肝炎 炎症性癌症 El-Serag HB. Clin Liver Dis. 2001;5:87-107. Subject to PATH Program Disclaimer El-Serag HB, Rudolph KL. Gastro. 2007;132:2557-76. HCC地域死亡率 (每100,000人 ) 50% of HCC Annual mortality per region: Europe: 54,000 USA: 19,000 ChinaKoreaJapan: 390,000 Subject to PATH Program Disclaimer HCC高危因素和发病率 80% HCC 与HBV或 HCV相关 Llovet JM, et al. Lancet. 2003;362:1907-7. Pisani et al. Cancer Epidemiol Biomarkers Prev. 1997 ;6:387-400.Subject to PATH Program Disclaimer 肝癌风险合并超重肥胖与正常体重人群对比 荟萃分析 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 controls (0.87 x 105 person-years) 肝细胞高位因素: 糖尿病 Subject to PATH Program Disclaimer 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 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. Hepatology. 2006;43(2 Suppl 1):S145-50. Avila MA, et al. Oncogene. 2006;25:3866-84. Subject to PATH Program Disclaimer 2 +ve for arterial hypervascularization among: Angiography CT MRI Doppler US or 1 +ve plus AFP 400 ng/mL Bruix J, et al. J Hepatol. 2001;35:421-30.Subject to PATH Program Disclaimer 非转转移早期肝癌的诊诊断标标准 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 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. 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, 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. Subject to PATH Program Disclaimer HCC不同分期包含变量指标(2) Wildi S, et al. Br J Surg. 2004;91:400-8. 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. T1期评定中的问题 (1) 定义义太宽宽： 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 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 2, Child-Pugh C HCC Intermediate stage (B) multinodular, PST 0 Stage AC PST 02, Child-Pugh AB BCLC staging system and treatment strategy Subject to PATH Program Disclaimer 不能切除的HCC “不能切除的”患者并不代表晚期 HCC Terminal stage PST 0-2, ChildPugh AB Multinodular, PST 0 N1, M1, PST 12 Intermediate stage PST 2, ChildPugh C Very early stage Single 2, Child-Pugh C Very early stage (0) Single 2 cm carcinoma in situ Early stage (A) 13 nodules 3 cm, PS 0 Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 12 End stage (D) Single3 nodules 3 cm Portal pressure/bilirubin IncreasedAssociated diseases NormalNoYes Resection Liver transplantation (CLT/LDLT) PEI/RFAChemoembolizationSorafenib Curative treatmentsRandomized controlled trials Symptomatic treatment RFA = radiofrequency ablation; PEI = percutaneous ethanol injection.Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. Subject to PATH Program Disclaimer NCCN Guidelines (2009) NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer. V2.2009; Available at: . Accessed February 2010. Subject to PATH Program Disclaimer Japan Society of Hepatology: consensus-based treatment algorithm for HCC Kudo M. Oncology. 