肝癌综合治疗

肝癌的综合治疗 Multidisciplinary Strategies to Management of HCC,复旦大学肝癌研究所,背景,绝大多数（80-90）的HCC合并肝硬化 HCC治疗策略应考虑对肿瘤作用，并避免肝功能损害 HCC的分期系统也应同时考虑肿瘤因素，和肝功能损害的严重性 至今尚未有公认的HCC的分期系统 肝癌的BCLC分期系统目前在西方国家应用较广，对治疗有指导意义。,HCC的BCLC分期系统和治疗推荐,Liver transplant,PEI/RF,Curative treatments,TACE,HCC,Single,Increased,Associated diseases,Normal,No,Yes,No,Yes,Terminal stage,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, 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分期系统和治疗,Liver transplant,PEI/RF,TACE,HCC,Single,Increased,Associated diseases,Normal,No,Yes,No,Yes,Terminal stage,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, 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,治疗的目的,肿瘤缩小 改善生命质量 延长生存 QALY,HCC 治疗选择,早期HCC 外科切除（肝部分切除） 肝移植 经皮毁损（PEI，RFA，HIFU，冷冻，微波） 进展期HCC TACE 系统治疗（化疗） 新治疗 （分子靶向，放疗）,早期肝癌,早期HCC的手术切除,根治？ 根治术后5年生存率：50-70 术后5年复发率： 60-80 问题：如何达到根治？如何降低复发？,Pre-operative TACE + Resection,Downstaging resection：术后5年生存率 小肝癌 肝动脉插管结扎/ TACE/ Chemotherapy？ 减小瘤体：手术简单，且控制微小病灶 减少血供：手术安全 减少术中播散,Zhou 2009 Ann Surg 2009;249: 195202,Pre-operative TACE,Risk：可切除 不可切除 对肝功能差的病人：进一步损害肝功能 Japan：RCT 结果类似（Sasaki A. Eur J Surg Oncol. 2006;32:7739.）,肝移植,术后复发 （周俭教授） 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-term 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 offers any benefit when used prior to OLT, neither for early nor for advanced HCC.,American journal of transplantation 2006; 6(11):2644-50.,局部毁损,小肝癌：媲美于手术切除 复发率值得担心,小肝癌2.8cm,PEI or RFA?,PEI 3y 5y Child A (survival 3 vs. 5y.) 79% 47% Child B (survival 3 vs. 5y.) 63% 29% Child C (survival 3 vs. 5y.) 12% 0%,AASLD 2004: Leoncini et al. (n=104): PEI RFA Tumor destruction 82% 98% 2-y Survival 96% 98% 2-y Recurrence 32% 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 surgery 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 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,进展期肝癌,Staging Strategy and Treatment for Patients With HCC,Liver transplant,PEI/RF,Curative treatments,TACE,HCC,Single,Increased,Associated diseases,Normal,No,Yes,No,Yes,Terminal stage,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, 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 mos,Approved & Investigational Noncurative Agents for Unresectable HCC,AASLD 2005 recommendations Chemoembolization (TACE) (with doxorubicin, cisplatin, or mitomycin) is recommended as first-line, noncurative therapy for nonsurgical patients with large/multifocal HCC who do not have vascular invasion or extrahepatic spread (and are not eligible for percutaneous ablation) (level I) Tamoxifen, octreotide, antiandrogens, and hepatic artery ligation/embolization are not recommended (level I); 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 Therapy,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 Cancer 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% multifocal),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 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 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-Control 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 TACE: 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 Complications 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 patients 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 = 96),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),Extrahepatic disease (n = 5),Stable 18 Progress* 9,27 LT,Stable 21 Progress 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 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;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 Extrahepatic 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% No evidence of TACE-related hepatic infarction or acute liver failure,Safety & Efficacy of TACE in Patients With Unresectable HCC & PVT,Georgiades CS, et al. J Vasc Interv Radiol. 2005;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 emitter (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 JE, 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 toxicity: 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 HCC 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 stage disease Response rate (assessed by CT) at 6 months: 75% 1- and 2-year survival rates: 92% and 89% Median follow-up: 28 months,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,0,200,400,600,800,1000,0,200,400,600,800,1000,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, 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 treatment,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 microspheres 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),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 al. 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-eluting 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 molecular 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 Biomarkers,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 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 pathway 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 Advanced 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.,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 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 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. Sorafenib 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 advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.,Median OS Sorafenib: 10.7 mos Placebo: 7.9 mos,Median TTSP Sorafenib: 4.1 mos Placebo: 4.9 mos,Median TTRP Sorafenib: 5.5 mos Placebo: 2.8 mos,The SHARP Trial: OS and Time to Progression,Months 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,18,0.00,0.25,0.50,0.75,1.00,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, Massachusetts Medical Society. All rights reserved.,The SHARP Trial: OS and Baseline Prognostic Factors,0.0,0.5,1.0,1.5,Sorafenib Better,Placebo Better,Subgroup ECOG score 0 1-2 Extrahepatic spread No Yes Macroscopic vascular invasion No Yes Macroscopic vascular invasion, extrahepatic spread, or both No 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. 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) 2004; 18: