肝癌规范化治疗.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,致癌机理: - 无正常肝脏 - 继发于慢性肝炎,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 ),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,Database ITA.LI.CA, 2008.,Subject to PATH Program Disclaimer,肝细胞肝癌: 人种差别 (USA),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,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,非转移早期肝癌的诊断标准,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 according to UICC 2002,Wildi S, et al. Br J Surg. 2004;91:400-8.,Tumor single 2 cm without vascular invasion Evidence of Stage Score 3 factors T1 I 0 2 factors T2 II 1 1 factor T3 III 2 0 factors T4 or T1T3 + N1/M1 IV 3 Liver function: Child-Pugh class A 0 B 1 C 2 TOTAL range scores: 05,Japanese Integrated Staging (JIS) system TNM stage of Cancer Study Group Japan,Kudo M, et al. J Gastroenterol. 2003;38:207-15.,Subject to PATH Program Disclaimer,Child-Pugh 评分,Pugh RN, et al. Br J Surg. 1973;60:646-9.,Subject to PATH Program Disclaimer,HCC Child-Pugh 分期与生存,Kudo M, et al. J Gastroenterol. 2003;38:207-15.,Subject to PATH Program Disclaimer,CLIP评分系统,总 CLIP 评分范围 06,CLIP Investigators. Hepatology. 1998;28:751-5.,Subject to PATH Program Disclaimer,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% ) 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.,BCLC 分期,预后和治疗分配体系,*Grieco A, et al. Gut. 2005;54:411-18; Llovet JM, et al. Semin Liver Dis. 1999;19:329-38.,Subject to PATH Program Disclaimer,PEI/RFA,Sorafenib,Stage 0 PST 0, Child-Pugh A,Very early stage (0) 1 HCC 2 cm carcinoma in situ,Early stage (A) 1 HCC or 3 nodules 3 cm, PST 0,Advanced stage (C) Portal invasion, N1, M1, PST 12,End stage (D),Liver transplantation,TACE,Resection,Curative treatments,Randomized controlled trials,Associated diseases,Yes,No,3 nodules 3 cm,Increased,Normal,1 HCC,Portal pressure/ bilirubin,Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.,Stage D PST 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”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 cm,Early stage,Single or 3 nodules,Advanced stage,Portal invasion,PST 0, ChildPugh A,BCLC stage 0A,Survival 36 months,BCLC stage B,Survival 16 months,BCLC stage C,Survival 6 (48) months,BCLC stage D,Survival 3 months,Subject to PATH Program Disclaimer,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 ,*Surgical resection, liver transplantation or ethanol injection Okuda stage 3 or performance status 3,1. Llovet JM. Gastroenterology. 2005;40:225-35. 2. Llovet JM. Hepatology.1999;29:62-7.,HCC = hepatocellular carcinoma; OS = overall survival,Subject to PATH Program Disclaimer,化学治疗或内分泌治疗: 晚期肝癌几乎无效,1. Yeo W, et al. J Natl Cancer Inst. 2005;97:1532-8. 2. Sciarrino E, et al. Cancer. 1985;56:2751-6. 3. Leung TW, et al. Clin Cancer Res. 1999;5:1676-81. 4. Okada S, et al. Oncology. 1993;50:22-6. 5. Hochster HS, et al. J Clin Oncol. 1985;3:1535-40. 6. Pohl J, et al. Chemotherapy. 2001;47:359-65. 7. Dunk AA, et al. J Hepatol. 1985;1:394-404. 8. OReilly EM, et al. Cancer. 2001;91:101-5. 9. Chao Y, et al. Br J Cancer. 1998;78:34-9. 10. Fuchs CS, Cancer. 2002;94:3186-91. 11. Lin DY, et al. Gastroenterology. 1988;94:453-6. 12. GETCH. Hepatology. 2004;40:1361-9. 13. Llovet JM, et al. Hepatology. 2000;31:54-8. 14. Yuen MF, et al. Hepatology. 2002;36:687-9; 15. Dalhoff K, et al. British J Cancer. 2003;89:252-57.,PIAF = cisplatin, IFN -2b, doxorubicin, Adriamycin, and 5-fluorouracil,Subject to PATH Program Disclaimer,晚期肝细胞肝癌治疗 (BCLC C期),2005美国肝脏病研究协会(AASLD) 推荐是： 没有标准治疗. 患者可以入组随机临床研究1 2008更新: sorafenib 为标准治疗 延长44%肝功能较好患者的生存2,3 Sorafenib 疗效在 AsiaPacific trial同样被进一步证实 延长47% 亚洲肝细胞肝癌患者的生存4,1. Bruix J, et al. Hepatology. 2005;42:1208-36. 