2009;75 Suppl 1:1-12.Subject to PATH Program Disclaimer Extrahepatic metastasis Main portal vein tumor thrombus Resectable Sorafenib or systemic therapy trial Resection / RFA (for 3 cm HCC) Solitary tumor 5 cm 3 tumors 3 cm No venous invasion Child-Pugh A Child-Pugh B Child-Pugh C Child-Pugh A / B Child-Pugh C TransplantationTACE Supportive care Local ablation HCC Confined to the liver Main portal vein patent APASL working committee meeting consensus on treatment guidelines for HCC Tumor 5 cm 3 tumors Invasion of hepatic / portal vein branches Yes No Child Pugh A / B Child-Pugh C Omata M et al., APASL working committee meeting consensus on HCC, APASL February 1316, 2009, Hong Kong Subject to PATH Program Disclaimer HBV HCV 酒精 黄曲霉毒素B1 损伤损伤 干细细胞增殖停止 星形细胞活化 慢性肝病Liver cirrhosis Abnormal liver nodules Extensive scarring (collagen) 染色体不稳稳定 染色体重度不稳定 和P53缺失 Hepatocellular carcinoma 幼稚细细胞结节结节 Hyperplastic nodule 分化好的 中等分化的 分化差的 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 肝细胞肝癌的发病机制与多个信号传导通路相关 细胞膜 c-MYCc-JUN Wnt 受体 BcL-XL BAD ERK1/2 MEK1/2 -catenin GSK3 GBP DSH HBx Akt mTOR Raf PKC NF-B Ras NF-B PLC SHC GrB2 GEF PI3K PTEN p53 生存l 转录 和翻译 -catenin HBx RTK: FGFR EGFR IGF-IR c-MET 受体r Adapted from Avila MA, et al. Oncogene. 2006;25:3866-84. Subject to PATH Program Disclaimer 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 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 Adapted 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 VEGFVEGFRPDGFREGFRRafmTOR Bevacizumab Cediranib Thalidomide Erlotinib Gefitinib ABT-869 Sorafenib Lapatinib Sunitinib Cetuximab Brivanib SU6668 Everolimus Subject to PATH Program Disclaimer Agent 抗生成血管抗增殖 VEGFVEGFRPDGFREGFRRafmTOR Bevacizumab Cediranib Thalidomide Erlotinib Gefitinib ABT-869 Sorafenib Lapatinib Sunitinib Cetuximab Brivanib SU6668 Everolimus III期临床研究:分子靶向药物和其主要靶点 Sorafenib targets both tumor-cell proliferation and angiogenesis in vitro KIT/Flt-3/ RET Angiogenesis Raf Endothelial cell or pericyte Nucleus VEGFR-2 PDGFR- MEK Apoptosis Tumor cell Proliferation PDGF VEGF EGF Survival Wilhelm SM, et al. Cancer Res. 2004;64:7099-109 . Ras Nucleus Ras ERK Raf MEK Apoptosis ERK PDGF-VEGF Paracrine stimulation Sorafenib X X XX X X X X Subject to PATH Program Disclaimer Primary endpoints: OS, TTSP Secondary endpoints: TTP, DCR, safety Phase III SHARP and AsiaPacific studies Eligibility Advanced HCC, ECOG PS 02, Child-Pugh A, no prior systemic therapy Stratification MVS and/or EHS, ECOG PS (0 vs 12), geographic region RANDOMIZE 1:1 SHARP1AsiaPacific2 RANDOMIZE 2:1 Sorafenib 400 mg bid Placebo Sorafenib 400 mg bid Placebo Endpoints: OS, TTSP, TTP, DCR, safety (no primary endpoint defined) n=299n=303n=150n=76 1. 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 Sorafenib consistently increased overall survival in different global patient populations HR = 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 probability 1.00 0.75 0.50 0.25 Months 0468101214162 0.00 Sorafenib (n=299) Median OS: 10.7 months Placebo (n=303) Median OS: 7.9 months 18 HR = 0.69 Survival probability 1.00 0.75 0.50 0.25 Months 0481222 0.00 Sorafenib (n=150) Median OS: 6.5 months Placebo (n=76) Median OS: 4.2 months 261014161820 HR = 0.68 SHARP1AsiaPacific 2 Subject to PATH Program Disclaimer Asia-Pacific (N=226) SHARP (N=602) Median age (range), years51 (23-86)67 (21-89) Sex (male), %8587 ECOG PS (0/1/2), %26/69/554/38/8 MVI, %3538 EHS, %6951 BCLC stage (B/C), %4/9617/82 Hepatitis virus status (HBV/HCV), %73/818/28 No. of tumor sites, % 11144 23531 32012 43513 Sites of disease, % Lung5021 Lymph node3226 AsiaPacific trial1 vs SHARP2: baseline patient characteristics 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. Subject to PATH Program Disclaimer SHARP: sorafenib prolongs OS by 44% and TTP by 74% in patients with advanced HCC Llovet JM, et al. N Engl J Med. 2008;359:378-90. 