1、肝癌的綜合治療Multidisciplinary Strategies to Management of HCC,復(fù)旦大學(xué)肝癌研究所,背景,絕大多數(shù)（80-90）的HCC合并肝硬化 HCC治療策略應(yīng)考慮對(duì)腫瘤作用，并避免肝功能損害 HCC的分期系統(tǒng)也應(yīng)同時(shí)考慮腫瘤因素，和肝功能損害的嚴(yán)重性 至今尚未有公認(rèn)的HCC的分期系統(tǒng) 肝癌的BCLC分期系統(tǒng)目前在西方國(guó)家應(yīng)用較廣，對(duì)治療有指導(dǎo)意義。,HCC的BCLC分期系統(tǒng)和治療推薦,Liver transplant,PEI/RF,Curative treatments,TACE,HCC,Single,Increased,Associateddiseas

2、es,Normal,No,Yes,No,Yes,Terminalstage,PST 0-2, Child-Pugh A-B,Multinodular, PST 0,Portal invasion, N1, M1,Sorafenib,Portal pressure/bilirubin,3 nodules 3 cm,Intermediate stage,PST 2, Child-Pugh C,Very early stage,Single 2 cm,Early stage,Single or 3 nodules 3 cm, PST 0,Advanced stage,Portal invasion,

3、N1, M1, PST 1-2,PST 0, Child-Pugh A,Resection,Symptomatic (unless LT),Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.Bruix J, et al. Hepatology. 2005;42:1208-1236.,Surgical treatments: applicable overall to 30% of HCC at first diagnosis and 2% to 5% of recurrent HCC,HCC的BCLC分期系統(tǒng)和治療,Liver tra

4、nsplant,PEI/RF,TACE,HCC,Single,Increased,Associateddiseases,Normal,No,Yes,No,Yes,Terminalstage,PST 0-2, Child-Pugh A-B,Multinodular, PST 0,Portal invasion, N1, M1,Sorafenib,Portal pressure/bilirubin,3 nodules 3 cm,Intermediate stage,PST 2, Child-Pugh C,Very early stage,Single 2 cm,Early stage,Single

5、 or 3 nodules 3 cm, PST 0,Advanced stage,Portal invasion,N1, M1, PST 1-2,PST 0, Child-Pugh A,Resection,Symptomatic (unless LT)20%,Nonsurgical treatments: applicable overall to 50% of HCC at first diagnosis and 50% to 70% of recurrent HCC,治療的目的,腫瘤縮小 改善生命質(zhì)量 延長(zhǎng)生存 QALY,HCC 治療選擇,早期HCC 外科切除（肝部分切除） 肝移植 經(jīng)皮毀

6、損（PEI，RFA，HIFU，冷凍，微波） 進(jìn)展期HCC TACE 系統(tǒng)治療（化療） 新治療 （分子靶向，放療）,早期肝癌,早期HCC的手術(shù)切除,根治？ 根治術(shù)后5年生存率：50-70 術(shù)后5年復(fù)發(fā)率： 60-80 問(wèn)題：如何達(dá)到根治？如何降低復(fù)發(fā)？,Pre-operative TACE + Resection,Downstaging resection：術(shù)后5年生存率 小肝癌 肝動(dòng)脈插管結(jié)扎/ TACE/ Chemotherapy？ 減小瘤體：手術(shù)簡(jiǎn)單，且控制微小病灶 減少血供：手術(shù)安全 減少術(shù)中播散,Zhou 2009 Ann Surg 2009;249: 195202,Pre-opera

7、tive TACE,Risk：可切除 不可切除 對(duì)肝功能差的病人：進(jìn)一步損害肝功能 Japan：RCT 結(jié)果類(lèi)似（Sasaki A. Eur J Surg Oncol. 2006;32:7739.）,肝移植,術(shù)后復(fù)發(fā) （周儉教授） 肝源等待：Bridge Treatments of Hepatocellular Carcinoma in Cirrhotic Patients Submitted to Liver Transplantation. Dig Dis Sci (2008) 53:28302831,TACE: Bridge to OLT,Does not improve long-te

8、rm survival (grade C). No convincing evidence that TACE allows to expand the current selection criteria for OLT, nor that TACE decreases dropout rates on the waiting list (grade C). TACE does not increase the risk for postoperative complications (grade C). There is insufficient evidence that TACE of

