肝癌规范化治疗课件(PPT 79页).pptx

1、肝癌肝癌内科内科依荷芭丽依荷芭丽.迟迟 第1页，共79页。HCC 数据数据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.www.cancer.org.Accessed Jan 2010.4.Llovet J,J H

2、epatol.2000;33:423-9.5.Marrero CR,Marrero JA.Arch Med Res.2007;38:612-20.Subject to PATH Program Disclaimer 第2页，共79页。HCC流行病学流行病学HCC发病率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炎症性癌症El-Serag HB.Clin Liver Dis.2001;5:87-107.Subject to PATH Program Di

3、sclaimer 第3页，共79页。El-Serag HB,Rudolph KL.Gastro.2007;132:2557-76.HCC地域死亡率地域死亡率(每每100,000人人)50%of HCCAnnual mortality per region:Europe:54,000 USA:19,000 ChinaKoreaJapan:390,000Subject to PATH Program Disclaimer 第4页，共79页。HCC高危因素和发病率高危因素和发病率 80%HCC 与HBV或 HCV相关Llovet JM,et al.Lancet.2003;362:1907-7.Pis

4、ani et al.Cancer Epidemiol Biomarkers Prev.1997;6:387-400.Subject to PATH Program Disclaimer 第5页，共79页。肝癌风险合并超重肥胖与正常体重人群对比荟肝癌风险合并超重肥胖与正常体重人群对比荟萃分析萃分析 第6页，共79页。回顾性研究回顾性研究: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 住院治疗住院治疗 美国退伍军人美国退伍军人(1

5、9851990):肝细胞肝癌肝细胞肝癌:317 diabetes(2.39 x 105 person-years)515 controls (0.87 x 105 person-years)肝细胞高位因素肝细胞高位因素:糖尿病糖尿病Subject to PATH Program Disclaimer 第7页，共79页。肝细胞肝癌肝细胞肝癌:男性多于女性男性多于女性 24 倍倍 400,000 例/年 160,000 例/年Database ITA.LI.CA,2008.Subject to PATH Program Disclaimer 第8页，共79页。肝细胞肝癌肝细胞肝癌:人种差别人种差别

6、(USA)2 倍倍2 倍倍遗传多态性: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 第9页，共79页。2+ve for arterial hypervascularization among:Angiography CT MRI Doppler USor 1+

7、ve plus AFP 400 ng/mLBruix J,et al.J Hepatol.2001;35:421-30.Subject to PATH Program Disclaimer 非非转转移早期肝癌的移早期肝癌的诊诊断断标标准准第10页，共79页。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)-

8、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.第11页，

9、共79页。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.第12

10、页，共79页。Subject to PATH Program Disclaimer HCC不同分期包含变量指标不同分期包含变量指标(2)Wildi S,et al.Br J Surg.2004;91:400-8.第13页，共79页。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.第14页，共79页。T1期评定中的问题(1)定定义义太太宽宽：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

11、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 2002Wildi S,et al.Br J Surg.2004;91:400-8.第15页，共79页。Tumor single 2 cm without vascular invasionEvidence ofStage Score 3 factorsT1 I02 factorsT2II11 factorT3III20 factorsT4 or T1T3+N1/M1IV3Liver

12、function:Child-Pugh classA0 B1 C2TOTAL range scores:05Japanese Integrated Staging(JIS)systemTNM stage of Cancer Study Group JapanKudo M,et al.J Gastroenterol.2003;38:207-15.Subject to PATH Program Disclaimer 第16页，共79页。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

13、400 ng/ml0 400 ng/ml1门静脉血栓形成No0Yes1 第19页，共79页。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

14、 M,et al.J Gastroenterol.2003;38:207-15;Llovet JM,et al.Semin Liver Dis.1999;19:329-38.第20页，共79页。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 肿瘤肿瘤伴随特征伴随特征肝脏特征肝脏特征 中位生存中位生存(月月)*A期(早期 HCC)A1 PST 0单一无门静脉高血压,胆红素无异常4