1.00 Survival probability 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Sorafenib (n=299) = 10.7 months Placebo (n=303) = 7.9 months Time from randomization (months) Probability of radiologic progression 0 1 2 3 4 5 6 7 8 9 10 11 12 Sorafenib (n=299) = 5.5 months Placebo (n=303) = 2.8 months Time from randomization (months) 1.00 0.75 0.50 0.25 0 HR = 0.69 (95% CI: 0.550.87) p0.001 0.75 0.50 0.25 0 HR = 0.58 (95% CI: 0.450.74) p0.001 Overall survival Time to progression (independent central review) Subject to PATH Program Disclaimer Sorafenib prolongs OS by 47% and TTP by 74% in AsiaPacific patients with advanced HCC Cheng A-L, et al. Lancet Oncol. 2009;10:25-34. Overall survivalTime to progression Sorafenib Median: 6.5 months (95% CI: 5.67.6) Placebo Median: 4.2 months (95% CI: 3.75.5 Sorafenib Median: 2.8 months (95% CI: 2.63.6) Placebo Median: 1.4 months (95% CI: 1.31.5 HR (S/P): 0.57 (95% CI: 0.420.79) p 0.001 SorafenibSorafenib Subject to PATH Program Disclaimer AsiaPacific study1 vs SHARP2: efficacy similar in both patient populations EndpointAsiaPacific SHARP Hazard ratio (95% CI)P-value Hazard ratio (95% CI)P-value OS 0.68 0.014 0.69 0.001 (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. Llovet JM et al. Hepatology. 2008;48:1312-27. Subject to PATH Program Disclaimer Sorafenib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 al. Lancet Oncol. 2009;10:25-34. Subject to PATH Program Disclaimer 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)1 Survival TTP 0.69 (0.550.87) 0.58 (0.450.74) Renal cell carcinoma (advanced) Sorafenib (n=384) vs placebo (n=385)8,9PFS Survival 0.44 (0.350.55) 0.78 (0.620.97) Colorectal cancer (metastatic) IFL + bevacizumab (n=402) vs IFL (n=411)2 Cetuximab (n=287) vs best supportive care (n=285)3 Survival Survival 0.66 (NA) 0.77 (0.640.92) Lung cancer Pac/carbo + bevacizumab (n=434) vs pac/carbo (n=444)4 Erlotinib (n=488) vs placebo (n=243)5 Survival Survival 0.79 (0.690.93) 0.79 (0.580.85) Breast cancer (advanced, HER2+ve) Chemo + trastuzumab (n=235) vs chemo (n=234)6 Paclitaxel + bevacizumab vs paclitaxel (n=326)7 TTP PFS 0.51 (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 Engl 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. 2007;356:125-34. 9. Escudier B, et al. J Clin Oncol. 2009;27:3312-18. Table adapted from Llovet and Bruix, Hepatology 2008. Subject to PATH Program Disclaimer 抗血管生成药物耐药方式 适应应性 (逃逸) 耐药药 原发发无效 Bergers G, Hanahan D. Nat Rev Cancer. 2008;8:592-603. Subject to PATH Program Disclaimer 诱导预血管生成因子替代重建新生血管生成 Bergers G, Hanahan D. Nat Rev Cancer. 2008;8:592-603. Subject to PATH Program Disclaimer Bergers G, Hanahan D. Nat Rev Cancer. 2008;8:592-603. 募集骨髓衍生细胞促使新生血管生成 Subject to PATH Program Disclaimer Bergers G, Hanahan D. Nat Rev Cancer. 