肝癌规范化治疗

肝癌,中国医学科学院肿瘤医院内科依荷芭丽.迟,HCC 数据,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,3,男,女,数据来源：(中国2014年肿瘤登记年报),HCC流行病学,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 ),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,El-Serag HB, et al. Gastroenterology. 2004;26:460-8.,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),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,HBVHCV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 livernodules,Extensive 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,结节增生,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TNMVauthey (改良的TNM )Izumi (改良的TNM )JS (日本分期)联合分期(肝功能和肿瘤) OkudaCancer 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),Subject to PATH Program Disclaimer,TNM stage according to UICC 2002,Wildi S, et al. Br J Surg. 2004;91:400-8.,18,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,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 5 cm,3 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,34,HCC肝脏移植手术: 生存与肿瘤体积呈负相关,35,Subject to PATH Program Disclaimer,Cucchetti A, et al. Am J Transplant.2010;Jan 29 Epub ahead of print.,Yes,No,3 nodules 3 cm,37,细胞热效应,105C,100C,60C,46C,42C,40C,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,38,RF ablation: armamentarium,Expandable needle (Radiotherapeutics RITA),Single needle cooled tip (Radionics),Catheter needle (Miras),Cluster needle (Radionics),Subject to PATH Program Disclaimer,39,小肝癌研究 (13 cm),PEI组: pCR 48/60 (80%)RF组: pCR 47/52 (80%),1. Livraghi T, et al. Radiology. 1999;210:655-61. 2. Livraghi T, et al. Hepatology. 2008;47:82-9.,1,Subject to PATH Program Disclaimer,40,Alcohol,胞质蛋白的脱水和由此产生的肿瘤细胞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,41,PEI-治疗的生存结果(回顾性研究),Author and year,Shiina 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, single/multiple 5 cm,44,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 AB,TACE理想选择,ORR: 30%60%死亡率 2,ChildPugh C,Very early stage,Single 2,Child-Pugh C,Very early stage (0)Single 2 cmcarcinoma in situ,Early stage (A)13 nodules 5 cm 3 tumorsInvasion 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,肝细胞肝癌的发病机制与多个信号传导通路相关,细胞膜,Wnt 受体,p53,RTK: FGFR EGFRIGF-IRc-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/mTORWnt/-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, TTSPSecondary endpoints: TTP, DCR, safety,Phase III SHARP and AsiaPacific studies,Endpoints: OS, TTSP, TTP, DCR, safety (no primary endpoint defined),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,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,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 monthsPlacebo (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 monthsPlacebo (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,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,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,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 weeksArm B (Doxorubicin):- Doxorubicin 50 mg/m2 iv. on Day 1, every 3 weeks,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/BBCLC分期:B/CKPS70,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。,90,90,91,91,92,92,2010 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,94,EACH 研究奥沙利铂（乐沙定）+ 5FU/LV（FOLFOX4）与单药阿霉素在不适合进行手术切除治疗或局部治疗的晚期肝细胞癌受试者中进行的姑息性化疗比较的研究,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 weeksArm B (Doxorubicin):- Doxorubicin 50 mg/m2 iv. on Day 1, every 3 weeks,N = 184,分层因素 不同国家和地区， 疾病状态， BCLC 分期,N = 187,95,EACH研究:研究目的,主要研究终点:比较两种方案的生存获益 评价FOLFOX 4与DOX相比,是否能够延长晚期HCC患 者的总生存时间（OS） 次要研究终点: 进一步比较两种方案的有效性与安全性，包括:无进展生存期 (PFS); 有效率（RR）/疾病控制率 (DCR）; 二期切除率；生活质量；安全性,96,研究人员及研究时限,研究人员与机构 中国大陆、韩国、台湾、泰国的38 个中心，103 位研究者 - 中国大陆：23 个中心，68 位研究者； - 台湾：2 个中心，6 位研究者主要研究者 秦叔逵教授，南京八一医院研究时限首位受试者的招