晚期肝癌.ppt

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EXTERNAL DISTRIBUTION.,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,FOR INTERNAL EDUCATIONAL USE.NOT FOR EXTERNAL DISTRIBUTION.,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,晚期肝细胞癌的内科治疗,原发性肝癌,:,全球高发常见的恶性肿瘤，其中,90%,为肝细胞癌,(HCC),，其他病理类型有胆管细胞癌,(ICC),和混合型肝癌等,;,因此,通常所谓的肝癌主要是指,HCC,。,HCC,的发病率,:,全球范围内呈现上升趋势，年发病,74.8,万人，居于恶性肿瘤的第,5,位，中位年龄,50,60,岁，男：女,=4,：,1,；业已成为癌症致死主要原因，每年高达,69.6,万人死于该病。,肝癌的概述,HCC,的多学科治疗手段,根治性治疗,:,外科治疗：切除手术或肝移植,局部消融,姑息性治疗：,局部消融,肝动脉介入治疗,立体精确放疗,内科系统治疗：,抗肿瘤治疗,(,分子靶向，化疗，中医药等,),支持对症治疗,(,保肝利胆，抗病毒等,),。,肝癌演变及治疗选择,早期局部病变,手术切除、消融治疗、放射,治疗、高聚焦超声,全肝治疗,肝移植和TACE、TARE,肝内播散,远处转移,局部治疗,全身治疗,化疗、靶向药物,HCC:,联合治疗,早期肝癌,BCLC A期,手术切除/消融,+TACE/PEI,局部+全肝+全身,多种治疗手段联合,中期,BCLC B、C期,晚期肝癌,BCLC D期,局部+全肝,局部+全肝+全身,对症支持+靶向、,TACE+靶向,BCLC,分期,定义,BCLC,主要包含了四类预后因素,(1),病人的一般状态,(2),肿瘤的状态,(3),肝功能状态,(4),可供选择的治疗方法,系统治疗联合局部治疗，提高临床获益,全身治疗,（药物：分子靶向,/,化疗等）,局部治疗,（手术,/TACE,/,消融）,长期生存,减少局部瘤负荷,控制疾病进展,晚期,HCC:,预后很差,由于HCC起病隐匿、侵袭性高和生长迅速，在确诊时，大多数患者（特别是亚洲患者）已达局部晚期和/或远处转移，往往不适合局部治疗（包括手术切除、射频或微波消融以及TACE），一般将此类患者归于晚期HCC,包括,BCLC,分期为,C,期和,D,期的患者。,晚期HCC患者的预后很差，因此俗称,“,癌中之王,”,。如果仅仅给予支持对症治疗(BSC)，在欧美国家，患者的平均生存期在,6-9,个月，而在亚洲国家（不包括日本）仅有,3-4,个月。,HCC,系统治疗的复杂性,HCC,系统治疗的基本原则,：,抗肿瘤与抗病毒相结合,;,控制癌灶与保肝利胆相结合,;,祛邪与扶正相结合,西药与中药相结合。,HCC,的内科系统治疗,HCC,：系统治疗的范畴,生物治疗,分子靶向治疗,化 疗,保肝、抗病毒治疗,中药治疗,支持对症治疗,HCC,分子发病机制涉及多条信号通路,Wnt,pathway,EGFR pathway,Raf,/MAPK pathway,Akt,pathway,Jak,/Stat pathway,VEGFR pathway,HCC,分子发病机制极其复杂，涉及多条信号通路：,信号传导途径异常导致细胞,异常增生及存活,异常的生长因子激活,(TGF-,EGFR),细胞分裂信号途径的持续活化,(,Raf,/MEK/ERK,PI3K/AKT,Wnt,),抗细胞凋亡信号途径失调,(p53,PTEN),新生血管异常增生,(,如,VEGF,途径,),促进肿瘤生长及进展,Hanahan,D,Weinberg RA.Cell 2000;100:57,70,分子靶向治疗：索拉非尼,索拉非尼是一种口服的新型多靶点、多激酶抑制剂，既可通过抑制,VEGFR,和,PDGFR,阻断肿瘤血管生成，又通过阻断,Raf,/MEK/ERK,的信号传导通路抑制肿瘤细胞增殖，从而发挥双重抑制和阻断的抗,HCC,作用。