9、fers any benefit when used prior to OLT, neither for early nor for advanced HCC.,American journal of transplantation 2006; 6(11):2644-50.,局部毀損,小肝癌：媲美于手術(shù)切除 復(fù)發(fā)率值得擔(dān)心,小肝癌2.8cm,PEI or RFA?,PEI3y5y Child A (survival 3 vs. 5y.)79%47% Child B (survival 3 vs. 5y.) 63%29% Child C (survival 3 vs. 5y.) 12%0%,AA

10、SLD 2004: Leoncini et al. (n=104): PEIRFA Tumor destruction82%98% 2-y Survival96%98% 2-y Recurrence32%10%,RF vs PEI,Local ablative therapies in HCC: percutaneous ethanol injection and radiofrequency ablation RFA is superior to PEI for treating small HCC survival after PEI or RFA in comparison with s

11、urgery TACE+ PEI/RFA survival was improved further.,Dig Dis. 2009;27(2):148-56.,RF+PEI,操作性的,RF vs Resection,Ann Surg 2006;243: 321328),Chen MS. Ann Surg 2006;243: 321328,Puzzle,Pre-TACE +Resection no use Pre-TACE + RF improved RF = Resection,Radical resection IFN-a,resection + IFN resection OS: 63.8

12、 months 38.8 months P=0.0003 DFS: 31.2 months 17.7 months P=0.142,Sun HC. J Cancer Res Clin Oncol 2006; 132:458-65,Evidence of Benefit in Treatment of HCC,Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.,Post adjuvant TACE,Post adjuvant TACE,進(jìn)展期肝癌,Staging Strategy and Treatment for Patients W

13、ith HCC,Liver transplant,PEI/RF,Curative treatments,TACE,HCC,Single,Increased,Associateddiseases,Normal,No,Yes,No,Yes,Terminalstage,PST 0-2, Child-Pugh A-B,Multinodular, PST 0,Portal invasion, N1, M1,Sorafenib,Portal pressure/bilirubin,3 nodules 3 cm,Intermediate stage,PST 2, Child-Pugh C,Very early

14、 stage,Single 2 cm,Early stage,Single or 3 nodules 3 cm, PST 0,Advanced stage,Portal invasion,N1, M1, PST 1-2,PST 0, Child-Pugh A,Resection,Symptomatic (unless LT),Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.Bruix J, et al. Hepatology. 2005;42:1208-1236.,RCTs (50%) Median survival: 11-20

15、mos,Approved other options such as drug-eluting beads, radiolabelled yttrium glass beads, radiolabelled lipiodol, or immunotherapy cannot be recommended as standard therapy for advanced HCC outside clinical trials,Bruix J, et al. Hepatology. 2005;42:1208-1236.,TACE,Intra-arterial Locoregional Therap

16、y,Established TACE Radioembolization: yttrium-90 radioactive microspheres Undergoing clinical trials Drug-eluting beads,Primary Treatment Modality Used in Korea,TACE 48.2%,RFA 1.5%,Surgery 11.2%,Chemotherapy 7.5%,Radiotherapy 2.1%,Conservative treatment 29.5%,N = 1078,Joong-Won Park, MD, National Ca

17、ncer Center. Adapted with permission.,Chemoembolization: Randomized Trials (Nearly Identical Techniques),Llovet et al2: N = 112 with unresectable HCC, 80% to 90% HCV positive, 5-cm tumors ( 70% multifocal),Lo et al1: N = 80 with newly diagnosed unresectable HCC, 80% HBV positive, 7-cm tumors (60% mu

18、ltifocal),1. Lo CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.,Chemoembolization: Predictors of Survival,Lo et al1 Absence of presenting symptoms (ECOG PS 5 cm) Okuda stage (I vs II) Llovet et al2 Absence of constitutional syndrome (ECOG PS 6 months),1. Lo

19、CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.,Largest Prospective Study of TACE for Unresectable HCC to Date,N = 8510 patients Primary endpoint: OS Multivariate analysis conducted of factors affecting survival OS Year 1: 82%; Year 3: 47%; Year 5: 26%; Year

20、 7: 16% OS better with lesser degree of liver damage Factors affecting survival Child-Pugh stage TNM stage (OS better with stage I, increasingly worse progressing toward stage IV) Alpha-fetoprotein level,Takayasu K, et al. Gastroenterology. 2006;131:461-469.,TACE vs Surgical Resection: A Case-Contro

21、l Prospective Study,N = 182, 70% HBV positive, 99% Okuda stage I, 76% with tumors 3 cm,Surgery superior to TACE for tumors smaller than 2 cm and/or CLIP stage 0 BUT for tumors 3 cm and/or CLIP stage 1-2, 5-year survival identical for both groups (27%) Median OS (P = .1529) Resection: 65.1 months TAC