15、3A2 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 12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-第21页，共79页。PEI/RFASorafenibStage 0PST 0,Child-Pugh AVery early stage(0)1 HCC 2 cmcar

16、cinoma 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 第22页，共79页。不能切除的不能切除的HCC“不能切除的不能切除的”患者并不代表晚期患者并不代表晚期 HCCTerminalstagePST 0-2,ChildPugh ABMult

17、inodular,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 DSurvival 3 monthsSubject to P

18、ATH Program Disclaimer 第23页，共79页。中期或晚期肝癌患者的预后不佳17080%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 status 31.Llovet JM.Gastroe

19、nterology.2005;40:225-35.2.Llovet JM.Hepatology.1999;29:62-7.HCC=hepatocellular carcinoma;OS=overall survivalSubject to PATH Program Disclaimer 第24页，共79页。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%Epirubicin5,6II6211%Mitoxantrone

20、7II2227%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 nodules 3 cm,PS 0Intermediate stage(B)

21、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 treatmentsRandomized controlled trialsSymptomatictreatmentRFA

22、=radiofrequency ablation;PEI=percutaneous ethanol injection.Llovet JM,et al.J Natl Cancer Inst.2008;100:698-711.Subject to PATH Program Disclaimer 第27页，共79页。NCCN Guidelines(2009)NCCN Clinical Practice Guidelines in Oncology.Hepatobiliary Cancer.V2.2009;Available at:www.nccn.org.Accessed February 201

23、0.Subject to PATH Program Disclaimer 第28页，共79页。Japan Society of Hepatology:consensus-based treatment algorithm for HCCKudo M.Oncology.2009;75 Suppl 1:1-12.Subject to PATH Program Disclaimer 第29页，共79页。Extrahepatic metastasis Main portal vein tumor thrombus ResectableSorafenib or systemic therapy tria

24、l Resection/RFA(for 3 cm HCC)Solitary tumor 5 cm 3 tumors 3 cmNo venous invasion Child-Pugh A Child-Pugh B Child-Pugh C Child-Pugh A/B Child-Pugh CTransplantationTACE Supportive careLocal ablationHCCConfined to the liverMain portal vein patentAPASL working committee meeting consensus on treatment gu

25、idelines for HCCTumor 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 第30页，共79页。HBV HCV 酒精酒精 黄曲霉毒素黄曲霉毒素B1损伤损伤干细胞增殖停止干细胞增殖停止星形细胞活

26、化星形细胞活化慢性肝病慢性肝病Liver cirrhosisAbnormal livernodulesExtensive scarring(collagen)染色体不稳定染色体不稳定染色体重度不稳定染色体重度不稳定和和P53缺失缺失Hepatocellularcarcinoma幼稚细胞结节幼稚细胞结节Hyperplasticnodule分化好的分化好的中等分化的中等分化的分化差的分化差的增殖增殖坏死坏死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 Disc

27、laimer 肝硬化肝硬化广泛瘢痕形成广泛瘢痕形成肝脏结节形成肝脏结节形成结节增生肝细胞肝癌肝细胞肝癌第31页，共79页。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-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

28、to PATH Program Disclaimer 第32页，共79页。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.20

29、06;25:3866-84.Subject to PATH Program Disclaimer 第33页，共79页。肝细胞肝癌靶向治疗肝细胞肝癌靶向治疗:临床研究临床研究 肝细胞肝癌临床研究全面展开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，主要在早期和晚期患者临床研究，一线治疗、二线治疗一线治疗、二线治疗及辅助治疗方面的研究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 Discla