,索拉非尼已经国际多中心大型对照临床研究证实，可以延长晚期,HCC,患者的生存时间，故被多国批准用于治疗晚期,HCC,患者。,内皮细胞或周细胞,肿瘤细胞,三大临床研究奠定肝癌内科治疗基础,EACH,Oriental,SHARP,索拉非尼的关键性注册研究,两项关于索拉非尼的随机、双盲、平行对照的国际多中心,期临床研究，目的是评估索拉非尼在不同,HCC,人群中的疗效和安全性。,索拉非尼治疗晚期HCC 的期研究,-显著改善患者的OS,1.N Engl J Med 2008;359:378-90.,2.Lancet Oncol 2009;10:25,34,GIDEON,研究,GIDEON,研究共纳入,3371,例,HCC,患者（均无法手术切除）,来自,39,个国家，预期寿命,8,周，通过评估身体条件，进行索拉非尼治疗，主要终点事件为索拉非尼用于临床的安全性评估,J,Clin,Oncol,31,2013(,suppl,;,abstr,4126),欧洲,22,个国家,1143,例患者,美国,645,例患者,亚洲太平洋地区,11,个国家,974,例患者,日本,517,例患者,拉丁美洲,4,个国家,92,例患者,GIDEON,研究,:,索拉非尼改善无法手术,HCC,患者的,OS,和,TTP,收集全球,3,213,位索拉非尼治疗患者数据，统计结果表明，,ChildA,级、,B,级和,C,级无法手术的,HCC,患者的中位生存时间分别为,13.6,个月、,5.2,个月和,2.6,个月，,OS,显著延长；中位疾病进展时间分别为,4.7,个月、,4.4,个月和,3.6,个月。,提示越早治疗，获益越多,J,Clin,Oncol,31,2013(,suppl,;,abstr,4126),OS,TTP,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,200,400,600,800,1000,1200,治疗时间,(,天,),Child-Pugh A,中位,TTP 4.7,个月,(95%CI 4.3-5.2),Child-Pugh B,中位,TTP 4.4,个月,(95%CI 3.5-5.5),Child-Pugh C,中位,TTP 3.6,个月,(95%CI 32.1-6.0),1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,200,400,600,800,1000,1200,从治疗开始的时间,(days),Child-Pugh A,中位,OS13.6,个月,(95%CI 12.8-14.7),Child-Pugh B,中位,OS 5.2,个月,(95%CI 4.6-6.3),Child-Pugh C,中位,OS 2.6,个月,(95%CI 1.5-4.0),生存分布函数,疾病进展分布函数,HCC,分子靶向治疗研究现状,-,大型,III,期临床试验纷纷失败,靶向药物,临床研究,例数,RR,OS(m,),Sorafenib,III,期,-,阳性,602,2.30%,10.7,vs,7.9(,对照组,),Llovet,et al.N,Engl,J Med 2008,Cheng et,al.Lancet,Oncol,2009;10:25,34,226,-,6.5,vs,4.2(,对照组,),Sunitinib,III,期,-,失败,该试验因严重不良事件,及疗效未达到预设终点，于,2010,年,4,月,22,日终止，已在,2011,年,ASCO,上宣布失败,www.clinicaltrials.gov/ct2/show/NCT00699374,Erlotinib,II,期,38,9%,13,Philip et al.J Clin Oncol 2005,40,0%,6.3,Thomas et al.Cancer 2007,III,期,SEARCH-,失败,结果为阴性：跟安慰剂相比不能显著延长,OS,Andrew X.Zhu et al.ESMO 2012,Gefitinib,II,期,31,3%,6.5,ODwyer,et