22、E: 50.4 months,Lee HS, et al. J Clin Oncol. 2002;20:4459-4465.,Chemoembolization: Efficacy Before Transplantation,Major issue: dropout rate ( 20%) Lower in US since adoption of MELD criteria Role of TACE Control tumor and prevent progression Should be considered if waiting time 6 months Complication

23、s from TACE: rare (no increased rate of hepatic artery complications),Richard HM 3rd, et al. Radiology. 2000;214:775-779. Graziadei IW, et al. Liver Transpl. 2003;9:557-563. Alba E, et al. Am J Roentgenol. 2008;190:1341-1348.,Can TACE Be Used as a Determinant of Tumor Biology?,96 consecutive patient

24、s treated with TACE 62 exceeded Milan criteria 34 meeting Milan criteria listed immediately 50 patients transplanted 27 exceeded Milan criteria,Otto G, et al. Liver Transpl. 2006;12:1260-1267.,Functional Decompensation (n = 1),Patients with HCC; age 65 years without contraindication against LT(n = 9

25、6),Milan criteria fulfilled (n = 34),Listing,TACE,Milan criteria exceeded (n = 62),6 weeks,6 weeks,6 weeks,TACE,Listing (n = 34),WL (n = 4),WL (n = 1),Progress (n = 6),Functional decompensation (n = 5),Functional decompensation (n = 1),Extrahepaticdisease (n = 5),Stable18 Progress*9,27 LT,Stable21 P

26、rogress 2,23 LT,TACE,Regress,Stable or progress (n = 23),Restaging,Otto G, et al. Liver Transpl. 2006;12:1260-1267.,Transplanted,All patients,TACE nonresponders,Overall 5-year survival: 51.9% Highly significant difference in 5-year survival between downstaged (transplanted) patients and patients not

27、 responding to TACE (P .0001) Survival calculated from the beginning of TACE treatment,Survival,0,0.2,0.4,0.6,0.8,1.0,0,365,730,1095,1460,1825,Days,80.9%,51.9%,0%,Response to TACE as a Biological Selection Criterion for LT in HCC,TACE nonresponders,TACE responders,Otto G, et al. Liver Transpl. 2006;

28、12:1260-1267.,Response to TACE as a Biological Selection Criterion for LT in HCC,0,Freedom From Recurrence,0,0.2,0.4,0.6,0.8,1.0,365,730,1095,1460,1825,Days,35.4%,94.5%,P = .0017,Absolute contraindications Child-Pugh class C disease Poor performance status (ECOG PS 2) Relative contraindication Extra

29、hepatic disease (benefit unclear) Former contraindication PVT Minimize embolization and be more selective,Chemoembolization: Ineligibility Criteria,32 patients with HCC and PVT Median OS: 10 months Child-Pugh score: best prognostic factor (ie, most strongly related to survival) 30-day mortality: 0%

30、No evidence of TACE-related hepatic infarction or acute liver failure,Safety 16:1653-1659.,Radioembolization: Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for the treatment of liver tumors Yttrium-90 microspheres Average diameter: 20-30 m 100% pure beta emit

31、ter (0.9367 MeV) Physical half-life: 64.2 hours Irradiates tissue with average path length of 2.5 mm (maximum: 11 mm),Intra-arterial Radioembolization With Yttrium-90: Rationale and History,Murthy R, et al. Biomed Imaging Interv J. 2006;3:e43.,Clinical Response to Yttrium-90 Microspheres,1. Dancey J

32、E, et al. J Nucl Med. 2000;41:1673-1681. 2. Carr BI. Liver Transpl. 2004;10(2 suppl 1):S107-S110. 3. Geschwind JF, et al. Gastroenterology. 2004;127(5 suppl 1):S194-S205. 4. Salem R, et al. J Vasc Interv Radiol. 2005;16:1627-1639.,Phase II study: N = 108 (37 with PVT, 71 without PVT) Stratified by t

33、oxicity: Child-Pugh score (in cirrhotics), dose, location of PVT Median dose: 134 Gy Partial response rate: 42% (WHO), 70% (EASL) Adverse event rate highest in patients with main PVT and cirrhosis Median survival, main PVT: 260 days Branch PVT: 370 days No PVT: 460 days,Yttrium-90 Radiotherapy for H