30、imer 第34页，共79页。Adapted from Tanaka S,Arii S.Cancer Sci.2009;100:1-8.临床开发临床开发:分子靶向药物和其主要靶点分子靶向药物和其主要靶点 Agent 抗血管生存抗血管生存抗增殖抗增殖VEGFVEGFRPDGFREGFRRafmTORBevacizumabCediranibThalidomideErlotinibGefitinibABT-869SorafenibLapatinibSunitinibCetuximabBrivanib SU6668EverolimusSubject to PATH Program Disclaimer

31、 第35页，共79页。Agent 抗生成血管抗生成血管抗增殖抗增殖VEGFVEGFRPDGFREGFRRafmTORBevacizumabCediranibThalidomideErlotinibGefitinibABT-869SorafenibLapatinibSunitinibCetuximabBrivanib SU6668EverolimusIII期临床研究:分子靶向药物和其主要靶点分子靶向药物和其主要靶点 第36页，共79页。Sorafenib targets both tumor-cell proliferation and angiogenesis in vitroKIT/Flt-

32、3/RETAngiogenesisRafEndothelial cell or pericyteNucleusVEGFR-2PDGFR-MEKApoptosisTumor cellProliferationPDGFVEGFEGFSurvivalWilhelm SM,et al.Cancer Res.2004;64:7099-109.RasNucleusRasERKRafMEKApoptosisERKPDGF-VEGFParacrine stimulationSorafenibXXXXXXXXSubject to PATH Program Disclaimer 第37页，共79页。Primary

33、 endpoints:OS,TTSPSecondary 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 bidPlaceboSor

34、afenib400 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 第38页，共79页。Sorafenib consistently increased overall survival in differe

35、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 probability1.000.750.500.25Months04681012141620.00Sorafenib(n=299)

36、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=0.68 SHARP1 AsiaPacific 2Subject to PATH Program Disclaimer 第39页，共79页。Asia-Pacific(N=226)SHARP(N=60

37、2)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 node3226AsiaPacific trial1 vs SHARP2:baseline patie

38、nt 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.第40页，共79页。SHARP:sorafenib prolongs OS by 44%and TTP by 74%in patients with advanced HCCLlovet JM,et al.N Engl J Med.2008;359

39、: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 7 8 9 10 11 12 Sorafenib(n=299)=5.5 monthsPlacebo(n=303)=2.8 monthsTime from randomization

40、(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 Disclaimer 第41页，共79页。Sorafenib prolongs OS by 47%and TTP by 74%in AsiaPacific patients with advanced HCCCheng A-L,et

41、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)PlaceboMedian:1.4 months(95%CI:1.31.5HR(S/P):0.57(95%CI:0.420.79)p 0.001SorafenibSorafenibSubject to PATH Program Disc

42、laimer 第42页，共79页。AsiaPacific study1 vs SHARP2:efficacy similar in both patient populationsEndpointAsiaPacific SHARPHazard ratio(95%CI)P-valueHazard ratio(95%CI)P-valueOS0.680.0140.690.001(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,e

43、t 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 第43页，共79页。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

44、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 第44页，共79页。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)Hepatoce

45、llular 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)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 support

46、ive care(n=285)3SurvivalSurvival 0.66(NA)0.77(0.640.92)Lung cancerPac/carbo+bevacizumab(n=434)vs pac/carbo(n=444)4Erlotinib(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(

47、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 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:

48、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 第45页，共79页。抗血管生成药物耐药方式 适应性适应性(逃逸逃逸)耐药耐药 原发无效原发无效Bergers G,Hanahan

49、D.Nat Rev Cancer.2008;8:592-603.Subject to PATH Program Disclaimer 第46页，共79页。诱导预血管生成因子替代重建新生血管生成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 第47页，共79页。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 Progra

50、m Disclaimer 第48页，共79页。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 第49页，共79页。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营养缺乏和缺氧至肿瘤细胞侵袭增加Subject to PATH Program Disclaimer 第50页，共79页。抗血管生成药物耐药方式 适应性适应性(逃逸逃逸)耐药耐药 原发无效原发无效Berge