al.J,Clin,Oncol,2006,Brivanib,III,期,:BRISK PS,失败,2011,年底,BMS,公司宣布结果为阴性：跟安慰剂相比不能显著延长,OS,clinicaltrials.gov/ct2/show/NCT00825955?term=,brivanib+HCC&rank,=4,III,期,:BRISK FL,失败,2012,年,7,月,19,日,BMS,公司宣布结果为阴性：跟安慰剂相比不能显著延长,OS,NCT00908752,Lapatinib,II,期,26,0%,12.6,Bekaii-Saab et al.Clin Cancer Res 2009,III,期,失败,1050,NCT01009593,Bevacizumab,II,期,30,13%,12.4,Siegel et al.J Clin Oncol 2008,Bevacizumab,II,期,40,25%,15.65,Thomas et al.J Clin Oncol 2009,+,Erlotinib,Cetuximab,II,期,30,3%,6.5,Zhu et al.Cancer 2007,Linifanib,III,期,失败,www.clinicaltrials.gov/ct2/show/NCT01009593,预计,2013,年第二季度出结果,Everolimus,),III,期,-,进行中,www.clinicaltrials.gov/ct2/show/NCT01035229,预计,2012,年出结果,由于肝癌发病原因、过程和机制的复杂性，肝病背景的特殊性，也是特别缺乏,临床,研究的经验和没有吸取教训，一系列的新药研发试验屡遭失败；,目前，索拉非尼仍然是唯一的获得III期临床研究证据,强力支持的治疗HCC的分子靶向药物！,索拉非尼治疗,HCC,：地位稳定,索拉非尼,国内外权威性指南,/,共识一致,推荐索拉非尼治疗,HCC,美国国家综合癌症网(NCCN)HCC临床实践指南,巴塞罗那,(,BCLC,)HCC分期和治疗策略,亚太肝病学会,(,APASL,)HCC治疗指南,日本肝脏病学会(JSH)HCC,临床实践指南,原发性肝癌诊疗规范（,2011,年版）,美国肝病研究协会(AASLD)HCC临床治疗指南,EASL/EORTC,HCC,诊疗指南,索拉非尼,指南证据充足,ES,M,O/ESDO,治疗、诊断及随访临床实践指南,注：,ESMO,：欧洲肿瘤内科协会；,ESDO,：欧洲消化道肿瘤学会；,EASL,：欧洲肝脏研究学会；,EORTC,：欧洲癌症研究与治疗组织,2012 EASL,指南：索拉非尼为晚期肝癌标准治疗,EASL-EORTC clinical practice guidelines:management of,hepatocellular,carcinoma.J,Hepatol.2012;56(4):908-43.,EASL-EORTC clinical practice guidelines:management of,hepatocellular,carcinoma.J,Hepatol.2012;56(4):908-43.,2012 EASL,指南：索拉非尼作为,1A,级证据推荐,索拉菲尼的联合治疗,索拉菲尼的联合治疗,联合TACE和消融,联合化疗,联合靶向治疗,三大临床研究奠定肝癌内科治疗基础,EACH,Oriental,SHARP,设计：主要针对中国,HCC,患者,EACH,研究主要是为中国患者而设计的，是基于中国已经进行的,FOLFOX4,方案的,I,期、,期的研究结果,样本量计算时采用的疗效假设，亦源于,FOLFOX4 I,期和,期研究和临床实践中所取得的经验,在总试验人群中，中国人群将占绝大多数（,7,%,），也是,EACH,研究的主要观察人群,考虑我国临床试验法规要求以及亚洲其他国家的医疗需求，,EACH,研究包括了韩国和泰国，以便能够获得批准，探索有效的化疗方案。