34、CC Patients With and Without PVT,Kulik LM, et al. Hepatology. 2008;47:5-7.,Lessons Learned,Patient selection Good performance status (ECOG PS 2) Total bilirubin 2.0 mg/dL (possibly 1.4 mg/dL) Tumor burden 50% 90Y or TACE: Which is best for first-line treatment of HCC?,27 patients with Child-Pugh A s

35、tage disease Response rate (assessed by CT) at 6months: 75% 1- and 2-year survival rates: 92% and 89% Median follow-up: 28months,Varela M, et al. J Hepatol. 2007;46:474-481.,Doxorubicin at Serum (ng/mL),Doxorubicin at Serum (ng/mL),DEB-TACE,Conventional TACE,Time Postprocedure,Time Postprocedure,0,2

36、00,400,600,800,1000,0,200,400,600,800,1000,BL,5 mins,20 mins,40 mins,60 mins,2 hrs,6 hrs,24 hrs,48 hrs,7 days,BL,5 mins,20 mins,40 mins,60 mins,2 hrs,6 hrs,24 hrs,48 hrs,7 days,TACE With Doxorubicin-Eluting Beads: Efficacy and Pharmacokinetics,Courtesy Jean-Francois Geschwind, MD.,65-Year-Old Woman,

37、 Child-Pugh B Disease, and Large HCC: First Treatment,Posttreatment 1: Residual Viable Tumor,Pretreatment,Pretreatment and Posttreatment 1,Courtesy Jean-Francois Geschwind, MD.,Second Treatment,Courtesy Jean-Francois Geschwind, MD.,Underwent successful resection Tumor free 16 months after initial tr

38、eatment,MRI Posttreatment 2,Courtesy Jean-Francois Geschwind, MD.,TACE accepted as treatment of choice for unresectable (nonablatable?) HCC Prolonged survival established through randomized trials and prospective studies Best vs good performance status, Child-Pugh class A-B Role for yttrium-90 micro

39、spheres Growing role for doxorubicin-loaded beads, pending outcome of clinical trials,Conclusions,Chemotherapy,Chemo-immunotherapy,Radiotherapy,Conclusion,There is lack of effective treatment for patients with advanced HCC New treatment options are needed,分子靶向,Treatment of Advanced HCC (BCLC Stage C

40、),AASLD 2005 recommendation: no standard therapy; patients should enroll in a randomized clinical trial1 2008 recommendation: sorafenib has become the standard of care for advanced HCC2 Prolongs OS by 3 months3 1-year survival: 44%4,1. Bruix J, et al. Hepatology. 2005;42:1208-1236.2. Llovet JM, et a

41、l. J Hepatol. 2008;48:S20-S37.3. Llovet J, et al. ASCO 2007. Abstract LBA 1.4. Llovet J, et al. N Engl J Med. 2008;359:378-390.,Intermediate/Advanced HCC: Future Directions,499 trials registered at for HCC as of August 21, 2008, including Improving efficacy of RF and TACE (drug-el

42、uting beads) Exploring alternative treatments for intermediate HCC (yttrium-90) Molecularly targeted agents in combination regimens (advanced HCC) Molecularly targeted agents in combination with current modalities (early/intermediate HCC) Improving tumor targeting of chemotherapeutic agents New mole

43、cular targets and new molecularly targeted agents,Sorafenib: Ongoing Studies in HCC,Europe 10 studies approved 4 TACE + sorafenib (1 phase I, 1 phase II, 2 phase III) Sorafenib + tegafur Sorafenib + erlotinib Sorafenib + temsirolimus Sorafenib dose escalation Sorafenib + gemcitabine/oxaliplatin Biom

44、arkers,Asia-Pacific 4 studies approved Sorafenib + tegafur Sorafenib + capecitabine/oxaliplatin Sorafenib + bevacizumab Sorafenib + gemcitabine United States 4 studies (nonactivated) 2 TACE + sorafenib Sorafenib + erlotinib Sorafenib + lapatinib,Evidence of Benefit in Treatment of HCC,Llovet JM, et

45、al. J Natl Cancer Inst. 2008;100:698-711.,Evidence of Benefit in Treatment of HCC (contd),Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.,Key Pathways in Hepatocarcinogenesis: Possible Targets for Novel Therapies,Growth factor-stimulated receptor tyrosine kinase signaling Wnt/beta-catenin pa

46、thway p13Kinase/AKT/mTOR JAK/STAT signaling Angiogenic signaling pathways p53 and cell cycle regulatory pathways Ubiquitin-proteasome pathway Epigenetic promoter methylation and histone acetylation pathways Ras-Raf-MEK-MAPK pathway,Roberts LR, et al. Semin Liver Dis. 2005;25:212-225.,Sorafenib in Ad

47、vanced HCC: The SHARP Trial,Entry criteria Advanced HCC Not eligible for or failed surgical or locoregional therapies Child-Pugh class A disease At least 1 untreated target lesion Exclusions Previous chemotherapy Previous molecularly targeted therapy,Llovet JM, et al. N Engl J Med. 2008;359:378-390.