2008;8:592-603. 肿瘤血管外周防御细胞增加 Subject to PATH Program Disclaimer Bergers G, Hanahan D. Nat Rev Cancer. 2008;8:592-603. 营养缺乏和缺氧至肿瘤细胞侵袭增加 Subject to PATH Program Disclaimer 抗血管生成药物耐药方式 适应应性 (逃逸) 耐药药 原发发无效 Bergers G, Hanahan D. Nat Rev Cancer. 2008;8:592-603. Subject to PATH Program Disclaimer EACH 研究 : 试验设计 大型、开放、随机对照、多中心的期临床试验 ，包括中国大陆、台湾，韩国和泰国等38家中心 参与 Arm A (FOLFOX4): - OXA 85mg/m2 iv. h0 h2 Day 1 - LV 200mg/m2 iv. h0 h2 Day 1,2 - 5FU 400mg/m2 iv. bolus Day 1, 2 then 600 mg/m2 over 22 hours in Day 1 9:143-50. Subject to PATH Program Disclaimer 美国肝脏病研究协会（AASLD）肝细胞肝 癌临床研究指南 Subject to PATH Program Disclaimer Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. 贝伐单抗联合厄洛替尼 II期临床, 开放 , 单臂, 单中心 (MDACC) 入选条件 进展期HCC 既往接受过一线治疗 ChildPugh AB ECOG评分 012 治疗 bevacizumab 10 mg/kg 每 2 周一次 erlotinib 150 mg 1次/日 主要终点 PFS16 ( 16 无进展期病例) Thomas MB, et al. J Clin Oncol. 2009;27:843-50. Subject to PATH Program Disclaimer Thomas MB, et al. J Clin Oncol. 2009;27:843-50. 贝伐单抗联合厄洛替尼 :结果 Subject to PATH Program Disclaimer “II期单臂临床研究结果不能客观反应 细胞生长抑制剂疗效 ” Freidlin B, Simon R. J Clin Oncol. 2005;23:5094-8. Subject to PATH Program Disclaimer 随机对比II期临床研究 60 patients Bevacizumab + erlotinib 60 patients Sorafenib Patients with advanced HCC; no previous systemic treatment; ChildPugh class A; ECOG PS 02 Primary end point TTP Secondary end points PFS Response rate Overall survival Safety and tolerability Study start date: March 2009 Estimated final analysis: March 2011 R A N D O M I Z A T I O N Subject to PATH Program Disclaimer /ct2/show/NCT00881751. Agent 抗生成血管抗增殖 VEGFVEGFRPDGFREGFRRafmTOR Bevacizumab Cediranib Thalidomide Erlotinib Gefitinib ABT-869 Sorafenib Lapatinib Sunitinib Cetuximab Brivanib SU6668 Everolimus III期临床研究:分子靶向药物和其主要靶点 肝细胞肝癌III期临床研究 晚期HCC 方案A: X vs sorafenib 一线治疗 方案 B: X + sorafenib vs sorafenib一线治疗 方案 C: X vs 最佳支持治疗 (BSC) 二线治疗( Sorafenib失败) 其他 早期肝癌 中期肝癌 Subject to PATH Program Disclaimer 600 patients Sorafenib 600 patients Sunitinib malate /ct2/show/NCT00699374. Patients with advanced HCC; no previous systemic treatment; ChildPugh class A; ECOG PS 0-1 Primary end point Overall survival Secondary end points PFS TTP Safety Health status Study start date: July 2008 Estimated final analysis: July 2012 R A N D O M I Z A T I O N 方案 A: X vs sorafenib 一线治疗 Subject to PATH Program Disclaimer 525 patients Sorafenib 525 patients Brivanib Patients with advanced HCC; no previous treatment; ChildPugh class A; ECOG PS 0-1 Primary end point Overall survival Secondary end points TTP Objective response Safety PK TTSP QoL Study start date: May 2009 Estimated final analysis: February 2013 + brivanib placebo + sorafenib placebo R A N D O M I Z A T I O N 方案 A: X vs sorafenib 一线治疗 /ct2/show/NCT00858871. Subject to PATH Program Disclaimer 450 patients Sorafenib 450 patients ABT-869 Patients with advanced HCC; no previous treatment; ChildPugh class A; ECOG PS 0-1 Primary end point Overall survival Secondary end points TTP Objective response Study start date: October 2009 Estimated final analysis: February 2012 R A N D O M I Z A T I O N 方案 A: X vs sorafenib 一线治疗 /ct2/sh