,EACH,研究,:,患者的地区分布,韩国（,52,例）,泰国（,40,例）,中国台湾（,20,例）,中国大陆（,259,例）,70%,11%,14%,5%,EACH,研究,:,试验设计,随机、对照、多中心的国际,期临床试验,Arm A (FOLFOX4):,-OXA 85mg/m,2,iv.h0,h2 Day 1,-LV 200mg/m,2,iv.h0,h2 Day 1,2,-5FU 400mg/m,2,iv.bolus Day 1,2 then 600 mg/m,2,over 22 hours in,Day 1&2,every 2 weeks,Arm B(Doxorubicin):,-,Doxorubicin 50 mg/m,2,iv.in 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,(,计划,N=,440,，,实际,入组,371),N=184,分层因素：,不同国家和地区,疾病状态,-BCLC,分期,N=187,结果：中国患者群,ITT,分析（,305,事件）,中国患者,FOLFOX4,(n=140),DOX,(n=139),P,值,HR,(95%CI),mOS,months,(95%CI),5.9,(4.8,6.9),4.3,(4.0,5.1),0.0281,0.754,(0.580,0.980),mPFS,months,(95%CI)*,2.7,(2.1,3.3),1.7,(1.6,2.2),0.0003,0.549,(0.451,0.782),RR,8.6,(4.5,14.5),1.4,(0.2,5.1),0.0064,N/A,*,At the,post-hoc,cut-off date for analysis(31 Dec 2009),DCR,47.1,26.6,0.0004,N/A,研究终点,FOLFOX4,(N=183),DOX,(N=174),P,值,mOS,(moths,，,95%CI),6.47(5.33,7.03),4.90(4.20,6.03),0.0425,mPFS,(months,，,95%CI),2.97(2.53,3.67),1.80(1.67,2.43),0.0003,RR(95%CI),8.70(5.05,13.74),2.76(0.36,6.13),0.0142,DCR(95%CI),53.26(45.78,60.64),32.62(25.96,39.84),0.0001,结果：全部患者,ITT,分析（,305,事件）,*,At the cut-off date for analysis(31 Dec 2009),该项研究主要是针对中国人群设计的，已成功地达到了预设的所有疗效指标；没有发现含,OXA,的,FOLFOX4,方案引起新的不良反应,即,:,与,DOX,相比，,FOLFOX 4,方案明显提高了晚期,HCC,患者的,RR,、,DCR,、,mPFS,和,mOS,;,特别是中国的晚期,HCC,患者获益更明显；,不良反应与治疗结直肠癌一致，易于处理，患者耐受性好，安全性高,EACH,研究：结论,国家规范,:HCC,系统化疗的适应证,目前认为，HCC是对含OXA等新一代化疗方案具有一定敏感性的肿瘤。对于没有禁忌证的晚期HCC患者，系统化疗明显优于一般性支持治疗，不失为一种可选择的治疗方法。,系统化疗的主要适应证：,合并有肝外转移的晚期患者；,不适合进行栓塞化疗者，如肝脏弥漫性病变或肝血管变异,合并门静脉主干或者有下腔静脉瘤栓者；,多次进行TACE后,肝血管阻塞和/或介入治疗后复发的患者。,当然,在进行系统化疗时，应当严格掌握其临床适应证，及时评估疗效，密切监测和防治不良反应。,国家规范：肝癌多学科综合治疗模式,HCC,PS 0-2,PS 3-4,血管侵犯,Child-Pugh C,无,有,全身状况,肝功能,肝外转移,Child-Pugh A/B,无,有,肿瘤数目,支持对症治疗,支持对症治疗,肝移植,故息放疗,分子靶向治疗,系统化疗,TACE,手术切除,放疗,分子靶向治疗,系统化疗,1,个,2,、,3,个,4,个,肿瘤大小,3cm,3cm,治疗选择,TACE,手术切除,+,局部消融,肝移植,手术切除,局部消融,3cm,肝移植,手术切除,TACE+,消融,肝移植,5cm,5cm,重视保肝、抗病毒，统筹兼顾，全程防治！,谢谢,!,