48、,226 discontinued sorafenib 86 had an adverse event 61 had radiologic and systematic progression 28 withdrew consent 1 had ECOG score of 4 3 died 47 had other reason,297 received sorafenib (safety population),71 included in the ongoing study,1 had an adverse event 1 had a protocol violation,299 were

49、 assigned to receive sorafenib (intent-to-treat population),602 underwent randomization,902 patients were screened,300 were excluded 244 had protocol exclusion criteria 24 withdrew consent 15 had an adverse event 11 died 6 were lost to follow-up,303 were assigned to receive placebo (intent-to-treat

50、population),1 had a protocol violation,302 received placebo (safety population),242 discontinued placebo 90 had an adverse event 62 had radiologic and systematic progression 25 withdrew consent 7 had ECOG score of 4 6 died 52 had other reason,60 included in the ongoing study,Llovet JM, et al. Sorafe

51、nib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.,Sorafenib in Advanced HCC:The SHARP Trial,SHARP Trial: Baseline Characteristics,Llovet JM, et al. N Engl J Med. 2008;359:378-390.,Llovet JM, et al. Sorafenib in advance

52、d hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.,Median OSSorafenib: 10.7 mosPlacebo: 7.9 mos,Median TTSPSorafenib: 4.1 mosPlacebo: 4.9 mos,Median TTRPSorafenib: 5.5 mosPlacebo: 2.8 mos,The SHARP Trial: OS and Time to Progression,M

53、onths Since Randomization,Probability of Survival,0.00,0.25,0.50,0.75,1.00,0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,P .001,A OS,Months Since Randomization,Probability of No Symptomatic Progression,0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,P - 0.77,B Time to Symptomatic Progression,18,0.00,0.25,

54、0.50,0.75,1.00,Months Since Randomization,Probability of Radiologic Progression,0,1,2,3,4,5,6,7,8,9,10,11,Placebo,Sorafenib,P 0.001,C Time to Radiologic Progression,0.00,0.25,0.50,0.75,1.00,12,Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. 2008, Mas

55、sachusetts Medical Society. All rights reserved.,The SHARP Trial: OS and Baseline Prognostic Factors,0.0,0.5,1.0,1.5,Sorafenib Better,PlaceboBetter,Subgroup ECOG score 0 1-2 Extrahepatic spread No Yes Macroscopic vascular invasion No Yes Macroscopic vascular invasion, extrahepatic spread, or both No

56、 Yes,Hazard Ratio (95% CI),0 0.68 (0.50-0.95) 0.71 (0.52-0.96) 0.55 (0.39-0.77) 0.85 (0.64-1.14) 0.74 (0.54-1.00) 0.68 (0.49-0.93) 0.52 (0.32-0.85) 0.77 (0.60-0.99),Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. 2008, Massachusetts Medical Society.

57、All rights reserved.,The SHARP Trial: Drug-Related AEs,The SHARP Trial: Drug-Related AEs (Contd),Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.,Scheithauer W, et al. Oncology (Williston Park)

58、 2004; 18:1161.,Hand-Foot Syndrome,Grading of Hand-Foot Syndrome,Common Terminology Criteria for Adverse Events, Version 3.0. Available at: . Accessed October 13, 2008.,Strategies for Managing AEs,Hand-foot syndrome Creams and lotions Avoid tight footwear May require dose reduct

59、ion Diarrhea Antidiarrheal agents if severe Fatigue Consider modafinil 新型提神醒腦藥物莫達(dá)芬尼酸 or methylphenidate 利他林 if severe Hypertension Start or adjust antihypertensives,Oriental,中位OS： 索拉非尼：6.5月 安慰劑：4.2月 HR=0.68,Erlotinib in HCC: EGFR Inhibitor,Phase II study in patients with unresectable HCC (N = 40) Oral erlotinib 150 mg/day, 28-day cycles No CRs or PRs PFS rate at 16 weeks: 43% Drug-related adverse events: diarrhea, folliculi