2. Llovet J et al. N Engl J Med. 2008;359:378-90. 3. Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711 4. Cheng A-L et al. Lancet Oncol 2009;10:25-34.,Subject to PATH Program Disclaimer,BCLC staging and treatment strategy,HCC,Stage AC Okuda 12, PST 02, Child-Pugh AB,Stage 0 PST 0, Child-Pugh A,Stage D PST 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),Single,3 nodules 3 cm,Portal pressure/bilirubin,Increased,Associated diseases,Normal,No,Yes,Resection,Liver transplantation (CLT/LDLT),PEI/RFA,Chemoembolization,Sorafenib,Curative treatments,Randomized controlled trials,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,Transplantation,TACE,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,干细胞增殖停止 星形细胞活化,慢性肝病,Liver cirrhosis,Abnormal liver nodules,Extensive scarring (collagen),染色体不稳定,染色体重度不稳定 和P53缺失,Hepatocellular carcinoma,幼稚细胞结节,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-MYC,c-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,Subject to PATH Program Disclaimer,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,Endothelial cell or pericyte,VEGFR-2,PDGFR-,Tumor cell,Wilhelm SM, et al. Cancer Res. 2004;64:7099-109 .,Ras,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,SHARP1,AsiaPacific2,RANDOMIZE 2:1,Sorafenib 400 mg bid,Placebo,Sorafenib 400 mg bid,Placebo,Endpoints: OS, TTSP, TTP, DCR, safety (no primary endpoint defined),n=299,n=303,n=150,n=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,0,4,6,8,10,12,14,16,2,0.00,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,0,4,8,12,22,0.00,Sorafenib (n=150) Median OS: 6.5 months,Placebo (n=76) Median OS: 4.2 months,2,6,10,14,16,18,20,HR = 0.68,SHARP1,AsiaPacific 2,Subject to PATH Program Disclaimer,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 survival,Time 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,Sorafenib,Sorafenib,Subject to PATH Program Disclaimer,AsiaPacific study1 vs SHARP2: efficacy similar in both patient populations,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,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,适应性 (逃逸) 耐药,原发无效,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,适应性 (逃逸) 耐药,原发无效,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 & 2 , every 2 weeks Arm B (Doxorubicin): - Doxorubicin 50 mg/m2 iv. on Day 1, every 3 weeks,患者持续接受治疗直至疾病进展、出现不可耐受的毒性反应、死亡或原病灶已适合手术切除,随机分组 (N = 371),N = 184,N = 187,分层因素 不同国家和地区 疾病状态 - BCLC 分期,EACH 研究 : 研究目的,主要研究目的: 评价FOLFOX4与阿霉素（DOX）相比是否能够延长晚期 HCC患者的总生存时间（OS） 次要研究目的: 比较两种方案的有效性与安全性: 无进展生存期 (PFS) RECIST标准评价反应率（RR）/疾病控制率（DCR） 根据NCI-CTC AE V.3.0评价安全性,EACH 研究: 主要入组标准,晚期无法手术切除的肝细胞肝癌（HCC） 至少有1个可测量病灶 (普通CT2cm, 螺旋CT或MRI1cm) 未接受过抗肿瘤治疗(手术除外)，或介入/局部治疗后进展的患者 足够的器官和骨髓功能储备: Child Pugh分期:A/B BCLC分期:B/C KPS70,EACH 研究 : 患者的地区分布,Percentage of patients,70,14,11,Total N = 371,5,EACH 研究 : 全部患者基线特征,EACH 研究 : 全部患者基线特征,EACH 研究 : 305 例事件发生时RR和DCR差异,Analysis at 266 events,EACH 研究 : 305例事件时ITT分析两组PFS差异,Probability of progression,Months,* Stratified log-rank test,EACH 研究 : 305 例事件时ITT分析两组OS差异,Overall survival rate,* Stratified log-rank test,Months,EACH 研究 : 305事件发生时ITT分析,EACH 研究 : 结论 (1),与应用DOX单药相比，FOLFOX4方案显著提高了中位总生存时间(mOS)： mOS: 6.47 mo vs. 4.90 mo (P=0.0425) 与与应用DOX单药相比，FOLFOX 4方案显著延长了中位无进展生存时间(mOS)； mPFS: 2.97 mo vs. 1.80 mo (P=0.0003),EACH 研究 : 结论 (2),与应用DOX单药相比，FOLFOX 4方案显著提高了疾病控制率（DCR）和治疗反应率(RR)： DCR: 52% vs. 32% (P0.0001) RR: 8.70% vs. 2.76% (P=0.0142) FOLFOX 4方案的耐受性良好，不良反应易于控制，安全性较好。,2010 靶向治疗前景,“在欧洲和美国已推荐Sorafenib治疗肝细胞肝癌的临床应用，主要由于其能够延长患者生存。 当然, 还需要进一步开发晚期肝细胞肝癌治疗手段”,Zhu AX, Raymond E. Expert Rev Anticancer Ther. 2009;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.,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