肝癌綜合治療課件

1、肝癌的綜合治療肝癌的綜合治療 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的的BCLC分期系統(tǒng)和治療推薦分期系統(tǒng)和治療推薦 Liver transplantPEI/RF Curative treatments TACE HCC Single Increa

2、sed Associated diseases Normal NoYesNoYes 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, Child-Pugh C Very early stage Single 5cm) TACE(5cm) TACE(5

3、cm) Recurrence curves Patients with high risk factors for residual tumor 進(jìn)展期肝癌進(jìn)展期肝癌 Staging Strategy and Treatment for Patients With HCC Liver transplantPEI/RF Curative treatments TACE HCC Single Increased Associated diseases Normal NoYesNoYes Terminal stage PST 0-2, Child-Pugh A-B Multinodular, PST

4、 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 J

5、M, 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 other options such as drug-eluting beads, radiolabelled yttrium glass beads, radiolabelled lipiodol, or immunotherapy cannot be recommended as standard therap

6、y 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%

7、 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) Technique Survival, % Year 1Year 2Year 3 TACE573126 Supportive car

8、e32113 Technique Survival, % Year 1Year 2 TACE8263 Supportive care6327 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. Hepatol

9、ogy. 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;35:11

10、64-1171. 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 de

11、gree 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 Technique S

12、urvival, % Year 1Year 2Year 3Year 5 TACE96805630 Surgical resection90807052 N = 182, 70% HBV positive, 99% Okuda stage I, 76% with 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 O

13、ncol. 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 o

14、f 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

15、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)

16、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) Stable18 Progress*9 27 LT Stable21 Progress 2 23 LT TACE RegressStable or

17、 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 2) Relative con

18、traindication 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

19、-day mortality: 0% 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

20、 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 Micr

21、ospheres OutcomeDancey et al1 (N = 20) Carr et al2 (N = 65) Geschwind et al3 (N = 80) Salem et al4 (N = 43) Response rate, %3947 Median survival378 days ( 104 Gy) Okuda stage I 649 days628 days24.4 mos Okuda stage II302 days384 days12.5 mos 1. Dancey JE, et al. J Nucl Med. 2000;41:1673-1681. 2. Carr

22、 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,

23、 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

24、. 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

25、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

26、 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 T

27、reatment 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-Fra

28、ncois 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 b

29、eads, 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 分子靶向分子靶向 Treatment of Advanced HCC (BCLC Stage C) AASLD 2005 recommendation: no standard

30、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

31、 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 tre

32、atments 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 targ

33、eted 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

34、 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 TreatmentBenefitEvidence Surgical treatments Resecti

35、onIncreased survivalCase series Adjuvant therapiesUncertainRandomized trial, meta-analysis, nonblinded Liver transplantationIncreased survivalCase series Neoadjuvant therapiesTreatment responseNonrandomized trials Locoregional treatment Percutaneous treatmentIncreased survivalCase series RFA vs PEIB

36、etter local control Randomized trial, meta-analysis, nonblinded ChemoembolizationIncreased survival Randomized trial, meta-analysis, nonblinded Arterial chemotherapyTreatment responseCase series Internal radiationTreatment responseCase series Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. E

37、vidence of Benefit in Treatment of HCC (contd) TreatmentBenefitEvidence Systemic therapies Sorafenib Increased survival Randomized trial, meta- analysis, double blinded TamoxifenNo benefit Randomized trial, meta- analysis, double blinded ChemotherapyNo benefit Randomized trial, meta- analysis, nonbl

38、inded IFNNo benefit Randomized trial, meta- analysis, nonblinded 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

39、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 Tri

40、al 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 sorafen

41、ib 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 sora

42、fenib (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 proto

43、col 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 hepatocel

44、lular 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 CharacteristicSorafenib (n = 299) Placebo (n = 303) Median age, yrs64.966.3 Male, %8787 BCLC stage, % B (interme

45、diate)1817 C (advanced)8283 Vascular invasion, %7070 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.

46、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 101112 1314151617 P .001 A OS Months Since Randomization P

47、robability of No Symptomatic Progression 0 1 2 3 4 5 6 7 8 9 10 11121314151617 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 01234567891011 Placebo Sorafenib P 0.001 C Time to Radiologic Progression 0.00 0.25 0

48、.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 0.00.51.01.5 Sorafenib Better Placebo Better Subgroup ECOG score 0 1-2 Extr

49、ahepatic 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

50、 al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved. AEs, %Sorafenib (N = 297)Placebo (N = 302)P Value Any Grade Grade 3Grade 4Any Grade Grade 3Grade 4 Any Grade Grade 3 or 4 Overall incidence8052 Constitutiona

51、l symptoms Fatigue2231163 1.071.00 Weight Loss920100 .001.03 Dermatologic events Alopecia1400200 .001NA Dry skin800400.04NA Hand-foot skin reaction 21803 10 .001 .001 Pruritus8007 10.651.00 Rash or desquamation 16101100.12.12 Other510100 .001.12 The SHARP Trial: Drug-Related AEs The SHARP Trial: Dru

52、g-Related AEs (Contd) AEs, %Sorafenib (N = 297)Placebo (N = 302)P Value Any Grade Grade 3Grade 4Any Grade Grade 3Grade 4 Any Grade Grade 3 or 4 Gastrointestinal events Anorexia14 10310 .0011.0 Diarrhea39801120 .001 .001 Nausea11 10810.16.62 Vomiting510310.14.68 Voice changes600100 .001NA Hypertensio

53、n520210.05.28 Liver dysfunction 1 10000.50.50 Abdominal pain not otherwise specified 820310.007.17 Bleeding71041 1.071.00 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.

54、Oncology (Williston Park) 2004; 18:1161. Hand-Foot Syndrome Grading of Hand-Foot Syndrome Grade Symptom 1 Minimal skin changes or dermatitis (eg, erythema) without pain 2 Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function 3 Skin changes with pain, interferin

55、g with function 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 reduction Diarrhea Antidiarrheal agents if severe Fatig

56、ue 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 中位中位OS： 索拉非尼：索拉非尼：6.5月月 安慰劑：安慰劑：4.2月月 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, folliculitis, fatigue, pruritus, dry skin, xerostomia, epistaxis Thomas MB, et al. Cancer. 2007;110:1059-1067.